JP2003267974A - Medicine composition containing aminoalcohol derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicine composition which contains an aminoalcohol derivative having general formula (I), its pharmacologically acceptable salt, its ester or another derivative as an active ingredient. <P>SOLUTION: The medicine composition contains the aminoalcohol derivative having the general formula (I) [R<SP>1</SP>and R<SP>2</SP>are each a hydrogen atom or an amino group-protecting group; R<SP>3</SP>is a hydrogen atom, a hydroxy-protecting group; R<SP>4</SP>is a lower alkyl group; n is an integer of 1 to 6; X is an ethylene group; Y is a 1-10C alkylene group; R<SP>5</SP>is an aryl group or a substituted aryl group; R<SP>6</SP>and R<SP>7</SP>are each a hydrogen atom; when R<SP>5</SP>is a hydrogen atom, Y is a group except a single bond and a straight-chain 1-10C alkylene group], its pharmacologically acceptable salt, its ester or another derivative as an active ingredient. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing an amino alcohol derivative, a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof as an active ingredient.

Furthermore, the present invention is a novel optically active amino alcohol compound useful as a synthetic intermediate for pharmaceuticals such as the above amino alcohol derivative, and in particular, optically active 4,4.
-Disubstituted oxazolidin-2-one compounds.

Furthermore, the present invention is an optically active 2-substituted-2-amino-1,3-propanediol which is important as a synthetic intermediate for the above-mentioned optically active aminoalcohol compound.
The present invention relates to a novel method for producing a monoester derivative having excellent selectivity.

[0004]

2. Description of the Related Art Conventionally, in the treatment of immune-related diseases such as rheumatism and other autoimmune diseases, anti-inflammatory drugs such as steroids have been used for inflammatory reactions caused by abnormal immune reactions. However, these are symptomatic treatments and not fundamental treatments.

It has been reported that abnormalities of the immune system are involved in the onset of diabetes and nephritis (for example,
See Non-Patent Document 1. ), The development of a drug to improve the abnormality has not been achieved.

On the other hand, the development of a method for suppressing the immune response was
It is also extremely important in preventing rejection in organ and cell transplantation and in treating and preventing various autoimmune diseases. However, conventionally known immunosuppressive agents such as cyclosporin A (CsA) and tacrolimus (TRL) are known to be toxic to the kidney and liver, and in order to reduce such side effects, Although treatments such as the combined use of steroids have been widely used, the current situation is that they do not necessarily exhibit sufficient immunosuppressive effects without necessarily showing side effects.

Under these circumstances, it has been attempted to find compounds having low toxicity and excellent immunosuppressive action.

The following compounds are known as immunosuppressants. (1) WO94 / 08943 (EP627406) (see Patent Document 1) In this publication, the following general formula (a) is used.

[0009]

[Chemical 7]

[In the above compound (a), R is a linear or branched carbon chain which may have a substituent (in the chain, a double bond, a triple bond, oxygen, sulfur, -N ( R ⁶⁾ -
(In the formula, R ⁶ is hydrogen), optionally substituted arylene, and optionally substituted heteroarylene, having a substituent at the chain end. Optionally aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl. } And R ² ,
R ³ , R ⁴ and R ⁵ are the same or different and each is hydrogen or alkyl. ] Are disclosed as immunosuppressants.

The above-mentioned compound (a) of the prior art has two oxymethyl groups (--CH ₂ O) as essential substituents.
R ⁴ and —CH ₂ OR ⁵ ) are included, but the compound of the present invention is different from the above compound (a) in that it has a —CH ₂ OR ³ group and a lower alkyl group as the corresponding groups.

This publication does not specifically disclose a compound having a structure similar to that of the compound (I) of the present invention, and is most similar to the structure of the compound (I) of the present invention. Even if the above compound is selected, at most, only the following compounds are disclosed.

[0013]

[Chemical 8]

(2) WO96 / 06068 (Patent Document 2)
In this publication, the following general formula (b)

[0015]

[Chemical 9]

[In the above compound (b), R ¹ , R ² and R ³ are hydrogen atoms or the like, W is a hydrogen atom, an alkyl group or the like, Z is a single bond or an alkylene group,
X is a hydrogen atom or an alkoxy group, and Y is a hydrogen atom, an alkyl, an alkoxy, an acyl, an acyloxy, an amino, an acylamino group or the like. Is a compound having
It is disclosed as an immunosuppressant.

The above compound (b) essentially requires a phenyl group in the basic skeleton, but the compound (I) of the present invention is the above compound (b) in that the corresponding group is a thiophene group which is a heterocycle. Is different from.

Further, the present publication does not specifically disclose a compound having a structure similar to that of the compound (I) of the present invention, and the compound having the same structure as the compound (I) of the present invention is most disclosed. Even if a similar compound is selected, at most, only the following compounds are disclosed.

[0019]

[Chemical 10]

(3) WO98 / 45249 (Patent Document 3)
In this publication, the following general formula (c)

[0021]

[Chemical 11]

[In the above compound (c), R ¹ , R ² ,
R ³ and R ⁴ are the same or different and each is hydrogen or an acyl group. ] Are disclosed as immunosuppressive agents. The compound (c), as essential substituents, groups have two oxymethyl groups (-CH ₂ OR ³ and -CH ₂ OR ^4), the compounds of the invention corresponding, -CH
_It differs from the compound (c) in that it has a ₂ OR ³ group and a lower alkyl group. Further, the compound (c), in the basic skeleton - (CH _{2) 2} - group and -CO- (CH _{2) 4} - Although the essential basis of the phenyl group between the group, the compound (I ) Is also different from the above compound (c) in that the corresponding group is a thiophene group which is a heterocycle.

Further, the above compound (c) is --CO-(C
Although it has a phenyl group at the chain end as an essential substituent of the H ₂ ) ₄ -group, the compound (I) of the present invention is also different in that it may have a cycloalkyl group or a heterocyclic group as the corresponding group.

Further, this publication does not specifically disclose a compound having a structure similar to that of the compound (I) of the present invention, and most of the compounds having the structure of the compound (I) of the present invention are not disclosed. Even if a similar compound is selected, at most, only the following compounds are disclosed.

[0025]

[Chemical 12]

On the other hand, optically active substituted amino acids and substituted amino alcohol derivatives (particularly α-substituted amino acids and α
There are many important compounds such as -substituted aminoalcohol derivatives) which have physiological activity per se, partial components of natural products and pharmaceuticals, and synthetic intermediates.

For example, α-methyl-α-vinyl amino acid is an inhibitor of amino acid decarboxylase, and α-ethynyl-α-methyl amino acid is glutamic acid decarboxylas.
It is a useful compound as an inhibitor of e and is involved in the regulation of immune responses by ISP-1 (Myriocin) and T cells isolated from metabolites of Isalia sinclairii, which is an immunosuppressant Is known as Cona
[alpha] -Substituted amino acids and aminoalcohol derivatives, which are optically active as partial constituents of physiologically active natural products such as genin, are of great interest in biochemistry and organic synthetic chemistry.

Since these α-substituted amino acids and aminoalcohol derivatives have an asymmetric carbon, a means for efficiently synthesizing one of the enantiomers has been desired.

Process for producing optically active substituted amino acid and amino alcohol derivative, and optically active 4,4-disubstituted oxazolidine useful as a synthetic intermediate for pharmaceuticals such as optically active substituted amino acid and amino alcohol derivative
There are very few synthetic examples of optically active aminoalcohol compounds such as -2-one compounds. For example, the review of Tetrahedron: Asymmetry, 9, 3517 (1998) by C. Cativiela et al. "Synthesis of
Optically Active α-Amino Acids "(Pergamon Pres
s) (Non-Patent Document 3), many methods are known and are roughly classified into two methods.

First, a method using diastereoselective alkylation using an asymmetric auxiliary group, and a typical method is Seebach et al., Helv. Chim. Acta., 71, 224 (198).
8) (Non-Patent Document 4), or by Nagao, Sano et al., Tetrahedron Lett., 36, 209.
7 (1995) and Tetrahedron Lett., 36, 4101 (1995) (Non-patent document 5), chiral bislactam ether carboxylic acid ester compounds and Mg (II) and Sn (II).
It is known to synthesize α-substituted serine derivatives by a highly diastereoselective aldol reaction utilizing a Lewis acid.

Second, by Nagao, Tamai et al., Chemistry
Lett., 239 (1989) and Chemistry Lett., 2381 (1994).
Α-Substituted-α-protected aminomalone as represented by the synthetic method of α-substituted serine derivatives by enantioselective enzymatic hydrolysis of prochiral σ-symmetric diesters reported in (Non-Patent Document 6). There is a method using an enantioselective enzymatic hydrolysis reaction of acid diester.

Each of the production methods classified into the first method has a large number of steps and requires the use of a stoichiometric amount of an asymmetric source. In addition, the second method has a drawback in that there is a reduction step, and thus there is a limitation when there are unstable substituents under reducing conditions.

As described above, although there are many reports, there are very few practical methods. In general, a method of optically resolving a racemate to obtain one of the optical isomers is general, and in that case, there is a problem that a decrease in total yield cannot be avoided.

[0034]

[Patent Document 1] WO94 / 08943 (EP62
7406 publication)

[Patent Document 2] WO96 / 06068

[Patent Document 3] WO98 / 45249

[Non-Patent Document 1] Kidney International, vol.51, 9
4 (1997); Journal of Immunology, vol.157, 4691 (1
(996)

[Non-Patent Document 2] C. Cativiela et. Al., Tetrahedron:
Asymmetry, 9, 3517 (1998)

[Non-Patent Document 3] RM Williams, "Synthesis of Opt
"ically Active α-Amino Acids" (Pergamon Press)

[Non-Patent Document 4] Seebach et. Al., Helv. Chim. Act
a., 71, 224 (1988)

[Non-Patent Document 5] Nagao et al., Tetrahedron Lett., 3
6, 2097 (1995) and Tetrahedron Lett., 36,4101 (1995)

[Non-Patent Document 6] Nagao et al., Chemistry Lett., 239.
(1989) and Chemistry Lett., 2381 (1994).

[0035]

Means for Solving the Problems (1) An amino alcohol derivative, a pharmacologically acceptable salt thereof, an ester or other derivative thereof which is an active ingredient of the pharmaceutical composition of the present invention is represented by the following general formula (I ) Has.

[0036]

[Chemical 13]

In the formula, R ¹ and R ² are the same or different,
A hydrogen atom or an amino group protecting group is shown, R ³ is a hydrogen atom or a hydroxy group protecting group, R ⁴ is a lower alkyl group, n is an integer of 1 to 6, and X is an ethylene group, vinylene group, ethynylene group, a group represented by the formula -D-CH ₂
A group having-(wherein D is a carbonyl group, a group of formula -CH
A group having (OH)-, an oxygen atom, a sulfur atom or a nitrogen atom is shown. ), An aryl group or an aryl group in which 1 to 3 substituents are substituted with a group selected from the substituent group a, and Y is
Single bond, C ₁ -C ₁₀ alkylene group, and 1 to 3 substituted with a group selected from Substituent group a and b the C ₁ -C ₁₀ alkylene group, an oxygen atom or a sulfur atom in the carbon chain or the chain ends A C ₁ -C ₁₀ alkylene group having _{1 to} 3, or a C ₁ -C ₁₀ having an oxygen atom or a sulfur atom in the carbon chain or at the chain end, which is substituted with 1 to 3 groups selected from the substituent groups a and b. An alkylene group, R ⁵ is a cycloalkyl group substituted with 1 to 3 groups selected from a hydrogen atom, a cycloalkyl group, an aryl group, a heterocyclic group, and substituent groups a and b; And an aryl group substituted with 1 to 3 groups selected from b or a heterocyclic group substituted with 1 to 3 groups selected from substituent groups a and b,
R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a group selected from the substituent group a, provided that when R ⁵ is a hydrogen atom, Y is a single bond or a straight chain C ₁ -C. ₁₀ represents a group other than an alkylene group, and the substituent group a is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxy group, a lower aliphatic acyl group. Group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower aliphatic acylamino group, a cyano group and a nitro group, and the substituent group b is a cycloalkyl group, an aryl group, a hetero group. A cyclic group, a cycloalkyl group substituted by 1 to 3 groups with a substituent group a, an aryl group substituted with 1 to 3 groups with a group selected from a substituent group a, and Shows a group consisting of 1 to 3 substituted heterocyclic group with a group selected from Group a.

In the above (1), suitable pharmaceutical compositions can be mentioned below. (2) In (1), the compound having the formula (I), a pharmacologically acceptable salt thereof, an ester or other derivative thereof is a compound represented by the formula (Ia):

[0039]

[Chemical 14]

A pharmaceutical composition having the formula (3) (1), wherein the compound having the formula (I), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof has the formula (Ib):

[0041]

[Chemical 15]

In any one of (4), (1) to (3), R ¹ and R ² are the same or different and are a hydrogen atom, a lower alkoxycarbonyl group, or an aralkyl. A pharmaceutical composition which is an aralkyloxycarbonyl group substituted with 1 to 3 oxycarbonyl groups or a group selected from the substituent group a, (5)
The pharmaceutical composition according to any one of (1) to (3), wherein R ¹ and R ² are hydrogen atoms, (6)
In any one of (1) to (5), R ³ is a hydrogen atom, a lower alkyl group, a lower aliphatic acyl group, an aromatic acyl group or a group selected from the substituent group a. To (3) a substituted aromatic acyl group, (7) (1) to (5), wherein R ³ is a hydrogen atom,
(8) In any one item selected from (1) to (7), R ⁴ is a pharmaceutical composition in which C ₁ -C ₄ alkyl group is selected, and (9) is selected from (1) to (7). Either 1
In the item, R ⁴ is a C ₁ -C ₂ alkyl group, and (10) (1) to (7), wherein R ⁴ is a methyl group. object,
(11) Any one selected from (1) to (10)
In the paragraph, the pharmaceutical composition in which n is 2 or 3, (1
2) In any one item selected from (1) to (10), n is 2, a pharmaceutical composition, (13) In any one item selected from (1) to (12), X
Selected from the group consisting of ethylene group, ethynylene group, aryl group or aryl group substituted with 1 to 3 groups selected from the substituent group a, (14) (1) to (12) The pharmaceutical composition in which X is an ethylene group in any one item, (15) The pharmaceutical composition in which X is an ethynylene group in any one of (1) to (12), (16) ) In any one item selected from (1) to (12), X is a pharmaceutical composition in which X is a group having the formula -D-CH _2-,
X is a compound represented by the formula-
A pharmaceutical composition which is a group having D-CH ₂ — (wherein D represents a carbonyl group or a group having the formula —CH (OH) —), selected from (18), (1) to (17). 1 is a C ₁ -C ₁₀ alkylene group or a C ₁ -C ₁₀ alkylene group substituted by 1 to 3 groups selected from the substituent groups a and b. , (1
9) In any one item selected from (1) to (17), Y is a C ₁ -C ₆ alkylene group or a C selected from 1 to 3 substituted with a group selected from the substituent groups a and b. ₁ -C ₆
A pharmaceutical composition which is an alkylene group, in any one of (20), (1) to (17), Y is
A pharmaceutical composition which is an ethylene, trimethylene or tetramethylene group, which is substituted with 1 to 3 groups of an ethylene group, a trimethylene group, a tetramethylene group or a group selected from the substituent groups a and b, (21) (1) In any one of items (1) to (17), Y is an ethylene group,
A pharmaceutical composition which is a trimethylene group or a tetramethylene group, (22) A pharmaceutical composition in which Y is an ethylene group or a trimethylene group, in any one selected from (1) to (17), (23) ( In any one of 1) to (17), Y is C ₁ -C ₁₀ having an oxygen atom or a sulfur atom in the carbon chain or at the chain end.
A pharmaceutical composition which is a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in the carbon chain or at the chain end, which is substituted with 1 to 3 alkylene groups or groups selected from the substituent groups a and b. , (24) (1) to (17), Y is C ₁ -C ₁₀ having an oxygen atom or a sulfur atom in the carbon chain or at the chain end.
A pharmaceutical composition which is an alkylene group, (25) In any one selected from (1) to (17), Y is
A pharmaceutical composition having a C ₁ -C ₁₀ alkylene group having an oxygen atom in the carbon chain or at the chain end, (26) (1) to (1)
The pharmaceutical composition according to any one of 7), wherein Y is a C ₁ -C ₆ alkylene group having an oxygen atom in the carbon chain or at the chain end, (27) (1) to (17) In any one of the items selected, Y is -O-CH.
_{2 -, - O- (CH 2} ) 2 -, - O- (CH 2) 3 -, - C
_{H 2 -O -, - (CH} 2) 2 -O- or - (CH _{2) 3} -O
In any one of (28) (1) to (17), Y is
A pharmaceutical composition which is a group having —CH ₂ —O—, (29)
(1) through at any one selected from (17), Y is, -O- (CH _{2) 2} - or - (CH _{2) 2} -O-
A pharmaceutical composition which is a group having: (30) (1) to (2)
The pharmaceutical composition according to any one of 9), wherein R ⁵ is a hydrogen atom, (31) (1) to (29)
In any one selected from, R ⁵ is a cycloalkyl group, a heterocyclic group, is 1 to 3 substituted with a group selected from Substituent group a and b cycloalkyl group or a substituent group a and (32) (1) to (2) A pharmaceutical composition comprising 1 to 3 heterocyclic groups substituted with a group selected from b.
9. The pharmaceutical composition according to any one of 9), wherein R ⁵ is a cycloalkyl group or a cycloalkyl group substituted with 1 to 3 groups selected from the substituent groups a and b. ) In any one selected from (1) to (29), the pharmaceutical composition in which R ⁵ is a cycloalkyl group, (34) In any one selected from (1) to (29) , R ⁵ is a cyclohexyl group, (35) In any one selected from (1) to (29), R ⁵ is selected from an aryl group or substituent groups a and b. A pharmaceutical composition which is an aryl group substituted with 1 to 3 groups represented by the formula (36), (1) to (29), wherein R is
⁵ is an aryl group or an aryl group substituted by 1 to 3 (wherein the substituent is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group or a lower aliphatic acyl group; Which is a group selected from the group), (37) (1) to (29), wherein R is
⁵ is an aryl group or an aryl group substituted with 1 to 3 (the substituent is a group selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower aliphatic acyl group) The pharmaceutical composition according to any one of (38), (1) to (29), wherein R ⁵ is a phenyl group or a 1 to 3 substituted phenyl group (the said substituent). Is a group selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower aliphatic acyl group.), (39) (1)
In any one of items (1) to (29), R
⁵ is a phenyl group or a phenyl group substituted by 1 to 3 (the substituent is a group selected from the group consisting of a fluorine atom, a chlorine atom, methyl, trifluoromethyl, methoxy and acetyl groups). A pharmaceutical composition, (40)
In any one of (1) to (29), R ⁵ is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5
-Difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3- Trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 3-
Methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,
A pharmaceutical composition having a 4,5-trimethoxyphenyl, 3-acetylphenyl or 4-acetylphenyl group, (4
1) In any one item selected from (1) to (40), R ⁶ and R ⁷ are the same or different and are hydrogen atoms,
A pharmaceutical composition comprising a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group or a lower alkylthio group, in any one of (42), (1) to (40), R ⁶ and R ⁷ In the pharmaceutical composition (43) (1), wherein is a hydrogen atom, 2-amino-2-methyl-4- [5- (6-cyclohexylhexyl) thiophene-2-
Il] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [ 5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-
Methyl-4- [5- (6-cyclohexylhex-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4
-[5- (5-Cyclohexylpent-1-ynyl) thiophene-2-
Il] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butane
-1-ol, 2-amino-2-methyl-4- [5- (6-cyclohexylhexanoyl) thiophen-2-yl] butan-1-ol,
2-Amino-2-methyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-
Methyl-4- [5- (4-cyclohexylbutanoyl) thiophene
-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (6
-Cyclohexylhexyl) thiophen-2-yl] butane-1
-Ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (4- Cyclohexylbutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5-
(6-Cyclohexylhex-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2- Il] Butane
-1-ol, 2-amino-2-ethyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (6-Cyclohexylhexanoyl) thiophen-2-yl] butan-1-ol, 2-amino
-2-Ethyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4
-[5- (4-Cyclohexylbutanoyl) thiophen-2-yl]
Butan-1-ol, 2-amino-2-methyl-4- [5- (6-phenylhexyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpentyl) thiophene-
2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-
(Phenylbutyl) thiophen-2-yl] butan-1-ol,
2-amino-2-methyl-4- [5- (6-phenylhex-1-ynyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino -2-Methyl-4- [5- (4-phenylbut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (6-phenylhexanoyl) ) Thiophen-2-yl] butan-1-ol, 2-amino-2-
Methyl-4- [5- (5-phenylpentanoyl) thiophene-2-
Ill] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenylbutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-Cyclohexyloxypent-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexyloxybut-1-ynyl) Thiophen-2-yl] butan-1-ol, 2
-Amino-2-methyl-4- [5- (3-cyclohexyloxypropynyl) thiophen-2-yl] butan-1-ol, 2-amino
-2-Methyl-4- [5- (5-cyclohexyloxypentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl
-4- [5- (4-cyclohexyloxybutyl) thiophene-2-
Il] butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexyloxypropyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-Cyclohexyloxypentanoyl) thiophen-2-yl] butane-1-
2-amino-2-methyl-4- [5- (4-cyclohexyloxybutanoyl) thiophen-2-yl] butan-1-ol,
2-Amino-2-methyl-4- [5- (3-cyclohexyloxypropanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenoxy Pento-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4
-[5- (4-phenoxybut-1-ynyl) thiophen-2-yl]
Butan-1-ol, 2-amino-2-methyl-4- [5- (3-phenoxypropynyl) thiophen-2-yl] butan-1-ol,
2-Amino-2-methyl-4- [5- (5-phenoxypentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4
-[5- (4-phenoxybutyl) thiophen-2-yl] butane-1
-Ol, 2-amino-2-methyl-4- [5- (3-phenoxypropyl) thiophen-2-yl] butan-1-ol, 2-amino-2
-Methyl-4- [5- (5-phenoxypentanoyl) thiophene-
2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-
Phenoxybutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-phenoxypropanoyl) thiophen-2-yl] butan-1-ol, 2- Amino-2
-Methyl-4- [5- (4-benzyloxyphenyl) thiophene-
2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-
Cyclohexylmethoxyphenyl) thiophen-2-yl]
Butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylethoxyphenyl) thiophen-2-yl] butane-
1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- ( 3-Cyclohexylmethoxypropyl) thiophen-2-yl] butan-1-ol and 2-
Any one compound selected from amino-2-methyl-4- [5- (3-cyclohexylmethoxypropanoyl) thiophen-2-yl] butan-1-ol, its pharmacologically acceptable salt, its ester Or (44) (1), wherein 2-amino-2-methyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butane-1 -Ol, 2-amino-2-methyl-4- [5-
(5-Cyclohexylpentyl) thiophen-2-yl] butane
-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl] butan-1-ol, 2-amino-2
-Methyl-4- [5- (4-cyclohexyloxybutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4-
[5- [4- (4-Fluorophenoxy) butyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [4- (4-
Methoxyphenoxy) butyl] thiophen-2-yl] butane
-1-ol, 2-amino-2-methyl-4- [5- (4-benzyloxybutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-Cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl
-4- [5- (4-phenylbut-1-ynyl) thiophen-2-yl]
Butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1
-Ol, 2-amino-2-methyl-4- [5- (5-phenylpent-
1-Inyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [5- (4-fluorophenyl) pent-1-
Inyl] thiophen-2-yl] butan-1-ol, 2-amino
-2-methyl-4- [5- [5- (4-methoxyphenyl) pent-1-ynyl] thiophen-2-yl] butan-1-ol, 2-amino-2
-Methyl-4- [5- [3- (4-methylcyclohexyloxy) propynyl] thiophen-2-yl] butan-1-ol, 2-amino
-2-Methyl-4- [5- [3- (4-methylphenoxy) propynyl]
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [3- (4-ethylphenoxy) propynyl] thiophen-2-yl] butan-1-ol, 2- Amino-2-methyl-4- [5-
[3- (4-methylthiophenoxy) propynyl] thiophene-2
-Yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-
Cyclohexyloxybut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [4- (4-
Fluorophenoxy) but-1-ynyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [4- (4-
Methylphenoxy) but-1-ynyl] thiophen-2-yl]
Butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5 -(4-Phenylmethoxybut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] Butan-1-ol, 2-amino
-2-Methyl-4- [5- (4-phenylbutanoyl) thiophene-2-
Il] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butane-
1-ol, 2-amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol, 2-amino
-2-Methyl-4- [5- [5- (4-fluorophenyl) pentanoyl] thiophen-2-yl] butan-1-ol, 2-amino-2-
Ethyl-4- [5- (5-cyclohexylpentyl) thiophene-2
-Yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-
Cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol , 2-amino-2-methyl-4- [5- [3- (4-chlorophenoxy)
Propynyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [3- (3-methylphenoxy) propynyl] thiophen-2-yl] butan-1-ol, 2-amino-2-
Methyl-4- [5- [3- (3,4-dimethylphenoxy) propynyl]
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [3- (3-methoxyphenoxy) propynyl] thiophen-2-yl] butan-1-ol, 2- Amino-2-methyl-4-
[5- [3- (3,4-dimethoxyphenoxy) propynyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4-
[5- [3- (3,5-dimethoxyphenoxy) propynyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4-
[5- [3- (3-acetylphenoxy) propynyl] thiophene-
2-yl] butan-1-ol and 2-amino-2-methyl-4- [5-
[3- (4-acetylphenoxy) propynyl] thiophene-2-
A pharmaceutical composition containing any one compound selected from il] butan-1-ol, a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof as an active ingredient.

Particularly preferably, (45) the pharmaceutical composition according to any one of (1) to (44), which is used as an immunosuppressant. (46) The pharmaceutical composition according to any one of (1) to (44) for preventing or treating an autoimmune disease. (47)
To prevent or treat rheumatoid arthritis,
The pharmaceutical composition according to any one of (1) to (44). (48) The pharmaceutical composition according to any one of (1) to (44) for suppressing rejection in various organ transplants.

In the compound (I) which is an active ingredient of the pharmaceutical composition of the present invention, (2) or (3); (4) or (5); (6) or (7); (8) to (10) ); (1
1) or (12); (13) to (17); (18) to (29); (30) to (40); and any one selected from the group consisting of (41) or (42). A pharmaceutical composition containing a compound in which any of the above is arbitrarily combined as an active ingredient is also suitable. (49) Further, the novel optically active amino alcohol compound of the present invention has the following general formula (La) or (Lb).

[0045]

[Chemical 16]

[In the formula, R¹And R²Are the same or different
Represents a hydrogen atom or an amino-protecting group, and R^3aIs water
Shows a protecting group for an elementary atom or a hydroxy group, or
R¹Is a hydrogen atom, and R²And R^3aBut together
Represents a group of formula (-(C = O)-), R^4aIs C₁-C
₂₀Alkyl group, C intervening hetero atom₂-C₂₀Archi
Substituted with an aryl group, an aryl group or an aromatic heterocyclic group
C₁-C₂₀Alkyl group, C₂-C ₂₀Alkynyl group, hetero
C with an atom₃-C₂₀Alkynyl group, aryl group
C substituted with an aromatic heterocyclic group₂-C₂₀Alkini
Lu group, C₂-C₂₀Alkenyl group, intervening hetero atom
C₃-C₂₀Alkenyl group, aryl group or aromatic compound
C substituted with a cyclic group₂-C₂₀Alkenyl group, aryl
A heteroatom substituted by a group or an aromatic heterocyclic group
Existing C₂-C₂₀Alkyl group or cycloalkyl group
, M is an integer of 0 to 4, Ar is aryl
Group selected from the group consisting of aromatic group, aromatic heterocyclic group, and substituent group a.
1 to 5 substituted aryl groups, selected from substituent group a
Represents an aromatic heterocyclic group substituted with 1 to 5 groups represented by
You However, when Ar is an aryl group, R¹Is hydrogen
Not showing a child and R²And / or R^3aDoes not represent a hydrogen atom
Yes. ] The compound represented by. <Substituent group a> Halogen source
Child, lower alkyl group, halogeno lower alkyl group, lower alkyl group
Lucoxy group, lower alkylthio group, carboxyl group, low
Grade alkoxycarbonyl group, hydroxy group, lower aliphatic
Acyl group, amino group, mono-lower alkylamino group, di
-Lower alkylamino group, lower aliphatic acylamino group,
Cyano group and nitro group.

In the above compound (La) or (Lb), suitable compounds can be mentioned below. (50) (49), the compound having the general formula (La), (51) (49) or (50), R
^In the compound selected from the group consisting of (52), (49) to (51), wherein ¹ is a hydrogen atom, R ² and R ^3a are taken together to form a compound represented by the formula (-(C = O)- A compound which is a) group, and in any one selected from (53), (49) to (51), R ^3a is a compound which is a hydrogen atom, and is selected from (54), (49) to (53). In any one of the above items, R ^4a is a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group in which a hetero atom is present, an aryl group or a C ₁ -C ₁₀ alkyl group substituted with an aromatic heterocyclic group. , C ₂ -C ₁₀ alkynyl groups, C ₃ with a heteroatom intervening
-C ₁₀ alkynyl group, an aryl group or an aromatic heterocyclic C ₂ -C ₁₀ alkynyl group substituted with a group, C ₂ -C ₁₀ alkenyl group, C ₃ -C ₁₀ alkenyl group which heteroatoms are interposed,
C ₂ -C ₁₀ substituted with an aryl group or an aromatic heterocyclic group
Alkenyl group, C ₂ -C ₁₀ alkyl group hetero atom substituted by an aryl group or an aromatic heterocyclic group is interposed, or the compound is a C ₅ -C ₁₀ cycloalkyl group, (5
5) In any one item selected from (49) to (53), R ^4a represents a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group in which a hetero atom is present, an aryl group or an aromatic hetero group. C ₁ -C ₁₀ alkyl group substituted with a ring group, C ₂ -C
₁₀ alkynyl, C ₂ -C ₁₀ alkenyl group, or, C ₅ -
Compounds which are C ₁₀ cycloalkyl groups, (56) (49)
In any one of items (1) to (53), R
^A compound in which ^4a is a C ₁ -C ₁₀ alkyl group, (57)
The compound according to any one of (49) to (53), wherein R ^4a is a C ₁ -C ₆ alkyl group,
8) A compound represented by any one of (49) to (53), wherein R ^4a is a methyl or ethyl group,
(59) In any one item selected from (49) to (58), Ar is phenyl, furyl, thienyl,
A compound which is a phenyl, furyl, thienyl or benzothienyl group substituted with 1 to 4 benzothienyl groups or a group selected from the above substituent group a, (60) (4
The compound of any one selected from 9) to (58), wherein Ar is a thienyl group or a thienyl group substituted with 1 to 4 groups selected from the substituent group a, (61) ( 49) to (58), wherein Ar is a benzothienyl group or a benzothienyl group substituted with 1 to 4 groups selected from the substituent group a, (62) ) In any one of items selected from (49) to (61), m is
In the compound selected from the group consisting of 0, (63), (49) to (61), the substituent group a is a halogen atom, a hydroxyl group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group or carboxy. Group, a lower aliphatic acyl group, a lower aliphatic acylamino group, an amino group, a cyano group and a nitro group. (64) Further, the compound represented by the general formula (XLIVa), which is important as a synthetic intermediate for the above-mentioned optically active aminoalcohol compound,
Or an optically active 2-substituted-2- having (XLIVb)
A novel and highly selective method for producing an amino-1,3-propanediol monoester derivative is as follows. That is, the general formula (XLII)

[0048]

[Chemical 17]

[Wherein R¹And R²Are the same or different
Represents a hydrogen atom or an amino-protecting group, and R^4aIs C
₁-C₂₀Alkyl group, C intervening hetero atom₂-C₂₀A
Substituted with an alkyl group, an aryl group or an aromatic heterocyclic group
C₁-C₂₀Alkyl group, C₂-C ₂₀Alkynyl group, f
C with a terror atom₃-C₂₀Alkynyl group, aryl
C substituted with a group or an aromatic heterocyclic group₂-C₂₀Al
Quinyl group, C₂-C₂₀Alkenyl group, hetero atom
To do C₃-C₂₀Alkenyl group, aryl group or aromatic
Substituted with a heterocyclic group₂-C₂₀Alkenyl group, ant
Group substituted with a hetero group or an aromatic heterocyclic group
C intervening₂-C₂₀Alkyl group or cycloalkyl
Represents a radical. ] 2-Substituted-2-amino-1, represented by
Only one hydroxy group of 3-propanediol derivative
With the formula (XLIII) in the presence of lipase: R¹¹COOCH = CH₂      (XLIII) Carboxylic acid vinyl ester derivative having¹¹
Is R^4aThe same group as in the definition of is shown. ) Is used
Of the general formula (X
2-substituted-, represented by LIVa) or (XLIVb)
2-amino-1,3-propanediol monoester
Derivative

[0050]

[Chemical 18]

[In the formula, R ¹ , R ² , R ^4a and R ¹¹ have the same meanings as described above. ] Manufacturing method.

In the above, (65) (6
4), in which ^one of R ¹ and R ² is a hydrogen atom and the other is a protecting group for an amino group, (66) (64) or (65), R ^4a is C ₁ -C ₁₀ alkyl Base,
C ₂ -C ₁₀ alkyl group which heteroatoms are mediated, C ₃ an aryl group or an aromatic heterocyclic C ₁ -C ₁₀ alkyl group substituted with a group, C ₂ -C ₁₀ alkynyl group, a hetero atom-mediated
-C ₁₀ alkynyl group, an aryl group or an aromatic heterocyclic C ₂ -C ₁₀ alkynyl group substituted with a group, C ₂ -C ₁₀ alkenyl group, C ₃ -C ₁₀ alkenyl group which heteroatoms are interposed,
C ₂ -C ₁₀ substituted with an aryl group or an aromatic heterocyclic group
A production method which is a C ₂ -C ₁₀ alkyl group or a C ₅ -C ₁₀ cycloalkyl group with a heteroatom substituted by an alkenyl group, an aryl group or an aromatic heterocyclic group interposed therebetween, (6
7) In (64) or (65), R ^4a is C ₁ -C
₁₀ alkyl group, C ₂ -C ₁₀ alkyl group which heteroatoms are mediated, C ₁ substituted with an aryl group or an aromatic heterocyclic group
-C ₁₀ alkyl group, C ₂ -C ₁₀ alkynyl group, C ₂ -C ₁₀
In the production method which is an alkenyl group or a C ₅ -C ₁₀ cycloalkyl group, any one selected from (68), (64) to (67), wherein R ¹¹ is a C ₁ -C ₂₀ alkyl group. Or a C ₁ -C ₂₀ alkyl group substituted with an aryl group or a heteroaryl group.

In the above formula, X, R ⁵ , Ar and the substituent group b
In the definition of "aryl group", "aryl group substituted with 1 to 3 groups selected from substituent group a", "1 to 3 groups substituted with groups selected from substituent groups a and b" The aryl moiety of the “aryl group” and the “aryl group substituted with 1 to 5 groups selected from the substituent group a” has, for example, 6 carbon atoms such as phenyl, indenyl and naphthyl.
To 10 aromatic hydrocarbon groups, preferably phenyl or naphthyl groups, most preferably phenyl groups.

In the above formula, "C ₁ -C ₁₀ " in the definition of Y
C ₁ -C ₁₀ alkylene moiety of the alkylene group "and" a 1 to 3 substituted with a group selected from Substituent group a and b the C ₁ -C ₁₀ alkylene group "include methylene, methylmethylene, ethylene, propylene , Trimethylene, 1-methylethylene, tetramethylene, 1-methyltrimethylene,
2-methyltrimethylene, 3-methyltrimethylene, 1
-Methyl propylene, 1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methyltetramethylene, 1,1-dimethyltrimethylene, 2,
2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentamethylene, 2
-Methylpentamethylene, 3-methylpentamethylene,
4-methylpentamethylene, 5-methylpentamethylene, 1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene, 3,3-dimethyltetramethylene,
4,4-dimethyltetramethylene, heptamethylene, 1
-Methylhexamethylene, 2-methylhexamethylene,
5-methylhexamethylene, 3-ethylpentamethylene, octamethylene, 2-methylheptamethylene, 5-
Methylheptamethylene, 2-ethylhexamethylene, 2
-Ethyl-3-methylpentamethylene, 3-ethyl-2
Such as -methylpentamethylene, nonamethylene, 2-methyloctamethylene, 7-methyloctamethylene, 4-ethylheptamethylene, 3-ethyl-2-methylhexamethylene, 2-ethyl-1-methylhexamethylene, decamethylene group. A linear or branched alkylene group having 1 to 10 carbon atoms, preferably a C ₁ -C ₆ alkylene group, more preferably a C ₁ -C ₅ alkylene group, and more preferably a C ₁ -C ₅ alkylene group. It is an ethylene, trimethylene or tetramethylene group, most preferably an ethylene or trimethylene group.

In the above formula, in the definition of Y, "carbon chain
C having an oxygen atom or a sulfur atom at the chain end₁−
C_TenAlkylene group ”and“ substituent groups a and b ”
In the carbon chain or chain ends substituted by 1 to 3 groups
C having an oxygen atom or a sulfur atom in₁-C_TenArchi
"Rene group", "Oxygen atom in the carbon chain or at the chain end
Is C having a sulfur atom₁-C_TenThe "alkylene" portion is on the
Note "C₁-C_TenAcid at the chain end or in the chain of "alkylene group"
A group having an elementary atom or a sulfur atom, for example,
O-CH₂-, -O- (CH₂)₂-, -O- (CH₂)₃
-, -O- (CH₂)_Four-, -O- (CH₂)_Five-, -O-
(CH₂)₆-, -O- (CH₂)₇-, -O- (CH₂)₈
-, -O- (CH₂)₉-, -O- (CH₂)_Ten-, -C
H₂-O-CH₂-, -CH₂-O- (CH₂)₂-, -C
H₂-O- (CH₂)₃-, -CH₂-O- (CH₂)_Four-,
-(CH₂)₂-O-CH₂-,-(CH₂)₂-O- (C
H₂)₂-,-(CH₂)₂-O- (CH₂)₃-,-(CH
₂)₂-O- (CH₂)_Four-,-(CH₂)₃-O-CH
₂-,-(CH₂)₃-O- (CH₂)₂-,-(CH₂)₃
-O- (CH₂)₃-,-(CH₂)_Four-O-CH₂-,-
(CH₂)_Four-O- (CH₂)₂-,-(CH₂)_Five-OC
H₂-, -CH₂-O-,-(CH₂)₂-O-,-(CH
₂)₃-O-,-(CH₂)_Four-O-,-(CH₂)_Five-O
-,-(CH₂)₆-O-,-(CH₂)₇-O-,-(C
H₂)₈-O-,-(CH₂)₉-O-,-(CH₂)_Ten−
O-, -S-CH₂-, -S- (CH₂)₂-, -S-
(CH₂)₃-, -S- (CH₂)_Four-, -S- (CH₂)_Five
-, -S- (CH₂)₆-, -S- (CH₂)₇-, -S-
(CH₂)₈-, -S- (CH₂)₉-, -S- (CH₂)
_Ten-, -CH₂-S-CH₂-, -CH₂-S- (CH₂)
₂-, -CH₂-S- (CH₂)₃-, -CH₂-S- (C
H₂)_Four-,-(CH₂)₂-S-CH₂-,-(CH₂)₂
-S- (CH₂)₂-,-(CH₂)₂-S- (CH₂)
₃-,-(CH₂)₂-S- (CH₂)_Four-,-(CH₂)₃
-S-CH₂-,-(CH₂)₃-S- (CH₂)₂-,-
(CH₂)₃-S- (CH₂)₃-,-(CH₂)_Four-SC
H₂-,-(CH₂)_Four-S- (CH₂)₂-,-(CH₂)
_Five-S-CH₂-, -CH₂-S-,-(CH₂)₂-S
-,-(CH₂)₃-S-,-(CH₂)_Four-S-,-(C
H₂)_Five-S-,-(CH₂)₆-S-,-(CH₂)₇-S
-,-(CH₂)₈-S-,-(CH₂)₉-S-,-(C
H₂)_TenA group having —S—, preferably in the carbon chain
Or C having an oxygen atom at the chain end₁-C_TenAlkylene
And more preferably oxygen in the carbon chain or at the chain end.
C with an atom₁-C₆More preferably an alkylene group
Is -O-CH ₂-, -O- (CH₂)₂-, -O- (C
H₂)₃-, -CH₂-O-,-(CH₂)₂-O- or-
(CH₂)₃A group having -O-, and most preferably-
CH₂-O-, -O- (CH₂)₂-Or- (CH₂)₂−
It is a group having O-.

In the above formula, R ^4a , R ⁵ , R ¹¹ and the “cycloalkyl group” and “substituent group a” in the definition of the substituent group b.
The cycloalkyl moiety of “a cycloalkyl group substituted with 1 to 3 groups selected from” and “a cycloalkyl group substituted with 1 to 3 groups selected from substituent groups a and b” is, for example, Examples thereof include saturated carbocyclic groups having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl and indanyl, and condensed rings with other cyclic groups such as benzene ring. You may have. As the cycloalkyl group in the definition of R ⁵ and the substituent group b,
Preferably a C ₅ -C ₆ cycloalkyl group, most preferably a cyclohexyl group. On the other hand, the cycloalkyl group in the definition of R ^4a and R ¹¹ is preferably C ₅ -C
_{10 is a} cycloalkyl group.

In the above formula, 1 to 5 are groups selected from the "aromatic heterocyclic group" and "substituent group a" in the definition of Ar.
The “substituted aromatic heterocyclic group” refers to a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, and examples thereof include furyl, thienyl, pyrrolyl and azepinyl. , Pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
Aromatic heterocyclic groups such as 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl can be mentioned.

The above "aromatic heterocyclic group" may be condensed with another cyclic group, and examples thereof include benzothienyl, isobenzofuranyl, chromenil, xanthenyl, phenoxathiinyl, indolizinyl, Isoindolyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,
Mention may be made of groups such as quinoxalinyl, quinazolinyl, carbazolyl, carborinyl, acridinyl, isoindolinyl. Such "aromatic heterocyclic group" is preferably a phenyl, furyl, thienyl or benzothienyl group, most preferably a thienyl or benzothienyl group.

In the above formula, R ⁵ and the “heterocyclic group” in the definition of the substituent group b and the group selected from the substituent group a are 1
To 3 substituted heterocyclic groups "and" substituent groups a and b
The heterocyclic group portion of the “heterocyclic group substituted with 1 to 3 groups selected from the group consisting of: represents a 5 to 7-membered heterocyclic group containing 1 to 3 sulfur, oxygen or / and nitrogen atoms For example, the above “aromatic heterocyclic group”, and tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,
Mention may be made of partially or fully reduced saturated heterocyclic groups corresponding to these groups such as pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, pyrazolidinyl. Such a heterocyclic group is preferably a 5- or 6-membered aromatic heterocyclic group, and most preferably a morpholinyl, thiomorpholinyl or piperidinyl group.

In the above formula, the "halogen atom" in the definition of the substituent group a is a fluorine, chlorine, bromine or iodine atom,
It is preferably a fluorine atom or a chlorine atom, and most preferably a fluorine atom.

In the above formula, “lower alkyl group” in the definition of R ⁴ and the substituent group a is, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,
3,3-dimethylbutyl, 2,2-dimethylbutyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, 1
1 carbon atom such as -ethylbutyl and 2-ethylbutyl groups
To 6 linear or branched alkyl groups, preferably C ₁ -C ₄ alkyl groups, more preferably C ₁ -C ₂ alkyl groups, and most preferably methyl groups. .

In the above formula, the "halogeno lower alkyl group" in the definition of the substituent group a is a group in which a halogen atom is substituted on the above "lower alkyl group", and examples thereof include trifluoromethyl, trichloromethyl, difluoromethyl, Dichloromethyl, dibromomethyl, fluoromethyl, 2,
2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-yo- Dohexyl 2,2
A halogeno C ₁ -C ₆ alkyl group such as a dibromoethyl group, preferably a halogeno C ₁ -C ₄ alkyl group, and more preferably a halogeno C ₁ -C ₂ alkyl group,
Most preferably, it is a trifluoromethyl group.

In the above formula, "lower alkoxy group" in the definition of Substituent group a represents a group in which the above "lower alkyl group" is bonded to an oxygen atom, for example, methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethylpropoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methyl. Pentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy. Carbon number 1 like a group
To 6 straight or branched chain alkoxy groups, preferably C ₁ -C ₄ alkoxy groups, and more preferably C ₁ -C ₂
It is an alkoxy group, most preferably a methoxy group.

In the above formula, the "lower alkylthio group" in the definition of the substituent group a is a group in which the above "lower alkyl group" is bonded to a sulfur atom, and examples thereof include methylthio, ethylthio, propylthio, isopropylthio, butylthio,
Isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3 -Dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-
Dimethylbutylthio, 1,3-dimethylbutylthio,
1 to 6 carbon atoms such as 2,3-dimethylbutylthio group
C straight-chain or branched alkylthio groups, preferably C
An ₁ -C ₄ alkylthio group, more preferably a C ₁ -C ₂ alkylthio group, most preferably a methylthio group.

In the above formula, "lower alkoxycarbonyl group" in the definition of Substituent group a represents a group in which the above "lower alkoxy group" is bonded to a carbonyl group, and examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and iso Propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl,
Isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2 , 2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl,
A linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms such as 1,3-dimethylbutoxycarbonyl and 2,3-dimethylbutoxycarbonyl group,
It is preferably a C ₁ -C ₄ alkoxycarbonyl group, more preferably a C ₁ -C ₂ alkoxycarbonyl group, and most preferably a methoxycarbonyl group.

In the above formula, the "lower aliphatic acyl group" in the definition of the substituent group a is a group in which a hydrogen atom or a saturated or unsaturated chain hydrocarbon group is bonded to a carbonyl group, for example, formyl, Acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl,
A linear or branched lower aliphatic acyl group having 1 to 7 carbon atoms such as a crotonoyl group, preferably a C ₁ -C ₄ lower aliphatic acyl group, more preferably an acetyl or propionyl group. And most preferably an acetyl group.

In the above formula, "mono-lower alkylamino group" in the definition of Substituent group a has the same meaning as described above in which one "lower alkyl group" is bonded to an amino group, for example, methyl. Amino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, Hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3
-Dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3
A mono-C ₁ -C ₆ alkylamino group such as dimethylbutylamino, 2-ethylbutylamino group, preferably a mono-C ₁ -C ₄ alkylamino group, and more preferably mono-C. _{It is a 1-} C ₂ alkylamino group, most preferably a methylamino group.

In the above formula, "di-lower alkylamino group" in the definition of Substituent group a is the above "lower alkyl group".
Represents a group bonded to two amino groups, and examples thereof include di-C ₁ -C such as dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino and dihexylamino groups. _{It is a 6} alkylamino group, preferably a di-C ₁ -C ₄ alkylamino group, more preferably a di-C ₁ -C ₂ alkylamino group, and most preferably a dimethylamino group.

In the above formula, the "lower aliphatic acylamino group" in the definition of the substituent group a is a group in which the above "lower aliphatic acyl group" is bonded to an amino group, and examples thereof include formylamino, acetylamino and propionyl. Linear or branched lower fatty acids having 1 to 7 carbon atoms such as amino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino and crotonoylamino groups. It is a group acylamino group, preferably an acetylamino or propionylamino group, and most preferably an acetylamino group.

In the above formula, the "amino group-protecting group" in the definition of R ¹ and R ² means an amino group-protecting group generally used in the field of synthetic organic chemistry, and for example, the above-mentioned " “Lower alkyl group”; the aforementioned “lower aliphatic acyl group”, halogeno lower aliphatic acyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, lower aliphatic substituted with lower alkoxy such as methoxyacetyl "Aliphatic acyls" such as acyl group; benzoyl, 1-indancarbonyl, 2-indanecarbonyl, aromatic acyl groups such as 1- or 2-naphthoyl, 4-chlorobenzoyl, 4-fluorobenzoyl, 2,4 , 6-trimethylbenzoyl, 4-
Toluoyl, 4-anisoyl 4-nitrobenzoyl, 2
“Aromatic acyls” such as aromatic acyl groups substituted with 1 to 3 groups selected from the substituent group a such as —nitrobenzoyl, 2- (methoxycarbonyl) benzoyl, 4-phenylbenzoyl; "Alkoxycarbonyls" such as the aforementioned "lower alkoxycarbonyl group", halogen such as 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or lower alkoxycarbonyl group substituted with tri-lower alkylsilyl; vinyloxy “Alkenyloxycarbonyls” such as carbonyl and allyloxycarbonyl;
An aralkyloxycarbonyl group such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
An aralkyloxycarbonyl group substituted by 1 to 3 groups such as 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl and the like, which is selected from the substituent group a, Aralkyloxycarbonyls "; tri-lower alkylsilyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl. "Silyls", such as aryl or aryl or aryl and lower alkyl trisubstituted silyl groups such as diphenylisopropylsilyl, phenyldiisopropylsilyl; benzyl,
Lower substituted with 1 to 3 aryl groups such as phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl Alkyl group, 4-methylbenzyl, 2,4,6-
Trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4 -Cyanobenzyldiphenylmethyl,
“Aralkyls such as bis (2-nitrophenyl) methyl, lower alkyl such as piperonyl, lower alkoxy, lower alkyl group substituted with 1 to 3 aryl groups whose aryl ring is substituted with nitro, halogen or cyano. Such as N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene, (5-chloro-2-hydroxyphenyl) phenylmethylene. “Substituted methylene group forming a Schiff base” is included, and preferably 1 to 3 aralkyloxycarbonyl substituted with a lower alkoxycarbonyl group, an aralkyloxycarbonyl group or a group selected from the substituent group a. It is a base.

In the definition of R ³ and R ^3a , the term "protecting group for hydroxy group" means hydrogenolysis, hydrolysis, electrolysis,
A "general protecting group in the reaction" that can be cleaved by a chemical method such as photolysis and a "protecting group that can be cleaved by a biological method such as hydrolysis in vivo" are shown.

Such “general protecting groups in the reaction”
Are, for example, the above "lower alkyl group"; the above "aliphatic acyls"; the above "aromatic acyls"; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2.
-Yl, 4-methoxytetrahydropyran-4-yl,
"Tetrahydropyranyl or tetrahydrothiopyranyls" such as tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2-yl, tetrahydrothiofuran-2-
“Tetrahydrofuranyl or tetrahydrothiofuranyl” such as yl; the above “silyls”; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t- Lower alkoxymethyl group such as butoxymethyl, lower alkoxylated lower alkoxymethyl group such as 2-methoxyethoxymethyl, 2,2,2-
"Alkoxymethyl group" such as halogeno lower alkoxymethyl such as trichloroethoxymethyl, bis (2-chloroethoxy) methyl; 1-ethoxyethyl, 1-
"Substituted ethyls" such as lower alkoxylated ethyl groups such as (isopropoxy) ethyl, halogenated ethyl groups such as 2,2,2-trichloroethyl; the above "aralkyls"; the above "alkoxycarbonyls"; The above "alkenyloxycarbonyls"; the above "aralkyloxycarbonyls" can be mentioned.

On the other hand, examples of the "protective group capable of being cleaved in vivo by a biological method such as hydrolysis" include, for example, ethylcarbonyloxymethyl, pivaloyloxymethyl, dimethylaminoacetyloxymethyl, 1-acetoxy. Acyloxyalkyls such as ethyl; 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl,
1- (t-butoxycarbonyloxy) ethyl, 1-
1-such as (ethoxycarbonyloxy) propyl, 1- (cyclohexyloxycarbonyloxy) ethyl
(Alkoxycarbonyloxy) alkyls; phthalidyl group; 4-methyl-oxodioxolenylmethyl, 4-
"Carbonyloxyalkyls" such as oxodioxolenylmethyl group such as phenyl-oxodioxolenylmethyl, oxodioxolenylmethyl; the above "aliphatic acyls"; the above "aromatic acyls";"Half-ester salt residue of succinic acid";"Phosphate salt residue";"Ester-forming residue of amino acid, etc."; Carbamoyl group; Aralkylidene group such as benzylidene; Alkoxyethylidene group such as methoxyethylidene and ethoxyethylidene Oxomethylene; "protecting group for two hydroxy groups" such as thioxomethylene; and "carbonyloxyalkyloxycarbonyl group" such as pivaloyloxymethyloxycarbonyl, and derivatives thereof. Whether or not it is injected into an experimental animal such as a rat or mouse by intravenous injection. And, it examines the body fluids of the subsequent animal,
It can be determined by the ability to detect the original compound or a pharmaceutically acceptable salt thereof. As such a hydroxy group-protecting group, preferably, an aromatic acyl group having 1 to 3 substituents selected from a lower alkyl group, a lower aliphatic acyl group, an aromatic acyl group or a substituent group a. Is.

In the above, specific examples of "a cycloalkyl group substituted with 1 to 3 groups selected from the substituent groups a and b" in the definition of R ⁵ are, for example, 2-fluorocyclopropyl and 2 -Chlorocyclopropyl, 2
-Or 3-fluorocyclopentyl, 2- or 3-chlorocyclopentyl, 2-, 3- or 4-fluorocyclohexyl, 2-, 3- or 4-chlorocyclohexyl, 2-, 3- or 4-bromocyclohexyl, 2- , 3- or 4-iodocyclohexyl, 2-methylcyclopropyl, 2-ethylcyclopropyl, 2- or 3-methylcyclopentyl, 2- or 3-ethylcyclopentyl, 2-, 3- or 4-methylcyclohexyl, 2-, 3- or 4-ethylcyclohexyl, 2-trifluoromethylcyclopropyl, 2- or 3-trifluoromethylcyclobutyl, 2- or 3-trifluoromethylcyclopentyl, 2-, 3- or 4-trifluoro Methylcyclohexyl, 2- Toxycyclopropyl, 2- or 3-methoxycyclobutyl, 2- or 3-methoxycyclopentyl, 2-, 3- or 4-methoxycyclohexyl, 2-, 3- or 4-ethoxycyclohexyl, 2-, 3- or 4 -Propoxycyclohexyl, 2-, 3- or 4-isopropoxycyclohexyl, 2-, 3- or 4- (1-ethylpropoxy) cyclohexyl, 2-, 3- or 4- (2-
Ethylpropoxy) cyclohexyl, 2-carboxylcyclopropyl, 2- or 3-carboxylcyclopentyl, 2-, 3- or 4-carboxylcyclohexyl, 2-methoxycarbonylcyclopropyl, 2
-Or 3-methoxycarbonylcyclopentyl, 2
-, 3- or 4-methoxycarbonylcyclohexyl, 2-hydroxycyclopropyl, 2- or 3-
Hydroxycyclopentyl, 2-, 3- or 4-hydroxycyclohexyl, 2-formylcyclopropyl, 2- or 3-formylcyclopentyl, 2-,
3- or 4-formylcyclohexyl, 2-acetylcyclopropyl, 2- or 3-acetylcyclopentyl, 2-, 3- or 4-acetylcyclohexyl, 2-aminocyclopropyl, 2- or 3-aminocyclopentyl, 2-, 3- or 4-aminocyclohexyl, 2-methylaminocyclopropyl, 2- or 3-methylaminocyclobutyl, 2- or 3
-Methylaminocyclopentyl, 2-, 3- or 4
-Methylaminocyclohexyl, 2-dimethylaminocyclopropyl, 2- or 3-dimethylaminocyclobutyl, 2- or 3-dimethylaminocyclopentyl, 2-, 3- or 4-dimethylaminocyclohexyl, 2-cyanocyclopropyl, 2 -Or 3-cyanocyclopentyl, 2-, 3- or 4-cyanocyclohexyl, 2- or 3-cyclohexylcyclopentyl, 2-, 3- or 4-cyclohexylcyclohexyl, 2-phenylcyclopropyl, 2- or 3-phenylcyclopentyl , 2-, 3- or 4
-Phenylcyclohexyl, 3,4-difluorocyclohexyl, 3,4-dichlorocyclohexyl, 2,3-
Dimethoxycyclohexyl, 3,4-dimethoxycyclohexyl, 3,5-dimethoxycyclohexyl, 3,
4,5-trimethoxycyclohexyl group, preferably 1 to 3 substituted cycloalkyl groups (the substituents are halogen atoms, lower alkyl groups, halogeno lower alkyl groups, lower alkoxy groups, lower alkylthio groups) And a group selected from the group consisting of lower aliphatic acyl groups), more preferably 1 to 3 substituted cycloalkyl groups (wherein the substituents are halogen atoms, lower alkyl groups, halogeno groups). It is a group selected from the group consisting of a lower alkyl group, a lower alkoxy group and a lower aliphatic acyl group, and more preferably 1 to 3 substituted cyclohexyl groups (wherein the substituent is a halogen atom). , A lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower aliphatic acyl group). The, 1 to 3-substituted cyclohexyl group (the substituent is a fluorine atom, a chlorine atom, a group selected from methyl, trifluoromethyl, from the group consisting of methoxy and acetyl groups.) Is.

In the above, specific examples of the "aryl group substituted with 1 to 3 groups selected from the substituent groups a and b" in the definition of R ⁵ are, for example, 2-, 3- or 4- Fluorophenyl, 2-, 3- or 4-
Chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-iodophenyl, 2-3
-Or 4-methylphenyl, 2-, 3- or 4
-Ethylphenyl, 2-, 3- or 4-propylphenyl, 2-, 3- or 4-butylphenyl, 2
-, 3- or 4-pentylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-
Ethoxyphenyl, 2-, 3- or 4-propoxyphenyl, 2-, 3- or 4-isopropoxyphenyl, 2-, 3- or 4-butoxyphenyl, 2
-, 3- or 4- (1-ethylpropoxy) phenyl, 2-, 3- or 4- (2-ethylpropoxy)
Phenyl, 2-, 3- or 4-methylthiophenyl, 2-, 3- or 4-ethylthiophenyl, 2
-, 3- or 4-carboxylphenyl, 2-, 3
-Or 4-methoxycarbonylphenyl, 2,3
-Or 4-ethoxycarbonylphenyl, 2,3
-Or 4-hydroxyphenyl, 2-, 3- or 4-formylphenyl, 2-, 3- or 4-acetylphenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-methylamino Phenyl, 2
-, 3- or 4-dimethylaminophenyl, 2-,
3- or 4-cyanophenyl, 2-, 3- or 4-cyclopentylphenyl, 2-, 3- or 4-
Cyclohexylphenyl, 2-, 3- or 4-biphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-
Dichlorophenyl, 3,4-dichlorophenyl, 3,5
-Dichlorophenyl, 3,4-dibromophenyl, 2,
3-dimethylphenyl, 3,4-dimethylphenyl,
3,5-Dimethylphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methyl 2-methoxyphenyl, 6-fluoro-4-methyl-2-methoxyphenyl, 5-fluoroinden-3-yl, 5-chloroinden-3-yl, 5-methylinden-3-yl, 5-methoxyindene -3-yl, 5-fluoroinden-2-yl, 5-chloroinden-2-yl, 5
-Methylinden-2-yl, 5-methoxyinden-
2-yl, 5-hydroxyinden-3-yl, 5-nitroinden-3-yl, 5-cyclohexylinden-3-yl, 5-phenylinden-3-yl, 5-phenoxyinden-3-yl, 5 -Benzyloxyinden-3-yl, 5-phenylthioinden-3-yl, 5-hydroxyinden-2-yl, 5-nitroinden-2-yl, 5-cyclohexylinden-2-
Yl, 5-phenylinden-2-yl, 5-fluoronaphthalen-2-yl, 5-chloronaphthalen-2-yl, 5-methylnaphthalen-2-yl, 5-methoxynaphthalen-2-yl, 5-fluoro Naphthalen-1-yl, 5-chloronaphthalen-1-yl, 5-methylnaphthalen-1-yl, 5-methoxynaphthalen-1-yl, 5-hydroxynaphthalen-2-yl, 5-nitronaphthalen-2-yl , 5-cyclohexylnaphthalen-2-yl, 5-phenylnaphthalen-2-yl, 5-
Phenoxynaphthalen-2-yl, 5-benzyloxynaphthalen-2-yl, 5-phenylthionaphthalene-
2-yl, 5-hydroxynaphthalen-1-yl, 5-
Nitronaphthalen-1-yl, 5-cyclohexylnaphthalen-1-yl, 5-phenylnaphthalen-1-yl groups, preferably 1 to 3 substituted aryl groups (wherein the substituents are halogen atoms, A lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, and a lower aliphatic acyl group), and more preferably 1 to 3 substituted aryls. A group (the substituent is a group selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a lower aliphatic acyl group), and more preferably 1 to A phenyl group substituted with three (wherein the substituent is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group or a lower aliphatic acyl group). It is a group selected from the group consisting of :, and more preferably 1 to 3 substituted phenyl groups (the substituents are fluorine atom, chlorine atom, methyl, trifluoromethyl, methoxy and acetyl). A group selected from the group consisting of groups), most preferably 3-fluorophenyl, 4-fluorophenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,
4-dichlorophenyl, 3,5-dichlorophenyl, 3
-Methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,4-ditrifluoromethylphenyl, 3,5-
Ditrifluoromethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-acetylphenyl or 4-acetylphenyl group is there.

In the above, specific examples of "heterocyclic group substituted with 1 to 3 groups selected from the substituent groups a and b" in the definition of R ⁵ are, for example, 3-, 4- or 5 -Methylfuran-2-yl, 2-, 4- or 5-methylfuran-3-yl, 3-, 4- or 5-
Fluorothiophen-2-yl, 2-, 4- or 5
-Fluorofuran-3-yl, 3-, 4- or 5-
Bromothiophen-2-yl, 2-, 4- or 5-
Bromofuran-3-yl, 3-, 4- or 5-methylthiophen-2-yl, 2-, 4- or 5-methylthiophen-3-yl, 3-, 4- or 5-ethylthiophen-2-yl , 2-, 4- or 5-ethylthiophen-3-yl, 3-, 4- or 5-methoxythiophen-2-yl, 2-, 4- or 5-methoxythiophen-3-yl, 3- or 4 -Methylthiazol-5-yl, 3-, 4- or 5-fluorobenzothiophen-2-yl, 3-, 4- or 5
-Bromobenzothiophen-2-yl, 3-, 4- or 5-methylbenzothiophen-2-yl, 3-, 4
-Or 5-methoxybenzothiophen-2-yl,
2-, 4- or 5-fluorobenzothiophene-3
-Yl, 2-, 4- or 5-bromobenzothiophen-3-yl, 2-, 4- or 5-methylbenzothiophen-3-yl, 2-, 4- or 5-methoxybenzothiophen-3-yl , 4-, 5-, 6- or 7-methylbenzothiophen-2-yl, 3-, 4-
Or 5-hydroxyfuran-2-yl, 2-, 4-
Or 5-hydroxyfuran-3-yl, 3-, 4-
Or 5-hydroxythiophen-2-yl, 3-,
4- or 5-nitrothiophen-2-yl, 3-,
4- or 5-phenylthiophen-2-yl, 2
-, 4- or 5-hydroxythiophen-3-yl, 2-, 4- or 5-cyanothiophen-3-yl, 1-, 2- or 3-hydroxypyridin-4-
Yl, 1-, 2- or 3-cyanopyridin-4-yl, 1-, 2- or 3-phenylpyridin-4-yl group, preferably 3-, 4- or 5-fluorothiophene- 2-yl or 2-, 4- or 5-fluorofuran-3-yl groups.

In the above, "C ₁ -C ₂₀ alkyl group" in the definition of R ^4a and R ¹¹ means, for example, the above "lower alkyl group", heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl. Hexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4
-Dimethylpentyl, octyl, 1-methylheptyl,
2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl,
1-propylpentyl, 2-ethylhexyl, 5,5-
Dimethylhexyl, nonyl, 3-methyloctyl, 4-
Methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl,
6,6-Dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl , Tridecyl, tetradecyl, pentadecyl,
3,7,11-trimethyldodecyl, hexadecyl,
4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, eicosyl, And a linear or branched alkyl group having 1 to 20 carbon atoms such as a 3,7,11,15-tetramethylhexadecyl group, preferably a C ₁ -C ₁₀ alkyl group. And more preferably C ₁ -C ₆
It is an alkyl group, most preferably a methyl or ethyl group.

[0078] In the above, the "C ₂ -C _{2 0} alkyl group having a heteroatom-mediated" in the definition of R ^4a and R ^11, the "number 2 to carbon atoms of the" C ₁ -C ₂₀ alkyl group ""20 alkyl groups" are the same or different and represent a group in which 1 or 2 sulfur atoms, oxygen atoms or nitrogen atoms are present, and examples thereof include methylthiomethyl, 1-methylthioethyl, 2- Methylthioethyl, ethylthiomethyl, 1-methylthiopropyl, 2-methylthiopropyl, 3-methylthiopropyl, 2-ethylthioethyl,
2-methyl-2-methylthioethyl, 1-methylthiobutyl, 2-methylthiobutyl, 3-methylthiobutyl,
2-ethylthiopropyl, 3-methyl-3-methylthiopropyl, 4-methylthiopentyl, 3-methylthiopentyl, 2-methylthiopentyl, 1-methylthiopentyl, 3,3-dimethylthiobutyl, 2,2-dimethylthiobutyl , 1,1-dimethylthiobutyl, 1-methyl-2-methylthiobutyl, 1,3-dimethylthiobutyl, 2,3-dimethylthiobutyl, 2-ethylthiobutyl, 1-methylthiohexyl, 2-methylthiohexyl, 3-methylthiohexyl, 4-methylthiohexyl, 5-methylthiohexyl, 1-propylthiobutyl, 4-methyl-4-methylthiopentyl, 1-methylthioheptyl, 2-methylthioheptyl, 3-methylthioheptyl, 4-methylthioheptyl, 5-methylthioheptyl, 6-methylthio Heptyl, 1-propyl thio-pentyl, 2-ethyl-thio-hexyl, 5-methyl-5-
Methylthiohexyl, 3-methylthiooctyl, 4-methylthiooctyl, 5-methylthiooctyl, 6-methylthiooctyl, 1-propylthiohexyl, 2-ethylthioheptyl, 6-methyl-6-methylthioheptyl, 1-methylthiononyl, 3 -Methylthiononyl, 8
-Methylthiononyl, 3-ethylthiooctyl, 3-methyl-7-methylthiooctyl, 7,7-dimethylthiooctyl, 4-methyl-8-methylthiononyl, 3,7
-Dimethyl-11-methylthiododecyl, 4,8-dimethyl-12-methylthiotridecyl, 1-methylthiopentadecyl, 14-methylthiopentadecyl, 13-methyl-13-methylthiotetradecyl, 15-methylthiohexadecyl, 1- Methylthioheptadecyl, and
An alkyl group having 2 to 20 carbon atoms which is interposed by one or two sulfur atoms such as 3,7,11-trimethyl-15-methylthiohexadecyl; methyloxymethyl,
1-methyloxyethyl, 2-methyloxyethyl, ethyloxymethyl, 1-methyloxypropyl, 2-methyloxypropyl, 3-methyloxypropyl, 2-
Ethyloxyethyl, 2-methyl-2-methyloxyethyl, 1-methyloxybutyl, 2-methyloxybutyl, 3-methyloxybutyl, 2-ethyloxypropyl, 3-methyl-3-methyloxypropyl, 4-methyl Oxypentyl, 3-methyloxypentyl, 2-methyloxypentyl, 1-methyloxypentyl, 3,
3-dimethyloxybutyl, 2,2-dimethyloxybutyl, 1,1-dimethyloxybutyl, 1-methyl-2
-Methyloxybutyl, 1,3-dimethyloxybutyl, 2,3-dimethyloxybutyl, 2-ethyloxybutyl, 1-methyloxyhexyl, 2-methyloxyhexyl, 3-methyloxyhexyl, 4-methyloxyhexyl , 5-methyloxyhexyl, 1-propyloxybutyl, 4-methyl-4-methyloxypentyl, 1-methyloxyheptyl, 2-methyloxyheptyl, 3-methyloxyheptyl, 4-methyloxyheptyl, 5-methyl Oxyheptyl, 6-methyloxyheptyl, 1-propyloxypentyl, 2-ethyloxyhexyl, 5-methyl-5-methyloxyhexyl, 3-methyloxyoctyl, 4-methyloxyoctyl, 5-methyloxyoctyl, 6 -Methyloxyoctyl, 1-propylo Shihekishiru, 2-ethyl-oxy-heptyl, 6-methyl-6-methyloxy-heptyl,
1-methyloxynonyl, 3-methyloxynonyl, 8
-Methyloxynonyl, 3-ethyloxyoctyl, 3
-Methyl-7-methyloxyoctyl, 7,7-dimethyloxyoctyl, 4-methyl-8-methyloxynonyl, 3,7-dimethyl-11-methyloxidedecyl,
4,8-dimethyl-12-methyloxytridecyl, 1
-Methyloxypentadecyl, 14-methyloxypentadecyl, 13-methyl-13-methyloxytetradecyl, 15-methyloxyhexadecyl, 1-methyloxyheptadecyl, and 3,7,11-trimethyl-
An alkyl group having 2 to 20 carbon atoms which is intervened by 1 or 2 oxygen atoms such as 15-methyloxyhexadecyl; N-methylaminomethyl, 1- (N-methylamino) ethyl, 2- ( N-methylamino) ethyl, N-ethylaminomethyl, 1- (N-methylamino) propyl, 2- (N-methylamino) propyl, 3- (N-methylamino) propyl, 2- (N-ethylamino) ) Ethyl, 2- (N, N-dimethylamino) ethyl, 1- (N
-Methylamino) butyl, 2- (N-methylamino) butyl, 3- (N-methylamino) butyl, 2- (N-ethylamino) propyl, 3- (N, N-dimethylamino) propyl, 4- (N-methylamino) pentyl, 3
-(N-methylamino) pentyl, 2- (N-methylamino) pentyl, 1- (N-methylamino) pentyl,
3- (N, N-dimethylamino) butyl, 2- (N, N
-Dimethylamino) butyl, 1- (N, N-dimethylamino) butyl, 1-methyl-2- (N-methylamino)
Butyl, 1,3-di (N-methylamino) butyl, 2,
3-di (N-methylamino) butyl, 2- (N-ethylamino) butyl, 1- (N-methylamino) hexyl,
2- (N-methylamino) hexyl, 3- (N-methylamino) hexyl, 4- (N-methylamino) hexyl, 5- (N-methylamino) hexyl, 1- (N-propylamino) butyl, 4-methyl-4- (N-methylamino) pentyl, 1- (N-methylamino) heptyl, 2- (N-methylamino) heptyl, 3- (N-methylamino) heptyl, 4- (N-methyl) Amino) heptyl, 5- (N-methylamino) heptyl, 6- (N-
Methylamino) heptyl, 1- (N-propylamino)
Pentyl, 2- (N-ethylamino) hexyl, 5-methyl-5- (N-methylamino) hexyl, 3- (N-
Methylamino) octyl, 4- (N-methylamino) octyl, 5- (N-methylamino) octyl, 6- (N
-Methylamino) octyl, 1- (N-propylamino) hexyl, 2- (N-ethylamino) heptyl, 6
-Methyl-6- (N-methylamino) heptyl, 1-
(N-methylamino) nonyl, 3- (N-methylamino) nonyl, 8- (N-methylamino) nonyl, 3-
(N-ethylamino) octyl, 3-methyl-7- (N
-Methylamino) octyl, 7,7-di (N-methylamino) octyl, 4-methyl-8- (N-methylamino) nonyl, 3,7-dimethyl-11- (N-methylamino) dodecyl, 4 , 8-dimethyl-12- (N-methylamino) tridecyl, 1- (N-methylamino) pentadecyl, 14- (N-methylamino) pentadecyl,
13-methyl-13- (N-methylamino) tetradecyl, 15- (N-methylamino) hexadecyl, 1-
(N-methylamino) heptadecyl and 3,7,1
Mention may be made of an alkyl group having 2 to 20 carbon atoms which is intervened by 1 or 2 nitrogen atoms such as 1-trimethyl-15- (N-methylamino) hexadecyl, preferably a hetero atom is a C ₂ -C ₁₀ alkyl group interposed.

In the above, "C ₁ -substituted by an aryl group or an aromatic heterocyclic group" in the definition of R ^4a and R ¹¹
The "C ₂₀ alkyl group" means the above "C ₁ -C ₂₀ alkyl group".
Are the same or different and each is a group substituted with 1 or 3 of the above "aryl group" or the above "aromatic heterocyclic group", preferably an aryl group or an aromatic heterocyclic group. a C ₁ -C ₁₀ alkyl group.

In the above, "C ₂ -C ₂₀ alkynyl group" in the definition of R ^4a and R ¹¹ means, for example, ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2
-Methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-
Butynyl, 1-methyl-3-butynyl, 2-methyl-3
-Butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl , 4-pentynyl, 1
-Methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, heptynyl, 1-methylhexynyl, 2-methylhexynyl, 3-methylhexynyl, 4
-Methylhexynyl, 5-methylhexynyl, 1-propylbutynyl, 4,4-dimethylpentynyl, octynyl, 1-methylheptinyl, 2-methylheptynyl, 3
-Methylheptinyl, 4-methylheptinyl, 5-methylheptinyl, 6-methylheptinyl, 1-propylpentynyl, 2-ethylhexynyl, 5,5-dimethylhexynyl, nonynyl, 3-methyloctynyl, 4-methyloctynyl, 5-methyl Octynyl, 6-methyloctynyl, 1-propylhexynyl, 2-ethylheptynyl, 6,6-dimethylheptynyl, decynyl, 1-methylnoninyl, 3-methylnonynyl, 8-methylnonynyl, 3-ethyloctynyl, 3,7- Dimethyloctynyl, 7,7-dimethyloctynyl, undecynyl, 4,
8-dimethylnoninyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, 3,7,11-trimethyldodecynyl, hexadecynyl, 4,8,12-trimethyltridecynyl, 1-methylpentadecynyl, 14
-Methylpentadecynyl, 13,13-dimethyltetradecynyl, heptadecynyl, 15-methylhexadecynyl, octadecynyl, 1-methylheptadecynyl, nonadecynyl, eicosinyl, and 3,7,11,15-
2 to 2 carbon atoms such as tetramethylhexadecynyl group
0 straight or branched chain alkynyl groups may be mentioned,
Preferably a C ₂ -C ₁₀ alkynyl group.

[0081] In the above, R ^4a and the "C ₃ -C _{2 0} alkynyl group having a heteroatom-mediated" in the definition of R ^11, the "carbon number 3 of the" C ₂ -C ₂₀ alkynyl group "
To 20 alkynyl groups "being the same or different,
Or a group intervening with two, a sulfur atom, an oxygen atom, or a nitrogen atom, for example, 1-methylthioethynyl, 2-methylthioethynyl, 1-methylthiopropynyl, 2-methylthiopropynyl, 3-methylthiopropynyl , 2-ethylthioethynyl, 2-methyl-2-methylthioethynyl, 1-methylthiobutynyl, 2-methylthiobutynyl, 3-methylthiobutynyl, 2-ethylthiopropynyl, 3-methyl-3-methylthiopropynyl, 4- Methylthiopentynyl, 3-methylthiopentynyl, 2-methylthiopentynyl, 1-methylthiopentynyl, 3,3-dimethylthiobutynyl, 2,2-dimethylthiobutynyl, 1,1-dimethylthiobutynyl, 1
-Methyl-2-methylthiobutynyl, 1,3-dimethylthiobutynyl, 2,3-dimethylthiobutynyl, 2-ethylthiobutynyl, 1-methylthiohexynyl, 2-methylthiohexynyl, 3-methylthiohexenyl Shinil, 4-
Methylthiohexynyl, 5-methylthiohexynyl, 1
-Propylthiobutynyl, 4-methyl-4-methylthiopentynyl, 1-methylthioheptinyl, 2-methylthioheptinyl, 3-methylthioheptinyl, 4-methylthioheptinyl, 5-methylthioheptynyl , 6-methylthioheptinyl, 1-propylthiopentynyl, 2-
Ethylthiohexynyl, 5-methyl-5-methylthiohexynyl, 3-methylthiooctynyl, 4-methylthiooctynyl, 5-methylthiooctynyl, 6-methylthiooctynyl, 1-propylthiohexynyl, 2-ethylthio Heptinyl, 6-methyl-6-methylthioheptinyl, 1-methylthiononinyl, 3-methylthiononinyl, 8-methylthiononinyl, 3-ethylthiooctynyl, 3-methyl-7-methylthiooctynyl, 7,7-
Dimethylthiooctynyl, 4-methyl-8-methylthiononinyl, 3,7-dimethyl-11-methylthiododecynyl, 4,8-dimethyl-12-methylthiotridecinyl, 1-methylthiopentadecynyl, 14-methylthio 1 or such as pentadecynyl, 13-methyl-13-methylthiotetradecynyl, 15-methylthiohexadecynyl, 1-methylthioheptadecynyl, and 3,7,11-trimethyl-15-methylthiohexadecynyl An alkynyl group having 3 to 20 carbon atoms interposed by two sulfur atoms; 1-methyloxyethynyl, 2-methyloxyethynyl, 1-methyloxypropynyl, 2-methyloxypropynyl, 3-methyloxypropynyl,
2-ethyloxyethynyl, 2-methyl-2-methyloxyethynyl, 1-methyloxybutynyl, 2-methyloxybutynyl, 3-methyloxybutynyl, 2-ethyloxypropynyl, 3-methyl-3-methyloxy Propynyl, 4-methyloxypentynyl, 3-methyloxypentynyl, 2-methyloxypentynyl, 1-methyloxypentynyl, 3,3-dimethyloxybutynyl, 2,2-dimethyloxybutynyl, 1, 1-dimethyloxybutynyl, 1-methyl-2-methyloxybutynyl, 1,3-dimethyloxybutynyl, 2,3-dimethyloxybutynyl, 2-ethyloxybutynyl, 1-
Methyloxyhexynyl, 2-methyloxyhexynyl, 3-methyloxyhexynyl, 4-methyloxyhexynyl, 5-methyloxyhexynyl, 1-propyloxybutynyl, 4-methyl-4-methyloxypentynyl , 1-methyloxyheptinyl, 2-methyloxyheptinyl, 3-methyloxyheptinyl, 4-methyloxyheptinyl, 5-methyloxyheptinyl, 6-
Methyloxyheptinyl, 1-propyloxypentynyl, 2-ethyloxyhexynyl, 5-methyl-5-methyloxyhexynyl, 3-methyloxyoctynyl,
4-methyloxyoctynyl, 5-methyloxyoctynyl, 6-methyloxyoctynyl, 1-propyloxyhexynyl, 2-ethyloxyheptynyl, 6-methyl-6-methyloxyheptynyl, 1- Methyloxynoninyl, 3-methyloxynoninyl, 8-methyloxynoninyl, 3-ethyloxyoctynyl, 3-methyl-
7-methyloxyoctynyl, 7,7-dimethyloxyoctynyl, 4-methyl-8-methyloxynonynyl,
3,7-dimethyl-11-methyl oxide decynyl,
4,8-dimethyl-12-methyloxytridecynyl,
1-methyloxypentadecynyl, 14-methyloxypentadecynyl, 13-methyl-13-methyloxytetradecynyl, 15-methyloxyhexadecynyl, 1
-Methyloxyheptadecinyl and 3,7,11-
Alkynyl group having 3 to 20 carbon atoms intervening with 1 or 2 oxygen atoms such as trimethyl-15-methyloxyhexadecynyl; 1- (N-methylamino) ethynyl, 2- (N-methyl) Amino) ethynyl, 1- (N-
Methylamino) propynyl, 2- (N-methylamino)
Propinyl, 3- (N-methylamino) propynyl, 2
-(N-ethylamino) ethynyl, 2- (N, N-dimethylamino) ethynyl, 1- (N-methylamino) butynyl, 2- (N-methylamino) butynyl, 3- (N-
Methylamino) butynyl, 2- (N-ethylamino) propynyl, 3- (N, N-dimethylamino) propynyl, 4- (N-methylamino) pentynyl, 3- (N-
Methylamino) pentynyl, 2- (N-methylamino)
Pentynyl, 1- (N-methylamino) pentynyl, 3
-(N, N-dimethylamino) butynyl, 2- (N, N
-Dimethylamino) butynyl, 1- (N, N-dimethylamino) butynyl, 1-methyl-2- (N-methylamino) butynyl, 1,3-di (N-methylamino) butynyl, 2,3-di (N-methylamino) butynyl, 2-
(N-ethylamino) butynyl, 1- (N-methylamino) hexynyl, 2- (N-methylamino) hexynyl, 3- (N-methylamino) hexynyl, 4- (N-
Methylamino) hexynyl, 5- (N-methylamino)
Hexynyl, 1- (N-propylamino) butynyl, 4
-Methyl-4- (N-methylamino) pentynyl, 1-
(N-methylamino) heptinyl, 2- (N-methylamino) heptinyl, 3- (N-methylamino) heptinyl, 4- (N-methylamino) heptinyl, 5- (N-
Methylamino) heptinyl, 6- (N-methylamino)
Heptynyl, 1- (N-propylamino) pentynyl,
2- (N-ethylamino) hexynyl, 5-methyl-5
-(N-methylamino) hexynyl, 3- (N-methylamino) octynyl, 4- (N-methylamino) octynyl, 5- (N-methylamino) octynyl, 6- (N
-Methylamino) octynyl, 1- (N-propylamino) hexynyl, 2- (N-ethylamino) heptinyl, 6-methyl-6- (N-methylamino) heptinyl, 1- (N-methylamino) noninyl, 3- (N-methylamino) nonynyl, 8- (N-methylamino) nonynyl, 3- (N-ethylamino) octynyl, 3-methyl-7- (N-methylamino) octynyl, 7,7-di ( N-methylamino) octynyl, 4-methyl-8-
(N-methylamino) nonynyl, 3,7-dimethyl-1
1- (N-methylamino) dodecynyl, 4,8-dimethyl-12- (N-methylamino) tridecynyl, 1-
(N-methylamino) pentadecynyl, 14- (N-methylamino) pentadecynyl, 13-methyl-13-
Such as (N-methylamino) tetradecynyl, 15- (N-methylamino) hexadecynyl, 1- (N-methylamino) heptadecynyl, and 3,7,11-trimethyl-15- (N-methylamino) hexadecynyl. 3 to 2 carbon atoms interposed by 1 or 2 nitrogen atoms
There may be mentioned 0 alkynyl groups, but preferred are C ₃ -C ₁₀ alkynyl groups with a heteroatom intervening.

In the above, "C _2- substituted with an aryl group or an aromatic heterocyclic group" in the definition of R ^4a and R ¹¹
The “C ₂₀ alkynyl group” is a group in which the “C ₂ -C ₂₀ alkynyl group” is the same or different and is substituted with 1 or 3 of the “aryl group” or the “aromatic heterocyclic group”. And is preferably a C ₂ -C ₁₀ alkynyl group substituted with an aryl group or an aromatic heterocyclic group.

In the above, "C ₂ -C ₂₀ alkenyl group" in the definition of R ^4a and R ¹¹ is, for example, ethenyl, 2-propenyl, 1-methyl-2-propenyl, 2
-Methyl-2-propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-
Butenyl, 1-methyl-3-butenyl, 2-methyl-3
-Butenyl, 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl , 4-pentenyl, 1
-Methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, heptenyl, 1-methylhexenyl, 2-methylhexenyl, 3-methylhexenyl, 4
-Methylhexenyl, 5-methylhexenyl, 1-propylbutenyl, 4,4-dimethylpentenyl, octenyl, 1-methylheptenyl, 2-methylheptenyl, 3
-Methylheptenyl, 4-methylheptenyl, 5-methylheptenyl, 6-methylheptenyl, 1-propylpentenyl, 2-ethylhexenyl, 5,5-dimethylhexenyl, nonenyl, 3-methyloctenyl, 4-methyloctenyl, 5-methyloctenyl Tenyl, 6-methyloctenyl, 1-propylhexenyl, 2-ethylheptenyl, 6,6-dimethylheptenyl, decenyl, 1-methylnonenyl, 3-methylnonenyl, 8-methylnonenyl, 3-ethyloctenyl, 3,7-dimethyloctenyl. , 7,7-dimethyloctenyl, undecenyl, 4,
8-dimethylnonenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, 3,7,11-trimethyldodecenyl, hexadecenyl, 4,8,12-trimethyltridecenyl, 1-methylpentadecenyl, 14
-Methylpentadecenyl, 13,13-dimethyltetradecenyl, heptadecenyl, 15-methylhexadecenyl, octadecenyl, 1-methylheptadecenyl, nonadecenyl, eicosenyl, and 3,7,11,15 −
2 to 2 carbon atoms such as tetramethylhexadecenyl group
There may be mentioned 0 straight or branched chain alkenyl groups,
Preferably a C ₂ -C ₁₀ alkenyl group.

[0084] In the above, R ^4a and the "C ₃ -C _{2 0} alkenyl group having a heteroatom-mediated" in the definition of R ^11, the "carbon number 3 of the" C ₂ -C ₂₀ alkenyl group "
To 20 alkenyl groups "are the same or different and are 1
Or a group in which two sulfur atoms, oxygen atoms, or nitrogen atoms are present, for example, 1-methylthioethenyl, 2-methylthioethenyl, 1-methylthiopropenyl, 2-methylthiopropenyl, 3- Methyl thiopropenyl, 2-ethyl thioethenyl, 2-methyl-2-methyl thioethenyl, 1-methyl thiobutenyl, 2-methyl thiobutenyl, 3-methyl thiobutenyl, 2-ethyl thiopropenyl, 3-methyl-3-methyl thio Propenyl, 4-methylthiopentenyl, 3-methylthiopentenyl, 2-methylthiopentenyl, 1-methylthiopentenyl, 3,3-dimethylthioobtenyl, 2,2-dimethylthioobtenyl, 1,1-dimethylthioobtenyl, 1
-Methyl-2-methylthioobthenyl, 1,3-dimethylthioobthenyl, 2,3-dimethylthioobthenyl, 2-ethylthioobthenyl, 1-methylthiohexenyl, 2-methylthiohexenyl, 3-methylthiohexenyl, 4 −
Methylthiohexenyl, 5-methylthiohexenyl, 1
-Propylthiobutenyl, 4-methyl-4-methylthiopentenyl, 1-methylthioheptenyl, 2-methylthioheptenyl, 3-methylthioheptenyl, 4-methylthioheptenyl, 5-methylthioheptenyl, 6-methylthioheptenyl , 1-propylthiopentenyl, 2-
Ethylthiohexenyl, 5-methyl-5-methylthiohexenyl, 3-methylthiooctenyl, 4-methylthiooctenyl, 5-methylthiooctenyl, 6-methylthiooctenyl, 1-propylthiohexenyl, 2-ethylthioheptenyl, 6-methyl-6-methylthioheptenyl, 1-methylthiononenyl, 3-methylthiononenyl, 8-methylthiononenyl, 3-ethylthiooctenyl, 3-methyl-7-methylthiooctenyl, 7,7-
Dimethylthiooctenyl, 4-methyl-8-methylthiononenyl, 3,7-dimethyl-11-methylthiododecenyl, 4,8-dimethyl-12-methylthiotridecenyl, 1-methylthiopentadecenyl, 14-methylthiopentadecenyl, 13-methyl-13-methylthiotetradecenyl, 15-methylthiohexadecenyl, 1-methylthioheptadecenyl, and 3,7,11-trimethyl-15-methylthiohexa An alkenyl group having 3 to 20 carbon atoms intervening with 1 or 2 sulfur atoms such as decenyl; 1-methyloxyethenyl, 2-methyloxyethenyl, 1-methyloxypropenyl, 2- Methyloxypropenyl, 3-methyloxypropenyl,
2-ethyloxyethenyl, 2-methyl-2-methyloxyethenyl, 1-methyloxybutenyl, 2-methyloxybutenyl, 3-methyloxybutenyl, 2-ethyloxypropenyl, 3-methyl-3- Methyloxypropenyl, 4-methyloxypentenyl, 3-methyloxypentenyl, 2-methyloxypentenyl, 1-methyloxypentenyl, 3,3-dimethyloxybutenyl, 2,2-dimethyloxybutenyl, 1,1- Dimethyloxybutenyl, 1-methyl-2-methyloxybutenyl, 1,3-dimethyloxybutenyl, 2,3-dimethyloxybutenyl, 2-ethyloxybutenyl, 1-
Methyloxyhexenyl, 2-methyloxyhexenyl, 3-methyloxyhexenyl, 4-methyloxyhexenyl, 5-methyloxyhexenyl, 1-propyloxybutenyl, 4-methyl-4-methyloxypentenyl, 1-methyloxyhepenyl Tenyl, 2-methyloxyheptenyl, 3-methyloxyheptenyl, 4-methyloxyheptenyl, 5-methyloxyheptenyl, 6-
Methyloxyheptenyl, 1-propyloxypentenyl, 2-ethyloxyhexenyl, 5-methyl-5-methyloxyhexenyl, 3-methyloxyoctenyl,
4-methyloxyoctenyl, 5-methyloxyoctenyl, 6-methyloxyoctenyl, 1-propyloxyhexenyl, 2-ethyloxyheptenyl, 6-methyl-6-methyloxyheptenyl, 1-methyloxynonene Nyl, 3-methyloxynonenyl, 8-methyloxynonenyl, 3-ethyloxyoctenyl, 3-methyl-
7-methyloxyoctenyl, 7,7-dimethyloxyoctenyl, 4-methyl-8-methyloxynonenyl,
3,7-dimethyl-11-methyl oxide decenyl,
4,8-dimethyl-12-methyloxytridecenyl,
1-methyloxypentadecenyl, 14-methyloxypentadecenyl, 13-methyl-13-methyloxytetradecenyl, 15-methyloxyhexadecenyl, 1
-Methyloxyheptadecenyl and 3,7,11-
Alkenyl group having 3 to 20 carbon atoms intervening with 1 or 2 oxygen atoms such as trimethyl-15-methyloxyhexadecenyl; 1- (N-methylamino) ethenyl, 2- (N- Methylamino) ethenyl, 1- (N-
Methylamino) propenyl, 2- (N-methylamino)
Propenyl, 3- (N-methylamino) propenyl, 2
-(N-ethylamino) ethenyl, 2- (N, N-dimethylamino) ethenyl, 1- (N-methylamino) butenyl, 2- (N-methylamino) butenyl, 3- (N-
Methylamino) butenyl, 2- (N-ethylamino) propenyl, 3- (N, N-dimethylamino) propenyl, 4- (N-methylamino) pentenyl, 3- (N-
Methylamino) pentenyl, 2- (N-methylamino)
Pentenyl, 1- (N-methylamino) pentenyl, 3
-(N, N-dimethylamino) butenyl, 2- (N, N
-Dimethylamino) butenyl, 1- (N, N-dimethylamino) butenyl, 1-methyl-2- (N-methylamino) butenyl, 1,3-di (N-methylamino) butenyl, 2,3-di (N-methylamino) butenyl, 2-
(N-ethylamino) butenyl, 1- (N-methylamino) hexenyl, 2- (N-methylamino) hexenyl, 3- (N-methylamino) hexenyl, 4- (N-
Methylamino) hexenyl, 5- (N-methylamino)
Hexenyl, 1- (N-propylamino) butenyl, 4
-Methyl-4- (N-methylamino) pentenyl, 1-
(N-methylamino) heptenyl, 2- (N-methylamino) heptenyl, 3- (N-methylamino) heptenyl, 4- (N-methylamino) heptenyl, 5- (N-
Methylamino) heptenyl, 6- (N-methylamino)
Heptenyl, 1- (N-propylamino) pentenyl,
2- (N-ethylamino) hexenyl, 5-methyl-5
-(N-methylamino) hexenyl, 3- (N-methylamino) octenyl, 4- (N-methylamino) octenyl, 5- (N-methylamino) octenyl, 6- (N
-Methylamino) octenyl, 1- (N-propylamino) hexenyl, 2- (N-ethylamino) heptenyl, 6-methyl-6- (N-methylamino) heptenyl, 1- (N-methylamino) nonenyl, 3- (N-methylamino) nonenyl, 8- (N-methylamino) nonenyl, 3- (N-ethylamino) octenyl, 3-methyl-7- (N-methylamino) octenyl, 7,7-di ( N-methylamino) octenyl, 4-methyl-8-
(N-methylamino) nonenyl, 3,7-dimethyl-1
1- (N-methylamino) dodecenyl, 4,8-dimethyl-12- (N-methylamino) tridecenyl, 1-
(N-methylamino) pentadecenyl, 14- (N-methylamino) pentadecenyl, 13-methyl-13-
Such as (N-methylamino) tetradecenyl, 15- (N-methylamino) hexadecenyl, 1- (N-methylamino) heptadecenyl, and 3,7,11-trimethyl-15- (N-methylamino) hexadecenyl. 3 to 2 carbon atoms interposed by 1 or 2 nitrogen atoms
There may be mentioned 0 alkenyl groups, preferably C ₃ -C ₁₀ alkenyl groups with a heteroatom intervening.

In the above, “C ₂ — substituted with an aryl group or an aromatic heterocyclic group” in the definition of R ^4a and R ¹¹
The “C ₂₀ alkenyl group” is a group in which the “C ₂ -C ₂₀ alkenyl group” is the same or different and is substituted with 1 or 3 of the “aryl group” or the “aromatic heterocyclic group”. And is preferably a C ₂ -C ₁₀ alkenyl group substituted with an aryl group or an aromatic heterocyclic group.

In the above, the "C ₂ -C ₂₀ alkyl group in which a hetero atom substituted by an aryl group or an aromatic heterocyclic group is present" in the definition of R ^4a and R ¹¹ is the above-mentioned "in which a hetero atom is present. “C ₂ -C ₂₀ alkyl group” is the same or different and is a group substituted with 1 or 3 of the above “aryl group” or the above “aromatic heterocyclic group”, preferably an aryl group or heteroatom substituted with an aromatic heterocyclic group is a C ₂ -C _{1 0} alkyl group interposed.

The "lipase" used in the present invention is not particularly limited and the optimum one varies depending on the kind of the raw material compound, but is preferably Pseudomonas sp. And Pseudomonas flu.
orescens, Pseudomonas cepacia, Chromobacterium vis
cosum, Aspergillus niger, Aspergillus oryzae, Cand
ida antarctica, Candida cylindracea, Candida lipol
ytica, Candida rugosa, Candida utilis, Penicillium
roqueforti, Rhizopus arrhizus, Rhizopus delemar,
Rhizopus javanicus, Rhizomucor miehei, Rhizopus ni
veus, Humicola lanuginosa, Mucor javanicus, Mucor m
iehei, Thermusaquaticus, Thermus flavus, Thermus ther
mophilus, human pancreas, hog pancreas, porcine
It is a lipase derived from pancreas and wheat germ. The enzyme can be used not only partially or completely purified, but also in an immobilized form. Most preferably, immobilized Pseudomonas sp. (Eg, immobilized lipase from Pseudomonas sp. (TOYOB
Company O)).

A carboxylic acid vinyl ester derivative (R ¹¹ COOC) having the formula (XLIII) used in the present invention.
H = as CH _2), the optimal depending on the kind of starting compound is different, but is generally preferred, n- hexanoic acid vinyl ester, n- heptanoic acid vinyl ester, n-
Linear aliphatic carboxylic acid vinyl esters such as pentanoic acid vinyl ester and acetic acid vinyl ester, and most preferably n-hexanoic acid vinyl ester.

The "pharmaceutically acceptable salt" means that the compound of the present invention represented by the general formula (I) is reacted with an acid when it has a basic group such as an amino group.
Further, when it has an acidic group such as a carboxyl group, it can be converted into a salt by reacting with a base, and therefore the salt is shown.

The salt based on the basic group is preferably
Hydrofluoride, Hydrochloride, Hydrobromide, Hydroiodide such as Hydrohalide, Nitrate, Perchlorate, Sulfate, Phosphate and other inorganic acid salts; Methanesulfonic acid Salts, lower alkane sulfonates such as trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate,
aryl sulfonates such as p-toluene sulfonate, acetates, malates, fumarates, succinates,
Organic acid salts such as citrate, ascorbate, tartrate, oxalate and maleate; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and asparaginate And most preferably, an organic acid salt can be mentioned.

On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as calcium salt, magnesium salt, aluminum salt or iron salt. Metal salts such as salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts,
Diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) ) Amine salts such as organic salts such as aminomethane salts; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and asparaginate.

The compound having the general formula (I) of the present invention, its pharmacologically acceptable salt, its ester or other derivative is allowed to absorb water by leaving it in the air or by recrystallization. However, it may be adsorbed with water or become a hydrate, and such a hydrate is also included in the salt of the present invention.

The compound having the general formula (I), its pharmacologically acceptable salt, its ester or other derivative of the present invention has an asymmetric carbon atom in its molecule, and therefore, optical isomers exist. In the compounds of the present invention, optical isomers and mixtures of optical isomers are all represented by a single formula, that is, general formula (I). Therefore, the present invention includes all optical isomers and a mixture of optical isomers in any ratio. For example, the compound having the general formula (I) of the present invention, a pharmacologically acceptable salt thereof, an ester thereof or other derivative is represented by the following formula:

[0094]

[Chemical 19]

It has

In the above formula, the --NR ¹ R ² group is substituted on an asymmetric carbon atom, but a compound having an absolute R coordination is particularly preferable.

The above-mentioned "ester" refers to the ester of the compound (I) of the present invention, and therefore refers to such ester. Examples of such an ester include "ester of hydroxy group" and "carboxy group". Can be mentioned, and each ester residue means an ester in which "a general protecting group in the reaction" or "a protecting group which can be cleaved by a biological method such as hydrolysis in vivo".

The "general protecting group in the reaction" refers to a protecting group which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis.

Examples of the "general protecting group in the reaction" and the "protecting group which can be cleaved by a biological method such as hydrolysis in vivo" of the "ester of hydroxy group" include:
Synonymous with the above-mentioned "protecting group for hydroxy group".

The "general protecting group in the reaction" of the "ester of carboxy group" is preferably the above "lower alkyl group"; ethenyl, 1-propenyl, 2-
Propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-
Methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-
Butenyl, 1-ethyl-2-butenyl, 3-butenyl,
1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-
Pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-
Pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-
Lower alkenyl groups such as pentenyl 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl; ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2 −
Ethyl-2-propynyl, 2-butynyl, 1-methyl-
2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2- Pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1
-Methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2
Lower alkynyl group such as -methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl; the above "halogeno lower alkyl"; 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-
Hydroxypropyl, 3,4-dihydroxybutyl, 4
-Hydroxy "lower alkyl group" such as hydroxybutyl; "lower aliphatic acyl" such as acetylmethyl-
Examples thereof include "lower alkyl group"; the above "aralkyl group"; and the above "silyl group".

The term "protective group cleavable in vivo by a biological method such as hydrolysis" means that a free acid or a salt thereof is cleaved in the human body by a biological method such as hydrolysis. It refers to a protective group, and whether or not it is such a derivative is administered by intravenous injection to an experimental animal such as a rat or mouse,
After that, the body fluid of the animal is examined, and it can be determined by being able to detect the original compound or a pharmaceutically acceptable salt thereof. Protecting group capable of being cleaved by a method "
As, preferably, methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1- Lower alkoxy lower alkyl groups such as methoxyethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, t-butoxymethyl, lower alkoxylated lower alkoxy lower alkyl groups such as 2-methoxyethoxymethyl, "Alkoxyalkyl group" such as "aryl" oxy "lower alkyl group" such as phenoxymethyl, halogenated lower alkoxy lower alkyl group such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl ; "Lower alcohols such as methoxycarbonylmethyl Shi "carbonyl" lower alkyl group ""; cyanomethyl, 2-"cyano" lower alkyl groups such as cyanoethyl "; methylthiomethyl, such as ethylthiomethyl,""loweralkyl" thiomethyl group ";
"Aryl" thiomethyl group such as phenylthiomethyl, naphthylthiomethyl; "lower alkyl optionally substituted with halogen" sulfonyl "lower alkyl such as 2-methanesulfonylethyl, 2-trifluoromethanesulfonylethyl "Group"";" aryl "sulfonyl" lower alkyl group "such as 2-benzenesulfonylethyl, 2-toluenesulfonylethyl; the above" 1- (acyloxy) "lower alkyl group"; the above "phthalidyl group"; The "aryl group"; the "lower alkyl group"; the "carboxyalkyl group" such as carboxymethyl; and the "amide-forming residue of an amino acid" such as phenylalanine.

The "other derivative" means the above "pharmacologically acceptable salt" and the above "ester" when the compound having the general formula (I) of the present invention has an amino group and / or a carboxy group. Since other derivatives can be used, the derivatives are shown. Examples of such a derivative include an amide derivative such as an acyl group.

Specific examples of the compound having the general formula (I), which is the active ingredient of the pharmaceutical composition of the present invention, include the compounds shown in Table 1 and Table 2 below. Specific examples of the compounds having the formulas (La) and (La-1) include the compounds shown in Tables 3 and 4 below, but the present invention is limited to these compounds. is not.

The abbreviations in the table are as follows. Ac: Acetyl group Boc: t-butoxycarbonyl group Bpyrr: Benzopyrrolyl group Bu: Butyl group iBu: Isobutyl group Bz: benzyl group Bzt: benzothienyl group Et: ethyl group Fur: Furyl group cHx: cyclohexyl group Me: Methyl group Np (1): naphthalen-1-yl group Np (2): naphthalen-2-yl group Ph: Phenyl group cPn: cyclopentyl group Pr: propyl group iPr: isopropyl group Pyr: Pyridyl group TBDMS: t-butyldimethylsilyl group The: Thienyl group.

[0105]

[Table 1]

[0106]

[Chemical 20] Compd. R¹    R²   R³   R^Four   n -X-Y-R^Five                        R⁶  R⁷ 1-1 H H H Me 1-(CH₂)_Five-cHx H H 1-2 H H H Me 1-(CH₂)₆-cHx H H 1-3 H H H Me 1 -CH = CH- (CH₂)₃-cHx H H 1-4 H H H Me 1 -CH = CH- (CH₂)_Four-cHx H H 1-5 H H H Me 1 -C≡C- (CH₂)₃-cHx H H 1-6 H H H Me 1 -C≡C- (CH₂)_Four-cHx H H 1-7 H H H Me 1 -CO- (CH₂)_Four-cHx H H 1-8 H H H Me 1 -CO- (CH₂)_Five-cHx H H 1-9 H H H Me 1 -CH (OH)-(CH₂)_Four-cHx H H 1-10 H H H Me 1 -CH (OH)-(CH₂)_Five-cHx H H 1-11 H H H Me 1-4- (cHx-CH₂O) Ph H H 1-12 H H H Me 1-(4-BzO-Ph) H H 1-13 H H H Me 1 -C≡C-CH₂O-cPn H H 1-14 H H H Me 1 -C≡C- (CH₂)₂O-cPn H H 1-15 H H H Me 1 -C≡C-CH₂O-cHx H H 1-16 H H H Me 1 -C≡C- (CH₂)₂O-cHx H H 1-17 H H H Me 1 -C≡C-CH₂O-Ph H H 1-18 H H H Me 1 -C≡C- (CH₂)₂O-Ph H H 1-19 H H H Me 2-(CH₂)₂-cHx H H 1-20 H H Me Me 2-(CH₂)₂-cHx H H 1-21 Me H H Me 2-(CH₂)₂-cHx H H 1-22 CO₂Me H H Me 2-(CH₂)₂-cHx H H 1-23 H H H Me 2-(CH₂)₂-(4-F-cHx) H H 1-24 H H H Me 2-(CH₂)₂-(4-Me-cHx) H H 1-25 H H H Me 2-(CH₂)₂-(4-Et-cHx) H H 1-26 H H H Me 2-(CH₂)₂-(4-CF₃-cHx) H H 1-27 H H H Me 2-(CH₂)₂-(4-MeO-cHx) H H 1-28 H H H Me 2-(CH₂)₂-(4-EtO-cHx) H H 1-29 H H H Me 2-(CH₂)₂-(4-MeS-cHx) H H 1-30 H H H Me 2-(CH₂)₂-(4-cHx-cHx) H H 1-31 H H H Me 2-(CH₂)₂-(4-Ph-cHx) H H 1-32 H H H Me 2-(CH₂)₂-Ph H H 1-33 H H Me Me 2-(CH₂)₂-Ph H H 1-34 Me H H Me 2-(CH₂)₂-Ph H H 1-35 CO₂Me H H Me 2-(CH₂)₂-Ph H H 1-36 H H H Me 2-(CH₂)₂-(4-F-Ph) H H 1-37 H H H Me 2-(CH₂)₂-(4-Me-Ph) H H 1-38 H H H Me 2-(CH₂)₂-(4-Et-Ph) H H 1-39 H H H Me 2-(CH₂)₂-(4-CF₃-Ph) H H 1-40 H H H Me 2-(CH₂)₂-(4-MeO-Ph) H H 1-41 H H H Me 2-(CH₂)₂-(4-EtO-Ph) H H 1-42 H H H Me 2-(CH₂)₂-(4-MeS-Ph) H H 1-43 H H H Me 2-(CH₂)₂-(4-cHx-Ph) H H 1-44 H H H Me 2-(CH₂)₂-(4-Ph-Ph) H H 1-45 H H H Me 2-(CH₂)₃-cHx H H 1-46 H H Me Me 2-(CH₂)₃-cHx H H 1-47 Me H H Me 2-(CH₂)₃-cHx H H 1-48 CO₂Me H H Me 2-(CH₂)₃-cHx H H 1-49 H H H Me 2-(CH₂)₃-(4-F-cHx) H H 1-50 H H H Me 2-(CH₂)₃-(4-Me-cHx) H H 1-51 H H H Me 2-(CH₂)₃-(4-Et-cHx) H H 1-52 H H H Me 2-(CH₂)₃-(4-CF₃-cHx) H H 1-53 H H H Me 2-(CH₂)₃-(4-MeO-cHx) H H 1-54 H H H Me 2-(CH₂)₃-(4-EtO-cHx) H H 1-55 H H H Me 2-(CH₂)₃-(4-MeS-cHx) H H 1-56 H H H Me 2-(CH₂)₃-(4-cHx-cHx) H H 1-57 H H H Me 2-(CH₂)₃-(4-Ph-cHx) H H 1-58 H H H Me 2-(CH₂)₃-Ph H H 1-59 H H Me Me 2-(CH₂)₃-Ph H H 1-60 Me H H Me 2-(CH₂)₃-Ph H H 1-61 CO₂Me H H Me 2-(CH₂)₃-Ph H H 1-62 H H H Me 2-(CH₂)₃-(4-F-Ph) H H 1-63 H H H Me 2-(CH₂)₃-(4-Me-Ph) H H 1-64 H H H Me 2-(CH₂)₃-(4-Et-Ph) H H 1-65 H H H Me 2-(CH₂)₃-(4-CF₃-Ph) H H 1-66 H H H Me 2-(CH₂)₃-(4-MeO-Ph) H H 1-67 H H H Me 2-(CH₂)₃-(4-EtO-Ph) H H 1-68 H H H Me 2-(CH₂)₃-(4-MeS-Ph) H H 1-69 H H H Me 2-(CH₂)₃-(4-cHx-Ph) H H 1-70 H H H Me 2-(CH₂)₃-(4-Ph-Ph) H H 1-71 H H H Me 2-(CH₂)_Four-cHx H H 1-72 H H Me Me 2-(CH₂)_Four-cHx H H 1-73 Me H H Me 2-(CH₂)_Four-cHx H H 1-74 CO₂Me H H Me 2-(CH₂)_Four-cHx H H 1-75 H H H Me 2-(CH₂)_Four-(4-F-cHx) H H 1-76 H H H Me 2-(CH₂)_Four-(4-Me-cHx) H H 1-77 H H H Me 2-(CH₂)_Four-(4-Et-cHx) H H 1-78 H H H Me 2-(CH₂)_Four-(4-CF₃-cHx) H H 1-79 H H H Me 2-(CH₂)_Four-(4-MeO-cHx) H H 1-80 H H H Me 2-(CH₂)_Four-(4-EtO-cHx) H H 1-81 H H H Me 2-(CH₂)_Four-(4-MeS-cHx) H H 1-82 H H H Me 2-(CH₂)_Four-(4-cHx-cHx) H H 1-83 H H H Me 2-(CH₂)_Four-(4-Ph-cHx) H H 1-84 H H H Me 2-(CH₂)_Four-Ph H H 1-85 H H Me Me 2-(CH₂)_Four-Ph H H 1-86 Me H H Me 2-(CH₂)_Four-Ph H H 1-87 CO₂Me H H Me 2-(CH₂)_Four-Ph H H 1-88 H H H Me 2-(CH₂)_Four-(4-F-Ph) H H 1-89 H H H Me 2-(CH₂)_Four-(4-Me-Ph) H H 1-90 H H H Me 2-(CH₂)_Four-(4-Et-Ph) H H 1-91 H H H Me 2-(CH₂)_Four-(4-CF₃-Ph) H H 1-92 H H H Me 2-(CH₂)_Four-(4-MeO-Ph) H H 1-93 H H H Me 2-(CH₂)_Four-(4-EtO-Ph) H H 1-94 H H H Me 2-(CH₂)_Four-(4-MeS-Ph) H H 1-95 H H H Me 2-(CH₂)_Four-(4-cHx-Ph) H H 1-96 H H H Me 2-(CH₂)_Four-(4-Ph-Ph) H H 1-97 H H H Me 2-(CH₂)_Five-cPn H H 1-98 H H H Me 2-(CH₂)_Five-cHx H H 1-99 H H H Me 2-(CH₂)_Five-cHx Me H 1-100 H H H Me 2-(CH₂)_Five-cHx H Me 1-101 H H H Me 2-(CH₂)_Five-cHx F H 1-102 H H H Me 2-(CH₂)_Five-cHx HF 1-103 H H Me Me 2-(CH₂)_Five-cHx H H 1-104 Me H H Me 2-(CH₂)_Five-cHx H H 1-105 CO₂Me H H Me 2-(CH₂)_Five-cHx H H 1-106 H H H Me 2-(CH₂)_Five-(3-F-cHx) H H 1-107 H H H Me 2-(CH₂)_Five-(4-F-cHx) H H 1-108 H H H Me 2-(CH₂)_Five-(4-Cl-cHx) H H 1-109 H H H Me 2-(CH₂)_Five-(4-Br-cHx) H H 1-110 H H H Me 2-(CH₂)_Five-(3-Me-cHx) H H 1-111 H H H Me 2-(CH₂)_Five-(4-Me-cHx) H H 1-112 H H H Me 2-(CH₂)_Five-(3-Et-cHx) H H 1-113 H H H Me 2-(CH₂)_Five-(4-Et-cHx) H H 1-114 H H H Me 2-(CH₂)_Five-(3-Pr-cHx) H H 1-115 H H H Me 2-(CH₂)_Five-(4-Pr-cHx) H H 1-116 H H H Me 2-(CH₂)_Five-(4-iPr-cHx) H H 1-117 H H H Me 2-(CH₂)_Five-(3-Bu-cHx) H H 1-118 H H H Me 2-(CH₂)_Five-(4-Bu-cHx) H H 1-119 H H H Me 2-(CH₂)_Five-(3-CF₃-cHx) H H 1-120 H H H Me 2-(CH₂)_Five-(4-CF₃-cHx) H H 1-121 H H H Me 2-(CH₂)_Five-(3-MeO-cHx) H H 1-122 H H H Me 2-(CH₂)_Five-(4-MeO-cHx) H H 1-123 H H H Me 2-(CH₂)_Five-(3-EtO-cHx) H H 1-124 H H H Me 2-(CH₂)_Five-(4-EtO-cHx) H H 1-125 H H H Me 2-(CH₂)_Five-(3-PrO-cHx) H H 1-126 H H H Me 2-(CH₂)_Five-(4-PrO-cHx) H H 1-127 H H H Me 2-(CH₂)_Five-(3-iPrO-cHx) H H 1-128 H H H Me 2-(CH₂)_Five-(4-iPrO-cHx) H H 1-129 H H H Me 2-(CH₂)_Five-[3- (2-Et-PrO) -cHx] H H 1-130 H H H Me 2-(CH₂)_Five-[4- (2-Et-PrO) -cHx] H H 1-131 H H H Me 2-(CH₂)_Five-(3-iBuO-cHx) H H 1-132 H H H Me 2-(CH₂)_Five-(4-iBuO-cHx) H H 1-133 H H H Me 2-(CH₂)_Five-(3-MeS-cHx) H H 1-134 H H H Me 2-(CH₂)_Five-(4-MeS-cHx) H H 1-135 H H H Me 2-(CH₂)_Five-(3-EtS-cHx) H H 1-136 H H H Me 2-(CH₂)_Five-(4-EtS-cHx) H H 1-137 H H H Me 2-(CH₂)_Five-(3-PrS-cHx) H H 1-138 H H H Me 2-(CH₂)_Five-(4-PrS-cHx) H H 1-139 H H H Me 2-(CH₂)_Five-(3-iPrS-cHx) H H 1-140 H H H Me 2-(CH₂)_Five-(4-iPrS-cHx) H H 1-141 H H H Me 2-(CH₂)_Five-[3- (2-Et-PrS) -cHx] H H 1-142 H H H Me 2-(CH₂)_Five-[4- (2-Et-PrS) -cHx] H H 1-143 H H H Me 2-(CH₂)_Five-(3-iBuS-cHx) H H 1-144 H H H Me 2-(CH₂)_Five-(4-iBuS-cHx) H H 1-145 H H H Me 2-(CH₂)_Five-(3-cHx-cHx) H H 1-146 H H H Me 2-(CH₂)_Five-(4-cHx-cHx) H H 1-147 H H H Me 2-(CH₂)_Five-(3-Ph-cHx) H H 1-148 H H H Me 2-(CH₂)_Five-(4-Ph-cHx) H H 1-149 H H H Me 2-(CH₂)_Five-(2,4-diMe-cHx) H H 1-150 H H H Me 2-(CH₂)_Five-(3,4-diMe-cHx) H H 1-151 H H H Me 2-(CH₂)_Five-(3,5-diMe-cHx) H H 1-152 H H H Me 2-(CH₂)_Five-Ph H H 1-153 H H H Me 2-(CH₂)_Five-Ph Me H 1-154 H H H Me 2-(CH₂)_Five-Ph H Me 1-155 H H H Me 2-(CH₂)_Five-Ph F H 1-156 H H H Me 2-(CH₂)_Five-Ph H F 1-157 H H Me Me 2-(CH₂)_Five-Ph H H 1-158 Me H H Me 2-(CH₂)_Five-Ph H H 1-159 CO₂Me H H Me 2-(CH₂)_Five-Ph H H 1-160 H H H Me 2-(CH₂)_Five-(3-F-Ph) H H 1-161 H H H Me 2-(CH₂)_Five-(4-F-Ph) H H 1-162 H H H Me 2-(CH₂)_Five-(4-Cl-Ph) H H 1-163 H H H Me 2-(CH₂)_Five-(4-Br-Ph) H H 1-164 H H H Me 2-(CH₂)_Five-(3-Me-Ph) H H 1-165 H H H Me 2-(CH₂)_Five-(4-Me-Ph) H H 1-166 H H H Me 2-(CH₂)_Five-(3-Et-Ph) H H 1-167 H H H Me 2-(CH₂)_Five-(4-Et-Ph) H H 1-168 H H H Me 2-(CH₂)_Five-(3-Pr-Ph) H H 1-169 H H H Me 2-(CH₂)_Five-(4-Pr-Ph) H H 1-170 H H H Me 2-(CH₂)_Five-(3-iPr-Ph) H H 1-171 H H H Me 2-(CH₂)_Five-(4-iPr-Ph) H H 1-172 H H H Me 2-(CH₂)_Five-(3-Bu-Ph) H H 1-173 H H H Me 2-(CH₂)_Five-(4-Bu-Ph) H H 1-174 H H H Me 2-(CH₂)_Five-(3-CF₃-Ph) H H 1-175 H H H Me 2-(CH₂)_Five-(4-CF₃-Ph) H H 1-176 H H H Me 2-(CH₂)_Five-(3-MeO-Ph) H H 1-177 H H H Me 2-(CH₂)_Five-(4-MeO-Ph) H H 1-178 H H H Me 2-(CH₂)_Five-(3-EtO-Ph) H H 1-179 H H H Me 2-(CH₂)_Five-(4-EtO-Ph) H H 1-180 H H H Me 2-(CH₂)_Five-(3-PrO-Ph) H H 1-181 H H H Me 2-(CH₂)_Five-(4-PrO-Ph) H H 1-182 H H H Me 2-(CH₂)_Five-(3-iPrO-Ph) H H 1-183 H H H Me 2-(CH₂)_Five-(4-iPrO-Ph) H H 1-184 H H H Me 2-(CH₂)_Five-[3- (2-Et-PrO) -Ph] H H 1-185 H H H Me 2-(CH₂)_Five-[4- (2-Et-PrO) -Ph] H H 1-186 H H H Me 2-(CH₂)_Five-(3-iBuO-Ph) H H 1-187 H H H Me 2-(CH₂)_Five-(4-iBuO-Ph) H H 1-188 H H H Me 2-(CH₂)_Five-(3-MeS-Ph) H H 1-189 H H H Me 2-(CH₂)_Five-(4-MeS-Ph) H H 1-190 H H H Me 2-(CH₂)_Five-(3-EtS-Ph) H H 1-191 H H H Me 2-(CH₂)_Five-(4-EtS-Ph) H H 1-192 H H H Me 2-(CH₂)_Five-(3-PrS-Ph) H H 1-193 H H H Me 2-(CH₂)_Five-(4-PrS-Ph) H H 1-194 H H H Me 2-(CH₂)_Five-(3-iPrS-Ph) H H 1-195 H H H Me 2-(CH₂)_Five-(4-iPrS-Ph) H H 1-196 H H H Me 2-(CH₂)_Five-[3- (2-Et-PrS) -Ph] H H 1-197 H H H Me 2-(CH₂)_Five-[4- (2-Et-PrS) -Ph] H H 1-198 H H H Me 2-(CH₂)_Five-(3-iBuS-Ph) H H 1-199 H H H Me 2-(CH₂)_Five-(4-iBuS-Ph) H H 1-200 H H H Me 2-(CH₂)_Five-(3-cHx-Ph) H H 1-201 H H H Me 2-(CH₂)_Five-(4-cHx-Ph) H H 1-202 H H H Me 2-(CH₂)_Five-(3-Ph-Ph) H H 1-203 H H H Me 2-(CH₂)_Five-(4-Ph-Ph) H H 1-204 H H H Me 2-(CH₂)_Five-(2,4-diMe-Ph) H H 1-205 H H H Me 2-(CH₂)_Five-(3,4-diMe-Ph) H H 1-206 H H H Me 2-(CH₂)_Five-(3,5-diMe-Ph) H H 1-207 H H H Me 2-(CH₂)_Five-Np (1) H H 1-208 H H H Me 2-(CH₂)_Five-Np (2) H H 1-209 H H H Me 2-(CH₂)₆-cPn H H 1-210 H H H Me 2-(CH₂)₆-cHx H H 1-211 H H H Me 2-(CH₂)₆-cHx Me H 1-212 H H H Me 2-(CH₂)₆-cHx H Me 1-213 H H H Me 2-(CH₂)₆-cHx F H 1-214 H H H Me 2-(CH₂)₆-cHx HF 1-215 H H Me Me 2-(CH₂)₆-cHx H H 1-216 Me H H Me 2-(CH₂)₆-cHx H H 1-217 CO₂Me H H Me 2-(CH₂)₆-cHx H H 1-218 H H H Me 2-(CH₂)₆-(3-F-cHx) H H 1-219 H H H Me 2-(CH₂)₆-(4-F-cHx) H H 1-220 H H H Me 2-(CH₂)₆-(4-Cl-cHx) H H 1-221 H H H Me 2-(CH₂)₆-(4-Br-cHx) H H 1-222 H H H Me 2-(CH₂)₆-(3-Me-cHx) H H 1-223 H H H Me 2-(CH₂)₆-(4-Me-cHx) H H 1-224 H H H Me 2-(CH₂)₆-(3-Et-cHx) H H 1-225 H H H Me 2-(CH₂)₆-(4-Et-cHx) H H 1-226 H H H Me 2-(CH₂)₆-(3-Pr-cHx) H H 1-227 H H H Me 2-(CH₂)₆-(4-Pr-cHx) H H 1-228 H H H Me 2-(CH₂)₆-(4-iPr-cHx) H H 1-229 H H H Me 2-(CH₂)₆-(3-Bu-cHx) H H 1-230 H H H Me 2-(CH₂)₆-(4-Bu-cHx) H H 1-231 H H H Me 2-(CH₂)₆-(3-CF₃-cHx) H H 1-232 H H H Me 2-(CH₂)₆-(4-CF₃-cHx) H H 1-233 H H H Me 2-(CH₂)₆-(3-MeO-cHx) H H 1-234 H H H Me 2-(CH₂)₆-(4-MeO-cHx) H H 1-235 H H H Me 2-(CH₂)₆-(3-EtO-cHx) H H 1-236 H H H Me 2-(CH₂)₆-(4-EtO-cHx) H H 1-237 H H H Me 2-(CH₂)₆-(3-PrO-cHx) H H 1-238 H H H Me 2-(CH₂)₆-(4-PrO-cHx) H H 1-239 H H H Me 2-(CH₂)₆-(3-iPrO-cHx) H H 1-240 H H H Me 2-(CH₂)₆-(4-iPrO-cHx) H H 1-241 H H H Me 2-(CH₂)₆-[3- (2-Et-PrO) -cHx] H H 1-242 H H H Me 2-(CH₂)₆-[4- (2-Et-PrO) -cHx] H H 1-243 H H H Me 2-(CH₂)₆-(3-iBuO-cHx) H H 1-244 H H H Me 2-(CH₂)₆-(4-iBuO-cHx) H H 1-245 H H H Me 2-(CH₂)₆-(3-MeS-cHx) H H 1-246 H H H Me 2-(CH₂)₆-(4-MeS-cHx) H H 1-247 H H H Me 2-(CH₂)₆-(3-EtS-cHx) H H 1-248 H H H Me 2-(CH₂)₆-(4-EtS-cHx) H H 1-249 H H H Me 2-(CH₂)₆-(3-PrS-cHx) H H 1-250 H H H Me 2-(CH₂)₆-(4-PrS-cHx) H H 1-251 H H H Me 2-(CH₂)₆-(3-iPrS-cHx) H H 1-252 H H H Me 2-(CH₂)₆-(4-iPrS-cHx) H H 1-253 H H H Me 2-(CH₂)₆-[3- (2-Et-PrS) -cHx] H H 1-254 H H H Me 2-(CH₂)₆-[4- (2-Et-PrS) -cHx] H H 1-255 H H H Me 2-(CH₂)₆-(3-iBuS-cHx) H H 1-256 H H H Me 2-(CH₂)₆-(4-iBuS-cHx) H H 1-257 H H H Me 2-(CH₂)₆-(3-cHx-cHx) H H 1-258 H H H Me 2-(CH₂)₆-(4-cHx-cHx) H H 1-259 H H H Me 2-(CH₂)₆-(3-Ph-cHx) H H 1-260 H H H Me 2-(CH₂)₆-(4-Ph-cHx) H H 1-261 H H H Me 2-(CH₂)₆-(2,4-diMe-cHx) H H 1-262 H H H Me 2-(CH₂)₆-(3,4-diMe-cHx) H H 1-263 H H H Me 2-(CH₂)₆-(3,5-diMe-cHx) H H 1-264 H H H Me 2-(CH₂)₆-Ph H H 1-265 H H H Me 2-(CH₂)₆-Ph Me H 1-266 H H H Me 2-(CH₂)₆-Ph H Me 1-267 H H H Me 2-(CH₂)₆-Ph F H 1-268 H H H Me 2-(CH₂)₆-Ph H F 1-269 H H Me Me 2-(CH₂)₆-Ph H H 1-270 Me H H Me 2-(CH₂)₆-Ph H H 1-271 CO₂Me H H Me 2-(CH₂)₆-Ph H H 1-272 H H H Me 2-(CH₂)₆-(3-F-Ph) H H 1-273 H H H Me 2-(CH₂)₆-(4-F-Ph) H H 1-274 H H H Me 2-(CH₂)₆-(4-Cl-Ph) H H 1-275 H H H Me 2-(CH₂)₆-(4-Br-Ph) H H 1-276 H H H Me 2-(CH₂)₆-(3-Me-Ph) H H 1-277 H H H Me 2-(CH₂)₆-(4-Me-Ph) H H 1-278 H H H Me 2-(CH₂)₆-(3-Et-Ph) H H 1-279 H H H Me 2-(CH₂)₆-(4-Et-Ph) H H 1-280 H H H Me 2-(CH₂)₆-(3-Pr-Ph) H H 1-281 H H H Me 2-(CH₂)₆-(4-Pr-Ph) H H 1-282 H H H Me 2-(CH₂)₆-(3-iPr-Ph) H H 1-283 H H H Me 2-(CH₂)₆-(4-iPr-Ph) H H 1-284 H H H Me 2-(CH₂)₆-(3-Bu-Ph) H H 1-285 H H H Me 2-(CH₂)₆-(4-Bu-Ph) H H 1-286 H H H Me 2-(CH₂)₆-(3-CF₃-Ph) H H 1-287 H H H Me 2-(CH₂)₆-(4-CF₃-Ph) H H 1-288 H H H Me 2-(CH₂)₆-(3-MeO-Ph) H H 1-289 H H H Me 2-(CH₂)₆-(4-MeO-Ph) H H 1-290 H H H Me 2-(CH₂)₆-(3-EtO-Ph) H H 1-291 H H H Me 2-(CH₂)₆-(4-EtO-Ph) H H 1-292 H H H Me 2-(CH₂)₆-(3-PrO-Ph) H H 1-293 H H H Me 2-(CH₂)₆-(4-PrO-Ph) H H 1-294 H H H Me 2-(CH₂)₆-(3-iPrO-Ph) H H 1-295 H H H Me 2-(CH₂)₆-(4-iPrO-Ph) H H 1-296 H H H Me 2-(CH₂)₆-[3- (2-Et-PrO) -Ph] H H 1-297 H H H Me 2-(CH₂)₆-[4- (2-Et-PrO) -Ph] H H 1-298 H H H Me 2-(CH₂)₆-(3-iBuO-Ph) H H 1-299 H H H Me 2-(CH₂)₆-(4-iBuO-Ph) H H 1-300 H H H Me 2-(CH₂)₆-(3-MeS-Ph) H H 1-301 H H H Me 2-(CH₂)₆-(4-MeS-Ph) H H 1-302 H H H Me 2-(CH₂)₆-(3-EtS-Ph) H H 1-303 H H H Me 2-(CH₂)₆-(4-EtS-Ph) H H 1-304 H H H Me 2-(CH₂)₆-(3-PrS-Ph) H H 1-305 H H H Me 2-(CH₂)₆-(4-PrS-Ph) H H 1-306 H H H Me 2-(CH₂)₆-(3-iPrS-Ph) H H 1-307 H H H Me 2-(CH₂)₆-(4-iPrS-Ph) H H 1-308 H H H Me 2-(CH₂)₆-[3- (2-Et-PrS) -Ph] H H 1-309 H H H Me 2-(CH₂)₆-[4- (2-Et-PrS) -Ph] H H 1-310 H H H Me 2-(CH₂)₆-(3-iBuS-Ph) H H 1-311 H H H Me 2-(CH₂)₆-(4-iBuS-Ph) H H 1-312 H H H Me 2-(CH₂)₆-(3-cHx-Ph) H H 1-313 H H H Me 2-(CH₂)₆-(4-cHx-Ph) H H 1-314 H H H Me 2-(CH₂)₆-(3-Ph-Ph) H H 1-315 H H H Me 2-(CH₂)₆-(4-Ph-Ph) H H 1-316 H H H Me 2-(CH₂)₆-(2,4-diMe-Ph) H H 1-317 H H H Me 2-(CH₂)₆-(3,4-diMe-Ph) H H 1-318 H H H Me 2-(CH₂)₆-(3,5-diMe-Ph) H H 1-319 H H H Me 2-(CH₂)₆-Np (1) H H 1-320 H H H Me 2-(CH₂)₆-Np (2) H H 1-321 H H H Me 2-(CH₂)₇-cHx H H 1-322 H H Me Me 2-(CH₂)₇-cHx H H 1-323 Me H H Me 2-(CH₂)₇-cHx H H 1-324 CO₂Me H H Me 2-(CH₂)₇-cHx H H 1-325 H H H Me 2-(CH₂)₇-(4-F-cHx) H H 1-326 H H H Me 2-(CH₂)₇-(4-Me-cHx) H H 1-327 H H H Me 2-(CH₂)₇-(4-Et-cHx) H H 1-328 H H H Me 2-(CH₂)₇-(4-CF₃-cHx) H H 1-329 H H H Me 2-(CH₂)₇-(4-MeO-cHx) H H 1-330 H H H Me 2-(CH₂)₇-(4-EtO-cHx) H H 1-331 H H H Me 2-(CH₂)₇-(4-MeS-cHx) H H 1-332 H H H Me 2-(CH₂)₇-(4-cHx-cHx) H H 1-333 H H H Me 2-(CH₂)₇-(4-Ph-cHx) H H 1-334 H H H Me 2-(CH₂)₇-Ph H H 1-335 H H Me Me 2-(CH₂)₇-Ph H H 1-336 Me H H Me 2-(CH₂)₇-Ph H H 1-337 CO₂Me H H Me 2-(CH₂)₇-Ph H H 1-338 H H H Me 2-(CH₂)₇-(4-F-Ph) H H 1-339 H H H Me 2-(CH₂)₇-(4-Me-Ph) H H 1-340 H H H Me 2-(CH₂)₇-(4-Et-Ph) H H 1-341 H H H Me 2-(CH₂)₇-(4-CF₃-Ph) H H 1-342 H H H Me 2-(CH₂)₇-(4-MeO-Ph) H H 1-343 H H H Me 2-(CH₂)₇-(4-EtO-Ph) H H 1-344 H H H Me 2-(CH₂)₇-(4-MeS-Ph) H H 1-345 H H H Me 2-(CH₂)₇-(4-cHx-Ph) H H 1-346 H H H Me 2-(CH₂)₇-(4-Ph-Ph) H H 1-347 H H H Me 2-(CH₂)₈-cHx H H 1-348 H H Me Me 2-(CH₂)₈-cHx H H 1-349 Me H H Me 2-(CH₂)₈-cHx H H 1-350 CO₂Me H H Me 2-(CH₂)₈-cHx H H 1-351 H H H Me 2-(CH₂)₈-(4-F-cHx) H H 1-352 H H H Me 2-(CH₂)₈-(4-Me-cHx) H H 1-353 H H H Me 2-(CH₂)₈-(4-Et-cHx) H H 1-354 H H H Me 2-(CH₂)₈-(4-CF₃-cHx) H H 1-355 H H H Me 2-(CH₂)₈-(4-MeO-cHx) H H 1-356 H H H Me 2-(CH₂)₈-(4-EtO-cHx) H H 1-357 H H H Me 2-(CH₂)₈-(4-MeS-cHx) H H 1-358 H H H Me 2-(CH₂)₈-(4-cHx-cHx) H H 1-359 H H H Me 2-(CH₂)₈-(4-Ph-cHx) H H 1-360 H H H Me 2-(CH₂)₈-Ph H H 1-361 H H Me Me 2-(CH₂)₈-Ph H H 1-362 Me H H Me 2-(CH₂)₈-Ph H H 1-363 CO₂Me H H Me 2-(CH₂)₈-Ph H H 1-364 H H H Me 2-(CH₂)₈-(4-F-Ph) H H 1-365 H H H Me 2-(CH₂)₈-(4-Me-Ph) H H 1-366 H H H Me 2-(CH₂)₈-(4-Et-Ph) H H 1-367 H H H Me 2-(CH₂)₈-(4-CF₃-Ph) H H 1-368 H H H Me 2-(CH₂)₈-(4-MeO-Ph) H H 1-369 H H H Me 2-(CH₂)₈-(4-EtO-Ph) H H 1-370 H H H Me 2-(CH₂)₈-(4-MeS-Ph) H H 1-371 H H H Me 2-(CH₂)₈-(4-cHx-Ph) H H 1-372 H H H Me 2-(CH₂)₈-(4-Ph-Ph) H H 1-373 H H H Me 2-(CH₂)₃-O-cHx H H 1-374 H H Me Me 2-(CH₂)₃-O-cHx H H 1-375 Me H H Me 2-(CH₂)₃-O-cHx H H 1-376 CO₂Me H H Me 2-(CH₂)₃-O-cHx H H 1-377 H H H Me 2-(CH₂)₃-O- (4-F-cHx) H H 1-378 H H H Me 2-(CH₂)₃-O- (4-Me-cHx) H H 1-379 H H H Me 2-(CH₂)₃-O- (4-Et-cHx) H H 1-380 H H H Me 2-(CH₂)₃-O- (4-CF₃-cHx) H H 1-381 H H H Me 2-(CH₂)₃-O- (4-MeO-cHx) H H 1-382 H H H Me 2-(CH₂)₃-O- (4-EtO-cHx) H H 1-383 H H H Me 2-(CH₂)₃-O- (4-MeS-cHx) H H 1-384 H H H Me 2-(CH₂)₃-O- (4-cHx-cHx) H H 1-385 H H H Me 2-(CH₂)₃-O- (4-Ph-cHx) H H 1-386 H H H Me 2-(CH₂)₃-O-Ph H H 1-387 H H Me Me 2-(CH₂)₃-O-Ph H H 1-388 Me H H Me 2-(CH₂)₃-O-Ph H H 1-389 CO₂Me H H Me 2-(CH₂)₃-O-Ph H H 1-390 H H H Me 2-(CH₂)₃-O- (4-F-Ph) H H 1-391 H H H Me 2-(CH₂)₃-O- (4-Me-Ph) H H 1-392 H H H Me 2-(CH₂)₃-O- (4-Et-Ph) H H 1-393 H H H Me 2-(CH₂)₃-O- (4-CF₃-Ph) H H 1-394 H H H Me 2-(CH₂)₃-O- (4-MeO-Ph) H H 1-395 H H H Me 2-(CH₂)₃-O- (4-EtO-Ph) H H 1-396 H H H Me 2-(CH₂)₃-O- (4-MeS-Ph) H H 1-397 H H H Me 2-(CH₂)₃-O- (4-cHx-Ph) H H 1-398 H H H Me 2-(CH₂)₃-O- (4-Ph-Ph) H H 1-399 H H H Me 2-(CH₂)_Four-O-cPn H H 1-400 H H H Me 2-(CH₂)_Four-O-cHx H H 1-401 H H H Me 2-(CH₂)_Four-O-cHx Me H 1-402 H H H Me 2-(CH₂)_Four-O-cHx H Me 1-403 H H H Me 2-(CH₂)_Four-O-cHx F H 1-404 H H H Me 2-(CH₂)_Four-O-cHx HF 1-405 H H Me Me 2-(CH₂)_Four-O-cHx H H 1-406 Me H H Me 2-(CH₂)_Four-O-cHx H H 1-407 CO₂Me H H Me 2-(CH₂)_Four-O-cHx H H 1-408 H H H Me 2-(CH₂)_Four-O- (3-F-cHx) H H 1-409 H H H Me 2-(CH₂)_Four-O- (4-F-cHx) H H 1-410 H H H Me 2-(CH₂)_Four-O- (4-Cl-cHx) H H 1-411 H H H Me 2-(CH₂)_Four-O- (4-Br-cHx) H H 1-412 H H H Me 2-(CH₂)_Four-O- (3-Me-cHx) H H 1-413 H H H Me 2-(CH₂)_Four-O- (4-Me-cHx) H H 1-414 H H H Me 2-(CH₂)_Four-O- (3-Et-cHx) H H 1-415 H H H Me 2-(CH₂)_Four-O- (4-Et-cHx) H H 1-416 H H H Me 2-(CH₂)_Four-O- (3-Pr-cHx) H H 1-417 H H H Me 2-(CH₂)_Four-O- (4-Pr-cHx) H H 1-418 H H H Me 2-(CH₂)_Four-O- (4-iPr-cHx) H H 1-419 H H H Me 2-(CH₂)_Four-O- (3-Bu-cHx) H H 1-420 H H H Me 2-(CH₂)_Four-O- (4-Bu-cHx) H H 1-421 H H H Me 2-(CH₂)_Four-O- (3-CF₃-cHx) H H 1-422 H H H Me 2-(CH₂)_Four-O- (4-CF₃-cHx) H H 1-423 H H H Me 2-(CH₂)_Four-O- (3-MeO-cHx) H H 1-424 H H H Me 2-(CH₂)_Four-O- (4-MeO-cHx) H H 1-425 H H H Me 2-(CH₂)_Four-O- (3-EtO-cHx) H H 1-426 H H H Me 2-(CH₂)_Four-O- (4-EtO-cHx) H H 1-427 H H H Me 2-(CH₂)_Four-O- (3-PrO-cHx) H H 1-428 H H H Me 2-(CH₂)_Four-O- (4-PrO-cHx) H H 1-429 H H H Me 2-(CH₂)_Four-O- (3-iPrO-cHx) H H 1-430 H H H Me 2-(CH₂)_Four-O- (4-iPrO-cHx) H H 1-431 H H H Me 2-(CH₂)_Four-O- [3- (2-Et-PrO) -cHx] H H 1-432 H H H Me 2-(CH₂)_Four-O- [4- (2-Et-PrO) -cHx] H H 1-433 H H H Me 2-(CH₂)_Four-O- (3-iBuO-cHx) H H 1-434 H H H Me 2-(CH₂)_Four-O- (4-iBuO-cHx) H H 1-435 H H H Me 2-(CH₂)_Four-O- (3-MeS-cHx) H H 1-436 H H H Me 2-(CH₂)_Four-O- (4-MeS-cHx) H H 1-437 H H H Me 2-(CH₂)_Four-O- (3-EtS-cHx) H H 1-438 H H H Me 2-(CH₂)_Four-O- (4-EtS-cHx) H H 1-439 H H H Me 2-(CH₂)_Four-O- (3-PrS-cHx) H H 1-440 H H H Me 2-(CH₂)_Four-O- (4-PrS-cHx) H H 1-441 H H H Me 2-(CH₂)_Four-O- (3-iPrS-cHx) H H 1-442 H H H Me 2-(CH₂)_Four-O- (4-iPrS-cHx) H H 1-443 H H H Me 2-(CH₂)_Four-O- [3- (2-Et-PrS) -cHx] H H 1-444 H H H Me 2-(CH₂)_Four-O- [4- (2-Et-PrS) -cHx] H H 1-445 H H H Me 2-(CH₂)_Four-O- (3-iBuS-cHx) H H 1-446 H H H Me 2-(CH₂)_Four-O- (4-iBuS-cHx) H H 1-447 H H H Me 2-(CH₂)_Four-O- (3-cHx-cHx) H H 1-448 H H H Me 2-(CH₂)_Four-O- (4-cHx-cHx) H H 1-449 H H H Me 2-(CH₂)_Four-O- (3-Ph-cHx) H H 1-450 H H H Me 2-(CH₂)_Four-O- (4-Ph-cHx) H H 1-451 H H H Me 2-(CH₂)_Four-O- (2,4-diMe-cHx) H H 1-452 H H H Me 2-(CH₂)_Four-O- (3,4-diMe-cHx) H H 1-453 H H H Me 2-(CH₂)_Four-O- (3,5-diMe-cHx) H H 1-454 H H H Me 2-(CH₂)_Four-O-Ph H H 1-455 H H H Me 2-(CH₂)_Four-O-Ph Me H 1-456 H H H Me 2-(CH₂)_Four-O-Ph H Me 1-457 H H H Me 2-(CH₂)_Four-O-Ph F H 1-458 H H H Me 2-(CH₂)_Four-O-Ph H F 1-459 H H Me Me 2-(CH₂)_Four-O-Ph H H 1-460 Me H H Me 2-(CH₂)_Four-O-Ph H H 1-461 CO₂Me H H Me 2-(CH₂)_Four-O-Ph H H 1-462 H H H Me 2-(CH₂)_Four-O- (3-F-Ph) H H 1-463 H H H Me 2-(CH₂)_Four-O- (4-F-Ph) H H 1-464 H H H Me 2-(CH₂)_Four-O- (4-Cl-Ph) H H 1-465 H H H Me 2-(CH₂)_Four-O- (4-Br-Ph) H H 1-466 H H H Me 2-(CH₂)_Four-O- (3-Me-Ph) H H 1-467 H H H Me 2-(CH₂)_Four-O- (4-Me-Ph) H H 1-468 H H H Me 2-(CH₂)_Four-O- (3-Et-Ph) H H 1-469 H H H Me 2-(CH₂)_Four-O- (4-Et-Ph) H H 1-470 H H H Me 2-(CH₂)_Four-O- (3-Pr-Ph) H H 1-471 H H H Me 2-(CH₂)_Four-O- (4-Pr-Ph) H H 1-472 H H H Me 2-(CH₂)_Four-O- (3-iPr-Ph) H H 1-473 H H H Me 2-(CH₂)_Four-O- (4-iPr-Ph) H H 1-474 H H H Me 2-(CH₂)_Four-O- (3-Bu-Ph) H H 1-475 H H H Me 2-(CH₂)_Four-O- (4-Bu-Ph) H H 1-476 H H H Me 2-(CH₂)_Four-O- (3-CF₃-Ph) H H 1-477 H H H Me 2-(CH₂)_Four-O- (4-CF₃-Ph) H H 1-478 H H H Me 2-(CH₂)_Four-O- (3-MeO-Ph) H H 1-479 H H H Me 2-(CH₂)_Four-O- (4-MeO-Ph) H H 1-480 H H H Me 2-(CH₂)_Four-O- (3-EtO-Ph) H H 1-481 H H H Me 2-(CH₂)_Four-O- (4-EtO-Ph) H H 1-482 H H H Me 2-(CH₂)_Four-O- (3-PrO-Ph) H H 1-483 H H H Me 2-(CH₂)_Four-O- (4-PrO-Ph) H H 1-484 H H H Me 2-(CH₂)_Four-O- (3-iPrO-Ph) H H 1-485 H H H Me 2-(CH₂)_Four-O- (4-iPrO-Ph) H H 1-486 H H H Me 2-(CH₂)_Four-O- [3- (2-Et-PrO) -Ph] H H 1-487 H H H Me 2-(CH₂)_Four-O- [4- (2-Et-PrO) -Ph] H H 1-488 H H H Me 2-(CH₂)_Four-O- (3-iBuO-Ph) H H 1-489 H H H Me 2-(CH₂)_Four-O- (4-iBuO-Ph) H H 1-490 H H H Me 2-(CH₂)_Four-O- (3-MeS-Ph) H H 1-491 H H H Me 2-(CH₂)_Four-O- (4-MeS-Ph) H H 1-492 H H H Me 2-(CH₂)_Four-O- (3-EtS-Ph) H H 1-493 H H H Me 2-(CH₂)_Four-O- (4-EtS-Ph) H H 1-494 H H H Me 2-(CH₂)_Four-O- (3-PrS-Ph) H H 1-495 H H H Me 2-(CH₂)_Four-O- (4-PrS-Ph) H H 1-496 H H H Me 2-(CH₂)_Four-O- (3-iPrS-Ph) H H 1-497 H H H Me 2-(CH₂)_Four-O- (4-iPrS-Ph) H H 1-498 H H H Me 2-(CH₂)_Four-O- [3- (2-Et-PrS) -Ph] H H 1-499 H H H Me 2-(CH₂)_Four-O- [4- (2-Et-PrS) -Ph] H H 1-500 H H H Me 2-(CH₂)_Four-O- (3-iBuS-Ph) H H 1-501 H H H Me 2-(CH₂)_Four-O- (4-iBuS-Ph) H H 1-502 H H H Me 2-(CH₂)_Four-O- (3-cHx-Ph) H H 1-503 H H H Me 2-(CH₂)_Four-O- (4-cHx-Ph) H H 1-504 H H H Me 2-(CH₂)_Four-O- (3-Ph-Ph) H H 1-505 H H H Me 2-(CH₂)_Four-O- (4-Ph-Ph) H H 1-506 H H H Me 2-(CH₂)_Four-O- (2,4-diMe-Ph) H H 1-507 H H H Me 2-(CH₂)_Four-O- (3,4-diMe-Ph) H H 1-508 H H H Me 2-(CH₂)_Four-O- (3,5-diMe-Ph) H H 1-509 H H H Me 2-(CH₂)_Five-O-cHx H H 1-510 H H H Me 2-(CH₂)_Five-O-Ph H H 1-511 H H H Me 2-(CH₂)₆-O-cHx H H 1-512 H H H Me 2-(CH₂)₆-O-Ph H H 1-513 H H H Me 2-(CH₂)₃-OCH₂-cHx H H 1-514 H H Me Me 2-(CH₂)₃-OCH₂-cHx H H 1-515 Me H H Me 2-(CH₂)₃-OCH₂-cHx H H 1-516 CO₂Me H H Me 2-(CH₂)₃-OCH₂-cHx H H 1-517 H H H Me 2-(CH₂)₃-OCH₂-(4-F-cHx) H H 1-518 H H H Me 2-(CH₂)₃-OCH₂-(4-Me-cHx) H H 1-519 H H H Me 2-(CH₂)₃-OCH₂-(4-Et-cHx) H H 1-520 H H H Me 2-(CH₂)₃-OCH₂-(4-CF₃-cHx) H H 1-521 H H H Me 2-(CH₂)₃-OCH₂-(4-MeO-cHx) H H 1-522 H H H Me 2-(CH₂)₃-OCH₂-(4-EtO-cHx) H H 1-523 H H H Me 2-(CH₂)₃-OCH₂-(4-MeS-cHx) H H 1-524 H H H Me 2-(CH₂)₃-OCH₂-(4-cHx-cHx) H H 1-525 H H H Me 2-(CH₂)₃-OCH₂-(4-Ph-cHx) H H 1-526 H H H Me 2-(CH₂)₃-OCH₂-Ph H H 1-527 H H Me Me 2-(CH₂)₃-OCH₂-Ph H H 1-528 Me H H Me 2-(CH₂)₃-OCH₂-Ph H H 1-529 CO₂Me H H Me 2-(CH₂)₃-OCH₂-Ph H H 1-530 H H H Me 2-(CH₂)₃-OCH₂-(4-F-Ph) H H 1-531 H H H Me 2-(CH₂)₃-OCH₂-(4-Me-Ph) H H 1-532 H H H Me 2-(CH₂)₃-OCH₂-(4-Et-Ph) H H 1-533 H H H Me 2-(CH₂)₃-OCH₂-(4-CF₃-Ph) H H 1-534 H H H Me 2-(CH₂)₃-OCH₂-(4-MeO-Ph) H H 1-535 H H H Me 2-(CH₂)₃-OCH₂-(4-EtO-Ph) H H 1-536 H H H Me 2-(CH₂)₃-OCH₂-(4-MeS-Ph) H H 1-537 H H H Me 2-(CH₂)₃-OCH₂-(4-cHx-Ph) H H 1-538 H H H Me 2-(CH₂)₃-OCH₂-(4-Ph-Ph) H H 1-539 H H H Me 2-(CH₂)_Four-OCH₂-cPn H H 1-540 H H H Me 2-(CH₂)_Four-OCH₂-cHx H H 1-541 H H H Me 2-(CH₂)_Four-OCH₂-cHx Me H 1-542 H H H Me 2-(CH₂)_Four-OCH₂-cHx H Me 1-543 H H H Me 2-(CH₂)_Four-OCH₂-cHx F H 1-544 H H H Me 2-(CH₂)_Four-OCH₂-cHx HF 1-545 H H Me Me 2-(CH₂)_Four-OCH₂-cHx H H 1-546 Me H H Me 2-(CH₂)_Four-OCH₂-cHx H H 1-547 CO₂Me H H Me 2-(CH₂)_Four-OCH₂-cHx H H 1-548 H H H Me 2-(CH₂)_Four-OCH₂-(3-F-cHx) H H 1-549 H H H Me 2-(CH₂)_Four-OCH₂-(4-F-cHx) H H 1-550 H H H Me 2-(CH₂)_Four-OCH₂-(4-Cl-cHx) H H 1-551 H H H Me 2-(CH₂)_Four-OCH₂-(4-Br-cHx) H H 1-552 H H H Me 2-(CH₂)_Four-OCH₂-(3-Me-cHx) H H 1-553 H H H Me 2-(CH₂)_Four-OCH₂-(4-Me-cHx) H H 1-554 H H H Me 2-(CH₂)_Four-OCH₂-(3-Et-cHx) H H 1-555 H H H Me 2-(CH₂)_Four-OCH₂-(4-Et-cHx) H H 1-556 H H H Me 2-(CH₂)_Four-OCH₂-(3-Pr-cHx) H H 1-557 H H H Me 2-(CH₂)_Four-OCH₂-(4-Pr-cHx) H H 1-558 H H H Me 2-(CH₂)_Four-OCH₂-(4-iPr-cHx) H H 1-559 H H H Me 2-(CH₂)_Four-OCH₂-(3-Bu-cHx) H H 1-560 H H H Me 2-(CH₂)_Four-OCH₂-(4-Bu-cHx) H H 1-561 H H H Me 2-(CH₂)_Four-OCH₂-(3-CF₃-cHx) H H 1-562 H H H Me 2-(CH₂)_Four-OCH₂-(4-CF₃-cHx) H H 1-563 H H H Me 2-(CH₂)_Four-OCH₂-(3-MeO-cHx) H H 1-564 H H H Me 2-(CH₂)_Four-OCH₂-(4-MeO-cHx) H H 1-565 H H H Me 2-(CH₂)_Four-OCH₂-(3-EtO-cHx) H H 1-566 H H H Me 2-(CH₂)_Four-OCH₂-(4-EtO-cHx) H H 1-567 H H H Me 2-(CH₂)_Four-OCH₂-(3-PrO-cHx) H H 1-568 H H H Me 2-(CH₂)_Four-OCH₂-(4-PrO-cHx) H H 1-569 H H H Me 2-(CH₂)_Four-OCH₂-(3-iPrO-cHx) H H 1-570 H H H Me 2-(CH₂)_Four-OCH₂-(4-iPrO-cHx) H H 1-571 H H H Me 2-(CH₂)_Four-OCH₂-[3- (2-Et-PrO) -cHx] H H 1-572 H H H Me 2-(CH₂)_Four-OCH₂-[4- (2-Et-PrO) -cHx] H H 1-573 H H H Me 2-(CH₂)_Four-OCH₂-(3-iBuO-cHx) H H 1-574 H H H Me 2-(CH₂)_Four-OCH₂-(4-iBuO-cHx) H H 1-575 H H H Me 2-(CH₂)_Four-OCH₂-(3-MeS-cHx) H H 1-576 H H H Me 2-(CH₂)_Four-OCH₂-(4-MeS-cHx) H H 1-577 H H H Me 2-(CH₂)_Four-OCH₂-(3-EtS-cHx) H H 1-578 H H H Me 2-(CH₂)_Four-OCH₂-(4-EtS-cHx) H H 1-579 H H H Me 2-(CH₂)_Four-OCH₂-(3-PrS-cHx) H H 1-580 H H H Me 2-(CH₂)_Four-OCH₂-(4-PrS-cHx) H H 1-581 H H H Me 2-(CH₂)_Four-OCH₂-(3-iPrS-cHx) H H 1-582 H H H Me 2-(CH₂)_Four-OCH₂-(4-iPrS-cHx) H H 1-583 H H H Me 2-(CH₂)_Four-OCH₂-[3- (2-Et-PrS) -cHx] H H 1-584 H H H Me 2-(CH₂)_Four-OCH₂-[4- (2-Et-PrS) -cHx] H H 1-585 H H H Me 2-(CH₂)_Four-OCH₂-(3-iBuS-cHx) H H 1-586 H H H Me 2-(CH₂)_Four-OCH₂-(4-iBuS-cHx) H H 1-587 H H H Me 2-(CH₂)_Four-OCH₂-(3-cHx-cHx) H H 1-588 H H H Me 2-(CH₂)_Four-OCH₂-(4-cHx-cHx) H H 1-589 H H H Me 2-(CH₂)_Four-OCH₂-(3-Ph-cHx) H H 1-590 H H H Me 2-(CH₂)_Four-OCH₂-(4-Ph-cHx) H H 1-591 H H H Me 2-(CH₂)_Four-OCH₂-(2,4-diMe-cHx) H H 1-592 H H H Me 2-(CH₂)_Four-OCH₂-(3,4-diMe-cHx) H H 1-593 H H H Me 2-(CH₂)_Four-OCH₂-(3,5-diMe-cHx) H H 1-594 H H H Me 2-(CH₂)_Four-OCH₂-Ph H H 1-595 H H H Me 2-(CH₂)_Four-OCH₂-Ph Me H 1-596 H H H Me 2-(CH₂)_Four-OCH₂-Ph H Me 1-597 H H H Me 2-(CH₂)_Four-OCH₂-Ph F H 1-598 H H H Me 2-(CH₂)_Four-OCH₂-Ph H F 1-599 H H Me Me 2-(CH₂)_Four-OCH₂-Ph H H 1-600 Me H H Me 2-(CH₂)_Four-OCH₂-Ph H H 1-601 CO₂Me H H Me 2-(CH₂)_Four-OCH₂-Ph H H 1-602 H H H Me 2-(CH₂)_Four-OCH₂-(3-F-Ph) H H 1-603 H H H Me 2-(CH₂)_Four-OCH₂-(4-F-Ph) H H 1-604 H H H Me 2-(CH₂)_Four-OCH₂-(4-Cl-Ph) H H 1-605 H H H Me 2-(CH₂)_Four-OCH₂-(4-Br-Ph) H H 1-606 H H H Me 2-(CH₂)_Four-OCH₂-(3-Me-Ph) H H 1-607 H H H Me 2-(CH₂)_Four-OCH₂-(4-Me-Ph) H H 1-608 H H H Me 2-(CH₂)_Four-OCH₂-(3-Et-Ph) H H 1-609 H H H Me 2-(CH₂)_Four-OCH₂-(4-Et-Ph) H H 1-610 H H H Me 2-(CH₂)_Four-OCH₂-(3-Pr-Ph) H H 1-611 H H H Me 2-(CH₂)_Four-OCH₂-(4-Pr-Ph) H H 1-612 H H H Me 2-(CH₂)_Four-OCH₂-(3-iPr-Ph) H H 1-613 H H H Me 2-(CH₂)_Four-OCH₂-(4-iPr-Ph) H H 1-614 H H H Me 2-(CH₂)_Four-OCH₂-(3-Bu-Ph) H H 1-615 H H H Me 2-(CH₂)_Four-OCH₂-(4-Bu-Ph) H H 1-616 H H H Me 2-(CH₂)_Four-OCH₂-(3-CF₃-Ph) H H 1-617 H H H Me 2-(CH₂)_Four-OCH₂-(4-CF₃-Ph) H H 1-618 H H H Me 2-(CH₂)_Four-OCH₂-(3-MeO-Ph) H H 1-619 H H H Me 2-(CH₂)_Four-OCH₂-(4-MeO-Ph) H H 1-620 H H H Me 2-(CH₂)_Four-OCH₂-(3-EtO-Ph) H H 1-621 H H H Me 2-(CH₂)_Four-OCH₂-(4-EtO-Ph) H H 1-622 H H H Me 2-(CH₂)_Four-OCH₂-(3-PrO-Ph) H H 1-623 H H H Me 2-(CH₂)_Four-OCH₂-(4-PrO-Ph) H H 1-624 H H H Me 2-(CH₂)_Four-OCH₂-(3-iPrO-Ph) H H 1-625 H H H Me 2-(CH₂)_Four-OCH₂-(4-iPrO-Ph) H H 1-626 H H H Me 2-(CH₂)_Four-OCH₂-[3- (2-Et-PrO) -Ph] H H 1-627 H H H Me 2-(CH₂)_Four-OCH₂-[4- (2-Et-PrO) -Ph] H H 1-628 H H H Me 2-(CH₂)_Four-OCH₂-(3-iBuO-Ph) H H 1-629 H H H Me 2-(CH₂)_Four-OCH₂-(4-iBuO-Ph) H H 1-630 H H H Me 2-(CH₂)_Four-OCH₂-(3-MeS-Ph) H H 1-631 H H H Me 2-(CH₂)_Four-OCH₂-(4-MeS-Ph) H H 1-632 H H H Me 2-(CH₂)_Four-OCH₂-(3-EtS-Ph) H H 1-633 H H H Me 2-(CH₂)_Four-OCH₂-(4-EtS-Ph) H H 1-634 H H H Me 2-(CH₂)_Four-OCH₂-(3-PrS-Ph) H H 1-635 H H H Me 2-(CH₂)_Four-OCH₂-(4-PrS-Ph) H H 1-636 H H H Me 2-(CH₂)_Four-OCH₂-(3-iPrS-Ph) H H 1-637 H H H Me 2-(CH₂)_Four-OCH₂-(4-iPrS-Ph) H H 1-638 H H H Me 2-(CH₂)_Four-OCH₂-[3- (2-Et-PrS) -Ph] H H 1-639 H H H Me 2-(CH₂)_Four-OCH₂-[4- (2-Et-PrS) -Ph] H H 1-640 H H H Me 2-(CH₂)_Four-OCH₂-(3-iBuS-Ph) H H 1-641 H H H Me 2-(CH₂)_Four-OCH₂-(4-iBuS-Ph) H H 1-642 H H H Me 2-(CH₂)_Four-OCH₂-(3-cHx-Ph) H H 1-643 H H H Me 2-(CH₂)_Four-OCH₂-(4-cHx-Ph) H H 1-644 H H H Me 2-(CH₂)_Four-OCH₂-(3-Ph-Ph) H H 1-645 H H H Me 2-(CH₂)_Four-OCH₂-(4-Ph-Ph) H H 1-646 H H H Me 2-(CH₂)_Four-OCH₂-(2,4-diMe-Ph) H H 1-647 H H H Me 2-(CH₂)_Four-OCH₂-(3,4-diMe-Ph) H H 1-648 H H H Me 2-(CH₂)_Four-OCH₂-(3,5-diMe-Ph) H H 1-649 H H H Me 2-(CH₂)_Five-OCH₂-cHx H H 1-650 H H H Me 2-(CH₂)_Five-OCH₂-Ph H H 1-651 H H H Me 2-(CH₂)₆-OCH₂-cHx H H 1-652 H H H Me 2-(CH₂)₆-OCH₂-Ph H H 1-653 H H H Me 2 -CH = CH-cHx H H 1-654 H H H Me 2 -CH = CH-Ph H H 1-655 H H H Me 2 -CH = CH- (CH₂)₂-cHx H H 1-656 H H H Me 2 -CH = CH- (CH₂)₂-Ph H H 1-657 H H H Me 2 -CH = CH- (CH₂)₃-cHx H H 1-658 H H Me Me 2 -CH = CH- (CH₂)₃-cHx H H 1-659 Me H H Me 2 -CH = CH- (CH₂)₃-cHx H H 1-660 CO₂Me H H Me 2 -CH = CH- (CH₂)₃-cHx H H 1-661 H H H Me 2 -CH = CH- (CH₂)₃-(4-F-cHx) H H 1-662 H H H Me 2 -CH = CH- (CH₂)₃-(4-Me-cHx) H H 1-663 H H H Me 2 -CH = CH- (CH₂)₃-(4-Et-cHx) H H 1-664 H H H Me 2 -CH = CH- (CH₂)₃-(4-CF₃-cHx) H H 1-665 H H H Me 2 -CH = CH- (CH₂)₃-(4-MeO-cHx) H H 1-666 H H H Me 2 -CH = CH- (CH₂)₃-(4-EtO-cHx) H H 1-667 H H H Me 2 -CH = CH- (CH₂)₃-(4-MeS-cHx) H H 1-668 H H H Me 2 -CH = CH- (CH₂)₃-(4-cHx-cHx) H H 1-669 H H H Me 2 -CH = CH- (CH₂)₃-(4-Ph-cHx) H H 1-670 H H H Me 2 -CH = CH- (CH₂)₃-Ph H H 1-671 H H Me Me 2 -CH = CH- (CH₂)₃-Ph H H 1-672 Me H H Me 2 -CH = CH- (CH₂)₃-Ph H H 1-673 CO₂Me H H Me 2 -CH = CH- (CH₂)₃-Ph H H 1-674 H H H Me 2 -CH = CH- (CH₂)₃-(4-F-Ph) H H 1-675 H H H Me 2 -CH = CH- (CH₂)₃-(4-Me-Ph) H H 1-676 H H H Me 2 -CH = CH- (CH₂)₃-(4-Et-Ph) H H 1-677 H H H Me 2 -CH = CH- (CH₂)₃-(4-CF₃-Ph) H H 1-678 H H H Me 2 -CH = CH- (CH₂)₃-(4-MeO-Ph) H H 1-679 H H H Me 2 -CH = CH- (CH₂)₃-(4-EtO-Ph) H H 1-680 H H H Me 2 -CH = CH- (CH₂)₃-(4-MeS-Ph) H H 1-681 H H H Me 2 -CH = CH- (CH₂)₃-(4-cHx-Ph) H H 1-682 H H H Me 2 -CH = CH- (CH₂)₃-(4-Ph-Ph) H H 1-683 H H H Me 2 -CH = CH- (CH₂)_Four-cHx H H 1-684 H H Me Me 2 -CH = CH- (CH₂)_Four-cHx H H 1-685 Me H H Me 2 -CH = CH- (CH₂)_Four-cHx H H 1-686 CO₂Me H H Me 2 -CH = CH- (CH₂)_Four-cHx H H 1-687 H H H Me 2 -CH = CH- (CH₂)_Four-(4-F-cHx) H H 1-688 H H H Me 2 -CH = CH- (CH₂)_Four-(4-Me-cHx) H H 1-689 H H H Me 2 -CH = CH- (CH₂)_Four-(4-Et-cHx) H H 1-690 H H H Me 2 -CH = CH- (CH₂)_Four-(4-CF₃-cHx) H H 1-691 H H H Me 2 -CH = CH- (CH₂)_Four-(4-MeO-cHx) H H 1-692 H H H Me 2 -CH = CH- (CH₂)_Four-(4-EtO-cHx) H H 1-693 H H H Me 2 -CH = CH- (CH₂)_Four-(4-MeS-cHx) H H 1-694 H H H Me 2 -CH = CH- (CH₂)_Four-(4-cHx-cHx) H H 1-695 H H H Me 2 -CH = CH- (CH₂)_Four-(4-Ph-cHx) H H 1-696 H H H Me 2 -CH = CH- (CH₂)_Four-Ph H H 1-697 H H Me Me 2 -CH = CH- (CH₂)_Four-Ph H H 1-698 Me H H Me 2 -CH = CH- (CH₂)_Four-Ph H H 1-699 CO₂Me H H Me 2 -CH = CH- (CH₂)_Four-Ph H H 1-700 H H H Me 2 -CH = CH- (CH₂)_Four-(4-F-Ph) H H 1-701 H H H Me 2 -CH = CH- (CH₂)_Four-(4-Me-Ph) H H 1-702 H H H Me 2 -CH = CH- (CH₂)_Four-(4-Et-Ph) H H 1-703 H H H Me 2 -CH = CH- (CH₂)_Four-(4-CF₃-Ph) H H 1-704 H H H Me 2 -CH = CH- (CH₂)_Four-(4-MeO-Ph) H H 1-705 H H H Me 2 -CH = CH- (CH₂)_Four-(4-EtO-Ph) H H 1-706 H H H Me 2 -CH = CH- (CH₂)_Four-(4-MeS-Ph) H H 1-707 H H H Me 2 -CH = CH- (CH₂)_Four-(4-cHx-Ph) H H 1-708 H H H Me 2 -CH = CH- (CH₂)_Four-(4-Ph-Ph) H H 1-709 H H H Me 2 -CH = CH- (CH₂)_Five-cHx H H 1-710 H H H Me 2 -CH = CH- (CH₂)_Five-Ph H H 1-711 H H H Me 2 -CH = CH- (CH₂)₆-cHx H H 1-712 H H H Me 2 -CH = CH- (CH₂)₆-Ph H H 1-713 H H H Me 2 -C = C-CH₂O-cHx H H 1-714 H H H Me 2 -C = C-CH₂O-Ph H H 1-715 H H H Me 2 -C = C- (CH₂)₂O-cHx H H 1-716 H H H Me 2 -C = C- (CH₂)₂O-Ph H H 1-717 H H H Me 2 -C≡C-cHx H H 1-718 H H Me Me 2 -C≡C-c Hx H H 1-719 Me H H Me 2 -C≡C-cH x H H 1-720 CO₂Me H H Me 2 -C≡C-cH x H H 1-721 H H H Me 2 -C≡C- (4-F-cHx) H H 1-722 H H H Me 2 -C≡C- (4-Me-cHx) H H 1-723 H H H Me 2 -C≡C- (4-Et-cHx) H H 1-724 H H H Me 2 -C≡C- (4-CF₃-cHx) H H 1-725 H H H Me 2 -C≡C- (4-MeO-cHx) H H 1-726 H H H Me 2 -C≡C- (4-EtO-cHx) H H 1-727 H H H Me 2 -C≡C- (4-MeS-cHx) H H 1-728 H H H Me 2 -C≡C- (4-cHx-cHx) H H 1-729 H H H Me 2 -C≡C- (4-Ph-cHx) H H 1-730 H H H Me 2 -C≡C-Ph H H 1-731 H H Me Me 2 -C≡C-Ph H H 1-732 Me H H Me 2 -C≡C-Ph H H 1-733 CO₂Me H H Me 2 -C≡C-Ph H H 1-734 H H H Me 2 -C≡C- (4-F-Ph) H H 1-735 H H H Me 2 -C≡C- (4-Me-Ph) H H 1-736 H H H Me 2 -C≡C- (4-Pr-Ph) H H 1-737 H H H Me 2 -C≡C- (4-Bu-Ph) H H 1-738 H H H Me 2 -C≡C- (4-MeO-Ph) H H 1-739 H H H Me 2 -C≡C- (4-EtO-Ph) H H 1-740 H H H Me 2 -C≡C- (4-PrO-Ph) H H 1-741 H H H Me 2 -C≡C- (4-cHx-Ph) H H 1-742 H H H Me 2 -C≡C- (4-Ph-Ph) H H 1-743 H H H Me 2 -C≡C- (CH₂)₂-cHx H H 1-744 H H Me Me 2 -C≡C- (CH₂)₂-cHx H H 1-745 Me H H Me 2 -C≡C- (CH₂)₂-cHx H H 1-746 CO₂Me H H Me 2 -C≡C- (CH₂)₂-cHx H H 1-747 H H H Me 2 -C≡C- (CH₂)₂-(4-F-cHx) H H 1-748 H H H Me 2 -C≡C- (CH₂)₂-(4-Me-cHx) H H 1-749 H H H Me 2 -C≡C- (CH₂)₂-(4-Et-cHx) H H 1-750 H H H Me 2 -C≡C- (CH₂)₂-(4-CF₃-cHx) H H 1-751 H H H Me 2 -C≡C- (CH₂)₂-(4-MeO-cHx) H H 1-752 H H H Me 2 -C≡C- (CH₂)₂-(4-EtO-cHx) H H 1-753 H H H Me 2 -C≡C- (CH₂)₂-(4-MeS-cHx) H H 1-754 H H H Me 2 -C≡C- (CH₂)₂-(4-cHx-cHx) H H 1-755 H H H Me 2 -C≡C- (CH₂)₂-(4-Ph-cHx) H H 1-756 H H H Me 2 -C≡C- (CH₂)₂-Ph H H 1-757 H H Me Me 2 -C≡C- (CH₂)₂-Ph H H 1-758 Me H H Me 2 -C≡C- (CH₂)₂-Ph H H 1-759 CO₂Me H H Me 2 -C≡C- (CH₂)₂-Ph H H 1-760 H H H Me 2 -C≡C- (CH₂)₂-(4-F-Ph) H H 1-761 H H H Me 2 -C≡C- (CH₂)₂-(4-Me-Ph) H H 1-762 H H H Me 2 -C≡C- (CH₂)₂-(4-Et-Ph) H H 1-763 H H H Me 2 -C≡C- (CH₂)₂-(4-CF₃-Ph) H H 1-764 H H H Me 2 -C≡C- (CH₂)₂-(4-MeO-Ph) H H 1-765 H H H Me 2 -C≡C- (CH₂)₂-(4-EtO-Ph) H H 1-766 H H H Me 2 -C≡C- (CH₂)₂-(4-MeS-Ph) H H 1-767 H H H Me 2 -C≡C- (CH₂)₂-(4-cHx-Ph) H H 1-768 H H H Me 2 -C≡C- (CH₂)₂-(4-Ph-Ph) H H 1-769 H H H Me 2 -C≡C- (CH₂)₃-cPn H H 1-770 H H H Me 2 -C≡C- (CH₂)₃-cHx H H 1-771 H H H Me 2 -C≡C- (CH₂)₃-cHx Me H 1-772 H H H Me 2 -C≡C- (CH₂)₃-cHx H Me 1-773 H H H Me 2 -C≡C- (CH₂)₃-cHx F H 1-774 H H H Me 2 -C≡C- (CH₂)₃-cHx HF 1-775 H H Me Me 2 -C≡C- (CH₂)₃-cHx H H 1-776 Me H H Me 2 -C≡C- (CH₂)₃-cHx H H 1-777 CO₂Me H H Me 2 -C≡C- (CH₂)₃-cHx H H 1-778 H H H Me 2 -C≡C- (CH₂)₃-(3-F-cHx) H H 1-779 H H H Me 2 -C≡C- (CH₂)₃-(4-F-cHx) H H 1-780 H H H Me 2 -C≡C- (CH₂)₃-(4-Cl-cHx) H H 1-781 H H H Me 2 -C≡C- (CH₂)₃-(4-Br-cHx) H H 1-782 H H H Me 2 -C≡C- (CH₂)₃-(3-Me-cHx) H H 1-783 H H H Me 2 -C≡C- (CH₂)₃-(4-Me-cHx) H H 1-784 H H H Me 2 -C≡C- (CH₂)₃-(3-Et-cHx) H H 1-785 H H H Me 2 -C≡C- (CH₂)₃-(4-Et-cHx) H H 1-786 H H H Me 2 -C≡C- (CH₂)₃-(3-Pr-cHx) H H 1-787 H H H Me 2 -C≡C- (CH₂)₃-(4-Pr-cHx) H H 1-788 H H H Me 2 -C≡C- (CH₂)₃-(4-iPr-cHx) H H 1-789 H H H Me 2 -C≡C- (CH₂)₃-(3-Bu-cHx) H H 1-790 H H H Me 2 -C≡C- (CH₂)₃-(4-Bu-cHx) H H 1-791 H H H Me 2 -C≡C- (CH₂)₃-(3-CF₃-cHx) H H 1-792 H H H Me 2 -C≡C- (CH₂)₃-(4-CF₃-cHx) H H 1-793 H H H Me 2 -C≡C- (CH₂)₃-(3-MeO-cHx) H H 1-794 H H H Me 2 -C≡C- (CH₂)₃-(4-MeO-cHx) H H 1-795 H H H Me 2 -C≡C- (CH₂)₃-(3-EtO-cHx) H H 1-796 H H H Me 2 -C≡C- (CH₂)₃-(4-EtO-cHx) H H 1-797 H H H Me 2 -C≡C- (CH₂)₃-(3-PrO-cHx) H H 1-798 H H H Me 2 -C≡C- (CH₂)₃-(4-PrO-cHx) H H 1-799 H H H Me 2 -C≡C- (CH₂)₃-(3-iPrO-cHx) H H 1-800 H H H Me 2 -C≡C- (CH₂)₃-(4-iPrO-cHx) H H 1-801 H H H Me 2 -C≡C- (CH₂)₃-[3- (2-Et-PrO) -cHx] H H 1-802 H H H Me 2 -C≡C- (CH₂)₃-[4- (2-Et-PrO) -cHx] H H 1-803 H H H Me 2 -C≡C- (CH₂)₃-(3-iBuO-cHx) H H 1-804 H H H Me 2 -C≡C- (CH₂)₃-(4-iBuO-cHx) H H 1-805 H H H Me 2 -C≡C- (CH₂)₃-(3-MeS-cHx) H H 1-806 H H H Me 2 -C≡C- (CH₂)₃-(4-MeS-cHx) H H 1-807 H H H Me 2 -C≡C- (CH₂)₃-(3-EtS-cHx) H H 1-808 H H H Me 2 -C≡C- (CH₂)₃-(4-EtS-cHx) H H 1-809 H H H Me 2 -C≡C- (CH₂)₃-(3-PrS-cHx) H H 1-810 H H H Me 2 -C≡C- (CH₂)₃-(4-PrS-cHx) H H 1-811 H H H Me 2 -C≡C- (CH₂)₃-(3-iPrS-cHx) H H 1-812 H H H Me 2 -C≡C- (CH₂)₃-(4-iPrS-cHx) H H 1-813 H H H Me 2 -C≡C- (CH₂)₃-[3- (2-Et-PrS) -cHx] H H 1-814 H H H Me 2 -C≡C- (CH₂)₃-[4- (2-Et-PrS) -cHx] H H 1-815 H H H Me 2 -C≡C- (CH₂)₃-(3-iBuS-cHx) H H 1-816 H H H Me 2 -C≡C- (CH₂)₃-(4-iBuS-cHx) H H 1-817 H H H Me 2 -C≡C- (CH₂)₃-(3-cHx-cHx) H H 1-818 H H H Me 2 -C≡C- (CH₂)₃-(4-cHx-cHx) H H 1-819 H H H Me 2 -C≡C- (CH₂)₃-(3-Ph-cHx) H H 1-820 H H H Me 2 -C≡C- (CH₂)₃-(4-Ph-cHx) H H 1-821 H H H Me 2 -C≡C- (CH₂)₃-(2,4-diMe-cHx) H H 1-822 H H H Me 2 -C≡C- (CH₂)₃-(3,4-diMe-cHx) H H 1-823 H H H Me 2 -C≡C- (CH₂)₃-(3,5-diMe-cHx) H H 1-824 H H H Me 2 -C≡C- (CH₂)₃-Ph H H 1-825 H H H Me 2 -C≡C- (CH₂)₃-Ph Me H 1-826 H H H Me 2 -C≡C- (CH₂)₃-Ph H Me 1-827 H H H Me 2 -C≡C- (CH₂)₃-Ph F H 1-828 H H H Me 2 -C≡C- (CH₂)₃-Ph H F 1-829 H H Me Me 2 -C≡C- (CH₂)₃-Ph H H 1-830 Me H H Me 2 -C≡C- (CH₂)₃-Ph H H 1-831 CO₂Me H H Me 2 -C≡C- (CH₂)₃-Ph H H 1-832 H H H Me 2 -C≡C- (CH₂)₃-(3-F-Ph) H H 1-833 H H H Me 2 -C≡C- (CH₂)₃-(4-F-Ph) H H 1-834 H H H Me 2 -C≡C- (CH₂)₃-(4-Cl-Ph) H H 1-835 H H H Me 2 -C≡C- (CH₂)₃-(4-Br-Ph) H H 1-836 H H H Me 2 -C≡C- (CH₂)₃-(3-Me-Ph) H H 1-837 H H H Me 2 -C≡C- (CH₂)₃-(4-Me-Ph) H H 1-838 H H H Me 2 -C≡C- (CH₂)₃-(3-Et-Ph) H H 1-839 H H H Me 2 -C≡C- (CH₂)₃-(4-Et-Ph) H H 1-840 H H H Me 2 -C≡C- (CH₂)₃-(3-Pr-Ph) H H 1-841 H H H Me 2 -C≡C- (CH₂)₃-(4-Pr-Ph) H H 1-842 H H H Me 2 -C≡C- (CH₂)₃-(3-iPr-Ph) H H 1-843 H H H Me 2 -C≡C- (CH₂)₃-(4-iPr-Ph) H H 1-844 H H H Me 2 -C≡C- (CH₂)₃-(3-Bu-Ph) H H 1-845 H H H Me 2 -C≡C- (CH₂)₃-(4-Bu-Ph) H H 1-846 H H H Me 2 -C≡C- (CH₂)₃-(3-CF₃-Ph) H H 1-847 H H H Me 2 -C≡C- (CH₂)₃-(4-CF₃-Ph) H H 1-848 H H H Me 2 -C≡C- (CH₂)₃-(3-MeO-Ph) H H 1-849 H H H Me 2 -C≡C- (CH₂)₃-(4-MeO-Ph) H H 1-850 H H H Me 2 -C≡C- (CH₂)₃-(3-EtO-Ph) H H 1-851 H H H Me 2 -C≡C- (CH₂)₃-(4-EtO-Ph) H H 1-852 H H H Me 2 -C≡C- (CH₂)₃-(3-PrO-Ph) H H 1-853 H H H Me 2 -C≡C- (CH₂)₃-(4-PrO-Ph) H H 1-854 H H H Me 2 -C≡C- (CH₂)₃-(3-iPrO-Ph) H H 1-855 H H H Me 2 -C≡C- (CH₂)₃-(4-iPrO-Ph) H H 1-856 H H H Me 2 -C≡C- (CH₂)₃-[3- (2-Et-PrO) -Ph] H H 1-857 H H H Me 2 -C≡C- (CH₂)₃-[4- (2-Et-PrO) -Ph] H H 1-858 H H H Me 2 -C≡C- (CH₂)₃-(3-iBuO-Ph) H H 1-859 H H H Me 2 -C≡C- (CH₂)₃-(4-iBuO-Ph) H H 1-860 H H H Me 2 -C≡C- (CH₂)₃-(3-MeS-Ph) H H 1-861 H H H Me 2 -C≡C- (CH₂)₃-(4-MeS-Ph) H H 1-862 H H H Me 2 -C≡C- (CH₂)₃-(3-EtS-Ph) H H 1-863 H H H Me 2 -C≡C- (CH₂)₃-(4-EtS-Ph) H H 1-864 H H H Me 2 -C≡C- (CH₂)₃-(3-PrS-Ph) H H 1-865 H H H Me 2 -C≡C- (CH₂)₃-(4-PrS-Ph) H H 1-866 H H H Me 2 -C≡C- (CH₂)₃-(3-iPrS-Ph) H H 1-867 H H H Me 2 -C≡C- (CH₂)₃-(4-iPrS-Ph) H H 1-868 H H H Me 2 -C≡C- (CH₂)₃-[3- (2-Et-PrS) -Ph] H H 1-869 H H H Me 2 -C≡C- (CH₂)₃-[4- (2-Et-PrS) -Ph] H H 1-870 H H H Me 2 -C≡C- (CH₂)₃-(3-iBuS-Ph) H H 1-871 H H H Me 2 -C≡C- (CH₂)₃-(4-iBuS-Ph) H H 1-872 H H H Me 2 -C≡C- (CH₂)₃-(3-cHx-Ph) H H 1-873 H H H Me 2 -C≡C- (CH₂)₃-(4-cHx-Ph) H H 1-874 H H H Me 2 -C≡C- (CH₂)₃-(3-Ph-Ph) H H 1-875 H H H Me 2 -C≡C- (CH₂)₃-(4-Ph-Ph) H H 1-876 H H H Me 2 -C≡C- (CH₂)₃-(2,4-diMe-Ph) H H 1-877 H H H Me 2 -C≡C- (CH₂)₃-(3,4-diMe-Ph) H H 1-878 H H H Me 2 -C≡C- (CH₂)₃-(3,5-diMe-Ph) H H 1-879 H H H Me 2 -C≡C- (CH₂)₃-Np (1) H H 1-880 H H H Me 2 -C≡C- (CH₂)₃-Np (2) H H 1-881 H H H Me 2 -C≡C- (CH₂)_Four-cPn H H 1-882 H H H Me 2 -C≡C- (CH₂)_Four-cHx H H 1-883 H H H Me 2 -C≡C- (CH₂)_Four-cHx Me H 1-884 H H H Me 2 -C≡C- (CH₂)_Four-cHx H Me 1-885 H H H Me 2 -C≡C- (CH₂)_Four-cHx F H 1-886 H H H Me 2 -C≡C- (CH₂)_Four-cHx HF 1-887 H H Me Me 2 -C≡C- (CH₂)_Four-cHx H H 1-888 Me H H Me 2 -C≡C- (CH₂)_Four-cHx H H 1-889 CO₂Me H H Me 2 -C≡C- (CH₂)_Four-cHx H H 1-890 H H H Me 2 -C≡C- (CH₂)_Four-(3-F-cHx) H H 1-891 H H H Me 2 -C≡C- (CH₂)_Four-(4-F-cHx) H H 1-892 H H H Me 2 -C≡C- (CH₂)_Four-(4-Cl-cHx) H H 1-893 H H H Me 2 -C≡C- (CH₂)_Four-(4-Br-cHx) H H 1-894 H H H Me 2 -C≡C- (CH₂)_Four-(3-Me-cHx) H H 1-895 H H H Me 2 -C≡C- (CH₂)_Four-(4-Me-cHx) H H 1-896 H H H Me 2 -C≡C- (CH₂)_Four-(3-Et-cHx) H H 1-897 H H H Me 2 -C≡C- (CH₂)_Four-(4-Et-cHx) H H 1-898 H H H Me 2 -C≡C- (CH₂)_Four-(3-Pr-cHx) H H 1-899 H H H Me 2 -C≡C- (CH₂)_Four-(4-Pr-cHx) H H 1-900 H H H Me 2 -C≡C- (CH₂)_Four-(4-iPr-cHx) H H 1-901 H H H Me 2 -C≡C- (CH₂)_Four-(3-Bu-cHx) H H 1-902 H H H Me 2 -C≡C- (CH₂)_Four-(4-Bu-cHx) H H 1-903 H H H Me 2 -C≡C- (CH₂)_Four-(3-CF₃-cHx) H H 1-904 H H H Me 2 -C≡C- (CH₂)_Four-(4-CF₃-cHx) H H 1-905 H H H Me 2 -C≡C- (CH₂)_Four-(3-MeO-cHx) H H 1-906 H H H Me 2 -C≡C- (CH₂)_Four-(4-MeO-cHx) H H 1-907 H H H Me 2 -C≡C- (CH₂)_Four-(3-EtO-cHx) H H 1-908 H H H Me 2 -C≡C- (CH₂)_Four-(4-EtO-cHx) H H 1-909 H H H Me 2 -C≡C- (CH₂)_Four-(3-PrO-cHx) H H 1-910 H H H Me 2 -C≡C- (CH₂)_Four-(4-PrO-cHx) H H 1-911 H H H Me 2 -C≡C- (CH₂)_Four-(3-iPrO-cHx) H H 1-912 H H H Me 2 -C≡C- (CH₂)_Four-(4-iPrO-cHx) H H 1-913 H H H Me 2 -C≡C- (CH₂)_Four-[3- (2-Et-PrO) -cHx] H H 1-914 H H H Me 2 -C≡C- (CH₂)_Four-[4- (2-Et-PrO) -cHx] H H 1-915 H H H Me 2 -C≡C- (CH₂)_Four-(3-iBuO-cHx) H H 1-916 H H H Me 2 -C≡C- (CH₂)_Four-(4-iBuO-cHx) H H 1-917 H H H Me 2 -C≡C- (CH₂)_Four-(3-MeS-cHx) H H 1-918 H H H Me 2 -C≡C- (CH₂)_Four-(4-MeS-cHx) H H 1-919 H H H Me 2 -C≡C- (CH₂)_Four-(3-EtS-cHx) H H 1-920 H H H Me 2 -C≡C- (CH₂)_Four-(4-EtS-cHx) H H 1-921 H H H Me 2 -C≡C- (CH₂)_Four-(3-PrS-cHx) H H 1-922 H H H Me 2 -C≡C- (CH₂)_Four-(4-PrS-cHx) H H 1-923 H H H Me 2 -C≡C- (CH₂)_Four-(3-iPrS-cHx) H H 1-924 H H H Me 2 -C≡C- (CH₂)_Four-(4-iPrS-cHx) H H 1-925 H H H Me 2 -C≡C- (CH₂)_Four-[3- (2-Et-PrS) -cHx] H H 1-926 H H H Me 2 -C≡C- (CH₂)_Four-[4- (2-Et-PrS) -cHx] H H 1-927 H H H Me 2 -C≡C- (CH₂)_Four-(3-iBuS-cHx) H H 1-928 H H H Me 2 -C≡C- (CH₂)_Four-(4-iBuS-cHx) H H 1-929 H H H Me 2 -C≡C- (CH₂)_Four-(3-cHx-cHx) H H 1-930 H H H Me 2 -C≡C- (CH₂)_Four-(4-cHx-cHx) H H 1-931 H H H Me 2 -C≡C- (CH₂)_Four-(3-Ph-cHx) H H 1-932 H H H Me 2 -C≡C- (CH₂)_Four-(4-Ph-cHx) H H 1-933 H H H Me 2 -C≡C- (CH₂)_Four-(2,4-diMe-cHx) H H 1-934 H H H Me 2 -C≡C- (CH₂)_Four-(3,4-diMe-cHx) H H 1-935 H H H Me 2 -C≡C- (CH₂)_Four-(3,5-diMe-cHx) H H 1-936 H H H Me 2 -C≡C- (CH₂)_Four-Ph H H 1-937 H H H Me 2 -C≡C- (CH₂)_Four-Ph Me H 1-938 H H H Me 2 -C≡C- (CH₂)_Four-Ph H Me 1-939 H H H Me 2 -C≡C- (CH₂)_Four-Ph F H 1-940 H H H Me 2 -C≡C- (CH₂)_Four-Ph H F 1-941 H H Me Me 2 -C≡C- (CH₂)_Four-Ph H H 1-942 Me H H Me 2 -C≡C- (CH₂)_Four-Ph H H 1-943 CO₂Me H H Me 2 -C≡C- (CH₂)_Four-Ph H H 1-944 H H H Me 2 -C≡C- (CH₂)_Four-(3-F-Ph) H H 1-945 H H H Me 2 -C≡C- (CH₂)_Four-(4-F-Ph) H H 1-946 H H H Me 2 -C≡C- (CH₂)_Four-(4-Cl-Ph) H H 1-947 H H H Me 2 -C≡C- (CH₂)_Four-(4-Br-Ph) H H 1-948 H H H Me 2 -C≡C- (CH₂)_Four-(3-Me-Ph) H H 1-949 H H H Me 2 -C≡C- (CH₂)_Four-(4-Me-Ph) H H 1-950 H H H Me 2 -C≡C- (CH₂)_Four-(3-Et-Ph) H H 1-951 H H H Me 2 -C≡C- (CH₂)_Four-(4-Et-Ph) H H 1-952 H H H Me 2 -C≡C- (CH₂)_Four-(3-Pr-Ph) H H 1-953 H H H Me 2 -C≡C- (CH₂)_Four-(4-Pr-Ph) H H 1-954 H H H Me 2 -C≡C- (CH₂)_Four-(3-iPr-Ph) H H 1-955 H H H Me 2 -C≡C- (CH₂)_Four-(4-iPr-Ph) H H 1-956 H H H Me 2 -C≡C- (CH₂)_Four-(3-Bu-Ph) H H 1-957 H H H Me 2 -C≡C- (CH₂)_Four-(4-Bu-Ph) H H 1-958 H H H Me 2 -C≡C- (CH₂)_Four-(3-CF₃-Ph) H H 1-959 H H H Me 2 -C≡C- (CH₂)_Four-(4-CF₃-Ph) H H 1-960 H H H Me 2 -C≡C- (CH₂)_Four-(3-MeO-Ph) H H 1-961 H H H Me 2 -C≡C- (CH₂)_Four-(4-MeO-Ph) H H 1-962 H H H Me 2 -C≡C- (CH₂)_Four-(3-EtO-Ph) H H 1-963 H H H Me 2 -C≡C- (CH₂)_Four-(4-EtO-Ph) H H 1-964 H H H Me 2 -C≡C- (CH₂)_Four-(3-PrO-Ph) H H 1-965 H H H Me 2 -C≡C- (CH₂)_Four-(4-PrO-Ph) H H 1-966 H H H Me 2 -C≡C- (CH₂)_Four-(3-iPrO-Ph) H H 1-967 H H H Me 2 -C≡C- (CH₂)_Four-(4-iPrO-Ph) H H 1-968 H H H Me 2 -C≡C- (CH₂)_Four-[3- (2-Et-PrO) -Ph] H H 1-969 H H H Me 2 -C≡C- (CH₂)_Four-[4- (2-Et-PrO) -Ph] H H 1-970 H H H Me 2 -C≡C- (CH₂)_Four-(3-iBuO-Ph) H H 1-971 H H H Me 2 -C≡C- (CH₂)_Four-(4-iBuO-Ph) H H 1-972 H H H Me 2 -C≡C- (CH₂)_Four-(3-MeS-Ph) H H 1-973 H H H Me 2 -C≡C- (CH₂)_Four-(4-MeS-Ph) H H 1-974 H H H Me 2 -C≡C- (CH₂)_Four-(3-EtS-Ph) H H 1-975 H H H Me 2 -C≡C- (CH₂)_Four-(4-EtS-Ph) H H 1-976 H H H Me 2 -C≡C- (CH₂)_Four-(3-PrS-Ph) H H 1-977 H H H Me 2 -C≡C- (CH₂)_Four-(4-PrS-Ph) H H 1-978 H H H Me 2 -C≡C- (CH₂)_Four-(3-iPrS-Ph) H H 1-979 H H H Me 2 -C≡C- (CH₂)_Four-(4-iPrS-Ph) H H 1-980 H H H Me 2 -C≡C- (CH₂)_Four-[3- (2-Et-PrS) -Ph] H H 1-981 H H H Me 2 -C≡C- (CH₂)_Four-[4- (2-Et-PrS) -Ph] H H 1-982 H H H Me 2 -C≡C- (CH₂)_Four-(3-iBuS-Ph) H H 1-983 H H H Me 2 -C≡C- (CH₂)_Four-(4-iBuS-Ph) H H 1-984 H H H Me 2 -C≡C- (CH₂)_Four-(3-cHx-Ph) H H 1-985 H H H Me 2 -C≡C- (CH₂)_Four-(4-cHx-Ph) H H 1-986 H H H Me 2 -C≡C- (CH₂)_Four-(3-Ph-Ph) H H 1-987 H H H Me 2 -C≡C- (CH₂)_Four-(4-Ph-Ph) H H 1-988 H H H Me 2 -C≡C- (CH₂)_Four-(2,4-diMe-Ph) H H 1-989 H H H Me 2 -C≡C- (CH₂)_Four-(3,4-diMe-Ph) H H 1-990 H H H Me 2 -C≡C- (CH₂)_Four-(3,5-diMe-Ph) H H 1-991 H H H Me 2 -C≡C- (CH₂)_Four-Np (1) H H 1-992 H H H Me 2 -C≡C- (CH₂)_Four-Np (2) H H 1-993 H H H Me 2 -C≡C- (CH₂)_Five-cHx H H 1-994 H H Me Me 2 -C≡C- (CH₂)_Five-cHx H H 1-995 Me H H Me 2 -C≡C- (CH₂)_Five-cHx H H 1-996 CO₂Me H H Me 2 -C≡C- (CH₂)_Five-cHx H H 1-997 H H H Me 2 -C≡C- (CH₂)_Five-(4-F-cHx) H H 1-998 H H H Me 2 -C≡C- (CH₂)_Five-(4-Me-cHx) H H 1-999 H H H Me 2 -C≡C- (CH₂)_Five-(4-Et-cHx) H H 1-1000 H H H Me 2 -C≡C- (CH₂)_Five-(4-CF₃-cHx) H H 1-1001 H H H Me 2 -C≡C- (CH₂)_Five-(4-MeO-cHx) H H 1-1002 H H H Me 2 -C≡C- (CH₂)_Five-(4-EtO-cHx) H H 1-1003 H H H Me 2 -C≡C- (CH₂)_Five-(4-MeS-cHx) H H 1-1004 H H H Me 2 -C≡C- (CH₂)_Five-(4-cHx-cHx) H H 1-1005 H H H Me 2 -C≡C- (CH₂)_Five-(4-Ph-cHx) H H 1-1006 H H H Me 2 -C≡C- (CH₂)_Five-Ph H H 1-1007 H H Me Me 2 -C≡C- (CH₂)_Five-Ph H H 1-1008 Me H H Me 2 -C≡C- (CH₂)_Five-Ph H H 1-1009 CO₂Me H H Me 2 -C≡C- (CH₂)_Five-Ph H H 1-1010 H H H Me 2 -C≡C- (CH₂)_Five-(4-F-Ph) H H 1-1011 H H H Me 2 -C≡C- (CH₂)_Five-(4-Me-Ph) H H 1-1012 H H H Me 2 -C≡C- (CH₂)_Five-(4-Et-Ph) H H 1-1013 H H H Me 2 -C≡C- (CH₂)_Five-(4-CF₃-Ph) H H 1-1014 H H H Me 2 -C≡C- (CH₂)_Five-(4-MeO-Ph) H H 1-1015 H H H Me 2 -C≡C- (CH₂)_Five-(4-EtO-Ph) H H 1-1016 H H H Me 2 -C≡C- (CH₂)_Five-(4-MeS-Ph) H H 1-1017 H H H Me 2 -C≡C- (CH₂)_Five-(4-cHx-Ph) H H 1-1018 H H H Me 2 -C≡C- (CH₂)_Five-(4-Ph-Ph) H H 1-1019 H H H Me 2 -C≡C- (CH₂)₆-cHx H H 1-1020 H H Me Me 2 -C≡C- (CH₂)₆-cHx H H 1-1021 Me H H Me 2 -C≡C- (CH₂)₆-cHx H H 1-1022 CO₂Me H H Me 2 -C≡C- (CH₂)₆-cHx H H 1-1023 H H H Me 2 -C≡C- (CH₂)₆-(4-F-cHx) H H 1-1024 H H H Me 2 -C≡C- (CH₂)₆-(4-Me-cHx) H H 1-1025 H H H Me 2 -C≡C- (CH₂)₆-(4-Et-cHx) H H 1-1026 H H H Me 2 -C≡C- (CH₂)₆-(4-CF₃-cHx) H H 1-1027 H H H Me 2 -C≡C- (CH₂)₆-(4-MeO-cHx) H H 1-1028 H H H Me 2 -C≡C- (CH₂)₆-(4-EtO-cHx) H H 1-1029 H H H Me 2 -C≡C- (CH₂)₆-(4-MeS-cHx) H H 1-1030 H H H Me 2 -C≡C- (CH₂)₆-(4-cHx-cHx) H H 1-1031 H H H Me 2 -C≡C- (CH₂)₆-(4-Ph-cHx) H H 1-1032 H H H Me 2 -C≡C- (CH₂)₆-Ph H H 1-1033 H H Me Me 2 -C≡C- (CH₂)₆-Ph H H 1-1034 Me H H Me 2 -C≡C- (CH₂)₆-Ph H H 1-1035 CO₂Me H H Me 2 -C≡C- (CH₂)₆-Ph H H 1-1036 H H H Me 2 -C≡C- (CH₂)₆-(4-F-Ph) H H 1-1037 H H H Me 2 -C≡C- (CH₂)₆-(4-Me-Ph) H H 1-1038 H H H Me 2 -C≡C- (CH₂)₆-(4-Et-Ph) H H 1-1039 H H H Me 2 -C≡C- (CH₂)₆-(4-CF₃-Ph) H H 1-1040 H H H Me 2 -C≡C- (CH₂)₆-(4-MeO-Ph) H H 1-1041 H H H Me 2 -C≡C- (CH₂)₆-(4-EtO-Ph) H H 1-1042 H H H Me 2 -C≡C- (CH₂)₆-(4-MeS-Ph) H H 1-1043 H H H Me 2 -C≡C- (CH₂)₆-(4-cHx-Ph) H H 1-1044 H H H Me 2 -C≡C- (CH₂)₆-(4-Ph-Ph) H H 1-1045 H H H Me 2 -C≡C-CH₂-O-cHx H H 1-1046 H H Me Me 2 -C≡C-CH₂-O-cHx H H 1-1047 Me H H Me 2 -C≡C-CH₂-O-cHx H H 1-1048 CO₂Me H H Me 2 -C≡C-CH₂-O-cHx H H 1-1049 H H H Me 2 -C≡C-CH₂-O- (4-F-cHx) H H 1-1050 H H H Me 2 -C≡C-CH₂-O- (4-Me-cHx) H H 1-1051 H H H Me 2 -C≡C-CH₂-O- (4-Et-cHx) H H 1-1052 H H H Me 2 -C≡C-CH₂-O- (4-CF₃-cHx) H H 1-1053 H H H Me 2 -C≡C-CH₂-O- (4-MeO-cHx) H H 1-1054 H H H Me 2 -C≡C-CH₂-O- (4-EtO-cHx) H H 1-1055 H H H Me 2 -C≡C-CH₂-O- (4-MeS-cHx) H H 1-1056 H H H Me 2 -C≡C-CH₂-O- (4-cHx-cHx) H H 1-1057 H H H Me 2 -C≡C-CH₂-O- (4-Ph-cHx) H H 1-1058 H H H Me 2 -C≡C-CH₂-O-Ph H H 1-1059 H H Me Me 2 -C≡C-CH₂-O-Ph H H 1-1060 Me H H Me 2 -C≡C-CH₂-O-Ph H H 1-1061 CO₂Me H H Me 2 -C≡C-CH₂-O-Ph H H 1-1062 H H H Me 2 -C≡C-CH₂-O- (4-F-Ph) H H 1-1063 H H H Me 2 -C≡C-CH₂-O- (4-Me-Ph) H H 1-1064 H H H Me 2 -C≡C-CH₂-O- (4-Et-Ph) H H 1-1065 H H H Me 2 -C≡C-CH₂-O- (4-CF₃-Ph) H H 1-1066 H H H Me 2 -C≡C-CH₂-O- (4-MeO-Ph) H H 1-1067 H H H Me 2 -C≡C-CH₂-O- (4-EtO-Ph) H H 1-1068 H H H Me 2 -C≡C-CH₂-O- (4-MeS-Ph) H H 1-1069 H H H Me 2 -C≡C-CH₂-O- (4-cHx-Ph) H H 1-1070 H H H Me 2 -C≡C-CH₂-O- (4-Ph-Ph) H H 1-1071 H H H Me 2 -C≡C- (CH₂)₂O-cPn H H 1-1072 H H H Me 2 -C≡C- (CH₂)₂O-cHx H H 1-1073 H H H Me 2 -C≡C- (CH₂)₂O-cHx Me H 1-1074 H H H Me 2 -C≡C- (CH₂)₂O-cHx H Me 1-1075 H H H Me 2 -C≡C- (CH₂)₂O-cHx F H 1-1076 H H H Me 2 -C≡C- (CH₂)₂O-cHx H F 1-1077 H H Me Me 2 -C≡C- (CH₂)₂O-cHx H H 1-1078 Me H H Me 2 -C≡C- (CH₂)₂O-cHx H H 1-1079 CO₂Me H H Me 2 -C≡C- (CH₂)₂O-cHx H H 1-1080 H H H Me 2 -C≡C- (CH₂)₂O- (3-F-cHx) H H 1-1081 H H H Me 2 -C≡C- (CH₂)₂O- (4-F-cHx) H H 1-1082 H H H Me 2 -C≡C- (CH₂)₂O- (4-Cl-cHx) H H 1-1083 H H H Me 2 -C≡C- (CH₂)₂O- (4-Br-cHx) H H 1-1084 H H H Me 2 -C≡C- (CH₂)₂O- (3-Me-cHx) H H 1-1085 H H H Me 2 -C≡C- (CH₂)₂O- (4-Me-cHx) H H 1-1086 H H H Me 2 -C≡C- (CH₂)₂O- (3-Et-cHx) H H 1-1087 H H H Me 2 -C≡C- (CH₂)₂O- (4-Et-cHx) H H 1-1088 H H H Me 2 -C≡C- (CH₂)₂O- (3-Pr-cHx) H H 1-1089 H H H Me 2 -C≡C- (CH₂)₂O- (4-Pr-cHx) H H 1-1090 H H H Me 2 -C≡C- (CH₂)₂O- (4-iPr-cHx) H H 1-1091 H H H Me 2 -C≡C- (CH₂)₂O- (3-Bu-cHx) H H 1-1092 H H H Me 2 -C≡C- (CH₂)₂O- (4-Bu-cHx) H H 1-1093 H H H Me 2 -C≡C- (CH₂)₂O- (3-CF₃-cHx) H H 1-1094 H H H Me 2 -C≡C- (CH₂)₂O- (4-CF₃-cHx) H H 1-1095 H H H Me 2 -C≡C- (CH₂)₂O- (3-MeO-cHx) H H 1-1096 H H H Me 2 -C≡C- (CH₂)₂O- (4-MeO-cHx) H H 1-1097 H H H Me 2 -C≡C- (CH₂)₂O- (3-EtO-cHx) H H 1-1098 H H H Me 2 -C≡C- (CH₂)₂O- (4-EtO-cHx) H H 1-1099 H H H Me 2 -C≡C- (CH₂)₂O- (3-PrO-cHx) H H 1-1100 H H H Me 2 -C≡C- (CH₂)₂O- (4-PrO-cHx) H H 1-1101 H H H Me 2 -C≡C- (CH₂)₂O- (3-iPrO-cHx) H H 1-1102 H H H Me 2 -C≡C- (CH₂)₂O- (4-iPrO-cHx) H H 1-1103 H H H Me 2 -C≡C- (CH₂)₂O- [3- (2-Et-PrO) -cHx] H H 1-1104 H H H Me 2 -C≡C- (CH₂)₂O- [4- (2-Et-PrO) -cHx] H H 1-1105 H H H Me 2 -C≡C- (CH₂)₂O- (3-iBuO-cHx) H H 1-1106 H H H Me 2 -C≡C- (CH₂)₂O- (4-iBuO-cHx) H H 1-1107 H H H Me 2 -C≡C- (CH₂)₂O- (3-MeS-cHx) H H 1-1108 H H H Me 2 -C≡C- (CH₂)₂O- (4-MeS-cHx) H H 1-1109 H H H Me 2 -C≡C- (CH₂)₂O- (3-EtS-cHx) H H 1-1110 H H H Me 2 -C≡C- (CH₂)₂O- (4-EtS-cHx) H H 1-1111 H H H Me 2 -C≡C- (CH₂)₂O- (3-PrS-cHx) H H 1-1112 H H H Me 2 -C≡C- (CH₂)₂O- (4-PrS-cHx) H H 1-1113 H H H Me 2 -C≡C- (CH₂)₂O- (3-iPrS-cHx) H H 1-1114 H H H Me 2 -C≡C- (CH₂)₂O- (4-iPrS-cHx) H H 1-1115 H H H Me 2 -C≡C- (CH₂)₂O- [3- (2-Et-PrS) -cHx] H H 1-1116 H H H Me 2 -C≡C- (CH₂)₂O- [4- (2-Et-PrS) -cHx] H H 1-1117 H H H Me 2 -C≡C- (CH₂)₂O- (3-iBuS-cHx) H H 1-1118 H H H Me 2 -C≡C- (CH₂)₂O- (4-iBuS-cHx) H H 1-1119 H H H Me 2 -C≡C- (CH₂)₂O- (3-cHx-cHx) H H 1-1120 H H H Me 2 -C≡C- (CH₂)₂O- (4-cHx-cHx) H H 1-1121 H H H Me 2 -C≡C- (CH₂)₂O- (3-Ph-cHx) H H 1-1122 H H H Me 2 -C≡C- (CH₂)₂O- (4-Ph-cHx) H H 1-1123 H H H Me 2 -C≡C- (CH₂)₂O- (2,4-diMe-cHx) H H 1-1124 H H H Me 2 -C≡C- (CH₂)₂O- (3,4-diMe-cHx) H H 1-1125 H H H Me 2 -C≡C- (CH₂)₂O- (3,5-diMe-cHx) H H 1-1126 H H H Me 2 -C≡C- (CH₂)₂O-Ph H H 1-1127 H H H Me 2 -C≡C- (CH₂)₂O-Ph Me H 1-1128 H H H Me 2 -C≡C- (CH₂)₂O-Ph H Me 1-1129 H H H Me 2 -C≡C- (CH₂)₂O-Ph F H 1-1130 H H H Me 2 -C≡C- (CH₂)₂O-Ph H F 1-1131 H H Me Me 2 -C≡C- (CH₂)₂O-Ph H H 1-1132 Me H H Me 2 -C≡C- (CH₂)₂O-Ph H H 1-1133 CO₂Me H H Me 2 -C≡C- (CH₂)₂O-Ph H H 1-1134 H H H Me 2 -C≡C- (CH₂)₂O- (3-F-Ph) H H 1-1135 H H H Me 2 -C≡C- (CH₂)₂O- (4-F-Ph) H H 1-1136 H H H Me 2 -C≡C- (CH₂)₂O- (4-Cl-Ph) H H 1-1137 H H H Me 2 -C≡C- (CH₂)₂O- (4-Br-Ph) H H 1-1138 H H H Me 2 -C≡C- (CH₂)₂O- (3-Me-Ph) H H 1-1139 H H H Me 2 -C≡C- (CH₂)₂O- (4-Me-Ph) H H 1-1140 H H H Me 2 -C≡C- (CH₂)₂O- (3-Et-Ph) H H 1-1141 H H H Me 2 -C≡C- (CH₂)₂O- (4-Et-Ph) H H 1-1142 H H H Me 2 -C≡C- (CH₂)₂O- (3-Pr-Ph) H H 1-1143 H H H Me 2 -C≡C- (CH₂)₂O- (4-Pr-Ph) H H 1-1144 H H H Me 2 -C≡C- (CH₂)₂O- (3-iPr-Ph) H H 1-1145 H H H Me 2 -C≡C- (CH₂)₂O- (4-iPr-Ph) H H 1-1146 H H H Me 2 -C≡C- (CH₂)₂O- (3-Bu-Ph) H H 1-1147 H H H Me 2 -C≡C- (CH₂)₂O- (4-Bu-Ph) H H 1-1148 H H H Me 2 -C≡C- (CH₂)₂O- (3-CF₃-Ph) H H 1-1149 H H H Me 2 -C≡C- (CH₂)₂O- (4-CF₃-Ph) H H 1-1150 H H H Me 2 -C≡C- (CH₂)₂O- (3-MeO-Ph) H H 1-1151 H H H Me 2 -C≡C- (CH₂)₂O- (4-MeO-Ph) H H 1-1152 H H H Me 2 -C≡C- (CH₂)₂O- (3-EtO-Ph) H H 1-1153 H H H Me 2 -C≡C- (CH₂)₂O- (4-EtO-Ph) H H 1-1154 H H H Me 2 -C≡C- (CH₂)₂O- (3-PrO-Ph) H H 1-1155 H H H Me 2 -C≡C- (CH₂)₂O- (4-PrO-Ph) H H 1-1156 H H H Me 2 -C≡C- (CH₂)₂O- (3-iPrO-Ph) H H 1-1157 H H H Me 2 -C≡C- (CH₂)₂O- (4-iPrO-Ph) H H 1-1158 H H H Me 2 -C≡C- (CH₂)₂O- [3- (2-Et-PrO) -Ph] H H 1-1159 H H H Me 2 -C≡C- (CH₂)₂O- [4- (2-Et-PrO) -Ph] H H 1-1160 H H H Me 2 -C≡C- (CH₂)₂O- (3-iBuO-Ph) H H 1-1161 H H H Me 2 -C≡C- (CH₂)₂O- (4-iBuO-Ph) H H 1-1162 H H H Me 2 -C≡C- (CH₂)₂O- (3-MeS-Ph) H H 1-1163 H H H Me 2 -C≡C- (CH₂)₂O- (4-MeS-Ph) H H 1-1164 H H H Me 2 -C≡C- (CH₂)₂O- (3-EtS-Ph) H H 1-1165 H H H Me 2 -C≡C- (CH₂)₂O- (4-EtS-Ph) H H 1-1166 H H H Me 2 -C≡C- (CH₂)₂O- (3-PrS-Ph) H H 1-1167 H H H Me 2 -C≡C- (CH₂)₂O- (4-PrS-Ph) H H 1-1168 H H H Me 2 -C≡C- (CH₂)₂O- (3-iPrS-Ph) H H 1-1169 H H H Me 2 -C≡C- (CH₂)₂O- (4-iPrS-Ph) H H 1-1170 H H H Me 2 -C≡C- (CH₂)₂O- [3- (2-Et-PrS) -Ph] H H 1-1171 H H H Me 2 -C≡C- (CH₂)₂O- [4- (2-Et-PrS) -Ph] H H 1-1172 H H H Me 2 -C≡C- (CH₂)₂O- (3-iBuS-Ph) H H 1-1173 H H H Me 2 -C≡C- (CH₂)₂O- (4-iBuS-Ph) H H 1-1174 H H H Me 2 -C≡C- (CH₂)₂O- (3-cHx-Ph) H H 1-1175 H H H Me 2 -C≡C- (CH₂)₂O- (4-cHx-Ph) H H 1-1176 H H H Me 2 -C≡C- (CH₂)₂O- (3-Ph-Ph) H H 1-1177 H H H Me 2 -C≡C- (CH₂)₂O- (4-Ph-Ph) H H 1-1178 H H H Me 2 -C≡C- (CH₂)₂O- (2,4-diMe-Ph) H H 1-1179 H H H Me 2 -C≡C- (CH₂)₂O- (3,4-diMe-Ph) H H 1-1180 H H H Me 2 -C≡C- (CH₂)₂O- (3,5-diMe-Ph) H H 1-1181 H H H Me 2 -C≡C- (CH₂)₃O-cHx H H 1-1182 H H H Me 2 -C≡C- (CH₂)₃O-Ph H H 1-1183 H H H Me 2 -C≡C- (CH₂)_FourO-cHx H H 1-1184 H H H Me 2 -C≡C- (CH₂)_FourO-Ph H H 1-1185 H H H Me 2 -C≡C-CH₂-OCH₂-cHx H H 1-1186 H H Me Me 2 -C≡C-CH₂-OCH₂-cHx H H 1-1187 Me H H Me 2 -C≡C-CH₂-OCH₂-cHx H H 1-1188 CO₂Me H H Me 2 -C≡C-CH₂-OCH₂-cHx H H 1-1189 H H H Me 2 -C≡C-CH₂-OCH₂-(4-F-cHx) H H 1-1190 H H H Me 2 -C≡C-CH₂-OCH₂-(4-Me-cHx) H H 1-1191 H H H Me 2 -C≡C-CH₂-OCH₂-(4-Et-cHx) H H 1-1192 H H H Me 2 -C≡C-CH₂-OCH₂-(4-CF₃-cHx) H H 1-1193 H H H Me 2 -C≡C-CH₂-OCH₂-(4-MeO-cHx) H H 1-1194 H H H Me 2 -C≡C-CH₂-OCH₂-(4-EtO-cHx) H H 1-1195 H H H Me 2 -C≡C-CH₂-OCH₂-(4-MeS-cHx) H H 1-1196 H H H Me 2 -C≡C-CH₂-OCH₂-(4-cHx-cHx) H H 1-1197 H H H Me 2 -C≡C-CH₂-OCH₂-(4-Ph-cHx) H H 1-1198 H H H Me 2 -C≡C-CH₂-OCH₂-Ph H H 1-1199 H H Me Me 2 -C≡C-CH₂-OCH₂-Ph H H 1-1200 Me H H Me 2 -C≡C-CH₂-OCH₂-Ph H H 1-1201 CO₂Me H H Me 2 -C≡C-CH₂-OCH₂-Ph H H 1-1202 H H H Me 2 -C≡C-CH₂-OCH₂-(4-F-Ph) H H 1-1203 H H H Me 2 -C≡C-CH₂-OCH₂-(4-Me-Ph) H H 1-1204 H H H Me 2 -C≡C-CH₂-OCH₂-(4-Et-Ph) H H 1-1205 H H H Me 2 -C≡C-CH₂-OCH₂-(4-CF₃-Ph) H H 1-1206 H H H Me 2 -C≡C-CH₂-OCH₂-(4-MeO-Ph) H H 1-1207 H H H Me 2 -C≡C-CH₂-OCH₂-(4-EtO-Ph) H H 1-1208 H H H Me 2 -C≡C-CH₂-OCH₂-(4-MeS-Ph) H H 1-1209 H H H Me 2 -C≡C-CH₂-OCH₂-(4-cHx-Ph) H H 1-1210 H H H Me 2 -C≡C-CH₂-OCH₂-(4-Ph-Ph) H H 1-1211 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-cPn H H 1-1212 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-cHx H H 1-1213 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-cHx Me H 1-1214 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-cHx H Me 1-1215 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-cHx F H 1-1216 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-cHx HF 1-1217 H H Me Me 2 -C≡C- (CH₂)₂-OCH₂-CH₂-cHx H H 1-1218 Me H H Me 2 -C≡C- (CH₂)₂-OCH₂-cHx H H 1-1219 CO₂Me H H Me 2 -C≡C- (CH₂)₂-OCH₂-cHx H H 1-1220 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-F-cHx) H H 1-1221 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-F-cHx) H H 1-1222 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Cl-cHx) H H 1-1223 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Br-cHx) H H 1-1224 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-Me-cHx) H H 1-1225 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Me-cHx) H H 1-1226 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-Et-cHx) H H 1-1227 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Et-cHx) H H 1-1228 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-Pr-cHx) H H 1-1229 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Pr-cHx) H H 1-1230 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-iPr-cHx) H H 1-1231 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-Bu-cHx) H H 1-1232 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Bu-cHx) H H 1-1233 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-CF₃-cHx) H H 1-1234 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-CF₃-cHx) H H 1-1235 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-MeO-cHx) H H 1-1236 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-MeO-cHx) H H 1-1237 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-EtO-cHx) H H 1-1238 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-EtO-cHx) H H 1-1239 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-PrO-cHx) H H 1-1240 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-PrO-cHx) H H 1-1241 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-iPrO-cHx) H H 1-1242 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-iPrO-cHx) H H 1-1243 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-[3- (2-Et-PrO) cHx] H H 1-1244 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-[4- (2-Et-PrO) cHx] H H 1-1245 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-iBuO-cHx) H H 1-1246 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-iBuO-cHx) H H 1-1247 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-MeS-cHx) H H 1-1248 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-MeS-cHx) H H 1-1249 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-EtS-cHx) H H 1-1250 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-EtS-cHx) H H 1-1251 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-PrS-cHx) H H 1-1252 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-PrS-cHx) H H 1-1253 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-iPrS-cHx) H H 1-1254 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-iPrS-cHx) H H 1-1255 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-[3- (2-Et-PrS) cHx] H H 1-1256 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-[4- (2-Et-PrS) cHx] H H 1-1257 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-iBuS-cHx) H H 1-1258 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-iBuS-cHx) H H 1-1259 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-cHx-cHx) H H 1-1260 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-cHx-cHx) H H 1-1261 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-Ph-cHx) H H 1-1262 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Ph-cHx) H H 1-1263 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(2,4-diMe-cHx) H H 1-1264 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3,4-diMe-cHx) H H 1-1265 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3,5-diMe-cHx) H H 1-1266 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-Ph H H 1-1267 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-Ph Me H 1-1268 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-Ph H Me 1-1269 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-Ph F H 1-1270 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-Ph H F 1-1271 H H Me Me 2 -C≡C- (CH₂)₂-OCH₂-CH₂-Ph H H 1-1272 Me H H Me 2 -C≡C- (CH₂)₂-OCH₂-Ph H H 1-1273 CO₂Me H H Me 2 -C≡C- (CH₂)₂-OCH₂-Ph H H 1-1274 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-F-Ph) H H 1-1275 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-F-Ph) H H 1-1276 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Cl-Ph) H H 1-1277 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Br-Ph) H H 1-1278 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-Me-Ph) H H 1-1279 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Me-Ph) H H 1-1280 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-Et-Ph) H H 1-1281 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Et-Ph) H H 1-1282 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-Pr-Ph) H H 1-1283 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Pr-Ph) H H 1-1284 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-iPr-Ph) H H 1-1285 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-iPr-Ph) H H 1-1286 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-Bu-Ph) H H 1-1287 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Bu-Ph) H H 1-1288 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-CF₃-Ph) H H 1-1289 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-CF₃-Ph) H H 1-1290 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-MeO-Ph) H H 1-1291 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-MeO-Ph) H H 1-1292 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-EtO-Ph) H H 1-1293 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-EtO-Ph) H H 1-1294 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-PrO-Ph) H H 1-1295 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-PrO-Ph) H H 1-1296 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-iPrO-Ph) H H 1-1297 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-iPrO-Ph) H H 1-1298 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-[3- (2-Et-PrO) Ph] H H 1-1299 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-[4- (2-Et-PrO) Ph] H H 1-1300 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-iBuO-Ph) H H 1-1301 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-iBuO-Ph) H H 1-1302 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-MeS-Ph) H H 1-1303 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-MeS-Ph) H H 1-1304 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-EtS-Ph) H H 1-1305 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-EtS-Ph) H H 1-1306 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-PrS-Ph) H H 1-1307 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-PrS-Ph) H H 1-1308 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-iPrS-Ph) H H 1-1309 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-iPrS-Ph) H H 1-1310 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-[3- (2-Et-PrS) Ph] H H 1-1311 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-[4- (2-Et-PrS) Ph] H H 1-1312 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-iBuS-Ph) H H 1-1313 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-iBuS-Ph) H H 1-1314 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-cHx-Ph) H H 1-1315 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-cHx-Ph) H H 1-1316 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3-Ph-Ph) H H 1-1317 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(4-Ph-Ph) H H 1-1318 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(2,4-diMe-Ph) H H 1-1319 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3,4-diMe-Ph) H H 1-1320 H H H Me 2 -C≡C- (CH₂)₂-OCH₂-(3,5-diMe-Ph) H H 1-1321 H H H Me 2 -C≡C- (CH₂)₃-OCH₂-cHx H H 1-1322 H H H Me 2 -C≡C- (CH₂)₃-OCH₂-Ph H H 1-1323 H H H Me 2 -C≡C- (CH₂)_Four-OCH₂-cHx H H 1-1324 H H H Me 2 -C≡C- (CH₂)_Four-OCH₂-Ph H H 1-1325 H H H Me 2 -CO-CH₂-(4-cHx-Ph) H H 1-1326 H H H Me 2 -CO-CH₂-(4-Ph-Ph) H H 1-1327 H H H Me 2 -CO- (CH₂)₂-cHx H H 1-1328 H H H Me 2 -CO- (CH₂)₂-Ph H H 1-1329 H H H Me 2 -CO- (CH₂)₃-cHx H H 1-1330 H H H Me 2 -CO- (CH₂)₃-Ph H H 1-1331 H H H Me 2 -CO- (CH₂)_Four-cHx H H 1-1332 H H Me Me 2 -CO- (CH₂)_Four-cHx H H 1-1333 Me H H Me 2 -CO- (CH₂)_Four-cHx H H 1-1334 CO₂Me H H Me 2 -CO- (CH₂)_Four-cHx H H 1-1335 H H H Me 2 -CO- (CH₂)_Four-(4-F-cHx) H H 1-1336 H H H Me 2 -CO- (CH₂)_Four-(4-Me-cHx) H H 1-1337 H H H Me 2 -CO- (CH₂)_Four-(4-Et-cHx) H H 1-1338 H H H Me 2 -CO- (CH₂)_Four-(4-CF₃-cHx) H H 1-1339 H H H Me 2 -CO- (CH₂)_Four-(4-MeO-cHx) H H 1-1340 H H H Me 2 -CO- (CH₂)_Four-(4-EtO-cHx) H H 1-1341 H H H Me 2 -CO- (CH₂)_Four-(4-MeS-cHx) H H 1-1342 H H H Me 2 -CO- (CH₂)_Four-(4-cHx-cHx) H H 1-1343 H H H Me 2 -CO- (CH₂)_Four-(4-Ph-cHx) H H 1-1344 H H H Me 2 -CO- (CH₂)_Four-Ph H H 1-1345 H H Me Me 2 -CO- (CH₂)_Four-Ph H H 1-1346 Me H H Me 2 -CO- (CH₂)_Four-Ph H H 1-1347 CO₂Me H H Me 2 -CO- (CH₂)_Four-Ph H H 1-1348 H H H Me 2 -CO- (CH₂)_Four-(4-F-Ph) H H 1-1349 H H H Me 2 -CO- (CH₂)_Four-(4-Me-Ph) H H 1-1350 H H H Me 2 -CO- (CH₂)_Four-(4-Et-Ph) H H 1-1351 H H H Me 2 -CO- (CH₂)_Four-(4-CF₃-Ph) H H 1-1352 H H H Me 2 -CO- (CH₂)_Four-(4-MeO-Ph) H H 1-1353 H H H Me 2 -CO- (CH₂)_Four-(4-EtO-Ph) H H 1-1354 H H H Me 2 -CO- (CH₂)_Four-(4-MeS-Ph) H H 1-1355 H H H Me 2 -CO- (CH₂)_Four-(4-cHx-Ph) H H 1-1356 H H H Me 2 -CO- (CH₂)_Four-(4-Ph-Ph) H H 1-1357 H H H Me 2 -CO- (CH₂)_Five-cHx H H 1-1358 H H Me Me 2 -CO- (CH₂)_Five-cHx H H 1-1359 Me H H Me 2 -CO- (CH₂)_Five-cHx H H 1-1360 CO₂Me H H Me 2 -CO- (CH₂)_Five-cHx H H 1-1361 H H H Me 2 -CO- (CH₂)_Five-(4-F-cHx) H H 1-1362 H H H Me 2 -CO- (CH₂)_Five-(4-Me-cHx) H H 1-1363 H H H Me 2 -CO- (CH₂)_Five-(4-Et-cHx) H H 1-1364 H H H Me 2 -CO- (CH₂)_Five-(4-CF₃-cHx) H H 1-1365 H H H Me 2 -CO- (CH₂)_Five-(4-MeO-cHx) H H 1-1366 H H H Me 2 -CO- (CH₂)_Five-(4-EtO-cHx) H H 1-1367 H H H Me 2 -CO- (CH₂)_Five-(4-MeS-cHx) H H 1-1368 H H H Me 2 -CO- (CH₂)_Five-(4-cHx-cHx) H H 1-1369 H H H Me 2 -CO- (CH₂)_Five-(4-Ph-cHx) H H 1-1370 H H H Me 2 -CO- (CH₂)_Five-Ph H H 1-1371 H H Me Me 2 -CO- (CH₂)_Five-Ph H H 1-1372 Me H H Me 2 -CO- (CH₂)_Five-Ph H H 1-1373 CO₂Me H H Me 2 -CO- (CH₂)_Five-Ph H H 1-1374 H H H Me 2 -CO- (CH₂)_Five-(4-F-Ph) H H 1-1375 H H H Me 2 -CO- (CH₂)_Five-(4-Me-Ph) H H 1-1376 H H H Me 2 -CO- (CH₂)_Five-(4-Et-Ph) H H 1-1377 H H H Me 2 -CO- (CH₂)_Five-(4-CF₃-Ph) H H 1-1378 H H H Me 2 -CO- (CH₂)_Five-(4-MeO-Ph) H H 1-1379 H H H Me 2 -CO- (CH₂)_Five-(4-EtO-Ph) H H 1-1380 H H H Me 2 -CO- (CH₂)_Five-(4-MeS-Ph) H H 1-1381 H H H Me 2 -CO- (CH₂)_Five-(4-cHx-Ph) H H 1-1382 H H H Me 2 -CO- (CH₂)_Five-(4-Ph-Ph) H H 1-1383 H H H Me 2 -CO- (CH₂)₆-cHx H H 1-1384 H H H Me 2 -CO- (CH₂)₆-Ph H H 1-1385 H H H Me 2 -CO- (CH₂)₇-cHx H H 1-1386 H H H Me 2 -CO- (CH₂)₇-Ph H H 1-1387 H H H Me 2 -CO- (CH₂)₂-O-cHx H H 1-1388 H H Me Me 2 -CO- (CH₂)₂-O-cHx H H 1-1389 Me H H Me 2 -CO- (CH₂)₂-O-cHx H H 1-1390 CO₂Me H H Me 2 -CO- (CH₂)₂-O-cHx H H 1-1391 H H H Me 2 -CO- (CH₂)₂-O- (4-F-cHx) H H 1-1392 H H H Me 2 -CO- (CH₂)₂-O- (4-Me-cHx) H H 1-1393 H H H Me 2 -CO- (CH₂)₂-O- (4-Et-cHx) H H 1-1394 H H H Me 2 -CO- (CH₂)₂-O- (4-CF₃-cHx) H H 1-1395 H H H Me 2 -CO- (CH₂)₂-O- (4-MeO-cHx) H H 1-1396 H H H Me 2 -CO- (CH₂)₂-O- (4-EtO-cHx) H H 1-1397 H H H Me 2 -CO- (CH₂)₂-O- (4-MeS-cHx) H H 1-1398 H H H Me 2 -CO- (CH₂)₂-O- (4-cHx-cHx) H H 1-1399 H H H Me 2 -CO- (CH₂)₂-O- (4-Ph-cHx) H H 1-1400 H H H Me 2 -CO- (CH₂)₂-O-Ph H H 1-1401 H H Me Me 2 -CO- (CH₂)₂-O-Ph H H 1-1402 Me H H Me 2 -CO- (CH₂)₂-O-Ph H H 1-1403 CO₂Me H H Me 2 -CO- (CH₂)₂-O-Ph H H 1-1404 H H H Me 2 -CO- (CH₂)₂-O- (4-F-Ph) H H 1-1405 H H H Me 2 -CO- (CH₂)₂-O- (4-Me-Ph) H H 1-1406 H H H Me 2 -CO- (CH₂)₂-O- (4-Et-Ph) H H 1-1407 H H H Me 2 -CO- (CH₂)₂-O- (4-CF₃-Ph) H H 1-1408 H H H Me 2 -CO- (CH₂)₂-O- (4-MeO-Ph) H H 1-1409 H H H Me 2 -CO- (CH₂)₂-O- (4-EtO-Ph) H H 1-1410 H H H Me 2 -CO- (CH₂)₂-O- (4-MeS-Ph) H H 1-1411 H H H Me 2 -CO- (CH₂)₂-O- (4-cHx-Ph) H H 1-1412 H H H Me 2 -CO- (CH₂)₂-O- (4-Ph-Ph) H H 1-1413 H H H Me 2 -CO- (CH₂)₃-O-cPn H H 1-1414 H H H Me 2 -CO- (CH₂)₃-O-cHx H H 1-1415 H H H Me 2 -CO- (CH₂)₃-O-cHx Me H 1-1416 H H H Me 2 -CO- (CH₂)₃-O-cHx H Me 1-1417 H H H Me 2 -CO- (CH₂)₃-O-cHx F H 1-1418 H H H Me 2 -CO- (CH₂)₃-O-cHx HF 1-1419 H H Me Me 2 -CO- (CH₂)₃-O-cHx H H 1-1420 Me H H Me 2 -CO- (CH₂)₃-O-cHx H H 1-1421 CO₂Me H H Me 2 -CO- (CH₂)₃-O-cHx H H 1-1422 H H H Me 2 -CO- (CH₂)₃-O- (3-F-cHx) H H 1-1423 H H H Me 2 -CO- (CH₂)₃-O- (4-F-cHx) H H 1-1424 H H H Me 2 -CO- (CH₂)₃-O- (4-Cl-cHx) H H 1-1425 H H H Me 2 -CO- (CH₂)₃-O- (4-Br-cHx) H H 1-1426 H H H Me 2 -CO- (CH₂)₃-O- (3-Me-cHx) H H 1-1427 H H H Me 2 -CO- (CH₂)₃-O- (4-Me-cHx) H H 1-1428 H H H Me 2 -CO- (CH₂)₃-O- (3-Et-cHx) H H 1-1429 H H H Me 2 -CO- (CH₂)₃-O- (4-Et-cHx) H H 1-1430 H H H Me 2 -CO- (CH₂)₃-O- (3-Pr-cHx) H H 1-1431 H H H Me 2 -CO- (CH₂)₃-O- (4-Pr-cHx) H H 1-1432 H H H Me 2 -CO- (CH₂)₃-O- (4-iPr-cHx) H H 1-1433 H H H Me 2 -CO- (CH₂)₃-O- (3-Bu-cHx) H H 1-1434 H H H Me 2 -CO- (CH₂)₃-O- (4-Bu-cHx) H H 1-1435 H H H Me 2 -CO- (CH₂)₃-O- (3-CF₃-cHx) H H 1-1436 H H H Me 2 -CO- (CH₂)₃-O- (4-CF₃-cHx) H H 1-1437 H H H Me 2 -CO- (CH₂)₃-O- (3-MeO-cHx) H H 1-1438 H H H Me 2 -CO- (CH₂)₃-O- (4-MeO-cHx) H H 1-1439 H H H Me 2 -CO- (CH₂)₃-O- (3-EtO-cHx) H H 1-1440 H H H Me 2 -CO- (CH₂)₃-O- (4-EtO-cHx) H H 1-1441 H H H Me 2 -CO- (CH₂)₃-O- (3-PrO-cHx) H H 1-1442 H H H Me 2 -CO- (CH₂)₃-O- (4-PrO-cHx) H H 1-1443 H H H Me 2 -CO- (CH₂)₃-O- (3-iPrO-cHx) H H 1-1444 H H H Me 2 -CO- (CH₂)₃-O- (4-iPrO-cHx) H H 1-1445 H H H Me 2 -CO- (CH₂)₃-O- [3- (2-Et-PrO) cHx] H H 1-1446 H H H Me 2 -CO- (CH₂)₃-O- [4- (2-Et-PrO) cHx] H H 1-1447 H H H Me 2 -CO- (CH₂)₃-O- (3-iBuO-cHx) H H 1-1448 H H H Me 2 -CO- (CH₂)₃-O- (4-iBuO-cHx) H H 1-1449 H H H Me 2 -CO- (CH₂)₃-O- (3-MeS-cHx) H H 1-1450 H H H Me 2 -CO- (CH₂)₃-O- (4-MeS-cHx) H H 1-1451 H H H Me 2 -CO- (CH₂)₃-O- (3-EtS-cHx) H H 1-1452 H H H Me 2 -CO- (CH₂)₃-O- (4-EtS-cHx) H H 1-1453 H H H Me 2 -CO- (CH₂)₃-O- (3-PrS-cHx) H H 1-1454 H H H Me 2 -CO- (CH₂)₃-O- (4-PrS-cHx) H H 1-1455 H H H Me 2 -CO- (CH₂)₃-O- (3-iPrS-cHx) H H 1-1456 H H H Me 2 -CO- (CH₂)₃-O- (4-iPrS-cHx) H H 1-1457 H H H Me 2 -CO- (CH₂)₃-O- [3- (2-Et-PrS) cHx] H H 1-1458 H H H Me 2 -CO- (CH₂)₃-O- [4- (2-Et-PrS) cHx] H H 1-1459 H H H Me 2 -CO- (CH₂)₃-O- (3-iBuS-cHx) H H 1-1460 H H H Me 2 -CO- (CH₂)₃-O- (4-iBuS-cHx) H H 1-1461 H H H Me 2 -CO- (CH₂)₃-O- (3-cHx-cHx) H H 1-1462 H H H Me 2 -CO- (CH₂)₃-O- (4-cHx-cHx) H H 1-1463 H H H Me 2 -CO- (CH₂)₃-O- (3-Ph-cHx) H H 1-1464 H H H Me 2 -CO- (CH₂)₃-O- (4-Ph-cHx) H H 1-1465 H H H Me 2 -CO- (CH₂)₃-O- (2,4-diMe-cHx) H H 1-1466 H H H Me 2 -CO- (CH₂)₃-O- (3,4-diMe-cHx) H H 1-1467 H H H Me 2 -CO- (CH₂)₃-O- (3,5-diMe-cHx) H H 1-1468 H H H Me 2 -CO- (CH₂)₃-O-Ph H H 1-1469 H H H Me 2 -CO- (CH₂)₃-O-Ph Me H 1-1470 H H H Me 2 -CO- (CH₂)₃-O-Ph H Me 1-1471 H H H Me 2 -CO- (CH₂)₃-O-Ph F H 1-1472 H H H Me 2 -CO- (CH₂)₃-O-Ph H F 1-1473 H H Me Me 2 -CO- (CH₂)₃-O-Ph H H 1-1474 Me H H Me 2 -CO- (CH₂)₃-O-Ph H H 1-1475 CO₂Me H H Me 2 -CO- (CH₂)₃-O-Ph H H 1-1476 H H H Me 2 -CO- (CH₂)₃-O- (3-F-Ph) H H 1-1477 H H H Me 2 -CO- (CH₂)₃-O- (4-F-Ph) H H 1-1478 H H H Me 2 -CO- (CH₂)₃-O- (4-Cl-Ph) H H 1-1479 H H H Me 2 -CO- (CH₂)₃-O- (4-Br-Ph) H H 1-1480 H H H Me 2 -CO- (CH₂)₃-O- (3-Me-Ph) H H 1-1481 H H H Me 2 -CO- (CH₂)₃-O- (4-Me-Ph) H H 1-1482 H H H Me 2 -CO- (CH₂)₃-O- (3-Et-Ph) H H 1-1483 H H H Me 2 -CO- (CH₂)₃-O- (4-Et-Ph) H H 1-1484 H H H Me 2 -CO- (CH₂)₃-O- (3-Pr-Ph) H H 1-1485 H H H Me 2 -CO- (CH₂)₃-O- (4-Pr-Ph) H H 1-1486 H H H Me 2 -CO- (CH₂)₃-O- (3-iPr-Ph) H H 1-1487 H H H Me 2 -CO- (CH₂)₃-O- (4-iPr-Ph) H H 1-1488 H H H Me 2 -CO- (CH₂)₃-O- (3-Bu-Ph) H H 1-1489 H H H Me 2 -CO- (CH₂)₃-O- (4-Bu-Ph) H H 1-1490 H H H Me 2 -CO- (CH₂)₃-O- (3-CF₃-Ph) H H 1-1491 H H H Me 2 -CO- (CH₂)₃-O- (4-CF₃-Ph) H H 1-1492 H H H Me 2 -CO- (CH₂)₃-O- (3-MeO-Ph) H H 1-1493 H H H Me 2 -CO- (CH₂)₃-O- (4-MeO-Ph) H H 1-1494 H H H Me 2 -CO- (CH₂)₃-O- (3-EtO-Ph) H H 1-1495 H H H Me 2 -CO- (CH₂)₃-O- (4-EtO-Ph) H H 1-1496 H H H Me 2 -CO- (CH₂)₃-O- (3-PrO-Ph) H H 1-1497 H H H Me 2 -CO- (CH₂)₃-O- (4-PrO-Ph) H H 1-1498 H H H Me 2 -CO- (CH₂)₃-O- (3-iPrO-Ph) H H 1-1499 H H H Me 2 -CO- (CH₂)₃-O- (4-iPrO-Ph) H H 1-1500 H H H Me 2 -CO- (CH₂)₃-O- [3- (2-Et-PrO) -Ph] H H 1-1501 H H H Me 2 -CO- (CH₂)₃-O- [4- (2-Et-PrO) -Ph] H H 1-1502 H H H Me 2 -CO- (CH₂)₃-O- (3-iBuO-Ph) H H 1-1503 H H H Me 2 -CO- (CH₂)₃-O- (4-iBuO-Ph) H H 1-1504 H H H Me 2 -CO- (CH₂)₃-O- (3-MeS-Ph) H H 1-1505 H H H Me 2 -CO- (CH₂)₃-O- (4-MeS-Ph) H H 1-1506 H H H Me 2 -CO- (CH₂)₃-O- (3-EtS-Ph) H H 1-1507 H H H Me 2 -CO- (CH₂)₃-O- (4-EtS-Ph) H H 1-1508 H H H Me 2 -CO- (CH₂)₃-O- (3-PrS-Ph) H H 1-1509 H H H Me 2 -CO- (CH₂)₃-O- (4-PrS-Ph) H H 1-1510 H H H Me 2 -CO- (CH₂)₃-O- (3-iPrS-Ph) H H 1-1511 H H H Me 2 -CO- (CH₂)₃-O- (4-iPrS-Ph) H H 1-1512 H H H Me 2 -CO- (CH₂)₃-O- [3- (2-Et-PrS) -Ph] H H 1-1513 H H H Me 2 -CO- (CH₂)₃-O- [4- (2-Et-PrS) -Ph] H H 1-1514 H H H Me 2 -CO- (CH₂)₃-O- (3-iBuS-Ph) H H 1-1515 H H H Me 2 -CO- (CH₂)₃-O- (4-iBuS-Ph) H H 1-1516 H H H Me 2 -CO- (CH₂)₃-O- (3-cHx-Ph) H H 1-1517 H H H Me 2 -CO- (CH₂)₃-O- (4-cHx-Ph) H H 1-1518 H H H Me 2 -CO- (CH₂)₃-O- (3-Ph-Ph) H H 1-1519 H H H Me 2 -CO- (CH₂)₃-O- (4-Ph-Ph) H H 1-1520 H H H Me 2 -CO- (CH₂)₃-O- (2,4-diMe-Ph) H H 1-1521 H H H Me 2 -CO- (CH₂)₃-O- (3,4-diMe-Ph) H H 1-1522 H H H Me 2 -CO- (CH₂)₃-O- (3,5-diMe-Ph) H H 1-1523 H H H Me 2 -CO- (CH₂)_Four-O-cHx H H 1-1524 H H H Me 2 -CO- (CH₂)_Four-O-Ph H H 1-1525 H H H Me 2 -CO- (CH₂)_Five-O-cHx H H 1-1526 H H H Me 2 -CO- (CH₂)_Five-O-Ph H H 1-1527 H H H Me 2 -CO- (CH₂)₂-OCH₂-cHx H H 1-1528 H H Me Me 2 -CO- (CH₂)₂-OCH₂-cHx H H 1-1529 Me H H Me 2 -CO- (CH₂)₂-OCH₂-cHx H H 1-1530 CO₂Me H H Me 2 -CO- (CH₂)₂-OCH₂-cHx H H 1-1531 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-F-cHx) H H 1-1532 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-Me-cHx) H H 1-1533 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-Et-cHx) H H 1-1534 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-CF₃-cHx) H H 1-1535 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-MeO-cHx) H H 1-1536 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-EtO-cHx) H H 1-1537 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-MeS-cHx) H H 1-1538 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-cHx-cHx) H H 1-1539 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-Ph-cHx) H H 1-1540 H H H Me 2 -CO- (CH₂)₂-OCH₂-Ph H H 1-1541 H H Me Me 2 -CO- (CH₂)₂-OCH₂-Ph H H 1-1542 Me H H Me 2 -CO- (CH₂)₂-OCH₂-Ph H H 1-1543 CO₂Me H H Me 2 -CO- (CH₂)₂-OCH₂-Ph H H 1-1544 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-F-Ph) H H 1-1545 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-Me-Ph) H H 1-1546 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-Et-Ph) H H 1-1547 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-CF₃-Ph) H H 1-1548 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-MeO-Ph) H H 1-1549 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-EtO-Ph) H H 1-1550 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-MeS-Ph) H H 1-1551 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-cHx-Ph) H H 1-1552 H H H Me 2 -CO- (CH₂)₂-OCH₂-(4-Ph-Ph) H H 1-1553 H H H Me 2 -CO- (CH₂)₃-OCH₂-CH₂-cPn H H 1-1554 H H H Me 2 -CO- (CH₂)₃-OCH₂-cHx H H 1-1555 H H H Me 2 -CO- (CH₂)₃-OCH₂-cHx Me H 1-1556 H H H Me 2 -CO- (CH₂)₃-OCH₂-cHx H Me 1-1557 H H H Me 2 -CO- (CH₂)₃-OCH₂-cHx F H 1-1558 H H H Me 2 -CO- (CH₂)₃-OCH₂-cHx HF 1-1559 H H Me Me 2 -CO- (CH₂)₃-OCH₂-cHx H H 1-1560 Me H H Me 2 -CO- (CH₂)₃-OCH₂-cHx H H 1-1561 CO₂Me H H Me 2 -CO- (CH₂)₃-OCH₂-cHx H H 1-1562 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-F-cHx) H H 1-1563 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-F-cHx) H H 1-1564 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Cl-cHx) H H 1-1565 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Br-cHx) H H 1-1566 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-Me-cHx) H H 1-1567 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Me-cHx) H H 1-1568 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-Et-cHx) H H 1-1569 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Et-cHx) H H 1-1570 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-Pr-cHx) H H 1-1571 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Pr-cHx) H H 1-1572 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-iPr-cHx) H H 1-1573 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-Bu-cHx) H H 1-1574 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Bu-cHx) H H 1-1575 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-CF₃-cHx) H H 1-1576 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-CF₃-cHx) H H 1-1577 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-MeO-cHx) H H 1-1578 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-MeO-cHx) H H 1-1579 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-EtO-cHx) H H 1-1580 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-EtO-cHx) H H 1-1581 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-PrO-cHx) H H 1-1582 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-PrO-cHx) H H 1-1583 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-iPrO-cHx) H H 1-1584 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-iPrO-cHx) H H 1-1585 H H H Me 2 -CO- (CH₂)₃-OCH₂-[3- (2-Et-PrO) cHx] H H 1-1586 H H H Me 2 -CO- (CH₂)₃-OCH₂-[4- (2-Et-PrO) cHx] H H 1-1587 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-iBuO-cHx) H H 1-1588 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-iBuO-cHx) H H 1-1589 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-MeS-cHx) H H 1-1590 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-MeS-cHx) H H 1-1591 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-EtS-cHx) H H 1-1592 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-EtS-cHx) H H 1-1593 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-PrS-cHx) H H 1-1594 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-PrS-cHx) H H 1-1595 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-iPrS-cHx) H H 1-1596 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-iPrS-cHx) H H 1-1597 H H H Me 2 -CO- (CH₂)₃-OCH₂-[3- (2-Et-PrS) cHx] H H 1-1598 H H H Me 2 -CO- (CH₂)₃-OCH₂-[4- (2-Et-PrS) cHx] H H 1-1599 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-iBuS-cHx) H H 1-1600 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-iBuS-cHx) H H 1-1601 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-cHx-cHx) H H 1-1602 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-cHx-cHx) H H 1-1603 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-Ph-cHx) H H 1-1604 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Ph-cHx) H H 1-1605 H H H Me 2 -CO- (CH₂)₃-OCH₂-(2,4-diMe-cHx) H H 1-1606 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3,4-diMe-cHx) H H 1-1607 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3,5-diMe-cHx) H H 1-1608 H H H Me 2 -CO- (CH₂)₃-OCH₂-Ph H H 1-1609 H H H Me 2 -CO- (CH₂)₃-OCH₂-Ph Me H 1-1610 H H H Me 2 -CO- (CH₂)₃-OCH₂-Ph H Me 1-1611 H H H Me 2 -CO- (CH₂)₃-OCH₂-Ph F H 1-1612 H H H Me 2 -CO- (CH₂)₃-OCH₂-Ph H F 1-1613 H H Me Me 2 -CO- (CH₂)₃-OCH₂-Ph H H 1-1614 Me H H Me 2 -CO- (CH₂)₃-OCH₂-Ph H H 1-1615 CO₂Me H H Me 2 -CO- (CH₂)₃-OCH₂-Ph H H 1-1616 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-F-Ph) H H 1-1617 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-F-Ph) H H 1-1618 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Cl-Ph) H H 1-1619 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Br-Ph) H H 1-1620 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-Me-Ph) H H 1-1621 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Me-Ph) H H 1-1622 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-Et-Ph) H H 1-1623 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Et-Ph) H H 1-1624 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-Pr-Ph) H H 1-1625 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Pr-Ph) H H 1-1626 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-iPr-Ph) H H 1-1627 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-iPr-Ph) H H 1-1628 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-Bu-Ph) H H 1-1629 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Bu-Ph) H H 1-1630 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-CF₃-Ph) H H 1-1631 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-CF₃-Ph) H H 1-1632 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-MeO-Ph) H H 1-1633 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-MeO-Ph) H H 1-1634 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-EtO-Ph) H H 1-1635 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-EtO-Ph) H H 1-1636 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-PrO-Ph) H H 1-1637 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-PrO-Ph) H H 1-1638 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-iPrO-Ph) H H 1-1639 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-iPrO-Ph) H H 1-1640 H H H Me 2 -CO- (CH₂)₃-OCH₂-[3- (2-Et-PrO) Ph] H H 1-1641 H H H Me 2 -CO- (CH₂)₃-OCH₂-[4- (2-Et-PrO) Ph] H H 1-1642 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-iBuO-Ph) H H 1-1643 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-iBuO-Ph) H H 1-1644 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-MeS-Ph) H H 1-1645 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-MeS-Ph) H H 1-1646 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-EtS-Ph) H H 1-1647 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-EtS-Ph) H H 1-1648 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-PrS-Ph) H H 1-1649 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-PrS-Ph) H H 1-1650 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-iPrS-Ph) H H 1-1651 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-iPrS-Ph) H H 1-1652 H H H Me 2 -CO- (CH₂)₃-OCH₂-[3- (2-Et-PrS) Ph] H H 1-1653 H H H Me 2 -CO- (CH₂)₃-OCH₂-[4- (2-Et-PrS) Ph] H H 1-1654 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-iBuS-Ph) H H 1-1655 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-iBuS-Ph) H H 1-1656 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-cHx-Ph) H H 1-1657 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-cHx-Ph) H H 1-1658 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3-Ph-Ph) H H 1-1659 H H H Me 2 -CO- (CH₂)₃-OCH₂-(4-Ph-Ph) H H 1-1660 H H H Me 2 -CO- (CH₂)₃-OCH₂-(2,4-diMe-Ph) H H 1-1661 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3,4-diMe-Ph) H H 1-1662 H H H Me 2 -CO- (CH₂)₃-OCH₂-(3,5-diMe-Ph) H H 1-1663 H H H Me 2 -CO- (CH₂)_Four-OCH₂-cHx H H 1-1664 H H H Me 2 -CO- (CH₂)_Four-OCH₂-Ph H H 1-1665 H H H Me 2 -CO- (CH₂)_Five-OCH₂-cHx H H 1-1666 H H H Me 2 -CO- (CH₂)_Five-OCH₂-Ph H H 1-1667 H H H Me 2 -CH (OH) -CH₂-cHx H H 1-1668 H H H Me 2 -CH (OH) -CH₂-Ph H H 1-1669 H H H Me 2 -CH (OH)-(CH₂)₂-cHx H H 1-1670 H H H Me 2 -CH (OH)-(CH₂)₂-Ph H H 1-1671 H H H Me 2 -CH (OH)-(CH₂)₃-cHx H H 1-1672 H H H Me 2 -CH (OH)-(CH₂)₃-Ph H H 1-1673 H H H Me 2 -CH (OH)-(CH₂)_Four-cHx H H 1-1674 H H Me Me 2 -CH (OH)-(CH₂)_Four-cHx H H 1-1675 Me H H Me 2 -CH (OH)-(CH₂)_Four-cHx H H 1-1676 CO₂Me H H Me 2 -CH (OH)-(CH₂)_Four-cHx H H 1-1677 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-F-cHx) H H 1-1678 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-Me-cHx) H H 1-1679 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-Et-cHx) H H 1-1680 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-CF₃-cHx) H H 1-1681 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-MeO-cHx) H H 1-1682 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-EtO-cHx) H H 1-1683 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-MeS-cHx) H H 1-1684 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-cHx-cHx) H H 1-1685 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-Ph-cHx) H H 1-1686 H H H Me 2 -CH (OH)-(CH₂)_Four-Ph H H 1-1687 H H Me Me 2 -CH (OH)-(CH₂)_Four-Ph H H 1-1688 Me H H Me 2 -CH (OH)-(CH₂)_Four-Ph H H 1-1689 CO₂Me H H Me 2 -CH (OH)-(CH₂)_Four-Ph H H 1-1690 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-F-Ph) H H 1-1691 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-Me-Ph) H H 1-1692 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-Et-Ph) H H 1-1693 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-CF₃-Ph) H H 1-1694 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-MeO-Ph) H H 1-1695 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-EtO-Ph) H H 1-1696 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-MeS-Ph) H H 1-1697 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-cHx-Ph) H H 1-1698 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-Ph-Ph) H H 1-1699 H H H Me 2 -CH (OH)-(CH₂)_Five-cHx H H 1-1700 H H Me Me 2 -CH (OH)-(CH₂)_Five-cHx H H 1-1701 Me H H Me 2 -CH (OH)-(CH₂)_Five-cHx H H 1-1702 CO₂Me H H Me 2 -CH (OH)-(CH₂)_Five-cHx H H 1-1703 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-F-cHx) H H 1-1704 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-Me-cHx) H H 1-1705 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-Et-cHx) H H 1-1706 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-CF₃-cHx) H H 1-1707 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-MeO-cHx) H H 1-1708 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-EtO-cHx) H H 1-1709 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-MeS-cHx) H H 1-1710 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-cHx-cHx) H H 1-1711 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-Ph-cHx) H H 1-1712 H H H Me 2 -CH (OH)-(CH₂)_Five-Ph H H 1-1713 H H Me Me 2 -CH (OH)-(CH₂)_Five-Ph H H 1-1714 Me H H Me 2 -CH (OH)-(CH₂)_Five-Ph H H 1-1715 CO₂Me H H Me 2 -CH (OH)-(CH₂)_Five-Ph H H 1-1716 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-F-Ph) H H 1-1717 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-Me-Ph) H H 1-1718 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-Et-Ph) H H 1-1719 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-CF₃-Ph) H H 1-1720 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-MeO-Ph) H H 1-1721 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-EtO-Ph) H H 1-1722 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-MeS-Ph) H H 1-1723 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-cHx-Ph) H H 1-1724 H H H Me 2 -CH (OH)-(CH₂)_Five-(4-Ph-Ph) H H 1-1725 H H H Me 2 -CH (OH)-(CH₂)₆-cHx H H 1-1726 H H H Me 2 -CH (OH)-(CH₂)₆-Ph H H 1-1727 H H H Me 2 -CH (OH)-(CH₂)₇-cHx H H 1-1728 H H H Me 2 -CH (OH)-(CH₂)₇-Ph H H 1-1729 H H H Me 2 -4- (cHx-CH₂O) Ph H H 1-1730 H H Me Me 2 -4- (cHx-CH₂O) Ph H H 1-1731 Me H H Me 2 -4- (cHx-CH₂O) Ph H H 1-1732 CO₂Me H H Me 2 -4- (cHx-CH₂O) Ph H H 1-1733 H H H Me 2 -4- (cHx-CH₂O) -2-F-Ph H H 1-1734 H H H Me 2 -4- (cHx-CH₂O) -3-F-Ph H H 1-1735 H H H Me 2 -4- (cHx-CH₂O) -2,3-diF-Ph H H 1-1736 H H H Me 2 -4- (cHx-CH₂O) -2-Cl-Ph H H 1-1737 H H H Me 2 -4- (cHx-CH₂O) -3-Cl-Ph H H 1-1738 H H H Me 2 -4- (cHx-CH₂O) -2,3-diCl-Ph H H 1-1739 H H H Me 2 -4- (cHx-CH₂O) -2-Me-Ph H H 1-1740 H H H Me 2 -4- (cHx-CH₂O) -3-Me-Ph H H 1-1741 H H H Me 2 -4- (cHx-CH₂O) -2,3-diMe-Ph H H 1-1742 H H H Me 2 -4- [cHx- (CH₂)₂O] Ph H H 1-1743 H H H Me 2 -4- [cHx- (CH₂)₃O] Ph H H 1-1744 H H H Me 2-(4-BzO-Ph) H H 1-1745 H H Me Me 2-(4-BzO-Ph) H H 1-1746 Me H H Me 2-(4-BzO-Ph) H H 1-1747 CO₂Me H H Me 2-(4-BzO-Ph) H H 1-1748 H H H Me 2-(4-BzO-2-F-Ph) H H 1-1749 H H H Me 2-(4-BzO-3-F-Ph) H H 1-1750 H H H Me 2-(4-BzO-2,3-diF-Ph) H H 1-1751 H H H Me 2-(4-BzO-2-Cl-Ph) H H 1-1752 H H H Me 2-(4-BzO-3-Cl-Ph) H H 1-1753 H H H Me 2-(4-BzO-2,3-diCl-Ph) H H 1-1754 H H H Me 2-(4-BzO-2-Me-Ph) H H 1-1755 H H H Me 2-(4-BzO-3-Me-Ph) H H 1-1756 H H H Me 2-(4-BzO-2,3-diMe-Ph) H H 1-1757 H H H Me 2 -4- [Ph- (CH₂)₂O] -Ph H H 1-1758 H H H Me 2 -4- [Ph- (CH₂)₃O] -Ph H H 1-1759 H H H Et 2-(CH₂)₃-cHx H H 1-1760 H H H Et 2-(CH₂)₃-Ph H H 1-1761 H H H Et 2-(CH₂)_Four-cHx H H 1-1762 H H H Et 2-(CH₂)_Four-Ph H H 1-1763 H H H Et 2-(CH₂)_Five-cPn H H 1-1764 H H H Et 2-(CH₂)_Five-cHx H H 1-1765 H H H Et 2-(CH₂)_Five-cHx Me H 1-1766 H H H Et 2-(CH₂)_Five-cHx H Me 1-1767 H H H Et 2-(CH₂)_Five-cHx F H 1-1768 H H H Et 2-(CH₂)_Five-cHx HF 1-1769 H H Me Et 2-(CH₂)_Five-cHx H H 1-1770 Me H H Et 2-(CH₂)_Five-cHx H H 1-1771 CO₂Me H H Et 2-(CH₂)_Five-cHx H H 1-1772 H H H Et 2-(CH₂)_Five-(4-F-cHx) H H 1-1773 H H H Et 2-(CH₂)_Five-(4-Cl-cHx) H H 1-1774 H H H Et 2-(CH₂)_Five-(4-Br-cHx) H H 1-1775 H H H Et 2-(CH₂)_Five-(4-Me-cHx) H H 1-1776 H H H Et 2-(CH₂)_Five-(4-Et-cHx) H H 1-1777 H H H Et 2-(CH₂)_Five-(4-Pr-cHx) H H 1-1778 H H H Et 2-(CH₂)_Five-(4-iPr-cHx) H H 1-1779 H H H Et 2-(CH₂)_Five-(4-CF₃-cHx) H H 1-1780 H H H Et 2-(CH₂)_Five-(4-MeO-cHx) H H 1-1781 H H H Et 2-(CH₂)_Five-(4-EtO-cHx) H H 1-1782 H H H Et 2-(CH₂)_Five-(4-PrO-cHx) H H 1-1783 H H H Et 2-(CH₂)_Five-(4-iPrO-cHx) H H 1-1784 H H H Et 2-(CH₂)_Five-(3-MeS-cHx) H H 1-1785 H H H Et 2-(CH₂)_Five-(4-MeS-cHx) H H 1-1786 H H H Et 2-(CH₂)_Five-(2,4-diMe-cHx) H H 1-1787 H H H Et 2-(CH₂)_Five-(3,4-diMe-cHx) H H 1-1788 H H H Et 2-(CH₂)_Five-(3,5-diMe-cHx) H H 1-1789 H H H Et 2-(CH₂)_Five-Ph H H 1-1790 H H H Et 2-(CH₂)_Five-Ph Me H 1-1791 H H H Et 2-(CH₂)_Five-Ph H Me 1-1792 H H H Et 2-(CH₂)_Five-Ph F H 1-1793 H H H Et 2-(CH₂)_Five-Ph H F 1-1794 H H Me Et 2-(CH₂)_Five-Ph H H 1-1795 Me H H Et 2-(CH₂)_Five-Ph H H 1-1796 CO₂Me H H Et 2-(CH₂)_Five-Ph H H 1-1797 H H H Et 2-(CH₂)_Five-(4-F-Ph) H H 1-1798 H H H Et 2-(CH₂)_Five-(4-Cl-Ph) H H 1-1799 H H H Et 2-(CH₂)_Five-(4-Br-Ph) H H 1-1800 H H H Et 2-(CH₂)_Five-(4-Me-Ph) H H 1-1801 H H H Et 2-(CH₂)_Five-(4-Et-Ph) H H 1-1802 H H H Et 2-(CH₂)_Five-(4-Pr-Ph) H H 1-1803 H H H Et 2-(CH₂)_Five-(4-iPr-Ph) H H 1-1804 H H H Et 2-(CH₂)_Five-(4-Bu-Ph) H H 1-1805 H H H Et 2-(CH₂)_Five-(4-CF₃-Ph) H H 1-1806 H H H Et 2-(CH₂)_Five-(4-MeO-Ph) H H 1-1807 H H H Et 2-(CH₂)_Five-(4-EtO-Ph) H H 1-1808 H H H Et 2-(CH₂)_Five-(4-PrO-Ph) H H 1-1809 H H H Et 2-(CH₂)_Five-(4-iPrO-Ph) H H 1-1810 H H H Et 2-(CH₂)_Five-(3-MeS-Ph) H H 1-1811 H H H Et 2-(CH₂)_Five-(4-MeS-Ph) H H 1-1812 H H H Et 2-(CH₂)_Five-(2,4-diMe-Ph) H H 1-1813 H H H Et 2-(CH₂)_Five-(3,4-diMe-Ph) H H 1-1814 H H H Et 2-(CH₂)_Five-(3,5-diMe-Ph) H H 1-1815 H H H Et 2-(CH₂)₆-cPn H H 1-1816 H H H Et 2-(CH₂)₆-cHx H H 1-1817 H H H Et 2-(CH₂)₆-cHx Me H 1-1818 H H H Et 2-(CH₂)₆-cHx H Me 1-1819 H H H Et 2-(CH₂)₆-cHx F H 1-1820 H H H Et 2-(CH₂)₆-cHx HF 1-1821 H H Me Et 2-(CH₂)₆-cHx H H 1-1822 Me H H Et 2-(CH₂)₆-cHx H H 1-1823 CO₂Me H H Et 2-(CH₂)₆-cHx H H 1-1824 H H H Et 2-(CH₂)₆-(4-F-cHx) H H 1-1825 H H H Et 2-(CH₂)₆-(4-Cl-cHx) H H 1-1826 H H H Et 2-(CH₂)₆-(4-Br-cHx) H H 1-1827 H H H Et 2-(CH₂)₆-(4-Me-cHx) H H 1-1828 H H H Et 2-(CH₂)₆-(4-Et-cHx) H H 1-1829 H H H Et 2-(CH₂)₆-(4-Pr-cHx) H H 1-1830 H H H Et 2-(CH₂)₆-(4-iPr-cHx) H H 1-1831 H H H Et 2-(CH₂)₆-(4-Bu-cHx) H H 1-1832 H H H Et 2-(CH₂)₆-(4-CF₃-cHx) H H 1-1833 H H H Et 2-(CH₂)₆-(4-MeO-cHx) H H 1-1834 H H H Et 2-(CH₂)₆-(4-EtO-cHx) H H 1-1835 H H H Et 2-(CH₂)₆-(4-PrO-cHx) H H 1-1836 H H H Et 2-(CH₂)₆-(4-iPrO-cHx) H H 1-1837 H H H Et 2-(CH₂)₆-(3-MeS-cHx) H H 1-1838 H H H Et 2-(CH₂)₆-(4-MeS-cHx) H H 1-1839 H H H Et 2-(CH₂)₆-(2,4-diMe-cHx) H H 1-1840 H H H Et 2-(CH₂)₆-(3,4-diMe-cHx) H H 1-1841 H H H Et 2-(CH₂)₆-(3,5-diMe-cHx) H H 1-1842 H H H Et 2-(CH₂)₆-Ph H H 1-1843 H H H Et 2-(CH₂)₆-Ph Me H 1-1844 H H H Et 2-(CH₂)₆-Ph H Me 1-1845 H H H Et 2-(CH₂)₆-Ph F H 1-1846 H H H Et 2-(CH₂)₆-Ph H F 1-1847 H H Me Et 2-(CH₂)₆-Ph H H 1-1848 Me H H Et 2-(CH₂)₆-Ph H H 1-1849 CO₂Me H H Et 2-(CH₂)₆-Ph H H 1-1850 H H H Et 2-(CH₂)₆-(4-F-Ph) H H 1-1851 H H H Et 2-(CH₂)₆-(4-Cl-Ph) H H 1-1852 H H H Et 2-(CH₂)₆-(4-Br-Ph) H H 1-1853 H H H Et 2-(CH₂)₆-(4-Me-Ph) H H 1-1854 H H H Et 2-(CH₂)₆-(4-Et-Ph) H H 1-1855 H H H Et 2-(CH₂)₆-(4-Pr-Ph) H H 1-1856 H H H Et 2-(CH₂)₆-(4-iPr-Ph) H H 1-1857 H H H Et 2-(CH₂)₆-(4-Bu-Ph) H H 1-1858 H H H Et 2-(CH₂)₆-(4-CF₃-Ph) H H 1-1859 H H H Et 2-(CH₂)₆-(4-MeO-Ph) H H 1-1860 H H H Et 2-(CH₂)₆-(4-EtO-Ph) H H 1-1861 H H H Et 2-(CH₂)₆-(4-PrO-Ph) H H 1-1862 H H H Et 2-(CH₂)₆-(4-iPrO-Ph) H H 1-1863 H H H Et 2-(CH₂)₆-(3-MeS-Ph) H H 1-1864 H H H Et 2-(CH₂)₆-(4-MeS-Ph) H H 1-1865 H H H Et 2-(CH₂)₆-(2,4-diMe-Ph) H H 1-1866 H H H Et 2-(CH₂)₆-(3,4-diMe-Ph) H H 1-1867 H H H Et 2-(CH₂)₆-(3,5-diMe-Ph) H H 1-1868 H H H Et 2-(CH₂)₇-cHx H H 1-1869 H H H Et 2-(CH₂)₇-Ph H H 1-1870 H H H Et 2 -CH = CH-cHx H H 1-1871 H H H Et 2 -CH = CH-Ph H H 1-1872 H H H Et 2 -CH = CH- (CH₂)₃-cHx H H 1-1873 H H Me Et 2 -CH = CH- (CH₂)₃-cHx H H 1-1874 Me H H Et 2 -CH = CH- (CH₂)₃-cHx H H 1-1875 CO₂Me H H Et 2 -CH = CH- (CH₂)₃-cHx H H 1-1876 H H H Et 2 -CH = CH- (CH₂)₃-Ph H H 1-1877 H H Me Et 2 -CH = CH- (CH₂)₃-Ph H H 1-1878 Me H H Et 2 -CH = CH- (CH₂)₃-Ph H H 1-1879 CO₂Me H H Et 2 -CH = CH- (CH₂)₃-Ph H H 1-1880 H H H Et 2 -CH = CH- (CH₂)_Four-cHx H H 1-1881 H H Me Et 2 -CH = CH- (CH₂)_Four-cHx H H 1-1882 Me H H Et 2 -CH = CH- (CH₂)_Four-cHx H H 1-1883 CO₂Me H H Et 2 -CH = CH- (CH₂)_Four-cHx H H 1-1884 H H H Et 2 -CH = CH- (CH₂)_Four-Ph H H 1-1885 H H Me Et 2 -CH = CH- (CH₂)_Four-Ph H H 1-1886 Me H H Et 2 -CH = CH- (CH₂)_Four-Ph H H 1-1887 CO₂Me H H Et 2 -CH = CH- (CH₂)_Four-Ph H H 1-1888 H H H Et 2 -CH = CH-CH₂O-cHx H H 1-1889 H H H Et 2 -CH = CH-CH₂O-Ph H H 1-1890 H H H Et 2 -CH = CH- (CH₂)₂O-cHx H H 1-1891 H H H Et 2 -CH = CH- (CH₂)₂O-Ph H H 1-1892 H H H Et 2 -C≡C-CH₂-cHx H H 1-1893 H H Me Et 2 -C≡C-CH₂-cHx H H 1-1894 Me H H Et 2 -C≡C-CH₂-cHx H H 1-1895 CO₂Me H H Et 2 -C≡C-CH₂-cHx H H 1-1896 H H H Et 2 -C≡C-CH₂-Ph H H 1-1897 H H Me Et 2 -C≡C-CH₂-Ph H H 1-1898 Me H H Et 2 -C≡C-CH₂-Ph H H 1-1899 CO₂Me H H Et 2 -C≡C-CH₂-Ph H H 1-1900 H H H Et 2 -C≡C- (CH₂)₂-cHx H H 1-1901 H H Me Et 2 -C≡C- (CH₂)₂-cHx H H 1-1902 Me H H Et 2 -C≡C- (CH₂)₂-cHx H H 1-1903 CO₂Me H H Et 2 -C≡C- (CH₂)₂-cHx H H 1-1904 H H H Et 2 -C≡C- (CH₂)₂-Ph H H 1-1905 H H Me Et 2 -C≡C- (CH₂)₂-Ph H H 1-1906 Me H H Et 2 -C≡C- (CH₂)₂-Ph H H 1-1907 CO₂Me H H Et 2 -C≡C- (CH₂)₂-Ph H H 1-1908 H H H Et 2 -C≡C- (CH₂)₃-cPn H H 1-1909 H H H Et 2 -C≡C- (CH₂)₃-cHx H H 1-1910 H H H Et 2 -C≡C- (CH₂)₃-cHx Me H 1-1911 H H H Et 2 -C≡C- (CH₂)₃-cHx H Me 1-1912 H H H Et 2 -C≡C- (CH₂)₃-cHx F H 1-1913 H H H Et 2 -C≡C- (CH₂)₃-cHx HF 1-1914 H H Me Et 2 -C≡C- (CH₂)₃-cHx H H 1-1915 Me H H Et 2 -C≡C- (CH₂)₃-cHx H H 1-1916 CO₂Me H H Et 2 -C≡C- (CH₂)₃-cHx H H 1-1917 H H H Et 2 -C≡C- (CH₂)₃-(4-F-cHx) H H 1-1918 H H H Et 2 -C≡C- (CH₂)₃-(4-Cl-cHx) H H 1-1919 H H H Et 2 -C≡C- (CH₂)₃-(4-Br-cHx) H H 1-1920 H H H Et 2 -C≡C- (CH₂)₃-(4-Me-cHx) H H 1-1921 H H H Et 2 -C≡C- (CH₂)₃-(4-Et-cHx) H H 1-1922 H H H Et 2 -C≡C- (CH₂)₃-(4-Pr-cHx) H H 1-1923 H H H Et 2 -C≡C- (CH₂)₃-(4-iPr-cHx) H H 1-1924 H H H Et 2 -C≡C- (CH₂)₃-(4-Bu-cHx) H H 1-1925 H H H Et 2 -C≡C- (CH₂)₃-(4-CF₃-cHx) H H 1-1926 H H H Et 2 -C≡C- (CH₂)₃-(4-MeO-cHx) H H 1-1927 H H H Et 2 -C≡C- (CH₂)₃-(4-EtO-cHx) H H 1-1928 H H H Et 2 -C≡C- (CH₂)₃-(4-PrO-cHx) H H 1-1929 H H H Et 2 -C≡C- (CH₂)₃-(4-iPrO-cHx) H H 1-1930 H H H Et 2 -C≡C- (CH₂)₃-(3-MeS-cHx) H H 1-1931 H H H Et 2 -C≡C- (CH₂)₃-(4-MeS-cHx) H H 1-1932 H H H Et 2 -C≡C- (CH₂)₃-(2,4-diMe-cHx) H H 1-1933 H H H Et 2 -C≡C- (CH₂)₃-(3,4-diMe-cHx) H H 1-1934 H H H Et 2 -C≡C- (CH₂)₃-(3,5-diMe-cHx) H H 1-1935 H H H Et 2 -C≡C- (CH₂)₃-Ph H H 1-1936 H H H Et 2 -C≡C- (CH₂)₃-Ph Me H 1-1937 H H H Et 2 -C≡C- (CH₂)₃-Ph H Me 1-1938 H H H Et 2 -C≡C- (CH₂)₃-Ph F H 1-1939 H H H Et 2 -C≡C- (CH₂)₃-Ph H F 1-1940 H H Me Et 2 -C≡C- (CH₂)₃-Ph H H 1-1941 Me H H Et 2 -C≡C- (CH₂)₃-Ph H H 1-1942 CO₂Me H H Et 2 -C≡C- (CH₂)₃-Ph H H 1-1943 H H H Et 2 -C≡C- (CH₂)₃-(4-F-Ph) H H 1-1944 H H H Et 2 -C≡C- (CH₂)₃-(4-Cl-Ph) H H 1-1945 H H H Et 2 -C≡C- (CH₂)₃-(4-Br-Ph) H H 1-1946 H H H Et 2 -C≡C- (CH₂)₃-(4-Me-Ph) H H 1-1947 H H H Et 2 -C≡C- (CH₂)₃-(4-Et-Ph) H H 1-1948 H H H Et 2 -C≡C- (CH₂)₃-(4-Pr-Ph) H H 1-1949 H H H Et 2 -C≡C- (CH₂)₃-(4-iPr-Ph) H H 1-1950 H H H Et 2 -C≡C- (CH₂)₃-(4-Bu-Ph) H H 1-1951 H H H Et 2 -C≡C- (CH₂)₃-(4-CF₃-Ph) H H 1-1952 H H H Et 2 -C≡C- (CH₂)₃-(4-MeO-Ph) H H 1-1953 H H H Et 2 -C≡C- (CH₂)₃-(4-EtO-Ph) H H 1-1954 H H H Et 2 -C≡C- (CH₂)₃-(4-PrO-Ph) H H 1-1955 H H H Et 2 -C≡C- (CH₂)₃-(4-iPrO-Ph) H H 1-1956 H H H Et 2 -C≡C- (CH₂)₃-(3-MeS-Ph) H H 1-1957 H H H Et 2 -C≡C- (CH₂)₃-(4-MeS-Ph) H H 1-1958 H H H Et 2 -C≡C- (CH₂)₃-(2,4-diMe-Ph) H H 1-1959 H H H Et 2 -C≡C- (CH₂)₃-(3,4-diMe-Ph) H H 1-1960 H H H Et 2 -C≡C- (CH₂)₃-(3,5-diMe-Ph) H H 1-1961 H H H Et 2 -C≡C- (CH₂)_Four-cPn H H 1-1962 H H H Et 2 -C≡C- (CH₂)_Four-cHx H H 1-1963 H H H Et 2 -C≡C- (CH₂)_Four-cHx Me H 1-1964 H H H Et 2 -C≡C- (CH₂)_Four-cHx H Me 1-1965 H H H Et 2 -C≡C- (CH₂)_Four-cHx F H 1-1966 H H H Et 2 -C≡C- (CH₂)_Four-cHx HF 1-1967 H H Me Et 2 -C≡C- (CH₂)_Four-cHx H H 1-1968 Me H H Et 2 -C≡C- (CH₂)_Four-cHx H H 1-1969 CO₂Me H H Et 2 -C≡C- (CH₂)_Four-cHx H H 1-1970 H H H Et 2 -C≡C- (CH₂)_Four-(4-F-cHx) H H 1-1971 H H H Et 2 -C≡C- (CH₂)_Four-(4-Cl-cHx) H H 1-1972 H H H Et 2 -C≡C- (CH₂)_Four-(4-Br-cHx) H H 1-1973 H H H Et 2 -C≡C- (CH₂)_Four-(4-Me-cHx) H H 1-1974 H H H Et 2 -C≡C- (CH₂)_Four-(4-Et-cHx) H H 1-1975 H H H Et 2 -C≡C- (CH₂)_Four-(4-Pr-cHx) H H 1-1976 H H H Et 2 -C≡C- (CH₂)_Four-(4-iPr-cHx) H H 1-1977 H H H Et 2 -C≡C- (CH₂)_Four-(4-Bu-cHx) H H 1-1978 H H H Et 2 -C≡C- (CH₂)_Four-(4-CF₃-cHx) H H 1-1979 H H H Et 2 -C≡C- (CH₂)_Four-(4-MeO-cHx) H H 1-1980 H H H Et 2 -C≡C- (CH₂)_Four-(4-EtO-cHx) H H 1-1981 H H H Et 2 -C≡C- (CH₂)_Four-(4-PrO-cHx) H H 1-1982 H H H Et 2 -C≡C- (CH₂)_Four-(4-iPrO-cHx) H H 1-1983 H H H Et 2 -C≡C- (CH₂)_Four-(4-MeS-cHx) H H 1-1984 H H H Et 2 -C≡C- (CH₂)_Four-(2,4-diMe-cHx) H H 1-1985 H H H Et 2 -C≡C- (CH₂)_Four-(3,4-diMe-cHx) H H 1-1986 H H H Et 2 -C≡C- (CH₂)_Four-(3,5-diMe-cHx) H H 1-1987 H H H Et 2 -C≡C- (CH₂)_Four-Ph H H 1-1988 H H H Et 2 -C≡C- (CH₂)_Four-Ph Me H 1-1989 H H H Et 2 -C≡C- (CH₂)_Four-Ph H Me 1-1990 H H H Et 2 -C≡C- (CH₂)_Four-Ph F H 1-1991 H H H Et 2 -C≡C- (CH₂)_Four-Ph H F 1-1992 H H Me Et 2 -C≡C- (CH₂)_Four-Ph H H 1-1993 Me H H Et 2 -C≡C- (CH₂)_Four-Ph H H 1-1994 CO₂Me H H Et 2 -C≡C- (CH₂)_Four-Ph H H 1-1995 H H H Et 2 -C≡C- (CH₂)_Four-(4-F-Ph) H H 1-1996 H H H Et 2 -C≡C- (CH₂)_Four-(4-Cl-Ph) H H 1-1997 H H H Et 2 -C≡C- (CH₂)_Four-(4-Br-Ph) H H 1-1998 H H H Et 2 -C≡C- (CH₂)_Four-(4-Me-Ph) H H 1-1999 H H H Et 2 -C≡C- (CH₂)_Four-(4-Et-Ph) H H 1-2000 H H H Et 2 -C≡C- (CH₂)_Four-(4-Pr-Ph) H H 1-2001 H H H Et 2 -C≡C- (CH₂)_Four-(4-iPr-Ph) H H 1-2002 H H H Et 2 -C≡C- (CH₂)_Four-(4-Bu-Ph) H H 1-2003 H H H Et 2 -C≡C- (CH₂)_Four-(4-CF₃-Ph) H H 1-2004 H H H Et 2 -C≡C- (CH₂)_Four-(4-MeO-Ph) H H 1-2005 H H H Et 2 -C≡C- (CH₂)_Four-(4-EtO-Ph) H H 1-2006 H H H Et 2 -C≡C- (CH₂)_Four-(4-PrO-Ph) H H 1-2007 H H H Et 2 -C≡C- (CH₂)_Four-(4-iPrO-Ph) H H 1-2008 H H H Et 2 -C≡C- (CH₂)_Four-(3-MeS-Ph) H H 1-2009 H H H Et 2 -C≡C- (CH₂)_Four-(4-MeS-Ph) H H 1-2010 H H H Et 2 -C≡C- (CH₂)_Four-(2,4-diMe-Ph) H H 1-2011 H H H Et 2 -C≡C- (CH₂)_Four-(3,4-diMe-Ph) H H 1-2012 H H H Et 2 -C≡C- (CH₂)_Four-(3,5-diMe-Ph) H H 1-2013 H H H Et 2 -C≡C- (CH₂)_Five-cHx H H 1-2014 H H Me Et 2 -C≡C- (CH₂)_Five-cHx H H 1-2015 Me H H Et 2 -C≡C- (CH₂)_Five-cHx H H 1-2016 CO₂Me H H Et 2 -C≡C- (CH₂)_Five-cHx H H 1-2017 H H H Et 2 -C≡C- (CH₂)_Five-Ph H H 1-2018 H H Me Et 2 -C≡C- (CH₂)_Five-Ph H H 1-2019 Me H H Et 2 -C≡C- (CH₂)_Five-Ph H H 1-2020 CO₂Me H H Et 2 -C≡C- (CH₂)_Five-Ph H H 1-2021 H H H Et 2 -C≡C- (CH₂)₆-cHx H H 1-2022 H H Me Et 2 -C≡C- (CH₂)₆-cHx H H 1-2023 Me H H Et 2 -C≡C- (CH₂)₆-cHx H H 1-2024 CO₂Me H H Et 2 -C≡C- (CH₂)₆-cHx H H 1-2025 H H H Et 2 -C≡C- (CH₂)₆-Ph H H 1-2026 H H Me Et 2 -C≡C- (CH₂)₆-Ph H H 1-2027 Me H H Et 2 -C≡C- (CH₂)₆-Ph H H 1-2028 CO₂Me H H Et 2 -C≡C- (CH₂)₆-Ph H H 1-2029 H H H Et 2 -C≡C-CH₂O-cHx H H 1-2030 H H Me Et 2 -C≡C-CH₂O-cHx H H 1-2031 Me H H Et 2 -C≡C-CH₂O-cHx H H 1-2032 CO₂Me H H Et 2 -C≡C-CH₂O-cHx H H 1-2033 H H H Et 2 -C≡C-CH₂O-Ph H H 1-2034 H H Me Et 2 -C≡C-CH₂O-Ph H H 1-2035 Me H H Et 2 -C≡C-CH₂O-Ph H H 1-2036 CO₂Me H H Et 2 -C≡C-CH₂O-Ph H H 1-2037 H H H Et 2 -C≡C- (CH₂)₂O-cPn H H 1-2038 H H H Et 2 -C≡C- (CH₂)₂O-cHx H H 1-2039 H H H Et 2 -C≡C- (CH₂)₂O-cHx Me H 1-2040 H H H Et 2 -C≡C- (CH₂)₂O-cHx H Me 1-2041 H H H Et 2 -C≡C- (CH₂)₂O-cHx F H 1-2042 H H H Et 2 -C≡C- (CH₂)₂O-cHx H F 1-2043 H H Me Et 2 -C≡C- (CH₂)₂O-cHx H H 1-2044 Me H H Et 2 -C≡C- (CH₂)₂O-cHx H H 1-2045 CO₂Me H H Et 2 -C≡C- (CH₂)₂O-cHx H H 1-2046 H H H Et 2 -C≡C- (CH₂)₂O- (4-F-cHx) H H 1-2047 H H H Et 2 -C≡C- (CH₂)₂O- (4-Cl-cHx) H H 1-2048 H H H Et 2 -C≡C- (CH₂)₂O- (4-Br-cHx) H H 1-2049 H H H Et 2 -C≡C- (CH₂)₂O- (4-Me-cHx) H H 1-2050 H H H Et 2 -C≡C- (CH₂)₂O- (4-Et-cHx) H H 1-2051 H H H Et 2 -C≡C- (CH₂)₂O- (4-Pr-cHx) H H 1-2052 H H H Et 2 -C≡C- (CH₂)₂O- (4-iPr-cHx) H H 1-2053 H H H Et 2 -C≡C- (CH₂)₂O- (4-Bu-cHx) H H 1-2054 H H H Et 2 -C≡C- (CH₂)₂O- (4-CF₃-cHx) H H 1-2055 H H H Et 2 -C≡C- (CH₂)₂O- (4-MeO-cHx) H H 1-2056 H H H Et 2 -C≡C- (CH₂)₂O- (4-EtO-cHx) H H 1-2057 H H H Et 2 -C≡C- (CH₂)₂O- (4-PrO-cHx) H H 1-2058 H H H Et 2 -C≡C- (CH₂)₂O- (4-iPrO-cHx) H H 1-2059 H H H Et 2 -C≡C- (CH₂)₂O- (3-MeS-cHx) H H 1-2060 H H H Et 2 -C≡C- (CH₂)₂O- (4-MeS-cHx) H H 1-2061 H H H Et 2 -C≡C- (CH₂)₂O- (2,4-diMe-cHx) H H 1-2062 H H H Et 2 -C≡C- (CH₂)₂O- (3,4-diMe-cHx) H H 1-2063 H H H Et 2 -C≡C- (CH₂)₂O- (3,5-diMe-cHx) H H 1-2064 H H H Et 2 -C≡C- (CH₂)₂O-Ph H H 1-2065 H H H Et 2 -C≡C- (CH₂)₂O-Ph Me H 1-2066 H H H Et 2 -C≡C- (CH₂)₂O-Ph H Me 1-2067 H H H Et 2 -C≡C- (CH₂)₂O-Ph F H 1-2068 H H H Et 2 -C≡C- (CH₂)₂O-Ph H F 1-2069 H H Me Et 2 -C≡C- (CH₂)₂-OCH₂-Ph H H 1-2070 Me H H Et 2 -C≡C- (CH₂)₂O-Ph H H 1-2071 CO₂Me H H Et 2 -C≡C- (CH₂)₂O-Ph H H 1-2072 H H H Et 2 -C≡C- (CH₂)₂O- (4-F-Ph) H H 1-2073 H H H Et 2 -C≡C- (CH₂)₂O- (4-Cl-Ph) H H 1-2074 H H H Et 2 -C≡C- (CH₂)₂O- (4-Br-Ph) H H 1-2075 H H H Et 2 -C≡C- (CH₂)₂O- (4-Me-Ph) H H 1-2076 H H H Et 2 -C≡C- (CH₂)₂O- (4-Et-Ph) H H 1-2077 H H H Et 2 -C≡C- (CH₂)₂O- (4-Pr-Ph) H H 1-2078 H H H Et 2 -C≡C- (CH₂)₂O- (4-iPr-Ph) H H 1-2079 H H H Et 2 -C≡C- (CH₂)₂O- (4-Bu-Ph) H H 1-2080 H H H Et 2 -C≡C- (CH₂)₂O- (4-CF₃-Ph) H H 1-2081 H H H Et 2 -C≡C- (CH₂)₂O- (4-MeO-Ph) H H 1-2082 H H H Et 2 -C≡C- (CH₂)₂O- (4-EtO-Ph) H H 1-2083 H H H Et 2 -C≡C- (CH₂)₂O- (4-PrO-Ph) H H 1-2084 H H H Et 2 -C≡C- (CH₂)₂O- (4-iPrO-Ph) H H 1-2085 H H H Et 2 -C≡C- (CH₂)₂O- (4-MeS-Ph) H H 1-2086 H H H Et 2 -C≡C- (CH₂)₂O- (2,4-diMe-Ph) H H 1-2087 H H H Et 2 -C≡C- (CH₂)₂O- (3,4-diMe-Ph) H H 1-2088 H H H Et 2 -C≡C- (CH₂)₂O- (3,5-diMe-Ph) H H 1-2089 H H H Et 2 -CO- (CH₂)₃-cHx H H 1-2090 H H Me Et 2 -CO- (CH₂)₃-cHx H H 1-2091 Me H H Et 2 -CO- (CH₂)₃-cHx H H 1-2092 CO₂Me H H Et 2 -CO- (CH₂)₃-cHx H H 1-2093 H H H Et 2 -CO- (CH₂)₃-Ph H H 1-2094 H H Me Et 2 -CO- (CH₂)₃-Ph H H 1-2095 Me H H Et 2 -CO- (CH₂)₃-Ph H H 1-2096 CO₂Me H H Et 2 -CO- (CH₂)₃-Ph H H 1-2097 H H H Et 2 -CO- (CH₂)_Four-cHx H H 1-2098 H H Me Et 2 -CO- (CH₂)_Four-cHx H H 1-2099 Me H H Et 2 -CO- (CH₂)_Four-cHx H H 1-2100 CO₂Me H H Et 2 -CO- (CH₂)_Four-cHx H H 1-2101 H H H Et 2 -CO- (CH₂)_Four-Ph H H 1-2102 H H Me Et 2 -CO- (CH₂)_Four-Ph H H 1-2103 Me H H Et 2 -CO- (CH₂)_Four-Ph H H 1-2104 CO₂Me H H Et 2 -CO- (CH₂)_Four-Ph H H 1-2105 H H H Et 2 -CO- (CH₂)_Five-cHx H H 1-2106 H H Me Et 2 -CO- (CH₂)_Five-cHx H H 1-2107 Me H H Et 2 -CO- (CH₂)_Five-cHx H H 1-2108 CO₂Me H H Et 2 -CO- (CH₂)_Five-cHx H H 1-2109 H H H Et 2 -CO- (CH₂)_Five-Ph H H 1-2110 H H Me Et 2 -CO- (CH₂)_Five-Ph H H 1-2111 Me H H Et 2 -CO- (CH₂)_Five-Ph H H 1-2112 CO₂Me H H Et 2 -CO- (CH₂)_Five-Ph H H 1-2113 H H H Et 2 -CH (OH)-(CH₂)_Four-cHx H H 1-2114 H H Me Et 2 -CH (OH)-(CH₂)_Four-cHx H H 1-2115 Me H H Et 2 -CH (OH)-(CH₂)_Four-cHx H H 1-2116 CO₂Me H H Et 2 -CH (OH)-(CH₂)_Four-cHx H H 1-2117 H H H Et 2 -CH (OH)-(CH₂)_Four-Ph H H 1-2118 H H Me Et 2 -CH (OH)-(CH₂)_Four-Ph H H 1-2119 Me H H Et 2 -CH (OH)-(CH₂)_Four-Ph H H 1-2120 CO₂Me H H Et 2 -CH (OH)-(CH₂)_Four-Ph H H 1-2121 H H H Et 2 -CH (OH)-(CH₂)_Five-cHx H H 1-2122 H H Me Et 2 -CH (OH)-(CH₂)_Five-cHx H H 1-2123 Me H H Et 2 -CH (OH)-(CH₂)_Five-cHx H H 1-2124 CO₂Me H H Et 2 -CH (OH)-(CH₂)_Five-cHx H H 1-2125 H H H Et 2 -CH (OH)-(CH₂)_Five-Ph H H 1-2126 H H Me Et 2 -CH (OH)-(CH₂)_Five-Ph H H 1-2127 Me H H Et 2 -CH (OH)-(CH₂)_Five-Ph H H 1-2128 CO₂Me H H Et 2 -CH (OH)-(CH₂)_Five-Ph H H 1-2129 H H H Et 2 -4- (cHx-CH₂O) Ph H H 1-2130 H H Me Et 2 -4- (cHx-CH₂O) Ph H H 1-2131 Me H H Et 2 -4- (cHx-CH₂O) Ph H H 1-2132 CO₂Me H H Et 2 -4- (cHx-CH₂O) Ph H H 1-2133 H H H Et 2 -4- [cHx- (CH₂)₂O] Ph H H 1-2134 H H H Et 2 -4- [cHx- (CH₂)₃O] Ph H H 1-2135 H H H Et 2-(4-BzO-Ph) H H 1-2136 H H Me Et 2-(4-BzO-Ph) H H 1-2137 Me H H Et 2-(4-BzO-Ph) H H 1-2138 CO₂Me H H Et 2-(4-BzO-Ph) H H 1-2139 H H H Et 2-(4-BzO-2-F-Ph) H H 1-2140 H H H Et 2-(4-BzO-3-F-Ph) H H 1-2141 H H H Et 2-(4-BzO-2,3-diF-Ph) H H 1-2142 H H H Et 2-(4-BzO-2-Cl-Ph) H H 1-2143 H H H Et 2-(4-BzO-3-Cl-Ph) H H 1-2144 H H H Et 2-(4-BzO-2,3-diCl-Ph) H H 1-2145 H H H Et 2-(4-BzO-2-Me-Ph) H H 1-2146 H H H Et 2-(4-BzO-3-Me-Ph) H H 1-2147 H H H Et 2-(4-BzO-2,3-diMe-Ph) H H 1-2148 H H H Et 2 -4- [Ph- (CH₂)₂O] -Ph H H 1-2149 H H H Et 2 -4- [Ph- (CH₂)₃O] -Ph H H 1-2150 H H H Pr 2-(CH₂)_Five-cHx H H 1-2151 H H H Pr 2-(CH₂)_Five-Ph H H 1-2152 H H H Pr 2-(CH₂)₆-cHx H H 1-2153 H H H Pr 2-(CH₂)₆-Ph H H 1-2154 H H H Pr 2 -C≡C-CH₂-cHx H H 1-2155 H H H Pr 2 -C≡C- (CH₂)₃-cHx H H 1-2156 H H H Pr 2 -C≡C- (CH₂)₃-Ph H H 1-2157 H H H Pr 2 -C≡C- (CH₂)_Four-cHx H H 1-2158 H H H Pr 2 -C≡C- (CH₂)_Four-Ph H H 1-2159 Me H H Pr 2 -C≡C-CH₂O-Ph H H 1-2160 CO₂Me H H Pr 2 -C≡C-CH₂O-Ph H H 1-2161 H H H Pr 2 -C≡C- (CH₂)₂O-cHx H H 1-2162 H H H Pr 2 -C≡C- (CH₂)₂O-Ph H H 1-2163 H H H Pr 2 -4- (cHx-CH₂O) Ph H H 1-2164 H H H Pr 2-(4-BzO-Ph) H H 1-2165 H H H Me 3-(CH₂)_Five-cHx H H 1-2166 H H H Me 3-(CH₂)₆-cHx H H 1-2167 H H H Me 3 -CH = CH- (CH₂)₃-cHx H H 1-2168 H H H Me 3 -CH = CH- (CH₂)_Four-cHx H H 1-2169 H H H Me 3 -C≡C- (CH₂)₃-cHx H H 1-2170 H H H Me 3 -C≡C- (CH₂)_Four-cHx H H 1-2171 H H H Me 3 -CO- (CH₂)_Four-cHx H H 1-2172 H H H Me 3 -CO- (CH₂)_Five-cHx H H 1-2173 H H H Me 3 -CO- (CH₂)_Four-Ph H H 1-2174 H H H Me 3 -CO- (CH₂)_Five-Ph H H 1-2175 H H H Me 3 -CH (OH)-(CH₂)_Four-cHx H H 1-2176 H H H Me 3 -CH (OH)-(CH₂)_Five-cHx H H 1-2177 H H H Me 3 -4- (cHx-CH₂O) Ph H H 1-2178 H H H Me 3-(4-BzO-Ph) H H 1-2179 H H H Me 3 -C≡C-CH₂O-cPn H H 1-2180 H H H Me 3 -C≡C- (CH₂)₂O-cPn H H 1-2181 H H H Me 3 -C≡C-CH₂O-cHx H H 1-2182 H H H Me 3 -C≡C- (CH₂)₂O-cHx H H 1-2183 H H H Me 3 -C≡C-CH₂O-Ph H H 1-2184 H H H Me 3 -C≡C- (CH₂)₂O-Ph H H 1-2185 H H H Me 2-(CH₂)_Four-(3-F-Ph) H H 1-2186 H H H Me 2-(CH₂)_Four-(3,4-diF-Ph) H H 1-2187 H H H Me 2-(CH₂)_Four-(3,5-diF-Ph) H H 1-2188 H H H Me 2-(CH₂)_Four-(3-Cl-Ph) H H 1-2189 H H H Me 2-(CH₂)_Four-(4-Cl-Ph) H H 1-2190 H H H Me 2-(CH₂)_Four-(3,4-diCl-Ph) H H 1-2191 H H H Me 2-(CH₂)_Four-(3,5-diCl-Ph) H H 1-2192 H H H Me 2-(CH₂)_Four-(3-Me-Ph) H H 1-2193 H H H Me 2-(CH₂)_Four-(3,4-diMe-Ph) H H 1-2194 H H H Me 2-(CH₂)_Four-(3,5-diMe-Ph) H H 1-2195 H H H Me 2-(CH₂)_Four-(3-CF₃-Ph) H H 1-2196 H H H Me 2-(CH₂)_Four-(3,4-diCF₃-Ph) H H 1-2197 H H H Me 2-(CH₂)_Four-(3,5-diCF₃-Ph) H H 1-2198 H H H Me 2-(CH₂)_Four-(3-MeO-Ph) H H 1-2199 H H H Me 2-(CH₂)_Four-(3,4-diMeO-Ph) H H 1-2200 H H H Me 2-(CH₂)_Four-(3,5-diMeO-Ph) H H 1-2201 H H H Me 2-(CH₂)_Four-(3,4,5-triMeO-Ph) H H 1-2202 H H H Me 2-(CH₂)_Four-(3-Ac-Ph) H H 1-2203 H H H Me 2-(CH₂)_Four-(4-Ac-Ph) H H 1-2204 H H H Me 2-(CH₂)_Five-(3,4-diF-Ph) H H 1-2205 H H H Me 2-(CH₂)_Five-(3,5-diF-Ph) H H 1-2206 H H H Me 2-(CH₂)_Five-(3-Cl-Ph) H H 1-2207 H H H Me 2-(CH₂)_Five-(3,4-diCl-Ph) H H 1-2208 H H H Me 2-(CH₂)_Five-(3,5-diCl-Ph) H H 1-2209 H H H Me 2-(CH₂)_Five-(3,4-diCF₃-Ph) H H 1-2210 H H H Me 2-(CH₂)_Five-(3,5-diCF₃-Ph) H H 1-2211 H H H Me 2-(CH₂)_Five-(3,4-diMeO-Ph) H H 1-2212 H H H Me 2-(CH₂)_Five-(3,5-diMeO-Ph) H H 1-2213 H H H Me 2-(CH₂)_Five-(3,4,5-triMeO-Ph) H H 1-2214 H H H Me 2-(CH₂)_Five-(3-Ac-Ph) H H 1-2215 H H H Me 2-(CH₂)_Five-(4-Ac-Ph) H H 1-2216 H H H Me 2-(CH₂)₃-O- (3-F-Ph) H H 1-2217 H H H Me 2-(CH₂)₃-O- (3,4-diF-Ph) H H 1-2218 H H H Me 2-(CH₂)₃-O- (3,5-diF-Ph) H H 1-2219 H H H Me 2-(CH₂)₃-O- (3-Me-Ph) H H 1-2220 H H H Me 2-(CH₂)₃-O- (3,4-diMe-Ph) H H 1-2221 H H H Me 2-(CH₂)₃-O- (3,5-diMe-Ph) H H 1-2222 H H H Me 2-(CH₂)₃-O- (3-CF₃-Ph) H H 1-2223 H H H Me 2-(CH₂)₃-O- (3,4-diCF₃-Ph) H H 1-2224 H H H Me 2-(CH₂)₃-O- (3,5-diCF₃-Ph) H H 1-2225 H H H Me 2-(CH₂)₃-O- (3-MeO-Ph) H H 1-2226 H H H Me 2-(CH₂)₃-O- (3,4-diMeO-Ph) H H 1-2227 H H H Me 2-(CH₂)₃-O- (3,5-diMeO-Ph) H H 1-2228 H H H Me 2-(CH₂)₃-O- (3,4,5-triMeO-Ph) H H 1-2229 H H H Me 2-(CH₂)₃-O- (3-Ac-Ph) H H 1-2230 H H H Me 2-(CH₂)₃-O- (4-Ac-Ph) H H 1-2231 H H H Me 2-(CH₂)_Four-O- (3,4-diF-Ph) H H 1-2232 H H H Me 2-(CH₂)_Four-O- (3,5-diF-Ph) H H 1-2233 H H H Me 2-(CH₂)_Four-O- (3,4-diMeO-Ph) H H 1-2234 H H H Me 2-(CH₂)_Four-O- (3,5-diMeO-Ph) H H 1-2235 H H H Me 2-(CH₂)_Four-O- (3,4,5-triMeO-Ph) H H 1-2236 H H H Me 2-(CH₂)_Four-O- (3-Ac-Ph) H H 1-2237 H H H Me 2-(CH₂)_Four-O- (4-Ac-Ph) H H 1-2238 H H H Me 2 -C≡C- (CH₂)₂-(3-F-Ph) H H 1-2239 H H H Me 2 -C≡C- (CH₂)₂-(3,4-diF-Ph) H H 1-2240 H H H Me 2 -C≡C- (CH₂)₂-(3,5-diF-Ph) H H 1-2241 H H H Me 2 -C≡C- (CH₂)₂-(3-Cl-Ph) H H 1-2242 H H H Me 2 -C≡C- (CH₂)₂-(4-Cl-Ph) H H 1-2243 H H H Me 2 -C≡C- (CH₂)₂-(3,4-diCl-Ph) H H 1-2244 H H H Me 2 -C≡C- (CH₂)₂-(3,5-diCl-Ph) H H 1-2245 H H H Me 2 -C≡C- (CH₂)₂-(3-Me-Ph) H H 1-2246 H H H Me 2 -C≡C- (CH₂)₂-(3,4-diMe-Ph) H H 1-2247 H H H Me 2 -C≡C- (CH₂)₂-(3,5-diMe-Ph) H H 1-2248 H H H Me 2 -C≡C- (CH₂)₂-(3-CF₃-Ph) H H 1-2249 H H H Me 2 -C≡C- (CH₂)₂-(3,4-diCF₃-Ph) H H 1-2250 H H H Me 2 -C≡C- (CH₂)₂-(3,5-diCF₃-Ph) H H 1-2251 H H H Me 2 -C≡C- (CH₂)₂-(3-MeO-Ph) H H 1-2252 H H H Me 2 -C≡C- (CH₂)₂-(3,4-diMeO-Ph) H H 1-2253 H H H Me 2 -C≡C- (CH₂)₂-(3,5-diMeO-Ph) H H 1-2254 H H H Me 2 -C≡C- (CH₂)₂-(3,4,5-triMeO-Ph) H H 1-2255 H H H Me 2 -C≡C- (CH₂)₂-(3-Ac-Ph) H H 1-2256 H H H Me 2 -C≡C- (CH₂)₂-(4-Ac-Ph) H H 1-2257 H H H Me 2 -C≡C- (CH₂)₃-(3,4-diF-Ph) H H 1-2258 H H H Me 2 -C≡C- (CH₂)₃-(3,5-diF-Ph) H H 1-2259 H H H Me 2 -C≡C- (CH₂)₃-(3-Cl-Ph) H H 1-2260 H H H Me 2 -C≡C- (CH₂)₃-(3,4-diCl-Ph) H H 1-2261 H H H Me 2 -C≡C- (CH₂)₃-(3,5-diCl-Ph) H H 1-2262 H H H Me 2 -C≡C- (CH₂)₃-(3,4-diCF₃-Ph) H H 1-2263 H H H Me 2 -C≡C- (CH₂)₃-(3,5-diCF₃-Ph) H H 1-2264 H H H Me 2 -C≡C- (CH₂)₃-(3,4-diMeO-Ph) H H 1-2265 H H H Me 2 -C≡C- (CH₂)₃-(3,5-diMeO-Ph) H H 1-2266 H H H Me 2 -C≡C- (CH₂)₃-(3,4,5-triMeO-Ph) H H 1-2267 H H H Me 2 -C≡C- (CH₂)₃-(3-Ac-Ph) H H 1-2268 H H H Me 2 -C≡C- (CH₂)₃-(4-Ac-Ph) H H 1-2269 H H H Me 2 -C≡C-CH₂-O- (3-F-Ph) H H 1-2270 H H H Me 2 -C≡C-CH₂-O- (3,4-diF-Ph) H H 1-2271 H H H Me 2 -C≡C-CH₂-O- (3,5-diF-Ph) H H 1-2272 H H H Me 2 -C≡C-CH₂-O- (3-Cl-Ph) H H 1-2273 H H H Me 2 -C≡C-CH₂-O- (4-Cl-Ph) H H 1-2274 H H H Me 2 -C≡C-CH₂-O- (3,4-diCl-Ph) H H 1-2275 H H H Me 2 -C≡C-CH₂-O- (3,5-diCl-Ph) H H 1-2276 H H H Me 2 -C≡C-CH₂-O- (3-Me-Ph) H H 1-2277 H H H Me 2 -C≡C-CH₂-O- (2,4-diMe-Ph) H H 1-2278 H H H Me 2 -C≡C-CH₂-O- (3,4-diMe-Ph) H H 1-2279 H H H Me 2 -C≡C-CH₂-O- (3,5-diMe-Ph) H H 1-2280 H H H Me 2 -C≡C-CH₂-O- (3-CF₃-Ph) H H 1-2281 H H H Me 2 -C≡C-CH₂-O- (3,4-diCF₃-Ph) H H 1-2282 H H H Me 2 -C≡C-CH₂-O- (3,5-diCF₃-Ph) H H 1-2283 H H H Me 2 -C≡C-CH₂-O- (3-MeO-Ph) H H 1-2284 H H H Me 2 -C≡C-CH₂-O- (3,4-diMeO-Ph) H H 1-2285 H H H Me 2 -C≡C-CH₂-O- (3,5-diMeO-Ph) H H 1-2286 H H H Me 2 -C≡C-CH₂-O- (3,4,5-triMeO-Ph) H H 1-2287 H H H Me 2 -C≡C-CH₂-O- (3-Ac-Ph) H H 1-2288 H H H Me 2 -C≡C-CH₂-O- (4-Ac-Ph) H H 1-2289 H H H Me 2 -C≡C-CH₂-O- (4-CO₂H-Ph) H H 1-2290 H H H Me 2 -C≡C- (CH₂)₂-O- (3,4-diF-Ph) H H 1-2291 H H H Me 2 -C≡C- (CH₂)₂-O- (3,5-diF-Ph) H H 1-2292 H H H Me 2 -C≡C- (CH₂)₂-O- (3-Cl-Ph) H H 1-2293 H H H Me 2 -C≡C- (CH₂)₂-O- (3,4-diCl-Ph) H H 1-2294 H H H Me 2 -C≡C- (CH₂)₂-O- (3,5-diCl-Ph) H H 1-2295 H H H Me 2 -C≡C- (CH₂)₂-O- (3,4-diCF₃-Ph) H H 1-2296 H H H Me 2 -C≡C- (CH₂)₂-O- (3,5-diCF₃-Ph) H H 1-2297 H H H Me 2 -C≡C- (CH₂)₂-O- (3,4-diMeO-Ph) H H 1-2298 H H H Me 2 -C≡C- (CH₂)₂-O- (3,5-diMeO-Ph) H H 1-2299 H H H Me 2 -C≡C- (CH₂)₂-O- (3,4,5-triMeO-Ph) H H 1-2300 H H H Me 2 -C≡C- (CH₂)₂-O- (3-Ac-Ph) H H 1-2301 H H H Me 2 -C≡C- (CH₂)₂-O- (4-Ac-Ph) H H 1-2302 H H H Me 2 -CO- (CH₂)₃-(3-F-Ph) H H 1-2303 H H H Me 2 -CO- (CH₂)₃-(4-F-Ph) H H 1-2304 H H H Me 2 -CO- (CH₂)₃-(3,4-diF-Ph) H H 1-2305 H H H Me 2 -CO- (CH₂)₃-(3,5-diF-Ph) H H 1-2306 H H H Me 2 -CO- (CH₂)₃-(3-Cl-Ph) H H 1-2307 H H H Me 2 -CO- (CH₂)₃-(4-Cl-Ph) H H 1-2308 H H H Me 2 -CO- (CH₂)₃-(3,4-diCl-Ph) H H 1-2309 H H H Me 2 -CO- (CH₂)₃-(3,5-diCl-Ph) H H 1-2310 H H H Me 2 -CO- (CH₂)₃-(3-Me-Ph) H H 1-2311 H H H Me 2 -CO- (CH₂)₃-(4-Me-Ph) H H 1-2312 H H H Me 2 -CO- (CH₂)₃-(3,4-diMe-Ph) H H 1-2313 H H H Me 2 -CO- (CH₂)₃-(3,5-diMe-Ph) H H 1-2314 H H H Me 2 -CO- (CH₂)₃-(3-Et-Ph) H H 1-2315 H H H Me 2 -CO- (CH₂)₃-(4-Et-Ph) H H 1-2316 H H H Me 2 -CO- (CH₂)₃-(3-CF₃-Ph) H H 1-2317 H H H Me 2 -CO- (CH₂)₃-(4-CF₃-Ph) H H 1-2318 H H H Me 2 -CO- (CH₂)₃-(3,4-diCF₃-Ph) H H 1-2319 H H H Me 2 -CO- (CH₂)₃-(3,5-diCF₃-Ph) H H 1-2320 H H H Me 2 -CO- (CH₂)₃-(3-MeO-Ph) H H 1-2321 H H H Me 2 -CO- (CH₂)₃-(4-MeO-Ph) H H 1-2322 H H H Me 2 -CO- (CH₂)₃-(3,4-diMeO-Ph) H H 1-2323 H H H Me 2 -CO- (CH₂)₃-(3,5-diMeO-Ph) H H 1-2324 H H H Me 2 -CO- (CH₂)₃-(3,4,5-triMeO-Ph) H H 1-2325 H H H Me 2 -CO- (CH₂)₃-(4-MeS-Ph) H H 1-2326 H H H Me 2 -CO- (CH₂)₃-(3-Ac-Ph) H H 1-2327 H H H Me 2 -CO- (CH₂)₃-(4-Ac-Ph) H H 1-2328 H H H Me 2 -CO- (CH₂)_Four-(3-F-Ph) H H 1-2329 H H H Me 2 -CO- (CH₂)_Four-(3,4-diF-Ph) H H 1-2330 H H H Me 2 -CO- (CH₂)_Four-(3,5-diF-Ph) H H 1-2331 H H H Me 2 -CO- (CH₂)_Four-(3-Cl-Ph) H H 1-2332 H H H Me 2 -CO- (CH₂)_Four-(4-Cl-Ph) H H 1-2333 H H H Me 2 -CO- (CH₂)_Four-(3,4-diCl-Ph) H H 1-2334 H H H Me 2 -CO- (CH₂)_Four-(3,5-diCl-Ph) H H 1-2335 H H H Me 2 -CO- (CH₂)_Four-(3-Me-Ph) H H 1-2336 H H H Me 2 -CO- (CH₂)_Four-(3,4-diMe-Ph) H H 1-2337 H H H Me 2 -CO- (CH₂)_Four-(3,5-diMe-Ph) H H 1-2338 H H H Me 2 -CO- (CH₂)_Four-(3-CF₃-Ph) H H 1-2339 H H H Me 2 -CO- (CH₂)_Four-(3,4-diCF₃-Ph) H H 1-2340 H H H Me 2 -CO- (CH₂)_Four-(3,5-diCF₃-Ph) H H 1-2341 H H H Me 2 -CO- (CH₂)_Four-(3-MeO-Ph) H H 1-2342 H H H Me 2 -CO- (CH₂)_Four-(3,4-diMeO-Ph) H H 1-2343 H H H Me 2 -CO- (CH₂)_Four-(3,5-diMeO-Ph) H H 1-2344 H H H Me 2 -CO- (CH₂)_Four-(3,4,5-triMeO-Ph) H H 1-2345 H H H Me 2 -CO- (CH₂)_Four-(3-Ac-Ph) H H 1-2346 H H H Me 2 -CO- (CH₂)_Four-(4-Ac-Ph) H H 1-2347 H H H Me 2 -CH (OH)-(CH₂)₃-(3-F-Ph) H H 1-2348 H H H Me 2 -CH (OH)-(CH₂)₃-(4-F-Ph) H H 1-2349 H H H Me 2 -CH (OH)-(CH₂)₃-(3,4-diF-Ph) H H 1-2350 H H H Me 2 -CH (OH)-(CH₂)₃-(3,5-diF-Ph) H H 1-2351 H H H Me 2 -CH (OH)-(CH₂)₃-(3-Cl-Ph) H H 1-2352 H H H Me 2 -CH (OH)-(CH₂)₃-(4-Cl-Ph) H H 1-2353 H H H Me 2 -CH (OH)-(CH₂)₃-(3,4-diCl-Ph) H H 1-2354 H H H Me 2 -CH (OH)-(CH₂)₃-(3,5-diCl-Ph) H H 1-2355 H H H Me 2 -CH (OH)-(CH₂)₃-(3-Me-Ph) H H 1-2356 H H H Me 2 -CH (OH)-(CH₂)₃-(4-Me-Ph) H H 1-2357 H H H Me 2 -CH (OH)-(CH₂)₃-(3,4-diMe-Ph) H H 1-2358 H H H Me 2 -CH (OH)-(CH₂)₃-(3,5-diMe-Ph) H H 1-2359 H H H Me 2 -CH (OH)-(CH₂)₃-(3-Et-Ph) H H 1-2360 H H H Me 2 -CH (OH)-(CH₂)₃-(4-Et-Ph) H H 1-2361 H H H Me 2 -CH (OH)-(CH₂)₃-(3-CF₃-Ph) H H 1-2362 H H H Me 2 -CH (OH)-(CH₂)₃-(4-CF₃-Ph) H H 1-2363 H H H Me 2 -CH (OH)-(CH₂)₃-(3,4-diCF₃-Ph) H H 1-2364 H H H Me 2 -CH (OH)-(CH₂)₃-(3,5-diCF₃-Ph) H H 1-2365 H H H Me 2 -CH (OH)-(CH₂)₃-(3-MeO-Ph) H H 1-2366 H H H Me 2 -CH (OH)-(CH₂)₃-(4-MeO-Ph) H H 1-2367 H H H Me 2 -CH (OH)-(CH₂)₃-(3,4-diMeO-Ph) H H 1-2368 H H H Me 2 -CH (OH)-(CH₂)₃-(3,5-diMeO-Ph) H H 1-2369 H H H Me 2 -CH (OH)-(CH₂)₃-(3,4,5-triMeO-Ph) H H 1-2370 H H H Me 2 -CH (OH)-(CH₂)₃-(4-MeS-Ph) H H 1-2371 H H H Me 2 -CH (OH)-(CH₂)₃-(3-Ac-Ph) H H 1-2372 H H H Me 2 -CH (OH)-(CH₂)₃-(4-Ac-Ph) H H 1-2373 H H H Me 2 -CH (OH)-(CH₂)_Four-(3-F-Ph) H H 1-2374 H H H Me 2 -CH (OH)-(CH₂)_Four-(3,4-diF-Ph) H H 1-2375 H H H Me 2 -CH (OH)-(CH₂)_Four-(3,5-diF-Ph) H H 1-2376 H H H Me 2 -CH (OH)-(CH₂)_Four-(3-Cl-Ph) H H 1-2377 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-Cl-Ph) H H 1-2378 H H H Me 2 -CH (OH)-(CH₂)_Four-(3,4-diCl-Ph) H H 1-2379 H H H Me 2 -CH (OH)-(CH₂)_Four-(3,5-diCl-Ph) H H 1-2380 H H H Me 2 -CH (OH)-(CH₂)_Four-(3-Me-Ph) H H 1-2381 H H H Me 2 -CH (OH)-(CH₂)_Four-(3,4-diMe-Ph) H H 1-2382 H H H Me 2 -CH (OH)-(CH₂)_Four-(3,5-diMe-Ph) H H 1-2383 H H H Me 2 -CH (OH)-(CH₂)_Four-(3-CF₃-Ph) H H 1-2384 H H H Me 2 -CH (OH)-(CH₂)_Four-(3,4-diCF₃-Ph) H H 1-2385 H H H Me 2 -CH (OH)-(CH₂)_Four-(3,5-diCF₃-Ph) H H 1-2386 H H H Me 2 -CH (OH)-(CH₂)_Four-(3-MeO-Ph) H H 1-2387 H H H Me 2 -CH (OH)-(CH₂)_Four-(3,4-diMeO-Ph) H H 1-2388 H H H Me 2 -CH (OH)-(CH₂)_Four-(3,5-diMeO-Ph) H H 1-2389 H H H Me 2 -CH (OH)-(CH₂)_Four-(3,4,5-triMeO-Ph) H H 1-2390 H H H Me 2 -CH (OH)-(CH₂)_Four-(3-Ac-Ph) H H 1-2391 H H H Me 2 -CH (OH)-(CH₂)_Four-(4-Ac-Ph) H H 1-2392 H H H Me 2 -O- (CH₂)₃-cHx H H 1-2393 H H H Me 2 -O- (CH₂)_Four-cHx H H 1-2394 H H H Me 2 -O- (CH₂)_Five-cHx H H 1-2395 H H H Me 2 -O- (CH₂)₃-Ph H H 1-2396 H H H Me 2 -O- (CH₂)_Four-Ph H H 1-2397 H H H Me 2 -O- (CH₂)_Five-Ph H H .

[0107]

[Table 2]

[0108]

[Chemical 21] Compd. R ¹ R ² R ³ R ⁴ n -XYR ⁵ R ⁶ R ⁷ 2-1 HHH Me 1-(CH ₂ ) ₅ -cHx HH 2-2 HHH Me 1-(CH ₂ ) ₆ -cHx HH 2-3 HHH Me 1 -C≡C- (CH ₂ ) ₃ -cHx HH 2 -4 HHH Me 1 -C≡C- (CH ₂ ) ₄ -cHx HH 2-5 HHH Me 1 -4- (cHx-CH ₂ O) Ph HH 2-6 HHH Me 1-(4-BzO-Ph) HH 2-7 HHH Me 1 -C≡C- (CH ₂ ) ₂ O-cHx HH 2-8 HHH Me 1 -C≡C- (CH ₂ ) ₂ O-Ph HH 2-9 HHH Me 2-(CH ₂ ) ₃ -cHx HH 2-10 HHH Me 2-(CH ₂ ) ₃ -Ph HH 2-11 HHH Me 2-(CH ₂ ) ₄ -cHx HH 2-12 HHH Me 2-(CH ₂ ) ₄ -Ph HH 2-13 HHH Me 2-(CH ₂ ) ₅ -cPn HH 2-14 HHH Me 2-(CH ₂ ) ₅ -cHx HH 2-15 HHH Me 2-(CH ₂ ) ₅ -cHx Me H 2-16 HHH Me 2-(CH ₂ ) ₅ -cHx H Me 2-17 HHH Me 2-(CH ₂ ) ₅ -cHx FH 2-18 HHH Me 2-(CH ₂ ) ₅ -cHx HF 2-19 HH Me Me 2 -(CH ₂ ) ₅ -cHx HH 2-20 Me HH Me 2-(CH ₂ ) ₅ -cHx HH 2-21 CO ₂ Me HH Me 2-(CH ₂ ) ₅ -cHx HH 2-22 HHH Me 2- (CH ₂ ) _5- (4-F-cHx) HH 2-23 HHH Me 2-(CH ₂ ) _5- (4-Cl-cHx) HH 2-24 HHH Me 2-(CH ₂ ) _5- (4 -Br-cHx) HH 2-25 HHH Me 2-(CH ₂ ) _5- (4-Me-cHx) HH 2-26 HHH Me 2-(CH ₂ ) _5- (4-Et-cHx) HH 2- 27 HHH Me 2-(CH ₂ ) _5- (4-Pr-cHx) HH 2-28 HHH Me 2-(CH ₂ ) _5- (4-iPr-cHx) HH 2-29 HHH Me 2-(CH ₂ ) _5- (4-CF ₃ -cHx) HH 2-30 HHH Me 2-(CH ₂ ) _5- (4-MeO-cHx) HH 2-31 HHH Me 2- (CH ₂ ) _5- (4-EtO-cHx) HH 2-32 HHH Me 2-(CH ₂ ) _5- (4-PrO-cHx) HH 2-33 HHH Me 2-(CH ₂ ) _5- (4 -iPrO-cHx) HH 2-34 HHH Me 2-(CH ₂ ) _5- (3-MeS-cHx) HH 2-35 HHH Me 2-(CH ₂ ) _5- (4-MeS-cHx) HH 2- 36 HHH Me 2-(CH ₂ ) _5- (2,4-diMe-cHx) HH 2-37 HHH Me 2-(CH ₂ ) _5- (3,4-diMe-cHx) HH 2-38 HHH Me 2 -(CH ₂ ) _5- (3,5-diMe-cHx) HH 2-39 HHH Me 2-(CH ₂ ) ₅ -Ph HH 2-40 HHH Me 2-(CH ₂ ) ₅ -Ph Me H 2- 41 HHH Me 2-(CH ₂ ) ₅ -Ph H Me 2-42 HHH Me 2-(CH ₂ ) ₅ -Ph FH 2-43 HHH Me 2-(CH ₂ ) ₅ -Ph HF 2-44 HH Me Me 2-(CH ₂ ) ₅ -Ph HH 2-45 Me HH Me 2-(CH ₂ ) ₅ -Ph HH 2-46 CO ₂ Me HH Me 2-(CH ₂ ) ₅ -Ph HH 2-47 HHH Me 2 -(CH ₂ ) _5- (4-F-Ph) HH 2-48 HHH Me 2-(CH ₂ ) _5- (4-Cl-Ph) HH 2-49 HHH Me 2-(CH ₂ ) _5- ( 4-Br-Ph) HH 2-50 HHH Me 2-(CH ₂ ) _5- (4-Me-Ph) HH 2-51 HHH Me 2-(CH ₂ ) _5- (4-Et-Ph) HH 2 -52 HHH Me 2-(CH ₂ ) _5- (4-Pr-Ph) HH 2-53 HHH Me 2-(CH ₂ ) _5- (4-iPr-Ph) HH 2-54 HHH Me 2-(CH ₂ ) _5- (4-Bu-Ph ) HH 2-55 HHH Me 2-(CH ₂ ) _5- (4-CF ₃ -Ph) HH 2-56 HHH Me 2-(CH ₂ ) _5- (4-MeO-Ph) HH 2-57 HHH Me 2-(CH ₂ ) _5- (4-EtO-Ph) HH 2-58 HHH Me 2-(CH ₂ ) _5- (4-PrO-Ph) HH 2-59 HHH Me 2-(CH ₂ ) _5- (4-iPrO-Ph) HH 2-60 HHH Me 2-(CH ₂ ) _5- (3-MeS-Ph) HH 2-61 HHH Me 2-(CH ₂ ) _5- (4-MeS-Ph) HH 2-62 HHH Me 2-(CH ₂ ) _5- (2,4-diMe-Ph) HH 2-63 HHH Me 2-(CH ₂ ) _5- (3,4-diMe-Ph) HH 2-64 HHH Me 2-(CH ₂ ) _5- (3,5-diMe-Ph) HH 2-65 HHH Me 2-(CH ₂ ) ₆ -cPn HH 2-66 HHH Me 2-(CH ₂ ) ₆ -cHx HH 2 -67 HHH Me 2-(CH ₂ ) ₆ -cHx Me H 2-68 HHH Me 2-(CH ₂ ) ₆ -cHx H Me 2-69 HHH Me 2-(CH ₂ ) ₆ -cHx FH 2-70 HHH Me 2-(CH ₂ ) ₆ -cHx HF 2-71 HH Me Me 2-(CH ₂ ) ₆ -cHx HH 2-72 Me HH Me 2-(CH ₂ ) ₆ -cHx HH 2-73 CO ₂ Me HH Me 2-(CH ₂ ) ₆ -cHx HH 2-74 HHH Me 2-(CH ₂ ) _6- (4-F-cHx) HH 2-75 HHH Me 2-(CH ₂ ) _6- (4-Cl- cHx) HH 2-76 HHH Me 2-(CH ₂ ) _6- (4-Br-cHx) HH 2-77 HHH Me 2-(CH ₂ ) _6- (4-Me-cHx) HH 2-78 HHH Me 2-(CH ₂ ) _6- (4-Et-cHx) HH 2-79 HHH Me 2-(CH ₂ ) _6- (4-Pr-cHx) HH 2-80 HHH Me 2-(CH ₂ ) _6- (4-iPr -cHx) HH 2-81 HHH Me 2-(CH ₂ ) _6- (4-Bu-cHx) HH 2-82 HHH Me 2-(CH ₂ ) _6- (4-CF ₃ -cHx) HH 2-83 HHH Me 2-(CH ₂ ) _6- (4-MeO-cHx) HH 2-84 HHH Me 2-(CH ₂ ) _6- (4-EtO-cHx) HH 2-85 HHH Me 2-(CH ₂ ) _6- (4-PrO-cHx) HH 2-86 HHH Me 2-(CH ₂ ) _6- (4-iPrO-cHx) HH 2-87 HHH Me 2-(CH ₂ ) _6- (3-MeS-cHx ) HH 2-88 HHH Me 2-(CH ₂ ) _6- (4-MeS-cHx) HH 2-89 HHH Me 2-(CH ₂ ) _6- (2,4-diMe-cHx) HH 2-90 HHH Me 2-(CH ₂ ) _6- (3,4-diMe-cHx) HH 2-91 HHH Me 2-(CH ₂ ) _6- (3,5-diMe-cHx) HH 2-92 HHH Me 2-( CH ₂ ) ₆ -Ph HH 2-93 HHH Me 2-(CH ₂ ) ₆ -Ph Me H 2-94 HHH Me 2-(CH ₂ ) ₆ -Ph H Me 2-95 HHH Me 2-(CH ₂ ) ₆ -Ph FH 2-96 HHH Me 2-(CH ₂ ) ₆ -Ph HF 2-97 HH Me Me 2-(CH ₂ ) ₆ -Ph HH 2-98 Me HH Me 2-(CH ₂ ) ₆ -Ph HH 2-99 CO ₂ Me HH Me 2-(CH ₂ ) ₆ -Ph HH 2-100 HHH Me 2-(CH ₂ ) _6- (4-F-Ph) HH 2-101 HHH Me 2-(CH _{2 ) 6 - (4-Cl-} Ph) HH 2-102 HHH Me 2 - (CH 2) 6 - (4-Br-Ph) HH 2-103 HHH Me 2 - (CH 2) 6 - (4-Me- Ph) HH 2-104 HHH Me 2-(CH ₂ ) _6- (4-Et-Ph) HH 2-105 HHH Me 2-(CH ₂ ) _6- (4-Pr-Ph) HH 2-106 HHH Me 2-(CH ₂ ) _6- (4-iPr-Ph) HH 2-107 HHH Me 2-(CH ₂ ) _6- (4-Bu-Ph) HH 2-108 HHH Me 2-(CH ₂ ) _6- (4-CF ₃ -Ph) HH 2-109 HHH Me 2-(CH ₂ ) _6- (4-MeO-Ph) HH 2-110 HHH Me 2-(CH ₂ ) _6- (4-EtO-Ph) HH 2-111 HHH Me 2-(CH ₂ ) _6- (4-PrO-Ph) HH 2-112 HHH Me 2-(CH ₂ ) _6- (4-iPrO-Ph) HH 2-113 HHH Me 2-(CH ₂ ) _6- (3-MeS-Ph) HH 2-114 HHH Me 2-(CH ₂ ) _6- (4-MeS-Ph) HH 2-115 HHH Me 2-(CH ₂ ) _6- (2,4-diMe -Ph) HH 2-116 HHH Me 2-(CH ₂ ) _6- (3,4-diMe-Ph) HH 2-117 HHH Me 2-(CH ₂ ) _6- (3,5-diMe-Ph) HH 2-118 HHH Me 2-(CH ₂ ) ₇ -cHx HH 2-119 HHH Me 2-(CH ₂ ) ₇ -Ph HH 2-120 HHH Me 2-(CH ₂ ) ₈ -cHx HH 2-121 HHH Me 2-(CH ₂ ) ₈ -Ph HH 2-122 HHH Me 2 -CH = CH- (CH ₂ ) ₃ -cHx HH 2-123 HH Me Me 2 -CH = CH- (CH ₂ ) ₃ -cHx HH 2 -124 Me HH Me 2 -CH = CH- (CH ₂ ) ₃ -cHx HH 2-125 CO ₂ Me HH Me 2 -CH = CH- (CH ₂ ) ₃ -cHx HH 2-126 HHH Me 2 -CH = CH- (CH ₂ ) ₃ -Ph HH 2-127 HH Me Me 2 -CH = CH- (CH ₂ ) ₃ -Ph HH 2-128 Me HH Me 2 -CH = CH- (CH ₂ ) ₃ -Ph HH 2-129 CO ₂ Me HH Me 2 -CH = CH- (CH ₂ ) ₃ -Ph HH 2-130 HHH Me 2 -CH = CH- (CH ₂ ) ₄ -cHx HH 2-13 1 HH Me Me 2 -CH = CH- (CH ₂ ) ₄ -cHx HH 2-132 Me HH Me 2 -CH = CH- (CH ₂ ) ₄ -cHx HH 2-133 CO ₂ Me HH Me 2 -CH = CH- (CH ₂ ) ₄ -cHx HH 2-134 HHH Me 2 -CH = CH- (CH ₂ ) ₄ -Ph HH 2-135 HH Me Me 2 -CH = CH- (CH ₂ ) ₄ -Ph HH 2 -136 Me HH Me 2 -CH = CH- (CH ₂ ) ₄ -Ph HH 2-137 CO ₂ Me HH Me 2 -CH = CH- (CH ₂ ) ₄ -Ph HH 2-138 HHH Me 2 -C = C-CH ₂ O-cHx HH 2-139 HHH Me 2 -C = C-CH ₂ O-Ph HH 2-140 HHH Me 2 -C = C- (CH ₂ ) ₂ O-cHx HH 2-141 HHH Me 2 -C = C- (CH ₂ ) ₂ O-Ph HH 2-142 HHH Me 2 -C ≡ C-CH ₂ -cHx HH 2-143 HH Me Me ₂ -C ≡ C-CH ₂ -cHx HH 2- 144 Me HH Me 2 -C ≡ C-CH ₂ -cHx HH 2-145 CO ₂ Me HH Me ₂ -C ≡ C-CH ₂ -cHx HH 2-146 HHH Me 2 -C ≡ C-CH ₂ -Ph HH 2-147 HH Me Me 2 -C ≡ C-CH ₂ -Ph HH 2-148 Me HH Me 2 -C ≡ C-CH ₂ -Ph HH 2-149 CO ₂ Me HH Me 2 -C ≡ C-CH ₂ -Ph HH 2-150 HHH Me 2 -C≡C- (CH ₂ ) ₂ -cHx HH 2-151 HH Me Me 2 -C≡C- (CH ₂ ) ₂ -cHx HH 2-152 Me HH Me 2- C ≡ C- (CH ₂ ) ₂ -cHx HH 2-153 CO ₂ Me HH Me ₂ -C ≡ C- (CH ₂ ) ₂ -cHx HH 2-154 HHH Me 2 -C ≡ C- (CH ₂ ) ₂ -Ph HH 2-155 HH Me Me 2 -C≡C- (CH ₂ ) ₂ -Ph HH 2-156 Me HH M e 2 -C≡C- (CH ₂ ) ₂ -Ph HH 2-157 CO ₂ Me HH Me 2 -C≡C- (CH ₂ ) ₂ -Ph HH 2-158 HHH Me 2 -C≡C- (CH ₂ ) ₃ -cPn HH 2-159 HHH Me 2 -C≡C- (CH ₂ ) ₃ -cHx HH 2-160 HHH Me 2 -C≡C- (CH ₂ ) ₃ -cHx Me H 2-161 HHH Me 2 -C≡C- (CH ₂ ) ₃ -cHx H Me 2-162 HHH Me 2 -C≡C- (CH ₂ ) ₃ -cHx FH 2-163 HHH Me 2 -C≡C- (CH ₂ ) ₃ -cHx HF 2-164 HH Me Me 2 -C≡C- (CH ₂ ) ₃ -cHx HH 2-165 Me HH Me 2 -C≡C- (CH ₂ ) ₃ -cHx HH 2-166 CO ₂ Me HH Me 2 -C≡C- (CH ₂ ) ₃ -cHx HH 2-167 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-F-cHx) HH 2-168 HHH Me 2 -C≡C -(CH ₂ ) _3- (4-Cl-cHx) HH 2-169 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-Br-cHx) HH 2-170 HHH Me 2 -C≡C -(CH ₂ ) _3- (4-Me-cHx) HH 2-171 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-Et-cHx) HH 2-172 HHH Me 2 -C≡C -(CH ₂ ) _3- (4-Pr-cHx) HH 2-173 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-iPr-cHx) HH 2-174 HHH Me 2 -C≡C -(CH ₂ ) _3- (4-Bu-cHx) HH 2-175 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-CF ₃ -cHx) HH 2-176 HHH Me 2 -C≡ _{C- (CH 2) 3 - (} 4-MeO-cHx) HH 2-177 HHH Me 2 -C≡C- (CH 2) 3 - (4-EtO-cHx) HH 2-178 HHH Me 2 -C≡ C- (CH ₂ ) _3- (4-PrO-cHx) HH 2-179 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-iPrO-cHx) HH 2-180 HHH Me 2 -C≡C- (CH ₂ ) _3- (3-MeS-cHx) HH 2-181 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-MeS-cHx) HH 2-182 HHH Me 2 -C≡C- (CH ₂ ) _3- (2,4-diMe-cHx) HH 2-183 HHH Me 2 -C≡C- (CH ₂ ) _3- (3,4-diMe-cHx) HH 2-184 HHH Me 2 -C≡C- (CH ₂ ) _3- (3,5-diMe-cHx) HH 2-185 HHH Me 2 -C≡C- (CH ₂ ) ₃ -Ph HH 2-186 HHH Me 2 -C≡C- (CH ₂ ) ₃ -Ph Me H 2-187 HHH Me 2 -C≡C- (CH ₂ ) ₃ -Ph H Me 2-188 HHH Me 2 -C≡C- (CH ₂ ) ₃ -Ph FH 2-189 HHH Me 2 -C≡C- (CH ₂ ) ₃ -Ph HF 2-190 HH Me Me 2 -C ≡ C- (CH ₂ ) ₃ -Ph HH 2-191 Me HH Me 2 -C ≡ C- (CH ₂ ) ₃ -Ph HH 2-192 CO ₂ Me HH Me 2 -C≡C- (CH ₂ ) ₃ -Ph HH 2-193 HHH Me 2 -C ≡C- (CH ₂ ) _3- (4-F-Ph) HH 2-194 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-Cl-Ph) HH 2-195 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-Br-Ph) HH 2-196 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-Me-Ph) HH 2-197 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-Et-Ph) HH 2-198 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-Pr-Ph) HH 2-199 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-iPr-Ph) HH 2-200 HHH Me 2 -C≡C- (CH ₂ ) _3- ( 4-Bu-Ph) HH 2-201 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-CF ₃ -Ph) HH 2-202 HHH Me 2 -C ≡C- (CH ₂ ) _3- (4-MeO-Ph) HH 2-203 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-EtO-Ph) HH 2-204 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-PrO-Ph) HH 2-205 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-iPrO-Ph) HH 2-206 HHH Me 2 -C≡C- (CH ₂ ) _3- (3-MeS-Ph) HH 2-207 HHH Me 2 -C≡C- (CH ₂ ) _3- (4-MeS-Ph) HH 2-208 HHH Me 2 -C≡C- (CH ₂ ) _3- (2,4-diMe-Ph) HH 2-209 HHH Me 2 -C≡C- (CH ₂ ) _3- (3,4-diMe-Ph) HH 2-210 HHH Me 2 -C≡C- (CH _{2) 3 - (3,5-diMe} -Ph) HH 2-211 HHH Me 2 -C≡C- (CH 2) 4 -cPn HH 2-212 HHH Me 2 -C≡C- (CH 2) 4 - cHx HH 2-213 HHH Me 2 -C≡C- ( CH 2) 4 -cHx Me H 2-214 HHH Me 2 -C≡C- (CH 2) 4 -cHx H Me 2-215 HHH Me 2 -C ≡ C- (CH ₂ ) ₄ -cHx FH 2-216 HHH Me 2 -C ≡ C- (CH ₂ ) ₄ -cHx HF 2-217 HH Me Me 2 -C ≡ C- (CH ₂ ) ₄ -cHx HH 2-218 Me HH Me 2 -C≡C- (CH ₂ ) ₄ -cHx HH 2-219 CO ₂ Me HH Me 2 -C ≡ C- (CH ₂ ) ₄ -cHx HH 2-220 HHH Me 2 -C _{≡C- (CH 2) 4 - (} 4-F-cHx) HH 2-221 HHH Me 2 -C≡C- (CH 2) 4 - (4-Cl-cHx) HH 2-222 HHH Me 2 -C _{≡C- (CH 2) 4 - (} 4-Br -cHx) HH 2-223 HHH Me 2 -C≡C- (CH 2) 4 - (4-Me-cHx) HH 2-224 HHH Me 2 -C≡C- (CH 2) 4 - (4-Et -cHx) HH 2-225 HHH Me 2 -C≡C- (CH 2) 4 - (4-Pr-cHx) HH 2-226 HHH Me 2 -C≡C- (CH 2) 4 - (4-iPr -cHx) HH 2-227 HHH Me 2 -C≡C- (CH 2) 4 - (4-Bu-cHx) HH 2-228 HHH Me 2 -C≡C- (CH 2) 4 - (4-CF _{3 -cHx) HH 2-229 HHH Me 2} -C≡C- (CH 2) 4 - (4-MeO-cHx) HH 2-230 HHH Me 2 -C≡C- (CH 2) 4 - (4- EtO-cHx) HH 2-231 HHH Me 2 -C≡C- (CH 2) 4 - (4-PrO-cHx) HH 2-232 HHH Me 2 -C≡C- (CH 2) 4 - (4- iPrO-cHx) HH 2-233 HHH Me 2 -C≡C- (CH 2) 4 - (4-MeS-cHx) HH 2-234 HHH Me 2 -C≡C- (CH 2) 4 - (2, 4-diMe-cHx) HH 2-235 HHH Me 2 -C≡C- (CH 2) 4 - (3,4-diMe-cHx) HH 2-236 HHH Me 2 -C≡C- (CH 2) 4 -(3,5-diMe-cHx) HH 2-237 HHH Me 2 -C≡C- (CH ₂ ) ₄ -Ph HH 2-238 HHH Me 2 -C ≡ C- (CH ₂ ) ₄ -Ph Me H 2-239 HHH Me 2 -C≡C- (CH ₂ ) ₄ -Ph H Me 2-240 HHH Me 2 -C ≡ C- (CH ₂ ) ₄ -Ph FH 2-241 HHH Me 2 -C ≡ C- (CH ₂ ) ₄ -Ph HF 2-242 HH Me Me 2 -C≡C- (CH ₂ ) ₄ -Ph HH 2-243 Me HH Me 2 -C≡C- (CH ₂ ) ₄ -Ph HH 2- 244 CO ₂ Me HH Me 2 -C≡C- ( _{CH 2) 4 -Ph HH 2-245 HHH} Me 2 -C≡C- (CH 2) 4 - (4-F-Ph) HH 2-246 HHH Me 2 -C≡C- (CH 2) 4 - ( 4-Cl-Ph) HH 2-247 HHH Me 2 -C≡C- (CH 2) 4 - (4-Br-Ph) HH 2-248 HHH Me 2 -C≡C- (CH 2) 4 - ( 4-Me-Ph) HH 2-249 HHH Me 2 -C≡C- (CH 2) 4 - (4-Et-Ph) HH 2-250 HHH Me 2 -C≡C- (CH 2) 4 - ( 4-Pr-Ph) HH 2-251 HHH Me 2 -C≡C- (CH 2) 4 - (4-iPr-Ph) HH 2-252 HHH Me 2 -C≡C- (CH 2) 4 - ( 4-Bu-Ph) HH 2-253 HHH Me 2 -C≡C- (CH 2) 4 - (4-CF 3 -Ph) HH 2-254 HHH Me 2 -C≡C- (CH 2) 4 - (4-MeO-Ph) HH 2-255 HHH Me 2 -C≡C- (CH 2) 4 - (4-EtO-Ph) HH 2-256 HHH Me 2 -C≡C- (CH 2) 4 - (4-PrO-Ph) HH 2-257 HHH Me 2 -C≡C- (CH 2) 4 - (4-iPrO-Ph) HH 2-258 HHH Me 2 -C≡C- (CH 2) 4 - (3-MeS-Ph) HH 2-259 HHH Me 2 -C≡C- (CH 2) 4 - (4-MeS-Ph) HH 2-260 HHH Me 2 -C≡C- (CH 2) 4 - (2,4-diMe-Ph) HH 2-261 HHH Me 2 -C≡C- (CH 2) 4 - (3,4-diMe-Ph) HH 2-262 HHH Me 2 -C≡C- (CH _{2) 4 - (3,5-diMe} -Ph) HH 2-263 HHH Me 2 -C≡C- (CH 2) 5 -cHx HH 2-264 HH Me Me 2 -C≡C- (CH 2) 5 -cHx HH 2-265 Me HH Me 2 -C≡C- (CH ₂ ) ₅ -cHx HH 2-266 CO ₂ Me HH Me 2 -C ≡ C- (CH ₂ ) ₅ -cHx HH 2-267 HHH Me 2 -C ≡ C- (CH ₂ ) ₅ -Ph HH 2-268 HH Me Me 2 -C ≡ C- (CH ₂ ) ₅ -Ph HH 2-269 Me HH Me 2 -C≡C- (CH ₂ ) ₅ -Ph HH 2-270 CO ₂ Me HH Me 2 -C≡C- (CH ₂ ) ₅ -Ph HH 2- 271 HHH Me 2 -C≡C- (CH ₂ ) ₆ -cHx HH 2-272 HH Me Me 2 -C≡C- (CH ₂ ) ₆ -cHx HH 2-273 Me HH Me 2 -C≡C- ( CH ₂ ) ₆ -cHx HH 2-274 CO ₂ Me HH Me 2 -C≡C- (CH ₂ ) ₆ -cHx HH 2-275 HHH Me 2 -C≡C- (CH ₂ ) ₆ -Ph HH 2- 276 HH Me Me 2 -C≡C- (CH ₂ ) ₆ -Ph HH 2-277 Me HH Me 2 -C ≡ C- (CH ₂ ) ₆ -Ph HH 2-278 CO ₂ Me HH Me 2 -C ≡ C- (CH ₂ ) ₆ -Ph HH 2-279 HHH Me 2 -C≡C-CH ₂ O-cHx HH 2-280 HH Me Me 2 -C≡C-CH ₂ O-cHx HH 2-281 Me HH Me 2 -C ≡ C-CH ₂ O-cHx HH 2-282 CO ₂ Me HH Me 2 -C ≡ C-CH ₂ O-cHx HH 2-283 HHH Me 2 -C ≡ C-CH ₂ O-Ph HH 2-284 HH Me Me 2 -C ≡ C-CH ₂ O-Ph HH 2-285 Me HH Me 2 -C ≡ C-CH ₂ O-Ph HH 2-286 CO ₂ Me HH Me 2 -C ≡ C- CH ₂ O-Ph HH 2-287 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-cPn HH 2-288 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-cHx HH 2-289 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-cHx Me H 2-290 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-cHx H Me 2-291 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-cHx FH 2-292 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-cHx HF 2-293 HH Me Me 2 -C≡C- (CH ₂ ) ₂ -OCH ₂ -cHx HH 2-294 Me HH Me 2 -C≡C- (CH ₂ ) ₂ O-cHx HH 2-295 CO ₂ Me HH Me 2 -C≡C- (CH ₂ ) ₂ O-cHx HH 2-296 HHH Me 2 -C ≡ C- (CH ₂ ) ₂ O- (4-F-cHx) HH 2-297 HHH Me 2 -C ≡ C -(CH ₂ ) ₂ O- (4-Cl-cHx) HH 2-298 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-Br-cHx) HH 2-299 HHH Me 2 -C ≡ C- (CH ₂ ) ₂ O- (4-Me-cHx) HH 2-300 HHH Me 2 -C ≡ C- (CH ₂ ) ₂ O- (4-Et-cHx) HH 2-301 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-Pr-cHx) HH 2-302 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-iPr-cHx) HH 2-303 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-Bu-cHx) HH 2-304 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-CF ₃ -cHx) HH 2 -305 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-MeO-cHx) HH 2-306 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-EtO-cHx) HH 2-307 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-PrO-cHx) HH 2-308 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-iPrO- cHx) HH 2-309 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (3-MeS-cHx) HH 2-310 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4- MeS-cHx) HH 2-311 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (2,4-diMe-cHx) HH 2-312 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (3,4-diMe-cHx) HH 2-313 HHH Me 2 -C≡C -(CH ₂ ) ₂ O- (3,5-diMe-cHx) HH 2-314 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-Ph HH 2-315 HHH Me 2 -C ≡ C- ( CH ₂ ) ₂ O-Ph Me H 2-316 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-Ph H Me 2-317 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-Ph FH 2-318 HHH Me 2 -C≡C- (CH ₂ ) ₂ O-Ph HF 2-319 HH Me Me 2 -C ≡ C- (CH ₂ ) ₂ -OCH ₂ -Ph HH 2-320 Me HH Me 2 -C≡C- (CH ₂ ) ₂ O-Ph HH 2-321 CO ₂ Me HH Me 2 -C≡C- (CH ₂ ) ₂ O-Ph HH 2-322 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-F-Ph) HH 2-323 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-Cl-Ph) HH 2-324 HHH Me 2 -C ≡ C- (CH ₂ ) ₂ O- (4-Br-Ph) HH 2-325 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-Me-Ph) HH 2-326 HHH Me 2 -C≡ C- (CH ₂ ) ₂ O- (4-Et-Ph) HH 2-327 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-Pr-Ph) HH 2-328 HHH Me 2- C≡C- (CH ₂ ) ₂ O- (4-iPr-Ph) HH 2-329 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-Bu-Ph) HH 2-330 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-CF ₃ -Ph) HH 2-331 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-MeO-Ph) HH 2- 332 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-EtO-Ph) HH 2-333 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-PrO-Ph) HH 2-334 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-iPrO-Ph) HH 2-335 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (4-MeS-Ph) HH 2-336 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (2,4-diMe-Ph) HH 2-337 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (3,4-diMe-Ph) HH 2-338 HHH Me 2 -C≡C- (CH ₂ ) ₂ O- (3, 5-diMe-Ph) HH 2-339 HHH Me 2 -CO- (CH ₂ ) ₄ -cHx HH 2-340 HH Me Me 2 -CO- (CH ₂ ) ₄ -cHx HH 2-341 Me HH Me 2- CO- (CH ₂ ) ₄ -cHx HH 2-342 CO ₂ Me HH Me 2 -CO- (CH ₂ ) ₄ -cHx HH 2-343 HHH Me 2 -CO- (CH ₂ ) ₄ -Ph HH 2-344 HH Me Me 2 -CO- (CH ₂ ) ₄ -Ph HH 2-345 Me HH Me 2 -CO- (CH ₂ ) ₄ -Ph HH 2-346 CO ₂ Me HH Me 2 -CO- (CH ₂ ) ₄ -Ph HH 2-347 HHH Me 2 -CO- (CH ₂ ) ₅ -cHx HH 2-348 HH Me Me 2 -CO- (CH ₂ ) ₅ -cHx HH 2-349 Me HH Me 2 -CO- (CH ₂ ) ₅ -cHx HH 2-350 CO ₂ Me HH Me 2 -CO- (CH ₂ ) ₅ -cHx HH 2-351 HHH Me 2 -CO- (CH ₂ ) ₅ -Ph HH 2-352 HH Me Me 2 -CO- (CH ₂ ) ₅ -Ph HH 2-353 Me HH Me 2 -CO- (CH ₂ ) ₅ -Ph HH 2-354 CO ₂ Me HH Me 2 -CO- (CH ₂ ) ₅ -Ph HH 2 -355 HHH Me 2 -CH (OH)-(CH ₂ ) ₄ -cHx HH 2-356 HH Me Me 2 -CH (OH)-(CH ₂ ) ₄ -cHx HH 2-3 57 Me HH Me 2 -CH (OH)-(CH ₂ ) ₄ -cHx HH 2-358 CO ₂ Me HH Me 2 -CH (OH)-(CH ₂ ) ₄ -cHx HH 2-359 HHH Me 2 -CH (OH)-(CH ₂ ) ₄ -Ph HH 2-360 HH Me Me 2 -CH (OH)-(CH ₂ ) ₄ -Ph HH 2-361 Me HH Me 2 -CH (OH)-(CH ₂ ) ₄ -Ph HH 2-362 CO ₂ Me HH Me 2 -CH (OH)-(CH ₂ ) ₄ -Ph HH 2-363 HHH Me 2 -CH (OH)-(CH ₂ ) ₅ -cHx HH 2-364 HH Me Me 2 -CH (OH)-(CH ₂ ) ₅ -cHx HH 2-365 Me HH Me 2 -CH (OH)-(CH ₂ ) ₅ -cHx HH 2-366 CO ₂ Me HH Me 2 -CH (OH)-(CH ₂ ) ₅ -cHx HH 2-367 HHH Me 2 -CH (OH)-(CH ₂ ) ₅ -Ph HH 2-368 HH Me Me 2 -CH (OH)-(CH ₂ ) ₅ -Ph HH 2-369 Me HH Me 2 -CH (OH)-(CH ₂ ) ₅ -Ph HH 2-370 CO ₂ Me HH Me 2 -CH (OH)-(CH ₂ ) ₅ -Ph HH 2-371 HHH Me 2 -4- (cHx-CH ₂ O) Ph HH 2-372 HH Me Me 2 -4- (cHx-CH ₂ O) Ph HH 2-373 Me HH Me 2 -4- (cHx-CH ₂ O ) Ph HH 2-374 CO ₂ Me HH Me 2 -4- (cHx-CH ₂ O) Ph HH 2-375 HHH Me 2 -4- [cHx- (CH ₂ ) ₂ O] Ph HH 2-376 HHH Me 2 -4- [cHx- (CH ₂ ) ₃ O] Ph HH 2-377 HHH Me 2-(4-BzO-Ph) HH 2-378 HH Me Me 2-(4-BzO-Ph) HH 2-379 Me HH Me 2-(4-BzO-Ph) HH 2-380 CO ₂ Me HH Me 2-(4-BzO-Ph) HH 2-381 HHH Me 2-(4-BzO-2-F- Ph) HH 2-382 HHH Me 2-(4-BzO-3-F-Ph) HH 2-383 HHH Me 2-(4-BzO-2,3-diF-Ph) HH 2-384 HHH Me 2- (4-BzO-2-Cl-Ph) HH 2-385 HHH Me 2-(4-BzO-3-Cl-Ph) HH 2-386 HHH Me 2-(4-BzO-2,3-diCl-Ph ) HH 2-387 HHH Me 2-(4-BzO-2-Me-Ph) HH 2-388 HHH Me 2-(4-BzO-3-Me-Ph) HH 2-389 HHH Me 2-(4- BzO-2,3-diMe-Ph) HH 2-390 HHH Me 2 -4- [Ph- (CH ₂ ) ₂ O] -Ph HH 2-391 HHH Me 2 -4- [Ph- (CH ₂ ) ₃ O] -Ph HH 2-392 HHH Et 2-(CH ₂ ) ₅ -cHx HH 2-393 HHH Et 2-(CH ₂ ) ₆ -cHx HH 2-394 HHH Et 2 -C≡C- (CH ₂ ) ₃ -cHx HH 2-395 HHH Et 2 -C≡C- (CH ₂ ) ₄ -cHx HH 2-396 HHH Et 2 -4- (cHx-CH ₂ O) Ph HH 2-397 HHH Et 2-(4 -BzO-Ph) HH 2-398 HHH Et 2 -C≡C- (CH ₂ ) ₂ O-cHx HH 2-399 HHH Et 2 -C≡C- (CH ₂ ) ₂ O-Ph HH 2-400 HHH Pr 2-(CH ₂ ) ₅ -cHx HH 2-401 HHH Pr 2-(CH ₂ ) ₆ -cHx HH 2-402 HHH Pr 2 -C≡C- (CH ₂ ) ₃ -cHx HH 2-403 HHH Pr 2 -C≡C- (CH ₂ ) ₄ -cHx HH 2-404 HHH Pr 2 -4- (cHx-CH ₂ O) Ph HH 2-405 HHH Pr 2-(4-BzO-Ph) HH 2-406 HHH Pr 2 -C ≡ C- (CH ₂ ) ₂ O-cHx HH 2-407 HHH Pr 2 -C ≡ C- (CH ₂ ) ₂ O-Ph HH 2-408 HHH Me 3-(CH ₂ ) _5- cHx HH 2-409 HHH Me 3-(CH ₂ ) ₆ -cHx HH 2-410 HHH Me 3 -C≡C- (CH ₂ ) ₃ -cHx HH 2-411 HHH Me 3 -C ≡ C- (CH ₂ ) ₄ -cHx HH 2-412 HHH Me 3 -4- (cHx-CH ₂ O) Ph HH 2-413 HHH Me 3-(4-BzO-Ph) HH 2-414 HHH Me 3 -C≡C- (CH ₂ ) ₂ O-cHx HH 2-415 HHH Me 3 -C≡C- (CH ₂ ) ₂ O-Ph HH .

In Tables 1 and 2 above, the pharmaceutical set of the present invention is shown.
The compound (I) which is an active ingredient of the product is preferably exemplified by compound numbers: 1-19, 1-23 to 1-32, 1-36 to 1-45, 1-49.
~ 1-58, 1-62 ~ 1-71, 1-75 ~ 1-84, 1-88 ~ 1-102, 1-106
~ 1-156, 1-160 ~ 1-214, 1-218 ~ 1-268, 1-272 ~ 1-322,
1-325 ~ 1-334, 1-338 ~ 1-347, 1-351 ~ 1-360, 1-364 ~
1-373, 1-377 ~ 1-386, 1-390 ~ 1-404, 1-408 ~ 1-458, 1
-462 ~ 1-513, 1-517 ~ 1-526, 1-530 ~ 1-544, 1-548 ~ 1-
598, 1-602 ~ 1-657, 1-670, 1-674 ~ 1-683, 1-696, 1-7
00 ~ 1-717, 1-721 ~ 1-730, 1-734 ~ 1-743, 1-747 ~ 1-75
6, 1-760 ~ 1-774, 1-778 ~ 1-828, 1-832 ~ 1-886, 1-890
~ 1-940, 1-944 ~ 1-993, 1-997 ~ 1-1006, 1-1010 ~ 1-10
19,1-1045, 1-1049 ~ 1-1058, 1-1062 ~ 1-1076, 1-1080
~ 1-1130, 1-1134 ~ 1-1185, 1-1189 ~ 1-1198, 1-1202 ~ 1
-1208, 1-1212 to 1-1216, 1-1220 to 1-1270, 1-1274 to 1-1
331, 1-1335 ~ 1-1344, 1-1348 ~ 1-1357, 1-1361 ~ 1-137
0, 1-1374 ~ 1-1387, 1-1391 ~ 1-1400, 1-1404 ~ 1-1418,
1-1422 ~ 1-1472, 1-1476 ~ 1-1527, 1-1531 ~ 1-1540, 1-
1544 ~ 1-1558, 1-1562 ~ 1-1612, 1-1616 ~ 1-1673, 1-16
77 ~ 1-1686, 1-1690 ~ 1-1699, 1-1703 ~ 1-1712, 1-1716
~ 1-1729, 1-1733 ~ 1-1744, 1-1748 ~ 1-1767, 1-1772 ~
1-1793, 1-1797 to 1-1818, 1-1824 to 1-1846, 1-1850 to 1-
1869, 1-1872, 1-1876, 1-1880, 1-1884, 1-1888 to 1-189
2, 1-1896, 1-1900, 1-1908 ~ 1-1913, 1-1917 ~ 1-1939,
1-1943 ~ 1-1966, 1-1970 ~ 1-1991, 1-1995 ~ 1-2013,1-
2017, 1-2021, 1-2025, 1-2029, 1-2033, 1-2037 ~ 1-2
042, 1-2045 ~ 1-2068, 1-2072 ~ 1-2089, 1-2093, 1-209
7, 1-2101, 1-2105, 1-2109, 1-2113, 1-2117, 1-2121,
1-2125, 1-2129, 1-2133, 1-2135, 1-2139 ~ 1-2158, 1-
2161 ~ 1-2164, 1-2184 ~ 1-2346, 2-9 ~ 2-18, 2-22 ~ 2-43,
2-47 to 2-70, 2-74 to 2-96, 2-100 to 2-119, 2-142, 2-14
6, 2-150, 2-154, 2-158 to 2-163, 2-167 to 2-183, 2-185
~ 2-189, 2-193 ~ 2-216, 2-220 ~ 2-241, 2-245 ~ 2-263,
2-267, 2-271, 2-275, 2-279, 2-283, 2-287 to 2-292, 2
-296 ~ 2-318, 2-322 ~ 2-338, 2-343, 2-347, 2-351, 2-
371, 2-375〜2-377, 2-381〜2-407
More preferably, 1-19, 1-32, 1-36 to 1-45, 1-57, 1-
62 ~ 1-71, 1-84, 1-88, 1-97 ~ 1-100, 1-152 ~ 1-154, 1
-160 ~ 1-214, 1-218 ~ 1-227, 1-264 ~ 1-268, 1-272 ~ 1-
322, 1-334,1-347, 1-360, 1-373, 1-386, 1-390 ~ 1-40
2, 1-454 ~ 1-458, 1-462 ~ 1-513, 1-526, 1-530 ~ 1-54
2, 1-594 ~ 1-598, 1-602 ~ 1-653, 1-743, 1-756, 1-760
~ 1-768, 1-770 ~ 1-774, 1-778 ~ 1-828, 1-832 ~ 1-886,
1-890 ~ 1-940, 1-944 ~ 1-993, 1-1045, 1-1058, 1-1062
~ 1-1074, 1-1126 ~ 1-1130, 1-1134 ~ 1-1185, 1-1198, 1
-1202 ~ 1-1208, 1-1212, 1-1213, 1-1214, 1-1266 ~ 1-1
270, 1-1274 ~ 1-1331, 1-1344, 1-1348 ~ 1-1357, 1-137
0, 1-1374 ~ 1-1387, 1-1400, 1-1404 ~ 1-1416, 1-1468 ~
1-1472, 1-1476 ~ 1-1527, 1-1540, 1-1544 ~ 1-1556, 1-
1608 ~ 1-1612, 1-1616 ~ 1-1666, 1-1729, 1-1742, 1-174
4, 1-1759 ~ 1-1767, 1-1789 ~ 1-1793, 1-1797 ~ 1-1818,
1-1842 ~ 1-1846, 1-1900, 1-1908 ~ 1-1913, 1-1935 ~ 1-
1939, 1-1943 ~ 1-1966, 1-1987 ~ 1-1991, 1-2013, 1-201
7, 1-2029, 1-2033, 1-2037 ~ 1-2042, 1-2064 ~ 1-2068,
1-2072 ~ 1-2089, 1-2093, 1-2097, 1-2101, 1-2105, 1
-2109, 1-2129, 1-2133, 1-2135, 1-2184 ~ 1-2346, 2-11
~ 2-18, 2-39 ~ 2-43, 2-47 ~ 2-70, 2-185 ~ 2-189, 2-19
3 ~ 2-216, 2-287 ~ 2-292, 2-338, 2-343, 2-347, 2-351
And more preferably 1-45, 1-71, 1-8
4, 1-88, 1-97 ~ 1-100, 1-152 ~ 1-154, 1-160 ~ 1-206,
1-209 ~ 1-212, 1-264 ~ 1-266, 1-334, 1-373, 1-386, 1
-390 ~ 1-402, 1-454 ~ 1-458, 1-462 ~ 1-485, 1-509, 1-
510, 1-513, 1-526, 1-530 ~ 1-542, 1-594 ~ 1-598, 1-6
02 ~ 1-613, 1-649, 1-650, 1-743, 1-756, 1-760 ~ 1-76
8, 1-770 ~ 1-772, 1-824 ~ 1-828, 1-832 ~ 1-884, 1-93
6, 1-1045, 1-1058, 1-1062 ~ 1-1074, 1-1126 ~ 1-1130,
1-1134 ~ 1-1145, 1-1148 ~ 1-1151, 1-1162, 1-1163, 1
-1179 to 1-1182, 1-1185, 1-1198, 1-1202 to 1-1208, 1-1
212, 1-1213, 1-1214, 1-1266 ~ 1-1270, 1-1274 ~ 1-128
5, 1-1288 to 1-1291, 1-1319 to 1-1322, 1-1329 to 1-1331,
1-1344, 1-1348 to 1-1357, 1-1370, 1-1387, 1-1400, 1
-1404 ~ 1-1416, 1-1468 ~ 1-1472, 1-1476 ~ 1-1487, 1-1
490 ~ 1-1493, 1-1504, 1-1505, 1-1521 ~ 1-1524, 1-152
7, 1-1540, 1-1544 to 1-1556, 1-1608 to 1-1612, 1-1616
~ 1-1627, 1-1663, 1-1664, 1-1729, 1-1742, 1-1744,
1-1761 ~ 1-1766, 1-1789 ~ 1-1791, 1-1815 ~ 1-1818, 1-
1900, 1-1909, 1-1962, 1-2064 to 1-2066, 1-2089, 1-20
93, 1-2097, 1-2105, 1-2133, 1-2216 to 1-2288, 1-2290
To 1-2346, and even more suitable compounds
Are exemplified compound No. 1-71: 2-amino-2-methyl-4- [5- (4-cyclo)
Lohexylbutyl) thiophen-2-yl] butan-1-o
Exemplary Compound No. 1-84: 2-amino-2-methyl-4- [5- (4-phen
Nylbutyl) thiophen-2-yl] butan-1-ol, Exemplified compound number 1-98: 2-amino-2-methyl-4- [5- (5-cyclo)
Lohexylpentyl) thiophen-2-yl] butan-1-o
Compound No. 1-152: 2-amino-2-methyl-4- [5- (5-phenyl group)
Phenylpentyl) thiophen-2-yl] butan-1-ol, exemplified compound number 1-210: 2-amino-2-methyl-4- [5- (6-cyn
Chlohexylhexyl) thiophen-2-yl] butan-1-o
Compound No. 1-264: 2-amino-2-methyl-4- [5- (6-phenyl)
Phenylhexyl) thiophen-2-yl] butan-1-ol, exemplified compound number 1-373: 2-amino-2-methyl-4- [5- (3-cis
Chlohexyloxypropyl) thiophen-2-yl] pig
N-1-ol, exemplified compound number 1-386: 2-amino-2-methyl-4- [5- (3-phenyl
Enoxypropyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-400: 2-Amino-2-methyl-4- [5- (4-si
Chlohexyloxybutyl) thiophen-2-yl] butane-
1-ol, exemplified compound number 1-454: 2-amino-2-methyl-4- [5- (4-phenyl)
Enoxybutyl) thiophen-2-yl] butan-1-ol, exemplified compound number 1-509: 2-amino-2-methyl-4- [5- (5-cyn
Chlohexyloxypentyl) thiophen-2-yl] buta
1-ol, exemplified compound number 1-510: 2-amino-2-methyl-4- [5- (5-phenyl)
Enoxypentyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-513: 2-amino-2-methyl-4- [5- (3-si
Chlohexylmethoxypropyl) thiophen-2-yl] bu
Tan-1-ol, exemplified compound No. 1-743: 2-amino-2-methyl-4- [5- (4-si
Chlohexylbut-1-ynyl) thiophen-2-yl] butane
-1-ol, exemplified compound number 1-756: 2-amino-2-methyl-4- [5- (4-phenyl)
Phenylbut-1-ynyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-770: 2-amino-2-methyl-4- [5- (5-si
Chlohexylpent-1-ynyl) thiophen-2-yl] buta
N-1-ol, exemplified compound number 1-824: 2-amino-2-methyl-4- [5- (5-phenyl)
Phenylpent-1-ynyl) thiophen-2-yl] butane-1-
All, exemplified compound number 1-882: 2-amino-2-methyl-4- [5- (6-cis
Chlohexylhex-1-ynyl) thiophen-2-yl] buta
N-1-ol, exemplified compound number 1-936: 2-amino-2-methyl-4- [5- (6-phenyl)
Phenylhex-1-ynyl) thiophen-2-yl] butane-1-
All, Exemplified Compound No. 1-1045: 2-amino-2-methyl-4- [5- (3-cis
Chlohexyloxypropynyl) thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-1058: 2-amino-2-methyl-4- [5- (3-phenyl
Enoxypropynyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-1072: 2-Amino-2-methyl-4- [5- (4-si
Chlohexyloxybut-1-ynyl) thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-1126: 2-amino-2-methyl-4- [5- (4-phenyl)
Enoxybut-1-ynyl) thiophen-2-yl] butane-1-
All, exemplified compound number 1-1181: 2-amino-2-methyl-4- [5- (5-cis
Chlohexyloxypent-1-ynyl) thiophen-2-i
Compound] 1-1182: 2-amino-2-methyl-4- [5- (5-phenyl) butane-1-ol
Enoxypent-1-ynyl) thiophen-2-yl] butane-1
-Ol, exemplified compound number 1-1185: 2-amino-2-methyl-4- [5- (3-cis
Chlohexylmethoxypropynyl) thiophen-2-yl]
Butan-1-ol, Exemplified Compound No. 1-1329: 2-amino-2-methyl-4- [5- (4-si
Chlohexylbutanoyl) thiophen-2-yl] butane-1-
All, exemplified compound number 1-1330: 2-amino-2-methyl-4- [5- (4-phenyl
Phenylbutanoyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-1331: 2-Amino-2-methyl-4- [5- (5-si
Chlohexylpentanoyl) thiophen-2-yl] butane-
1-ol, exemplified compound No. 1-1344: 2-amino-2-methyl-4- [5- (5-phenyl)
Phenylpentanoyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-1357: 2-amino-2-methyl-4- [5- (6-si
Chlohexylhexanoyl) thiophen-2-yl] butane-
1-ol, exemplified compound number 1-1370: 2-amino-2-methyl-4- [5- (6-phenyl)
Phenylhexanoyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-1387: 2-amino-2-methyl-4- [5- (3-cis
Chlohexyloxypropanoyl) thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-1400: 2-amino-2-methyl-4- [5- (3-phenyl
Enoxypropanoyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-1414: 2-Amino-2-methyl-4- [5- (4-si
Chlohexyloxybutanoyl) thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-1468: 2-amino-2-methyl-4- [5- (4-phenyl)
Enoxybutanoyl) thiophen-2-yl] butan-1-o
Compound No. 1-1523: 2-amino-2-methyl-4- [5- (5-cy
Chlohexyloxypentanoyl) thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-1524: 2-amino-2-methyl-4- [5- (5-phenyl)
Enoxypentanoyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-1527: 2-Amino-2-methyl-4- [5- (3-si
Chlohexyl methoxypropanoyl) thiophen-2-i
L] butan-1-ol, exemplified compound number 1-1729: 2-amino-2-methyl-4- [5- (4-si
Chlohexylmethoxyphenyl) thiophen-2-yl] bu
Tan-1-ol, Exemplified Compound No. 1-1742: 2-Amino-2-methyl-4- [5- (4-si
Chlohexylethoxyphenyl) thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-1744: 2-amino-2-methyl-4- [5- (4-beta)
Nyloxyphenyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-1761: 2-amino-2-ethyl-4- [5- (4-si
Chlohexylbutyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-1764: 2-amino-2-ethyl-4- [5- (5-si
Chlohexylpentyl) thiophen-2-yl] butan-1-o
Example Compound No. 1-1816: 2-amino-2-ethyl-4- [5- (6-si
Chlohexylhexyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-1900: 2-amino-2-ethyl-4- [5- (4-si
Chlohexylbut-1-ynyl) thiophen-2-yl] butane
-1-ol, exemplified compound number 1-1909: 2-amino-2-ethyl-4- [5- (5-cis
Chlohexylpent-1-ynyl) thiophen-2-yl] buta
N-1-ol, exemplified compound number 1-1962: 2-amino-2-ethyl-4- [5- (6-si
Chlohexylhex-1-ynyl) thiophen-2-yl] buta
N-1-ol, exemplified compound No. 1-2089: 2-amino-2-ethyl-4- [5- (4-si
Chlohexylbutanoyl) thiophen-2-yl] butane-1-
All, exemplified compound number 1-2097: 2-amino-2-ethyl-4- [5- (5-si
Chlohexylpentanoyl) thiophen-2-yl] butane-
1-ol and exemplified compound number 1-2105: 2-amino-2-ethyl-4- [5- (6-cis
Chlohexylhexanoyl) thiophen-2-yl] butane-
1-ol and exemplified compound number 1-463: 2-amino-2-methyl-4- [5- [4- (4-
Fluorophenoxy) butyl] thiophen-2-yl] butane
-1-ol, exemplified compound number 1-479: 2-amino-2-methyl-4- [5- [4- (4-
Methoxyphenoxy) butyl] thiophen-2-yl] butane
-1-ol, exemplified compound number 1-594: 2-amino-2-methyl-4- [5- (4-beta)
Nyloxybutyl) thiophen-2-yl] butan-1-o
Exemplary Compound No. 1-760: 2-amino-2-methyl-4- [5- [4- (4-
(Fluorophenyl) but-1-ynyl] thiophen-2-yl]
Butan-1-ol, Exemplified Compound No. 1-761: 2-amino-2-methyl-4- [5- [4- (4-
Methylphenyl) but-1-ynyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-762: 2-amino-2-methyl-4- [5- [4- (4-
Ethylphenyl) but-1-ynyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-763: 2-amino-2-methyl-4- [5- [4- (4-
Trifluoromethylphenyl) but-1-ynyl] thiophe
N-2-yl] butan-1-ol, exemplified compound number 1-764: 2-amino-2-methyl-4- [5- [4- (4-
Methoxyphenyl) but-1-ynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-765: 2-amino-2-methyl-4- [5- [4- (4-
Ethoxyphenyl) but-1-ynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-766: 2-amino-2-methyl-4- [5- [4- (4-
Methylthiophenyl) but-1-ynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-832: 2-amino-2-methyl-4- [5- [5- (3-
(Fluorophenyl) pent-1-ynyl] thiophen-2-i
Lu] butan-1-ol, Exemplified Compound Number 1-833: 2-Amino-2-methyl-4- [5- [5- (4-
(Fluorophenyl) pent-1-ynyl] thiophen-2-i
Compound] 1-834: 2-amino-2-methyl-4- [5- [5- (4-
(Chlorophenyl) pent-1-ynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-836: 2-amino-2-methyl-4- [5- [5- (3-
Methylphenyl) pent-1-ynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-837: 2-amino-2-methyl-4- [5- [5- (4-
Methylphenyl) pent-1-ynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-846: 2-amino-2-methyl-4- [5- [5- (3-
Trifluoromethylphenyl) pent-1-ynyl] thiof
En-2-yl] butan-1-ol, exemplified compound number 1-847: 2-amino-2-methyl-4- [5- [5- (4-
Trifluorophenyl) pent-1-ynyl] thiophene-2-
Il] butan-1-ol, exemplified compound number 1-848: 2-amino-2-methyl-4- [5- [5- (3-
Methoxyphenyl) pent-1-ynyl] thiophen-2-i
Lu] butan-1-ol, Exemplified Compound No. 1-849: 2-amino-2-methyl-4- [5- [5- (4-
Methoxyphenyl) pent-1-ynyl] thiophen-2-i
Lu] butan-1-ol, Exemplified Compound No. 1-860: 2-Amino-2-methyl-4- [5- [5- (3-
Methylthiophenyl) pent-1-ynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound No. 1-861: 2-amino-2-methyl-4- [5- [5- (4-
Methylphenyl) pent-1-ynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-877: 2-amino-2-methyl-4- [5- [5- (3,
4-Dimethylphenyl) pent-1-ynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-878: 2-amino-2-methyl-4- [5- [5- (3,
5-Dimethylphenyl) pent-1-ynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-1050: 2-amino-2-methyl-4- [5- [3- (4
-Methylcyclohexyloxy) propynyl] thiophene-
2-yl] butan-1-ol, exemplified compound No. 1-1062: 2-amino-2-methyl-4- [5- [3- (4
-Fluorophenoxy) propynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-1063: 2-amino-2-methyl-4- [5- [3- (4
-Methylphenoxy) propynyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-1064: 2-amino-2-methyl-4- [5- [3- (4
-Ethylphenoxy) propynyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-1065: 2-amino-2-methyl-4- [5- [3- (4
-Trifluoromethylphenoxy) propynyl] thiophe
N-2-yl] butan-1-ol, exemplified compound No. 1-1066: 2-amino-2-methyl-4- [5- [3- (4
-Methoxyphenoxy) propynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-1067: 2-amino-2-methyl-4- [5- [3- (4
-Ethoxyphenoxy) propynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-1068: 2-amino-2-methyl-4- [5- [3- (4
-Methylthiophenoxy) propynyl] thiophen-2-i
Compound] 1-1134: 2-amino-2-methyl-4- [5- [4- (3
-Fluorophenoxy) but-1-ynyl] thiophen-2-i
Lu] butan-1-ol, Exemplified Compound Number 1-1135: 2-Amino-2-methyl-4- [5- [4- (4
-Fluorophenoxy) but-1-ynyl] thiophen-2-i
Lu] butan-1-ol, Exemplified Compound Number 1-1136: 2-Amino-2-methyl-4- [5- [4- (4
-Chlorophenoxy) but-1-ynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-1138: 2-amino-2-methyl-4- [5- [4- (3
-Methylphenoxy) but-1-ynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-1139: 2-amino-2-methyl-4- [5- [4- (4
-Methylphenoxy) but-1-ynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-1148: 2-amino-2-methyl-4- [5- [4- (3
-Trifluoromethylphenoxy) but-1-ynyl] thiof
En-2-yl] butan-1-ol, exemplified compound number 1-1149: 2-amino-2-methyl-4- [5- [4- (4
-Trifluoromethylphenoxy) but-1-ynyl] thiof
En-2-yl] butan-1-ol, exemplified compound No. 1-1150: 2-amino-2-methyl-4- [5- [4- (3
-Methoxyphenoxy) but-1-ynyl] thiophen-2-i
Compound] 1-1151: 2-amino-2-methyl-4- [5- [4- (4
-Methoxyphenoxy) but-1-ynyl] thiophen-2-i
Compound] 1-1162: 2-amino-2-methyl-4- [5- [4- (3
-Methylthiophenoxy) but-1-ynyl] thiophene-2-
Il] butan-1-ol, exemplified compound number 1-1163: 2-amino-2-methyl-4- [5- [4- (4
-Methylthiophenoxy) but-1-ynyl] thiophene-2-
Il] butan-1-ol, exemplified compound number 1-1179: 2-amino-2-methyl-4- [5- [4-
(3,4-Dimethylphenoxy) but-1-ynyl] thiophene-2
-Yl] butan-1-ol, exemplified compound number 1-1180: 2-amino-2-methyl-4- [5- [4-
(3,5-Dimethylphenoxy) but-1-ynyl] thiophene-2
-Yl] butan-1-ol, exemplified compound number 1-1198: 2-amino-2-methyl-4- [5- (3-phenyl
Phenylmethoxypropynyl) thiophen-2-yl] butane-
1-ol, exemplified compound number 1-1202: 2-amino-2-methyl-4- [5- [3- (4
-Fluorophenyl) methoxypropynyl] thiophene-2-
Il] butan-1-ol, exemplified compound number 1-1203: 2-amino-2-methyl-4- [5- [3- (4
-Methylphenyl) methoxypropynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-1204: 2-amino-2-methyl-4- [5- [3- (4
-Ethylphenyl) methoxypropynyl] thiophen-2-i
Compound] 1-1205: 2-amino-2-methyl-4- [5- [3- (4
-Trifluoromethylphenyl) methoxypropynyl] thio
Ofen-2-yl] butan-1-ol, exemplified compound number 1-1206: 2-amino-2-methyl-4- [5- [3- (4
-Methoxyphenyl) methoxypropynyl] thiophene-2-
Il] butan-1-ol, exemplified compound number 1-1207: 2-amino-2-methyl-4- [5- [3- (4
-Ethoxyphenyl) methoxypropynyl] thiophene-2-
Il] butan-1-ol, exemplified compound No. 1-1208: 2-amino-2-methyl-4- [5- [3- (4
-Methylthiophenyl) methoxypropynyl] thiophene-
2-yl] butan-1-ol, exemplified compound number 1-1212: 2-amino-2-methyl-4- [5- (4-cy
Chlohexyl methoxybut-1-ynyl) thiophen-2-i
Compound] 1-1266: 2-amino-2-methyl-4- [5- (4-phenyl) butane-1-ol
Phenylmethoxybut-1-ynyl) thiophen-2-yl] buta
N-1-ol, exemplified compound number 1-1274: 2-amino-2-methyl-4- [5- [4- (3
-Fluorophenyl) methoxybut-1-ynyl] thiophene
-2-yl] butan-1-ol, exemplified compound number 1-1275: 2-amino-2-methyl-4- [5- [4- (4
-Fluorophenyl) methoxybut-1-ynyl] thiophene
-2-yl] butan-1-ol, exemplified compound number 1-1276: 2-amino-2-methyl-4- [5- [4- (4
-Chlorophenyl) methoxybut-1-ynyl] thiophene-2
-Yl] butan-1-ol, exemplified compound number 1-1278: 2-amino-2-methyl-4- [5- [4- (3
-Methylphenyl) methoxybut-1-ynyl] thiophene-2
-Yl] butan-1-ol, exemplified compound number 1-1279: 2-amino-2-methyl-4- [5- [4- (4
-Methylphenyl) methoxybut-1-ynyl] thiophene-2
-Yl] butan-1-ol, exemplified compound number 1-1288: 2-amino-2-methyl-4- [5- [4- (3
-Trifluoromethylphenyl) methoxybut-1-ynyl]
Thiophen-2-yl] butan-1-ol, Exemplified Compound No. 1-1289: 2-Amino-2-methyl-4- [5- [4- (4
-Trifluoromethylphenyl) methoxybut-1-ynyl]
Thiophen-2-yl] butan-1-ol, exemplified compound number 1-1290: 2-amino-2-methyl-4- [5- [4- (3
-Methoxyphenyl) methoxybut-1-ynyl] thiophene
-2-yl] butan-1-ol, exemplified compound number 1-1291: 2-amino-2-methyl-4- [5- [4- (4
-Methoxyphenyl) methoxybut-1-ynyl] thiophene
-2-yl] butan-1-ol, exemplified compound number 1-1319: 2-amino-2-methyl-4- [5- [4-
(3,4-Dimethylphenyl) methoxybut-1-ynyl] thiof
En-2-yl] butan-1-ol, exemplified compound number 1-1320: 2-amino-2-methyl-4- [5- [4-
(3,5-Dimethylphenyl) methoxybut-1-ynyl] thiof
En-2-yl] butan-1-ol, exemplified compound number 1-1348: 2-amino-2-methyl-4- [5- [5- (4
-Fluorophenyl) pentanoyl] thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-1349: 2-amino-2-methyl-4- [5- [5- (4
-Methylphenyl) pentanoyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-1350: 2-amino-2-methyl-4- [5- [5- (4
-Ethylphenyl) pentanoyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-1351: 2-amino-2-methyl-4- [5- [5- (4
-Trifluoromethylphenyl) pentanoyl] thiophe
N-2-yl] butan-1-ol, exemplified compound number 1-1352: 2-amino-2-methyl-4- [5- [5- (4
-Methoxyphenyl) pentanoyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-1353: 2-amino-2-methyl-4- [5- [5- (4
-Ethoxyphenyl) pentanoyl] thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-1354: 2-amino-2-methyl-4- [5- [5- (4
-Methylthiophenyl) pentanoyl] thiophen-2-i
Lu] butan-1-ol, Exemplified Compound Number 1-1476: 2-Amino-2-methyl-4- [5- [4- (3
-Fluorophenoxy) butanoyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-1477: 2-amino-2-methyl-4- [5- [4- (4
-Fluorophenoxy) butanoyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-1478: 2-amino-2-methyl-4- [5- [4- (4
-Chlorophenoxy) butanoyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-1480: 2-amino-2-methyl-4- [5- [4- (3
-Methylphenoxy) butanoyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-1481: 2-amino-2-methyl-4- [5- [4- (4
-Methylphenoxy) butanoyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-1490: 2-amino-2-methyl-4- [5- [4- (3
-Trifluoromethylphenoxy) butanoyl] thiophe
N-2-yl] butan-1-ol, exemplified compound number 1-1491: 2-amino-2-methyl-4- [5- [4- (4
-Trifluoromethylphenoxy) butanoyl] thiophe
N-2-yl] butan-1-ol, exemplified compound number 1-1492: 2-amino-2-methyl-4- [5- [4- (3
-Methoxyphenoxy) butanoyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-1493: 2-amino-2-methyl-4- [5- [4- (4
-Methoxyphenoxy) butanoyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-1504: 2-amino-2-methyl-4- [5- [4- (3
-Methylthiophenoxy) butanoyl] thiophen-2-i
Lu] butan-1-ol, Exemplified Compound Number 1-1505: 2-Amino-2-methyl-4- [5- [4- (4
-Methylthiophenoxy) butanoyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-1521: 2-amino-2-methyl-4- [5- [4-
(3,4-Dimethylphenoxy) butanoyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-1522: 2-amino-2-methyl-4- [5- [4-
(3,5-Dimethylphenoxy) butanoyl] thiophen-2-i
Compound] No. 1-2093: 2-amino-ethyl-4- [5- (4-phenyl) butane-1-ol
Phenylbutanoyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-2101: 2-amino-ethyl-4- [5- (5-
Phenylpentanoyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-2109: 2-amino-ethyl-4- [5- (6-phenol
Phenylhexanoyl) thiophen-2-yl] butan-1-o
Compound No. 1-2257: 2-amino-2-methyl-4- [5- [5-
(3,4-Difluorophenyl) pent-1-ynyl] thiophene
-2-yl] butan-1-ol, exemplified compound number 1-2258: 2-amino-2-methyl-4- [5- [5-
(3,5-Difluorophenyl) pent-1-ynyl] thiophene
-2-yl] butan-1-ol, exemplified compound number 1-2259: 2-amino-2-methyl-4- [5- [5- (3
-Chlorophenyl) pent-1-ynyl] thiophen-2-yl]
Butan-1-ol, Exemplified Compound No. 1-2260: 2-Amino-2-methyl-4- [5- [5-
(3,4-Dichlorophenyl) pent-1-ynyl] thiophene-2
-Yl] butan-1-ol, exemplified compound number 1-2261: 2-amino-2-methyl-4- [5- [5-
(3,5-Dichlorophenyl) pent-1-ynyl] thiophene-2
-Yl] butan-1-ol, exemplified compound number 1-2262: 2-amino-2-methyl-4- [5- [5-
(3,4-Ditrifluoromethylphenyl) pent-1-ynyl]
Thiophen-2-yl] butan-1-ol, Exemplified Compound No. 1-2263: 2-Amino-2-methyl-4- [5- [5-
(3,5-Ditrifluoromethylphenyl) pent-1-ynyl]
Thiophen-2-yl] butan-1-ol, Exemplified Compound No. 1-2264: 2-Amino-2-methyl-4- [5- [5-
(3,4-Dimethoxyphenyl) pent-1-ynyl] thiophene
-2-yl] butan-1-ol, exemplified compound number 1-2265: 2-amino-2-methyl-4- [5- [5-
(3,5-Dimethoxyphenyl) pent-1-ynyl] thiophene
-2-yl] butan-1-ol, exemplified compound number 1-2266: 2-amino-2-methyl-4- [5- [5-
(3,4,5-Trimethoxyphenyl) pent-1-ynyl] thiof
En-2-yl] butan-1-ol, exemplified compound No. 1-2267: 2-amino-2-methyl-4- [5- [5- (3
-Acetylphenyl) pent-1-ynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-2268: 2-amino-2-methyl-4- [5- [5- (4
-Acetylphenyl) pent-1-ynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-2269: 2-amino-2-methyl-4- [5- [3- (3
-Fluorophenoxy) propynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-2270: 2-amino-2-methyl-4- [5- [3-
(3,4-Difluorophenoxy) propynyl] thiophene-2-
Il] butan-1-ol, exemplified compound number 1-2271: 2-amino-2-methyl-4- [5- [3-
(3,5-Difluorophenoxy) propynyl] thiophene-2-
Il] butan-1-ol, exemplified compound No. 1-2272: 2-amino-2-methyl-4- [5- [3- (3
-Chlorophenoxy) propynyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-2273: 2-amino-2-methyl-4- [5- [3- (4
-Chlorophenoxy) propynyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-2274: 2-amino-2-methyl-4- [5- [3-
(3,4-Dichlorophenoxy) propynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-2275: 2-amino-2-methyl-4- [5- [3-
(3,5-Dichlorophenoxy) propynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-2276: 2-amino-2-methyl-4- [5- [3- (3
-Methylphenoxy) propynyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-2278: 2-amino-2-methyl-4- [5- [3-
(3,4-Dimethylphenoxy) propynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-2279: 2-amino-2-methyl-4- [5- [3-
(3,5-Dimethylphenoxy) propynyl] thiophen-2-i
Compound] 1-2280: 2-amino-2-methyl-4- [5- [3- (3
-Trifluoromethylphenoxy) propynyl] thiophe
N-2-yl] butan-1-ol, exemplified compound number 1-2281: 2-amino-2-methyl-4- [5- [3-
(3,4-ditrifluoromethylphenoxy) propynyl] thio
Ofen-2-yl] butan-1-ol, exemplified compound number 1-2282: 2-amino-2-methyl-4- [5- [3-
(3,5-ditrifluoromethylphenoxy) propynyl] thio
Ofen-2-yl] butan-1-ol, exemplified compound number 1-2283: 2-amino-2-methyl-4- [5- [3- (3
-Methoxyphenoxy) propynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-2284: 2-amino-2-methyl-4- [5- [3-
(3,4-dimethoxyphenoxy) propynyl] thiophene-2-
Il] butan-1-ol, exemplified compound number 1-2285: 2-amino-2-methyl-4- [5- [3-
(3,5-Dimethoxyphenoxy) propynyl] thiophene-2-
Il] butan-1-ol, exemplified compound number 1-2286: 2-amino-2-methyl-4- [5- [3-
(3,4,5-Trimethoxyphenoxy) propynyl] thiophe
N-2-yl] butan-1-ol, exemplified compound number 1-2287: 2-amino-2-methyl-4- [5- [3- (3
-Acetylphenoxy) propynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-2288: 2-amino-2-methyl-4- [5- [3- (4
-Acetylphenoxy) propynyl] thiophen-2-yl]
Butan-1-ol, Exemplified Compound Number 1-2290: 2-Amino-2-methyl-4- [5- [4-
(3,4-difluorophenoxy) but-1-ynyl] thiophene
-2-yl] butan-1-ol, exemplified compound number 1-2291: 2-amino-2-methyl-4- [5- [4-
(3,5-Difluorophenoxy) but-1-ynyl] thiophene
-2-yl] butan-1-ol, exemplified compound number 1-2292: 2-amino-2-methyl-4- [5- [4- (3
-Chlorophenoxy) but-1-ynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-2293: 2-amino-2-methyl-4- [5- [4-
(3,4-Dichlorophenoxy) but-1-ynyl] thiophene-2
-Yl] butan-1-ol, exemplified compound number 1-2294: 2-amino-2-methyl-4- [5- [4-
(3,5-Dichlorophenoxy) but-1-ynyl] thiophene-2
-Yl] butan-1-ol, exemplified compound number 1-2295: 2-amino-2-methyl-4- [5- [4-
(3,4-ditrifluoromethylphenoxy) but-1-ynyl]
Thiophen-2-yl] butan-1-ol, Exemplified Compound Number 1-2296: 2-Amino-2-methyl-4- [5- [4-
(3,5-ditrifluoromethylphenoxy) but-1-ynyl]
Thiophen-2-yl] butan-1-ol, exemplified compound number 1-2297: 2-amino-2-methyl-4- [5- [4-
(3,4-dimethoxyphenoxy) but-1-ynyl] thiophene
-2-yl] butan-1-ol, exemplified compound number 1-2298: 2-amino-2-methyl-4- [5- [4-
(3,5-dimethoxyphenoxy) but-1-ynyl] thiophene
-2-yl] butan-1-ol, exemplified compound number 1-2299: 2-amino-2-methyl-4- [5- [4-
(3,4,5-Trimethoxyphenoxy) but-1-ynyl] thiof
En-2-yl] butan-1-ol, exemplified compound number 1-2300: 2-amino-2-methyl-4- [5- [4- (3
-Acetylphenoxy) but-1-ynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-2301: 2-amino-2-methyl-4- [5- [4- (4
-Acetylphenoxy) but-1-ynyl] thiophen-2-i
Lu] butan-1-ol, Exemplified Compound No. 1-2328: 2-Amino-2-methyl-4- [5- [5- (3
-Fluorophenyl) pentanoyl] thiophen-2-yl]
Butan-1-ol, Exemplified Compound No. 1-2329: 2-amino-2-methyl-4- [5- [5-
(3,4-Difluorophenyl) pentanoyl] thiophene-2
-Yl] butan-1-ol, exemplified compound number 1-2330: 2-amino-2-methyl-4- [5- [5-
(3,5-Difluorophenyl) pentanoyl] thiophene-2
-Yl] butan-1-ol, exemplified compound number 1-2331: 2-amino-2-methyl-4- [5- [5- (3
-Chlorophenyl) pentanoyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-2332: 2-amino-2-methyl-4- [5- [5- (4
-Chlorophenyl) pentanoyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-2333: 2-amino-2-methyl-4- [5- [5-
(3,4-Dichlorophenyl) pentanoyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-2334: 2-amino-2-methyl-4- [5- [5-
(3,5-Dichlorophenyl) pentanoyl] thiophen-2-i
Lu] butan-1-ol, Exemplified Compound Number 1-2335: 2-Amino-2-methyl-4- [5- [5- (3
-Methylphenyl) pentanoyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-2336: 2-amino-2-methyl-4- [5- [5-
(3,4-Dimethylphenyl) pentanoyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-2337: 2-amino-2-methyl-4- [5- [5-
(3,5-Dimethylphenyl) pentanoyl] thiophen-2-i
Lu] butan-1-ol, Exemplified Compound No. 1-2338: 2-Amino-2-methyl-4- [5- [5- (3
-Trifluoromethylphenyl) pentanoyl] thiophe
N-2-yl] butan-1-ol, exemplified compound number 1-2339: 2-amino-2-methyl-4- [5- [5-
(3,4-ditrifluoromethylphenyl) pentanoyl] thio
Ofen-2-yl] butan-1-ol, exemplified compound number 1-2340: 2-amino-2-methyl-4- [5- [5-
(3,5-ditrifluoromethylphenyl) pentanoyl]
Ofen-2-yl] butan-1-ol, exemplified compound number 1-2341: 2-amino-2-methyl-4- [5- [5- (3
-Methoxyphenyl) pentanoyl] thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-2342: 2-amino-2-methyl-4- [5- [5-
(3,4-Dimethoxyphenyl) pentanoyl] thiophene-2-
Il] butan-1-ol, exemplified compound number 1-2343: 2-amino-2-methyl-4- [5- [5-
(3,5-Dimethoxyphenyl) pentanoyl] thiophene-2-
Il] butan-1-ol, exemplified compound number 1-2344: 2-amino-2-methyl-4- [5- [5-
(3,4,5-Trimethoxyphenyl) pentanoyl] thiof
En-2-yl] butan-1-ol, exemplified compound number 1-2345: 2-amino-2-methyl-4- [5- [5- (3
-Acetylphenyl) pentanoyl] thiophen-2-yl]
Butan-1-ol and Exemplified Compound No. 1-2346: 2-Amino-2-methyl-4- [5- [5- (4
-Acetylphenyl) pentanoyl] thiophen-2-yl]
Butan-1-ol, and most preferably, Exemplified Compound No. 1-71: 2-amino-2-methyl-4- [5- (4-sic
Lohexylbutyl) thiophen-2-yl] butan-1-o
Exemplary Compound No. 1-98: 2-amino-2-methyl-4- [5- (5-cyclo)
Lohexylpentyl) thiophen-2-yl] butan-1-o
Compound No. 1-152: 2-amino-2-methyl-4- [5- (5-phenyl group)
Phenylpentyl) thiophen-2-yl] butan-1-ol, exemplified compound number 1-400: 2-amino-2-methyl-4- [5- (4-cyn
Chlohexyloxybutyl) thiophen-2-yl] butane-
1-ol, exemplified compound number 1-463: 2-amino-2-methyl-4- [5- [4- (4-
Fluorophenoxy) butyl] thiophen-2-yl] butane
-1-ol, exemplified compound number 1-479: 2-amino-2-methyl-4- [5- [4- (4-
Methoxyphenoxy) butyl] thiophen-2-yl] butane
-1-ol, exemplified compound number 1-594: 2-amino-2-methyl-4- [5- (4-beta)
Nyloxybutyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-743: 2-amino-2-methyl-4- [5- (4-si
Chlohexylbut-1-ynyl) thiophen-2-yl] butane
-1-ol, exemplified compound number 1-756: 2-amino-2-methyl-4- [5- (4-phenyl)
Phenylbut-1-ynyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-770: 2-amino-2-methyl-4- [5- (5-si
Chlohexylpent-1-ynyl) thiophen-2-yl] buta
N-1-ol, exemplified compound number 1-824: 2-amino-2-methyl-4- [5- (5-phenyl)
Phenylpent-1-ynyl) thiophen-2-yl] butane-1-
All, exemplified compound number 1-833: 2-amino-2-methyl-4- [5- [5- (4-
(Fluorophenyl) pent-1-ynyl] thiophen-2-i
Lu] butan-1-ol, Exemplified Compound No. 1-849: 2-amino-2-methyl-4- [5- [5- (4-
Methoxyphenyl) pent-1-ynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-1050: 2-amino-2-methyl-4- [5- [3- (4
-Methylcyclohexyloxy) propynyl] thiophene-
2-yl] butan-1-ol, exemplified compound No. 1-1063: 2-amino-2-methyl-4- [5- [3- (4
-Methylphenoxy) propynyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-1064: 2-amino-2-methyl-4- [5- [3- (4
-Ethylphenoxy) propynyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound No. 1-1068: 2-amino-2-methyl-4- [5- [3- (4
-Methylthiophenoxy) propynyl] thiophen-2-i
L] butan-1-ol, Exemplified Compound No. 1-1072: 2-amino-2-methyl-4- [5- (4-si
Chlohexyloxybut-1-ynyl) thiophen-2-yl]
Butan-1-ol, exemplified compound number 1-1135: 2-amino-2-methyl-4- [5- [4- (4
-Fluorophenoxy) but-1-ynyl] thiophen-2-i
Lu] butan-1-ol, exemplified compound number 1-1139: 2-amino-2-methyl-4- [5- [4- (4
-Methylphenoxy) but-1-ynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-1185: 2-amino-2-methyl-4- [5- (3-cis
Chlohexylmethoxypropynyl) thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-1266: 2-amino-2-methyl-4- [5- (4-phenyl)
Phenylmethoxybut-1-ynyl) thiophen-2-yl] buta
1-1-ol, exemplified compound number 1-1329: 2-amino-2-methyl-4- [5- (4-cy
Chlohexylbutanoyl) thiophen-2-yl] butane-1-
All, exemplified compound number 1-1330: 2-amino-2-methyl-4- [5- (4-phenyl
Phenylbutanoyl) thiophen-2-yl] butan-1-o
Exemplified Compound No. 1-1331: 2-Amino-2-methyl-4- [5- (5-si
Chlohexylpentanoyl) thiophen-2-yl] butane-
1-ol, exemplified compound No. 1-1344: 2-amino-2-methyl-4- [5- (5-phenyl)
Phenylpentanoyl) thiophen-2-yl] butan-1-o
Compound No. 1-1348: 2-amino-2-methyl-4- [5- [5- (4
-Fluorophenyl) pentanoyl] thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-1764: 2-amino-2-ethyl-4- [5- (5-si
Chlohexylpentyl) thiophen-2-yl] butan-1-o
Example Compound No. 1-1909: 2-amino-2-ethyl-4- [5- (5-si
Chlohexylpent-1-ynyl) thiophen-2-yl] buta
N-1-ol, exemplified compound No. 1-2097: 2-amino-2-ethyl-4- [5- (5-cis
Chlohexylpentanoyl) thiophen-2-yl] butane-
1-ol, exemplified compound number 1-2273: 2-amino-2-methyl-4- [5- [3- (4
-Chlorophenoxy) propynyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-2276: 2-amino-2-methyl-4- [5- [3- (3
-Methylphenoxy) propynyl] thiophen-2-yl] bu
Tan-1-ol, exemplified compound number 1-2278: 2-amino-2-methyl-4- [5- [3-
(3,4-Dimethylphenoxy) propynyl] thiophen-2-i
Compound] 1-2283: 2-amino-2-methyl-4- [5- [3- (3
-Methoxyphenoxy) propynyl] thiophen-2-yl]
Butan-1-ol, exemplified compound No. 1-2284: 2-amino-2-methyl-4- [5- [3-
(3,4-dimethoxyphenoxy) propynyl] thiophene-2-
Il] butan-1-ol, exemplified compound number 1-2285: 2-amino-2-methyl-4- [5- [3-
(3,5-Dimethoxyphenoxy) propynyl] thiophene-2-
Il] butan-1-ol, exemplified compound number 1-2287: 2-amino-2-methyl-4- [5- [3- (3
-Acetylphenoxy) propynyl] thiophen-2-yl]
Butan-1-ol and Exemplified Compound No. 1-2288: 2-Amino-2-methyl-4- [5- [3- (4
-Acetylphenoxy) propynyl] thiophen-2-yl]
Butan-1-ol can be mentioned.

[0110]

[Table 3]

[0111]

[Chemical formula 22]

[0112]

[0113]

[Table 4]

[0114]

[Chemical formula 23]

[0115] In Tables 3 and 4 above, preferably, 3-5, 3-6, 3-7, 3-
8, 3-11, 3-12, 4-4, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10,
4-11, 4-12, 4-13, 4-17, 4-23, 4-24, 4-27, 4-28, 4
-31 and 4-32, most preferred are exemplified compound No. 4-4: 4-methyl-4-[(thiophen-yl) ethyl] oxazolidin-one, exemplified compound No. 4-5: 4 -Methyl-4-[(thiophen-3-yl)
Ethyl] oxazolidin-one, exemplified compound No. 4-8: 4-methyl-4-[(5-bromothiophene
-Yl) ethyl] oxazolidin-one and exemplified compound No. 4-9: 4-methyl-4-[(5-bromothiophene
-3-yl) ethyl] oxazolidin-one.

[0116]

BEST MODE FOR CARRYING OUT THE INVENTION Compounds (I) and (XLI of the present invention
Va), (XLIVb), (La) and (Lb) can be produced according to the method described below.

Method A is the compound (I), and in the compound (I), R ¹ is a hydrogen atom and R ² is a group selected from a lower alkoxycarbonyl group, an aralkyloxycarbonyl group or a substituent group a. A method for producing a compound (Ic) which is an aralkyloxycarbonyl group substituted with 1 to 3 of the above.

[0118]

[Chemical formula 24]

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , X, Y and n have the same meanings as described above, R ⁸ represents a formyl group, a carboxyl group or a lower alkoxycarbonyl group, and R ⁹ and R ^9a are the same or different. , A hydrogen atom or a lower alkyl group, R
¹⁰ is an aralkyl group substituted by 1 to 3 groups selected from a lower alkyl group, an aralkyl group or a substituent group a, and R ^5a , R ^6a and R ^7a are each R ⁵ , R ⁶ and R ^The amino, hydroxy and / or carboxyl group contained as a substituent in the ⁷ group is an amino, hydroxy and / or carboxyl group which may be protected, and other groups in the definition of the R ⁵ , R ⁶ and R ⁷ groups. The same group is shown.

In the above, "protecting group" of "amino group which may be protected" in the definition of R ^5a , R ^6a and R ^7a.
Is not particularly limited as long as it is a protecting group for an amino group used in the field of synthetic organic chemistry, and has the same meaning as described above, preferably a lower alkoxycarbonyl group, and most preferably t. -A butoxycarbonyl group.

In the above, the “protecting group” of the “optionally protected hydroxy group” in the definition of R ^5a , R ^6a and R ^7a is a protecting group for a hydroxy group used in the field of synthetic organic chemistry. Although not particularly limited, for example, it has the same meaning as the above-mentioned “general protecting group in the reaction of ester of hydroxy group”, and preferably a lower aliphatic acyl group, an aromatic acyl group, a lower alkoxycarbonyl group or (Lower alkoxy) methyl group, more preferably lower aliphatic acyl group or (lower alkoxy) methyl group, most preferably acetyl group or methoxymethyl group.

In the above, the "protecting group" of the "optionally protected carboxyl group" in the definition of R ^5a , R ^6a and R ^7a is a protecting group for the carboxyl group used in the field of synthetic organic chemistry. Although not particularly limited, for example, it has the same meaning as the above-mentioned "general protecting group in the reaction of ester of carboxy group", preferably a lower alkyl group, and most preferably a methyl group.

The step A1 is a step for producing a compound having the general formula (III), wherein the compound having the general formula (II) is added in an inert solvent in the presence or absence of a base (preferably (In the presence), by reacting with a reducing agent.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene. Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; acetic acid, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, carbonic acid Esters such as diethyl; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol
, Isopropanol, n-butanol, isobutanol
, T-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide. Water; or a mixed solvent of water or the above solvent; preferably ethers (most preferably tetrahydrofuran)
Is.

The reducing agent used in the above reaction is, for example,
Alkali metal borohydrides such as sodium borohydride, lithium borohydride, sodium cyanoborohydride; aluminum hydride compounds such as diisobutylaluminum hydride, lithium aluminum hydride, lithium triethoxyaluminum hydride; Yes,
Preferred are alkali metal borohydrides (most preferably sodium borohydride).

The reaction temperature will differ depending on the raw material compounds, the reducing agent used, the type of solvent, etc., but is usually -50 ° C. to 100 ° C. (preferably 0 ° C. to 50 ° C.).

The reaction time varies depending on the raw material compound, the reducing agent used, the solvent, the reaction temperature and the like, but is usually 15 minutes to 150 hours (preferably 1 hour to 100 hours).

After completion of the reaction, the target compound (II
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, It can be obtained by washing with water or the like, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

The step A2 is a step of producing a compound having the general formula (IV), which comprises converting the hydroxy group of the compound (III) into a leaving group in the presence of a base in an inert solvent, and then iodine. It is carried out by reacting with a reagent to iodize the leaving group.

Examples of the reagent forming a leaving group include, for example,
Sulfonyl halides such as methanesulfonyl chloride, P-toluenesulfonyl chloride; thionyl halides such as thionyl chloride, thionyl bromide, thionyl iodide; sulfuryl halides such as sulfuryl chloride, sulfuryl bromide, sulfuryl iodide; phosphorus trichloride Phosphorus trihalides such as phosphorus tribromide, phosphorus triiodide; phosphorus pentahalides such as phosphorus pentachloride, phosphorus pentabromide, phosphorus pentaiodide; phosphorus oxychloride, phosphorus oxybromide, Examples thereof include halogenating agents such as phosphorus oxyhalides such as phosphorus oxyiodide; rhenium reagents such as methyltrioxorhenium (VII); and preferably sulfonyl halides.

Examples of the base used for converting the hydroxy group into a leaving group include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Alkali metal bicarbonates such as; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide;
Alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine. , N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.
4.0] -7-undecene (DBU); and preferably organic amines (most preferably triethylamine).

The inert solvent used for converting the hydroxy group into a leaving group is not particularly limited as long as it is inert to this reaction, and for example, hexane, heptane,
Aliphatic hydrocarbons such as ligroin, petroleum ether;
Aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol Ethers such as dimethyl ether; ketones such as acetone and 2-butanone; formamide,
Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; sulfolane; preferably halogenated hydrocarbons (most preferably,
Dichloromethane).

The reaction temperature for converting the hydroxy group into a leaving group varies depending on the raw material compound, the reagent used, the type of solvent and the like, but is usually -50 ° C to 200 ° C (preferably -10 ° C to 150 ° C).

The reaction time for converting the hydroxy group into a leaving group varies depending on the starting compound, the reagent used, the solvent, the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 12 minutes). Time).

The iodizing agent used in the above reaction is, for example, phosphorus pentaiodide, phosphorus oxyiodide, sodium iodide or potassium iodide, and preferably sodium iodide.

The reaction temperature for iodizing the leaving group varies depending on the raw material compound, the reagent used, the type of solvent, etc., but is usually 0 ° C. to 200 ° C. (preferably 10 ° C. to 15 ° C.).
0 ° C).

The reaction time for iodizing the leaving group varies depending on the raw material compound, the reagent used, the solvent, the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 12 hours). Is.

After completion of the reaction, the object compound (IV) of this reaction is
Is collected from the reaction mixture according to conventional methods. For example,
The reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, then water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, and the water, etc. After washing with water, it is obtained by drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and then distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

The step A3 is a step of producing a compound having the general formula (VI), which is carried out in an inert solvent.
V) is reacted with a compound having the general formula (V) in the presence of a base.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction, and examples thereof include diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether. Ethers; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; formamide, dimethylformamide, dimethylacetamide,
Amides such as hexamethylphosphoric triamide; water;
Or water or a mixed solvent of the above solvents; preferably alcohols or amides (most preferably dimethylformamide).

Examples of the base used in the above reaction include the same bases as those used for converting the hydroxy group in the A2 step of Method A into a leaving group, and preferably, , Alkali metal hydrides or alkali metal alkoxides (most preferably sodium hydride).

The reaction temperature will differ depending on the types of starting compounds, bases, solvents, etc., but is usually -78 ° C to 100 ° C.
(Preferably 0 ° C. to 50 ° C.).

The reaction time varies depending on the starting compound, the base, the solvent, the reaction temperature and the like, but is usually 15 minutes to 48 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the target compound (VI) of the reaction is
Is collected from the reaction mixture according to conventional methods. For example,
The reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, then water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, and the water, etc. After washing with water, it is obtained by drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and then distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

Step A4 is a step for producing a compound having the general formula (VII), which is carried out by reacting compound (VI) with a base in an inert solvent to hydrolyze an ester group into a carboxy group. Be seen.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction, and for example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene. , Aromatic hydrocarbons such as toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol
Alcohol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve. Or water or a mixed solvent of the above solvents, and preferably alcohols (most preferably ethanol).
It is).

Examples of the base used in the above reaction include the same bases as those used for converting the hydroxy group in the A2 step of Method A into a leaving group, and preferably, , Alkali metal hydroxides (most preferably potassium hydroxide).

The reaction temperature will differ depending on the types of starting compounds, bases, solvents, etc., but it is usually from -20 ° C to 200 ° C.
(Preferably 0 ° C. to 50 ° C.).

The reaction time varies depending on the raw material compound, base, solvent, reaction temperature and the like, but is usually 30 minutes to 120 hours (preferably 1 hour to 80 hours).

After completion of the reaction, the target compound (VI
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, It can be obtained by washing with water or the like, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

The step A5 is a step for producing a compound having the general formula (IX), and is a method for subjecting the carboxyl group of the compound (VII) to a Curtius rearrangement reaction to convert it into a carbamate. After reacting with a diarylphosphoric acid azide derivative such as diphenylphosphoric acid azide in the presence of a base in an inert solvent, the compound of the general formula (V
It is carried out by reacting with a compound having III) by heating.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction, and for example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene. , Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ethers such as; or water or a mixed solvent of the above solvents;
And preferably aromatic hydrocarbons (most preferably benzene).

Examples of the base used in the above reaction include the same bases as those used for converting the hydroxy group in the A2 step of Method A to a leaving group. , Organic amines (most preferably triethylamine).

Reaction temperature in reacting compound (VII) with diarylphosphoric acid azide derivative and compound (VII)
The reaction temperature for the reaction with I) varies depending on the starting compound, the base, the type of solvent, etc., but is usually 0 ° C. to 2 ° C.
The temperature is 00 ° C (preferably 20 ° C to 150 ° C).

Reaction temperature in reacting compound (VII) with diarylphosphoric acid azide derivative and compound (VII)
The reaction temperature when reacting with I) varies depending on the starting compound, the base, the solvent, the reaction temperature, etc., but is usually 15 minutes to 24 hours (preferably 30 minutes to 12 hours).

Further, when the compound (VII) is reacted with the diarylphosphoric acid azide derivative, by reacting together the compound (VIII) which is difficult to directly react with the diarylphosphoric acid azide derivative, the carboxyl group is immediately carbamate. Can be converted to.

After completion of the reaction, the object compound (IX) of this reaction is
Is collected from the reaction mixture according to conventional methods. For example,
The reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, then water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, and the water, etc. After washing with water, it is obtained by drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and then distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

Step A6 is a step for producing a compound having the general formula (X) and is carried out by reducing the ester of compound (IX). It is carried out by reacting with.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction, and for example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene. , Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ethers such as; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
Alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve
Or a mixed solvent of the above solvents, preferably a mixed solvent of alcohols and ethers (most preferably a mixed solvent of ethanol and tetrahydrofuran).

As the reducing agent used in the above reaction, for example, the same ones as those used in the above-mentioned Method A, step A1 can be mentioned, preferably alkali borohydrides (most preferably Is sodium borohydride or lithium borohydride).

The reaction temperature is usually -78 ° C to 150 ° C (preferably -20 ° C to 50 ° C), though it varies depending on the starting compound, the type of solvent and the like.

The reaction time varies depending on the starting compound, the solvent, the reaction temperature and the like, but is usually 5 minutes to 48 hours (preferably 30 minutes to 24 hours).

After completion of the reaction, the target compound (X) of the reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, It can be obtained by washing with water or the like, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

The step A7 is a step for producing a compound having the general formula (XI), and is carried out by reacting the compound (X) with a base to ring-close the oxazolidine ring.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction, and examples thereof include diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether. Ethers; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; formamide, dimethylformamide, dimethylacetamide,
Amides such as hexamethylphosphoric triamide; water;
Or water or a mixed solvent of the above solvents; preferably alcohols or amides (most preferably dimethylformamide).

As the base used in the above reaction, for example, the same bases as those used for converting the hydroxy group in the A2 step of Method A to a leaving group can be mentioned, and preferably , Alkali metal alkoxides (most preferably potassium t-butoxide).

The reaction temperature will differ depending on the types of starting compounds, bases, solvents, etc., but it is usually from -78 ° C to 100 ° C.
(Preferably -50 ° C to 50 ° C).

The reaction time varies depending on the starting compound, the base, the solvent, the reaction temperature and the like, but is usually 15 minutes to 48 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the object compound (XI) of this reaction is
Is collected from the reaction mixture according to conventional methods. For example,
The reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, then water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, and the water, etc. After washing with water, it is obtained by drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and then distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

The step A8 is a step for producing a compound having the general formula (I), which comprises reacting the compound (X
I) is reacted with a base to hydrolyze, and then optionally amino in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a ,
It is carried out by removing the protecting group of hydroxy and / or carboxyl group, protecting the amino group in R ¹ and / or R ^2, and / or protecting the hydroxy group in R ³ .

The inert solvent used when reacting the compound (XI) with a base is not particularly limited as long as it is inert to this reaction, and for example, hexane, heptane,
Aliphatic hydrocarbons such as ligroin, petroleum ether;
Aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol Ethers such as dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol.
Alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; water; or a mixed solvent of the above solvents, preferably a mixed solvent of alcohols and ethers. (Most preferably, a mixed solvent of methanol and tetrahydrofuran).

As the base used when reacting the compound (XI) with a base, for example, the same bases as those used for converting the hydroxy group in the A2 step of Method A to a leaving group can be used. Mention may be made of alkali metal hydrides (most preferably potassium hydroxide).

The reaction temperature will differ depending on the types of starting compounds, bases, solvents, etc., but it is usually from -20 ° C to 200 ° C.
(Preferably 0 ° C. to 100 ° C.).

The reaction time varies depending on the starting material compound, base, kind of solvent, reaction temperature and the like, but is usually 30 minutes to 4 minutes.
It is 8 hours (preferably 1 to 24 hours).

Removal of protecting groups for amino, hydroxy and carboxyl groups varies depending on the kind thereof, but is generally a method well known in the art of synthetic organic chemistry, for example, TWGree.
n, (Protective Groups in Organic Synthesis), John
Wiley & Sons: JFWMcOmis, (Protective Groups in
Organic Chemistry), Plenum Press can be carried out as follows.

When the amino-protecting group is a silyl compound, it is usually a compound which produces a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine and potassium fluoride. It is removed by treating with.

The solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether. Is preferred.

The reaction temperature and reaction time are not particularly limited, but they are usually carried out at 0 ° C. to 50 ° C. for 10 minutes to 18 hours.

When the protecting group for the amino group is an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group or a substituted methylene group forming a Schiff base, an acid or a base is present in the presence of an aqueous solvent. Can be removed by treating with.

The acid used in the above reaction is not particularly limited as long as it is one that is usually used as an acid and does not inhibit the reaction. For example, hydrobromic acid, hydrochloric acid, sulfuric acid,
An inorganic acid such as perchloric acid, phosphoric acid or nitric acid, preferably hydrochloric acid.

The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound, but preferably an alkali metal such as lithium carbonate, sodium carbonate or potassium carbonate is used. Carbonates; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; aqueous ammonia. ,
Concentrated ammonia-ammonia such as methanol;

The solvent used in the above reaction is not particularly limited as long as it is used in a usual hydrolysis reaction, and examples thereof include methanol, ethanol, n-propanol and isopropanol. Alcohols such as alcohol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve;
Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether;
Water; a mixed solvent of water and the above organic solvent; and preferably ethers (most preferably dioxane).

The reaction temperature and the reaction time vary depending on the starting compound, the solvent and the acid or base used, and are not particularly limited, but in order to suppress side reactions, it is usually at 0 ° C. to 150 ° C. for 1 hour. Allow to react for ~ 10 hours.

When the amino-protecting group is aralkyl or aralkyloxycarbonyl, it is usually contacted with a reducing agent in an inert solvent (preferably, catalytic reduction at room temperature under a catalyst). ) A method of removing or a method of removing using an oxidizing agent is preferable.

The solvent used for removal by catalytic reduction is not particularly limited as long as it is inert to this reaction, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; Aromatic hydrocarbons such as toluene, benzene, xylene; methyl acetate,
Esters such as ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n- Alcohols such as propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; Such organic acids; water; a mixed solvent of the above solvent and water; preferably alcohols, ethers,
Organic acids or water (most preferably alcohols or organic acids).

As the catalyst used for removal by catalytic reduction, any catalyst usually used for catalytic reduction reaction may be used.
Although not particularly limited, palladium-carbon, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate are preferably used.

The pressure is not particularly limited, but is usually 1 to 1
It is carried out at 0 atm.

The reaction temperature and reaction time in the removal by catalytic reduction vary depending on the starting compound, catalyst, solvent and the like, but are usually carried out at 0 ° C. to 100 ° C. for 5 minutes to 24 hours.

The solvent used for removal by oxidation is not particularly limited as long as it does not participate in this reaction, but a water-containing organic solvent is preferable.

Examples of such an organic solvent include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; nitriles such as acetonitrile, diethyl ether, diisopropyl ether, tetrahydrofuran, Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; and sulfoxides such as dimethyl sulfoxide; Sulfolane; preferably halogenated hydrocarbons, ethers or sulfoxides (most preferably halogenated hydrocarbons or sulfoxides).

The oxidizing agent used is not particularly limited as long as it is a compound used for oxidation, but preferably potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3-. Dichloro-5,6-
Dicyano-p-benzoquinone (DDQ) is used.

The reaction temperature and reaction time for the removal by oxidation will differ depending on the starting compounds, catalyst, solvent, etc., but are usually carried out at 0 ° C. to 150 ° C. for 10 minutes to 24 hours.

When the amino-protecting group is an aralkyl group, the protecting group can be removed by using an acid.

The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction, and examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid,
Inorganic acids such as phosphoric acid; Bronsted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and other organic acids; zinc chloride, tetrachloride Tin chloride, boron trichloride, boron trifluoride,
Lewis acids such as boron tribromide; acidic ion exchange resins; preferably inorganic or organic acids (most preferably hydrochloric acid, acetic acid or trifluoroacetic acid).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene. Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Such esters; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; formamide, dimethylformamide, dimethylacetamide,
Amides such as hexamethylphosphoric triamide; water;
Or water or a mixed solvent of the above solvents; preferably ethers, alcohols or water (most preferably dioxane, tetrahydrofuran, ethanol or water).

The reaction temperature depends on the starting compound, the acid used,
Although it varies depending on the solvent and the like, it is generally -20 ° C to the boiling point temperature (preferably 0 ° C to 100 ° C).

The reaction time depends on the starting compound, the acid used,
The time is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours), varying depending on the solvent, the reaction temperature and the like.

When the amino-protecting group is an alkenyloxycarbonyl, the amino-protecting group is usually a substituted methylene which forms the above-mentioned aliphatic acyl, aromatic acyl, alkoxycarbonyl or Schiff base. When it is a group, it is carried out by treating with a base in the same manner as the conditions for the removal reaction.

In the case of an allyloxycarbonyl group,
In particular, the method of removing using palladium and triphenylphosphine or nickel tetracarbonyl is simple and can be carried out with few side reactions.

When the hydroxy-protecting group is a silyl group, it is usually a compound which produces a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine and potassium fluoride. Treated or an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, It can be removed by treatment with an organic acid such as trifluoromethanesulfonic acid.

When removing with a fluorine anion,
The reaction may be accelerated by adding an organic acid such as formic acid, acetic acid or propionic acid.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction, but it is preferably diethyl ether or diisopropyl ether.
Ethers such as tellurium, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; organic acids such as acetic acid; water; mixed solvents of the above solvents.

The reaction temperature and reaction time will differ depending on the starting compounds, catalysts, solvents, etc., but are usually 0 ° C. to 100 ° C.
(Preferably 10 ° C. to 50 ° C.) for 1 hour to 24 hours.

When the hydroxy-protecting group is aralkyl or aralkyloxycarbonyl, it is usually contacted with a reducing agent in an inert solvent (preferably, catalytic reduction at room temperature under a catalyst). ) A method of removing or a method of removing using an oxidizing agent is preferable.

The solvent used for removal by catalytic reduction is not particularly limited as long as it does not participate in this reaction, but aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; toluene and benzene. , Aromatic hydrocarbons such as xylene; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; methanol; Ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
Alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve
Amides; amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide; fatty acids such as formic acid and acetic acid; water; a mixed solvent of the above solvents; Alcohols (most preferably methanol) are preferred.

As the catalyst used for removal by catalytic reduction, any catalyst usually used for catalytic reduction reaction may be used.
Although not particularly limited, for example, palladium-carbon, palladium-black, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate, preferably palladium- It is carbon.

The pressure is not particularly limited, but is usually 1 to 1
It is carried out at 0 atm.

The reaction temperature and reaction time in the removal by catalytic reduction vary depending on the starting compound, catalyst, solvent, etc., but are usually 0 ° C. to 100 ° C. (preferably 20 ° C. to 7 ° C.).
5 minutes to 48 hours (preferably 1 hour to 2)
4 hours).

The solvent used for removal by oxidation is not particularly limited as long as it does not participate in this reaction, but a water-containing organic solvent is preferable.

Suitable as such organic solvent are ketones such as acetone; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nitriles such as acetonitrile; diethyl ether, tetrahydrofuran, Mention may be made of ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; and sulfoxides such as dimethylsulfoxide.

The oxidizing agent used is not particularly limited as long as it is a compound used for oxidation, but preferably potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3- Dichloro-5,6-
Dicyano-p-benzoquinone (DDQ) is used.

The reaction temperature and the reaction time will differ depending on the starting compounds, the catalyst, the solvent, etc., but are usually 0 ° C. to 150 ° C.
For 10 minutes to 24 hours.

In liquid ammonia or methanol.
, Ethanol, n-propanol, isopropanol
, N-butanol, isobutanol, t-butanol
-78 ° C in alcohols such as alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve.
It can also be removed by reacting an alkali metal such as metallic lithium or metallic sodium at ˜0 ° C.

Further, it can be removed by using aluminum chloride-sodium iodide or alkylsilyl halides such as trimethylsilyl iodide in a solvent.

The solvent used is not particularly limited as long as it does not participate in this reaction, but preferably, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; such as acetonitrile. Nitriles;
A mixed solvent of the above solvents may be mentioned. The reaction temperature and the reaction time vary depending on the raw material compound, the solvent, etc., but are usually 0.
It is carried out at 50 to 50 ° C for 5 minutes to 72 hours.

When the reaction substrate has a sulfur atom,
Aluminum chloride-sodium iodide is preferably used.

When the hydroxy-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it is removed by treating with a base in a solvent.

The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound, and examples thereof include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate. Alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide, Metal alkoxides such as sodium ethoxide, potassium t-butoxide; ammonia water, ammonia such as concentrated ammonia-methanol, preferably alkali metal hydroxides, metal alkoxides or ammonia. (Most preferably, alkali metal hydroxides or metal alkoxides) It is the earth).

The solvent used is not particularly limited as long as it can be used in a usual hydrolysis reaction, and examples thereof include diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether. Ethers; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
Preference is given to alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; water; mixed solvents of the above solvents.

The reaction temperature and reaction time vary depending on the starting compounds, the base used, the solvent, etc., and are not particularly limited,
In order to suppress side reactions, it is usually -20 ° C to 150 ° C.
It is carried out for 1 to 10 hours.

When the hydroxy-protecting group is alkoxymethyls, tetrahydropyranyls, tetrahydrothiopyranyls, tetrahydrofuranyls, tetrahydrothiofuranyls or substituted ethyls, usually in a solvent. , Treated with acid to remove.

The acid to be used is not particularly limited as long as it is usually used as a Bronsted acid or a Lewis acid, preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid; or Bronsted acids such as organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid: Lewis acids such as boron trifluoride, but strong acidic cations such as Dowex 50W Exchange resins can also be used.

The solvent used in the above reaction is not particularly limited as long as it is inert to this reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,
Halogenated hydrocarbons such as dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ethers such as; methanol, ethanol
Alcohol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve. Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, and cyclohexanone; water; a mixed solvent of the above solvents; preferably ethers (most preferably tetrahydrofuran) or alcohols ( Most preferably, it is methanol).

The reaction temperature and reaction time will differ depending on the starting compounds, the acid used, the solvent, etc., but are usually -10 ° C to 200 ° C (preferably 0 ° C to 150 ° C), and 5 minutes to 48 hours. (Preferably 30 minutes to 10 hours).

When the hydroxy-protecting group is an alkenyloxycarbonyl, the conditions for the removal reaction are usually the case where the hydroxy-protecting group is the above-mentioned aliphatic acyl, aromatic acyl or alkoxycarbonyl. It is achieved by treating with a base in the same manner as in.

In case of an allyloxycarbonyl group,
Particularly, a method of removing using palladium, triphenylphosphine, or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) hexafluorophosphate is simple and there are few side reactions. You can

When the protecting group for the carboxyl group is a lower alkyl group, a lower alkenyl group or a lower alkynyl group, it can be removed by treating with an acid or a base.

The acid used in the above reaction is not particularly limited as long as it is an acid used in removing the above protecting group of the carboxyl group, and examples thereof include hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid. .

The base used in the above reaction is not particularly limited as long as it is a base used in removing the above protecting group for the carboxyl group, and examples thereof include alkali metal carbonates such as sodium carbonate and potassium carbonate. An alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; or a concentrated ammonia-methanol solution, preferably sodium hydroxide.

[0230] Incidentally, hydrolysis with a base sometimes causes isomerization.

The solvent used in the above reaction is, for example, water or alcohols such as methanol, ethanol and n-propanol; ethers such as tetrahydrofuran and dioxane; It is a mixed solvent of an organic solvent and water, preferably alcohols (most preferably methanol).

[0232] The reaction temperature and the reaction time differ depending on the starting compounds, the solvent, the reagents used, etc. and are not particularly limited,
In order to suppress side reactions, the reaction temperature is usually 0 ° C to 220 ° C, and the reaction time is 30 minutes to 10 hours.

When the protecting group for the carboxy group is a halogeno lower alkyl group, it is usually removed by reduction in a solvent.

As the reduction method, when the protecting group of the carboxy group is a halogeno lower alkyl group, a method by chemical reduction such as zinc-acetic acid is preferable, and when it is an aralkyl group, a palladium- It is carried out by a catalytic reduction method using a catalyst such as carbon or platinum, or by a chemical reduction method using an alkali metal sulfide such as potassium sulfide or sodium sulfide.

The solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; A fatty acid such as acetic acid; or a mixed solvent of the above organic solvent and water is preferable.

The reaction temperature and reaction time will differ depending on the starting compounds, solvent, reduction method, etc., but normally the reaction temperature will be
The reaction time is 5 minutes to 12 ° C.
It's time.

The protecting group for the carboxyl group is a lower alkyl group or 1 to 3 C ₆ -C ₁₀ aryl optionally substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, nitro, halogen or cyano. In the case of an aralkyl group such as a C ₁ -C ₆ alkyl group substituted by, the removal reaction in the case where the hydroxy group-protecting group is the above-mentioned aliphatic acyl, aromatic acyl or alkoxycarbonyl It is achieved by treating with a base in the same manner as the conditions.

The removal of the amino, hydroxy and / or carboxyl protecting groups can be carried out by carrying out the desired removal reactions in any order.

The method of protecting the amino and hydroxy groups varies depending on the kind of the protecting group, but can be generally performed by the method well known in the art of synthetic organic chemistry as follows.

The method of protecting the amino group is described by compound (I).
In the compound R ¹ and R ² are hydrogen atom, in an inert solvent (preferably, diethyl - ether, diisopropyl et - ethers - ether, et such as tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; Methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve In the presence or absence of a base (organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine and pyridine), or a compound R ^1a -Z (XII) [In the above formula, R ^1a represents an amino group. And a Z is a halogen atom. ]
And 0 ° C. to 50 ° C. (preferably around room temperature) for 30 minutes to 10 hours (preferably 1 hour to 5 hours).

The method of protecting the hydroxy group is as follows. In compound (I), the compound in which R ³ is a hydrogen atom is treated in an inert solvent (preferably chloroform, dichloromethane,
1,2-dichloroethane, halogenated hydrocarbons such as carbon tetrachloride; formamide, dimethylformamide,
Amides such as dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide) in the presence of a base (preferably alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride) Organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine and pyridine), the following compound R ^3a -Z (XIII) [wherein R ^3a is a hydroxyl-protecting group (as described above). , And Z has the same meaning as described above. ] And 30 at 0 ° C to 50 ° C (preferably near room temperature)
It is carried out by reacting for 1 minute to 24 hours (preferably 1 hour to 24 hours).

In addition, the removal of the protecting group for the amino, hydroxy and / or carboxyl group and the reaction for protecting the amino and / or hydroxy group can be carried out in any order and the desired reactions can be carried out sequentially.

After completion of the reaction, the target compound (I) of the reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, It can be obtained by washing with water or the like, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

The step A9 is a step for producing a compound having the general formula (I) from the compound (X), and after reacting the compound (X) with a base in an inert solvent for hydrolysis,
Optionally removing the protecting groups for amino, hydroxy and / or carboxyl groups on R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , protecting the amino group on R ¹ and / or R ² . , And / or by protecting the hydroxy group in R ³ , this step is performed in the same manner as in the method A, step A8.

Step A10 produces compound (Ic).
The step of reducing the ester of compound (IX)
Later, if desired, R¹, R², R³, R^5a, R^6aAnd R^7aTo
Amino, hydroxy and / or carboxyl in
Removing a protecting group of a group, R ¹And / or R²To
Protecting the amino group and / or R³To
By protecting the hydroxy group
The method of reducing the ester of (IX) is
The method is performed in the same manner as the step A6.

Method B is the compound (I) in which X is an ethynylene group, the compound (Ie) in which X is a vinylene group, and the compound (I in which X is an ethylene group).
f), X is -CO-CH ₂ - compound is a group having a (Ig), X is -CO-CH ₂ - is a radical having, R ¹
Compounds There is a ^{_{-CO 2 R 10 (Ig-1}} ), X is -CH
(OH) -CH ₂ - compound is a group having a (Ih),
A compound (Ii) in which X is an aryl group or an aryl group substituted with 1 to 3 groups selected from the substituent group a and a compound (Ij) in which X is an oxygen atom or a nitrogen atom are produced. Is the way.

[0247]

[Chemical 25]

[0248]

[Chemical formula 26]

[0249]

[Chemical 27]

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R
^{5a, R 6, R 6a,} R 7, R 7a, R 10, Y and n have the same meanings as described above, Xa represents an oxygen atom or a sulfur atom, Ya is C ₁ -C ₁₀ C ₁ substituted with 1 to 3 alkylene groups or groups selected from the substituent groups a and b
Is a C ₁₀ alkylene group, ring A represents an aryl group substituted with 1 to 3 aryl groups or groups selected from the substituent group a, and W is a compound represented by the following general formula:

[0251]

[Chemical 28]

[In the above formula, R ⁴ and R ¹⁰ have the same meanings as described above, and R ′ and R ″ are the same or different and selected from a lower alkyl group, an aryl group or a substituent group a. Represents an aryl group having 1 to 3 substituents. ] Is shown.

The step B1 is a step for producing a compound having the general formula (XVI), which is carried out in the presence of a base and a palladium catalyst in an inert solvent in the presence of the general formula (XV). ) And Sonogashira
It is performed by causing a coupling reaction.

The solvent used in the above reaction is not particularly limited as long as it is inert to this reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,
Halogenated hydrocarbons such as dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Such ethers; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; nitriles such as acetonitrile, isobutyl vitryl; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, etc. Amides; sulfoxides such as dimethyl sulfoxide and sulfolane;
Preferred are ethers, amides or sulfoxides (most preferably amides or ethers). In addition, the addition of a small amount of water to the reaction solvent may promote the progress of the reaction.

Examples of the base used in the above reaction include the same bases as those used for converting the hydroxy group in the A2 step of Method A to a leaving group, and preferably, , Organic amines (most preferably triethylamine).

The palladium catalyst used in the above reaction is not particularly limited as long as it is used in a usual Sonogashira coupling reaction. For example, palladium salts such as palladium acetate, palladium chloride and palladium carbonate, Mention may be made of palladium salt complexes such as bistriphenylphosphine palladium chloride complex which forms a complex with the ligand.

Further, by using cuprous iodide and benzyltriethylammonium chloride as additives,
The yield can be improved.

The reaction temperature will differ depending on the kinds of starting compounds, bases, solvents, etc., but it is usually from -20 ° C to 200 ° C.
(Preferably 0 ° C to 120 ° C).

The reaction time varies depending on the starting compound, the base, the solvent, the reaction temperature and the like, but is usually 5 minutes to 48 hours (preferably 15 minutes to 24 hours).

After completion of the reaction, the desired compound (XV
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, It can be obtained by washing with water or the like, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

The step B2 is a step for producing a compound having the general formula (Id), and when W of the compound (XVI) is a group (W-1), the above method A, step A7 and A.
It can be produced by reacting in 8 steps or in the same manner as in the above-mentioned Method A, 9th step. In addition, compound (XVI)
When W is a (W-2) or (W-3) group, a compound of the general formula (Id)
It is possible to produce a compound having

Step B3 is a step for producing a compound having the general formula (XVII). After reacting the compound (XV) with catechol borane, the compound (XIV) and Suzu are added.
It is carried out by reacting kicoupling.

The reaction temperature for reacting compound (XV) with catechol borane is usually 0 ° C to 150 ° C (preferably 10 ° C to 100 ° C).

The reaction time for reacting compound (XV) with catechol borane is usually 15 minutes to 24 hours (preferably 30 minutes to 12 hours).

Thereafter, the Suzuki coupling reaction is carried out in the same manner as the Sonogashira coupling reaction of the B method step B1.

As the solvent used in the above reaction, the same ones as those used in the above-mentioned Method B, step B1 can be mentioned, preferably aromatic hydrocarbons (most preferably toluene). Is.

Examples of the base used in the above reaction include the same bases as those used for converting the hydroxy group in the A2 step of Method A to a leaving group, and preferably, , Alkali metal alkoxides (most preferably sodium ethoxide).

As the palladium catalyst used in the above reaction, the same ones as those used in the above-mentioned Method B, step B1 can be mentioned. Preferably, the palladium salt complex (most preferably bistrichloride chloride) is used. Phenylphosphine palladium).

Step B4 is a step for producing a compound having the general formula (Ie), and when W of the compound (XVII) is (W-1) group, the method A, step A7 and A.
It can be produced by reacting in 8 steps or in the same manner as in the above-mentioned Method A, 9th step. In addition, the compound (XVI
When W in I) is a (W-2) or (W-3) group, A
By reacting in the same manner as in Process A8 step.
Compounds with e) can be prepared.

Step B5 is a step for producing a compound having the general formula (XVIII), wherein the compound (XVI) is reduced in an inert solvent (preferably, catalytic reduction at room temperature under a catalyst). Performed by.

The solvent used for removal by catalytic reduction is not particularly limited as long as it is inert to this reaction, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; Aromatic hydrocarbons such as toluene, benzene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; methyl acetate, ethyl acetate, propyl acetate, butyl acetate, Esters such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methano-
, Ethanol, n-propanol, isopropanol
, N-butanol, isobutanol, t-butanol
Alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; organic acids such as acetic acid and hydrochloric acid; water; mixed solvent of the above solvent and water; Includes alcohols or ethers (most preferably,
Methanol).

The catalyst used for removal by catalytic reduction is not particularly limited as long as it is usually used for catalytic reduction reaction, but preferably palladium-
Carbon, Raney-nickel, platinum oxide, platinum black, rhodium-
Aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate are used.

The reaction temperature will differ depending on the types of starting compounds, catalysts, solvents, etc., but is usually -20 ° C to 200 ° C.
(Preferably 0 ° C. to 100 ° C.).

The reaction time varies depending on the raw material compound, catalyst, solvent, reaction temperature and the like, but is usually 5 minutes to 96 hours (preferably 15 minutes to 72 hours).

After completion of the reaction, the target compound (XVI
II) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, After washing with water, etc., and drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc.,
Obtained by distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

Step B6 is a step for producing a compound having the general formula (If), and is the same as W of compound (XVIII).
Is a (W-1) group, it can be produced by reacting in the same manner as in the A method A7 step and A8 step, or the A method A9 step. In addition, the compound (XVI
When W in II) is a group (W-2) or (W-3), the compound having the general formula (If) can be produced by reacting in the same manner as in the method A, step A8.

Step B7 is a step for producing a compound having the general formula (XIX), and in the case where W of the compound (XVI) is a group (W-1), the above method A step A7 and step A
It can be produced by reacting in 8 steps or in the same manner as in the above-mentioned Method A, 9th step. In addition, compound (XVI)
When W of (W-2) or (W-3) is a group represented by the general formula (XI
Compounds with X) can be prepared.

Step B8 is a reaction of the general formula (Ig)
Compound (XIX) is a step of producing a compound
In water-soluble solvents, addition reaction of water using acid catalyst or mercury oxide
For the method via the oximerization reaction used
More, if desired R ¹, R², R³, R^5a, R^6a
And R^7aAmino, hydroxy and / or mosquito
Removing the protecting group of the ruboxyl group, R¹And / and young
Kuha R²Protecting the amino group in and / or
Is R³By protecting the hydroxy group in
Be seen.

The solvent used in the above reaction is not particularly limited as long as it is inert to this reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,
Halogenated hydrocarbons such as dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ethers such as; methanol, ethanol
Alcohol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve. Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; water; a mixed solvent of the above solvents; preferably alcohols (most preferably methanol).

The acid catalyst used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction, and for example, hydrochloric acid, hydrobromic acid, sulfuric acid,
Inorganic acids such as perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid,
Bronsted acids such as organic acids such as methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, boron trioxide There may be mentioned a Lewis acid such as bromide or an acidic ion exchange resin, preferably an inorganic acid (most preferably sulfuric acid).

The reaction temperature will differ depending on the types of starting compounds, acid catalysts, solvents, etc., but is usually -20 ° C to 200 ° C.
(Preferably 0 ° C. to 100 ° C.).

The reaction time depends on the starting compound, the acid catalyst, the solvent,
Although it varies depending on the reaction temperature and the like, it is usually 5 minutes to 96 hours (preferably 15 minutes to 72 hours).

R ¹ , R ² , R ³ , R optionally carried out
^5a , R ^6a and R ^7a , a method for removing a protecting group for an amino, hydroxy and / or carboxyl group, protecting an amino group for R ¹ and / or R ^2, and / or protecting a hydroxy group for R ³ . The method is performed in the same manner as in the method A, step A8.

Step B9 is a step for producing a compound having the general formula (Ig-1), and is compound (XVIa)
Is carried out by a method via an addition reaction of water using an acid catalyst or an oximerization reaction using mercury oxide in an inert solvent, and if desired, R ¹ , R ² , R ³ , R
^5a , R ^6a and R ^7a may be carried out by removing a protecting group for amino, hydroxy and / or carboxyl group and / or protecting the hydroxy group in R ³ , and this step is carried out by the method B method B8. It is performed similarly to the process.

Step B10 is a step for producing a compound having the general formula (XX), wherein compound (XIX) is added to water in an inert solvent using an acid catalyst or an oxylysis using mercury oxide. performed by a method via mercuric lay Deployment reaction, optionally ^{R 1, R 2, R 3} , R 5a, R
Removing a protecting group for amino, hydroxy and / or carboxyl group in ^6a and R ^7a , protecting the amino group in R ¹ and / or R ² , and /
Alternatively, it is carried out by protecting the hydroxy group in R ³ , and this step is carried out in the same manner as the above-mentioned B method step B8.

Step B11 is a step for producing a compound having the general formula (Ih). After reducing compound (XX) in an inert solvent, R ¹ , R ² , R ³ and R are optionally added.
^5a, amino in R ^{6 a} and R ^7a, removing the protecting group of the hydroxyl and / or carboxyl groups, protecting the amino group in R ¹ and / or R ^2, and / or, a hydroxy group in R ³ It is done by protecting.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction, and for example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene. , Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ethers such as; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
Alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve
Or a mixed solvent of the above solvents, preferably ethers or alcohols (most preferably methanol or ethanol).

Examples of the reducing agent used in the above reaction include alkali metal borohydrides such as sodium borohydride, lithium borohydride and sodium cyanoborohydride; diisobutylaluminum hydride.
Aluminum hydride compounds such as lithium aluminum hydride, lithium triethoxyaluminum hydride;
And preferably alkali metal borohydrides (sodium cyanoborohydride).

The reaction temperature will differ depending on the kinds of starting compounds, reducing agents, solvents, etc., but is usually -10 ° C to 100 ° C.
(Preferably -20 ° C to 20 ° C).

The reaction time depends on the starting compound, reducing agent, solvent,
Although it varies depending on the reaction temperature and the like, it is usually 10 minutes to 48 hours (preferably 30 minutes to 12 hours).

R ¹ , R ² , R ³ , R optionally carried out
^5a , R ^6a and R ^7a , a method for removing a protecting group for an amino, hydroxy and / or carboxyl group, protecting an amino group for R ¹ and / or R ^2, and / or protecting a hydroxy group for R ³ . The method is performed in the same manner as in the method A, step A8.

After completion of the reaction, the object compound (Ih) of this reaction is
Is collected from the reaction mixture according to conventional methods. For example,
The reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, then water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, and the water, etc. After washing with water, it is obtained by drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and then distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

Step B12 is a step for producing a compound having the general formula (XXII), which is carried out by subjecting compound (XXI) to Suzuki coupling reaction with compound (XIV). B3 process Sonoga
It is performed in the same way as the shira coupling reaction part.

Step B13 is a step for producing a compound having the general formula (Ii), which is the same as W of compound (XXII).
Is a (W-1) group, it can be produced by reacting in the same manner as in the A method A7 step and A8 step, or the A method A9 step. In addition, the compound (XXI
When W in I) is a (W-2) or (W-3) group, A
By reacting in the same manner as in Process A8 step.
Compounds with i) can be prepared.

Step B14 is a step for producing a compound of the general formula (XXIV), which comprises reacting the compound of the general formula (XXIV) in the absence of a solvent or an inert solvent in the presence of a copper catalyst to give a compound of the general formula (XXIII The reaction is carried out with an alkali metal salt of a compound having In this step, for example, the method described in J. Heterocyclic. Chem., 20, 1557 (1983) can be used.

The solvent used in the above reaction is not particularly limited as long as it is inert to this reaction, and for example, diethyl ether, dioxane, tetrahydrofuran,
Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; pyridines such as pyridine, picoline, lutidine and collidine; and preferably no solvent.

Examples of the copper catalyst used in the above reaction include cuprous iodide, cuprous bromide, cuprous oxide and cupric oxide, preferably cuprous oxide. is there.

The compound used in the above reaction (XXII
The alkali metal salt of I) is prepared from the general formula (XXIII) and an alkali metal or an alkali metal compound. Examples of the alkali metal include lithium, sodium,
Examples thereof include potassium, and examples of the alkali metal compound include alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride. It is preferably adjusted using sodium metal. Further, the use of potassium iodide as an additive can improve the yield.

The reaction temperature will differ depending on the kinds of raw material compounds, catalysts and solvents, but will usually be room temperature to 150 ° C. (preferably 60 ° C. to 120 ° C.).

The reaction time will differ depending on the kinds of starting compounds, catalysts and solvents, but will usually be 1 hour to 7 days (preferably 3 hours to 72 hours).

After completion of the reaction, the desired compound of the present reaction (XXI
V) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, It can be obtained by washing with water or the like, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

Step B15 is a step for producing a compound having the general formula (Ij), which is the same as W of compound (XXIV).
Is a (W-1) group, it can be produced by reacting in the same manner as in the A method A7 step and A8 step, or the A method A9 step. In addition, the compound (XXI
In the case where W in V) is a (W-2) or (W-3) group, the above A
By reacting in the same manner as in Process A8 step.
Compounds with j) can be prepared.

Step B16 is a step for producing a compound having the general formula (XXVI) and is carried out by reacting a compound having the general formula (XIV) with a compound having the general formula (XXV). Is performed in the same manner as in the above-mentioned B method step B1.

Step B17 is a reaction of the compound (XVI) wherein Y is a group having the formula —Ya—O—R ^5a.
This is a step of producing VIb), which is carried out by condensing compound (XXVI) with a compound having general formula (XXVII) by an Mitsunobu reaction in an inert solvent.

The reagent used for the Mitsunobu reaction is not particularly limited as long as it is a reagent that can be used for the Mitsunobu reaction, but it is preferable to use a di-lower solvent such as diethyl azodicarboxylate or diisopropyl azodicarboxylate. Azo compounds such as alkylazodicarboxylates or azodicarbonyls such as 1,1 ′-(azodicarbonyl) dipiperidine and triarylphosphines such as triphenylphosphine or tri-n-butylphosphine It is a combination with a phosphine such as a lower alkylphosphine, and more preferably a combination of a di-lower alkylazodicarboxylate and a triarylphosphine.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferably, aromatic hydrocarbons such as benzene, toluene and xylene; Methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,
Halogenated hydrocarbons such as dichlorobenzene; Esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Acetonitrile, nitriles such as isobutyronitrile, formamide, N, N-
Dimethylformamide, N, N-Dimethylacetamide, N-
Amides such as methyl-2-pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane can be mentioned, and aromatic hydrocarbons and ethers are preferable. is there.

[0307] The reaction temperature is -20 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 3 days, and preferably 30 minutes.
Minutes to 12 hours.

After completion of the reaction, the target compound (XVI
b) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, It can be obtained by washing with water or the like, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate or the like, and distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

Separately from this method, the compound (XI
After hydrolyzing the W group of V), compounds (XV), (X
Compounds (Id) to (Ij) can also be produced by reacting with (XI), (XXIII) or (XXV).

Starting compounds (II), (V), (VII
I), (XII), (XIII), (XIV), (X
V), (XXI), (XXIII), (XXV) and (XXVII) are readily produced according to known or known methods or methods analogous thereto.

Starting compounds (II) and (XIV)
Can also be manufactured by the following method.

Method C is the compound (XIV) and the compound (XIV) having a bromine atom at the 2-position of the thiophene group as a substituent and-(CH ₂ ) n at the 5-position of the thiophene group.
It is a method for producing a compound (XIVa) having a group having —W.

[0314]

[Chemical 29]

[0315]

[Chemical 30]

In the above formula, R ⁴ , R ^6a , R ^7a , R ⁸ and R ⁹ ,
R ^9a , R ¹⁰ , n and W have the same meanings as described above.

Step C1 is a step for producing a compound having the general formula (XXIX).
It is carried out by reacting the compound having I) with a reducing agent in the presence or absence (preferably in the presence) of a base in an inert solvent, and this step is the same as the above-mentioned Method A Step A1. To be done.

Step C2 is a step for producing a compound having the general formula (XXX), which comprises converting the hydroxy group of compound (XXIX) into a leaving group in the presence of a base in an inert solvent, and then converting it to iodine. This step is carried out in the same manner as the above-mentioned A method A2 step.

Step C3 is a step for producing a compound having the general formula (XXXI) and is carried out by reacting compound (XXX) with compound (V) in the presence of a base in an inert solvent. This step is performed in the same manner as in the method A, step A3.

Step C4 is a step for producing a compound having the general formula (XXXII), and is carried out by reacting compound (XXXI) with a base in an inert solvent and hydrolyzing the compound. The same process as the A-th step A4 is performed.

Step C5 is a step for producing a compound having the general formula (XXXIII),
I) is a method of subjecting the carboxyl group of I) to a Curtius rearrangement reaction to convert it into a carbamate.
I) is carried out by reacting I) with a diarylphosphorus azide derivative such as diphenylphosphoric azide in the presence of a base in an inert solvent, and then reacting with compound (VIII), and this step is carried out by the method A described above. It is performed in the same manner as the step A5.

Step C6 is a step for producing compound (XIV) and is carried out by reducing the ester of compound (XXXIII).
The process is performed in the same manner.

After completion of the reaction, the desired compound (XI
V) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, After washing with water, etc., and drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc.,
Obtained by distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

Step C7 is a step for producing a compound having the general formula (XXXV), and is represented by the general formula (XXXIV)
Is carried out in the presence or absence (preferably in the presence) of a base in an inert solvent with a reducing agent, and this step is carried out in the same manner as in the method A, step A1. Be seen.

Step C8 is a step for producing a compound having the general formula (XXXVI), and after converting the hydroxy group of compound (XXXV) into a leaving group in the presence of a base in an inert solvent, iodine is added. This step is carried out in the same manner as the above-mentioned A method A2 step.

Step C9 is a step for producing a compound having the general formula (XXXVII), and is carried out by reacting compound (XXXVI) with compound (V) in the presence of a base in an inert solvent. This step is the same as method A
It is performed in the same manner as the three steps.

Step C10 is a compound represented by the general formula (XXXVII:
I) is a step of producing a compound having I) and is performed by reacting compound (XXXVII) with a base in an inert solvent and hydrolyzing, and this step is performed in the same manner as in the above-mentioned Method A Step A4. .

Step C11 is a step for producing a compound having the general formula (XXXIX).
A method of converting the carboxyl group of III) to a carbamate by subjecting it to a Curtius rearrangement reaction,
XVIII) in the presence of a base in the presence of a base in the presence of a diarylphosphoric acid azide, followed by reacting with a compound (VIII), and this step is carried out. It is performed in the same manner as the step A5.

Step C12 is a step for producing a compound having the general formula (XL) and is carried out by reducing the ester of compound (XXXIX). This step is the same as step A6 of method A above. Done.

Step C13 is a step for producing compound (XIVa) and is carried out by reacting compound (XL) with a brominating agent in an inert solvent.

The solvent used in the above reaction is not particularly limited as long as it is inert to this reaction.
Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; preferably amides (most preferably dimethylformamide).

As the brominating agent used in the above reaction,
Although not particularly limited, for example, “Comprehensive Organic
Transformations ”(Larock, VCH, p316-317) and brominating agents may be mentioned, preferably,
N-bromosuccinimide or bromine.

The reaction temperature will differ depending on the types of starting compounds, brominating agent, solvent, etc., but is usually -78 ° C to 150 ° C.
C. (preferably -20.degree. C. to 100.degree. C.).

The reaction time varies depending on the starting compounds, brominating agent, solvent, reaction temperature and the like, but is usually 5 minutes to 48 minutes.
Time (preferably 30 minutes to 24 hours).

After completion of the reaction, the target compound (XIV
a) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added to separate the organic layer containing the target compound, After washing with water, etc., and drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc.,
Obtained by distilling off the solvent. If necessary, the desired compound thus obtained is eluted by a conventional method, for example, recrystallization, reprecipitation or the like, which is appropriately combined with a method usually used for separation and purification of organic compounds, chromatography is applied, and the compound is eluted with an appropriate eluent. By doing so, it can be separated and purified.

Method D is the compound (II) wherein X is an ethynylene group (IIa), X is an ethylene group (IIb), X is a vinylene group (IIc), and X is -CO. -CH ₂ - groups with a compound (IId), X is -CH (OH) -CH ₂ - a group compound is a group having a (IIe), X is selected from an aryl group or a substituent group a 1 to 3 substituted ants
In this method, a compound (IIf) which is a sulfur group and a compound (IIg) in which X is an oxygen atom or a sulfur atom are produced.

[0337]

[Chemical 31]

[0338]

[Chemical 32]

In the above formula, R ^5a , R ^6a , R ^7a , R ⁸ , n,
Xa, Y, Ya and ring A have the same meanings as described above.

Step D1 is a step for producing compound (IIa), which is carried out in an inert solvent.
To the compound (XV) in the presence of a base and a palladium catalyst.
Is carried out by a Sonogashira coupling reaction with a compound having the formula (1), and this step is carried out in the same manner as the above-mentioned B method, step B1.

Step D2 is a step for producing compound (IIb) and is carried out by reducing compound (IIa) in an inert solvent (preferably catalytic reduction at room temperature under a catalyst). This step is performed in the same manner as the B method step B5.

Step D3 is a step for producing compound (IIc). After reacting compound (XV) with catechol borane, compound (XXVIII) and Suzuki coupli are added.
This step is carried out in the same manner as in the above-mentioned Method B, Step B3.

The step D4 is a step for producing the compound (IId), which comprises subjecting the compound (IIa) to an addition reaction of water using an acid catalyst or an oximerization reaction using mercury oxide in an inert solvent. This step is performed in the same manner as the above-mentioned B method step B8.

Step D5 is a step for producing compound (IIe) and is carried out by reducing compound (IId) in an inert solvent. This step is carried out in the same manner as in method B, step B11. .

Step D6 is a step for producing compound (IIf), which comprises converting compound (XXI) into compound (XXVII).
I) and Suzuki coupling reaction are carried out, and this step is carried out in the same manner as the B method step B3 step.

Step D7 is a step for producing compound (IIg), which comprises reacting compound (XXVIII) with or without compound (XXII) in the presence of a copper catalyst in a solvent-free or inert solvent.
It is carried out by reacting with the alkali metal salt of I), and this step is carried out in the same manner as the above-mentioned B method, step B14.

Step D8 is a step for producing a compound having the general formula (XLI), which is compound (XXVIII).
Is performed by reacting with the compound (XXV), and this step is performed in the same manner as in the above-mentioned Method B, Step B1.

Step D9 is a compound (IIa-) in which Y in the compound (IIa) is a group having the formula -Ya-O-.
This step is a step for producing 1) and is carried out by reacting compound (XLI) with compound (XXVII). This step is carried out in the same manner as Method B, step B17.

Method E is particularly applicable to compound (I) of the present invention or compound (XLIVa), (XLIa) which is an intermediate of other pharmaceuticals.
It is a method for producing Vb), (La) and (Lb).

[0350]

[Chemical 33]

In the above formula, R ¹ , R ² , R ³ , R ^4a , R ¹¹ and
Ar, m, Z and Ph have the same meanings as described above, and R ^3b represents a hydrogen atom-protecting group.

Step E1 is a step for producing the general formula (XLIVa) or (XLIVb), and is the general formula (XLIa).
I) in the presence or absence of a solvent, only one hydroxyl group of the compound having the general formula (XLII
It is carried out by selective acylation with a compound having I).

The solvent used in the present invention is not particularly limited and may be only the compound (XLIII), and the optimum one differs depending on the kind of the raw material compound, but various organic solvents and water-containing organic solvents may be used. And preferably, ethers such as diisopropyl ether, t-butyl methyl ether, diethyl ether and tetrahydrofuran; aliphatic hydrocarbons such as n-hexane and n-pentane; aromatic carbons such as benzene and toluene. Hydrogens;
And halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, more preferably ethers, most preferably diisopropyl ether.

The reaction temperature depends on the starting compound, the solvent used, the lipase used, and the compound (XLIII).
It depends on the type of the product, but it is usually -50 ℃ to 50 ℃
And preferably 0 ° C. to 40 ° C.

The reaction time also depends on the starting compound, the solvent used, the lipase used, and the compound (XLIII).
The time is usually 15 minutes to 150 hours, preferably 30 minutes to 24 hours, although it varies depending on the kind of the above.

After completion of the reaction, the desired compound (XLI
Va) or (XLIVb) is collected from the reaction mixture according to a conventional method. For example, when an insoluble matter is present, it is removed by filtration, and then concentrated or an immiscible organic solvent such as ethyl acetate is added as it is, and the organic layer containing the target compound is separated, and anhydrous sodium sulfate and anhydrous magnesium sulfate are added. It is obtained by distilling off the solvent after drying with etc.

The desired product thus obtained can be separated and purified, if necessary, by applying a conventional method, for example, recrystallization, reprecipitation, or chromatography, and eluting with an appropriate eluent.

Step E2 is a step for producing a compound having the general formula (XLV), and is carried out by oxidizing the alcohol moiety of compound (XLIVa) to an aldehyde in the presence of an oxidizing agent in an inert solvent. .

The oxidation reaction used in this step is not particularly limited as long as it is an oxidation reaction which produces an aldehyde from a primary alcohol. For example, Collins oxidation carried out using pyridine and chromic acid in methylene chloride; PCC oxidation carried out with pyridinium chromate (PCC) in methylene chloride; PDC oxidation carried out with pyridinium dichromate (PDC) in methylene chloride; electrophilic agent in methylene chloride (eg acetic anhydride, Trifluoroacetic anhydride, thionyl chloride, sulfuryl chloride, oxalyl chloride,
Dicyclohexylcarbodiimide, diphenylketene-p
-Tolylimine, N, N-diethylaminoacetylene, sulfur trioxide / pyridine complex, etc.) and dimethyl sulfoxide
(DMSO), such as Swern oxidation, DMSO oxidation; and methylene chloride or in benzene, manganese dioxide oxidation performed using manganese dioxide, and the like, and preferably in methylene chloride. Done, pc
C oxidation or Swern oxidation.

The reaction temperature will differ depending on the types of starting compounds, solvent, oxidizing agent, etc., but it is usually -50 ° C to 50 ° C, preferably -10 ° C to 30 ° C.

The reaction time is usually 10 minutes to 2 days, preferably 30 minutes to 24 hours, varying based on the starting material compound, solvent, type of oxidizing agent, reaction temperature and the like.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the oxidizing agent is neutralized with aqueous sodium hydrogen sulfite, and if insoluble matter is present, it is removed by filtration, and then concentrated or added with water and an immiscible organic solvent such as ethyl acetate to obtain an organic compound containing the target compound. The layers are separated, dried over anhydrous sodium sulfate, anhydrous magnesium sulfate and the like, and then the solvent is distilled off.

The obtained desired product can be separated and purified, if necessary, by applying a conventional method, for example, recrystallization, reprecipitation, or chromatography, and eluting with an appropriate eluent.

The step E3 is a step for producing a compound having the general formula (XLVII). The compound having the general formula (XLVI) is added to the aldehyde of the compound (XLV) in the presence of a base in an inert solvent. It is carried out by reacting.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably aromatic hydrocarbons such as benzene, toluene and xylene. Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene;
Ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N,
Examples thereof include amides such as N-dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide and sulfolane, and ethers are more preferable.

The base used is not particularly limited as long as it is used as a base in a usual reaction, but preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, potassium hydroxide, hydroxide Alkali metal hydroxides such as barium and lithium hydroxide; Inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; Sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxy Alkali gold such as potassium, potassium t-butoxide, lithium methoxide Alkoxides; N- methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N- methylpiperidine, 4- pyrrolidinopyridine, picoline, 4- (N, N- dimethylamino) pyridine, 2,
6-di (t-butyl) -4-methylpyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,4-diazabicyclo [4.
3.0] Octane (DABCO), 1,8-diazabicyclo [5.4.0] -7-
Organic amines such as undecene (DBU), 1,5-diazabicyclo [4.3.0] -5-nonene (DBN); or butyllithium,
Examples thereof include organic metal bases such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and more preferable are alkali metal alkoxides, alkali metal hydrides and organic metal bases.

The reaction temperature varies depending on the starting compound, solvent, kind of phosphonium salt, kind of base, etc.
It is carried out at −80 ° C. to 100 ° C., preferably −20.
C. to 50.degree.

The reaction time varies depending on the starting compound, solvent, kind of phosphonium salt, kind of base, etc., but is usually 1
0 minutes to 2 days, preferably 30 minutes to 12
It's time.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture by a conventional method. For example, the reaction solution is neutralized with dilute hydrochloric acid, etc., and if insoluble matter is present, it is removed by filtration, and then concentrated or added with an immiscible organic solvent such as water and ethyl acetate to separate the organic layer containing the target compound. After drying over anhydrous sodium sulfate, anhydrous magnesium sulfate and the like, the solvent is distilled off.

The desired product thus obtained can be separated and purified, if necessary, by applying a conventional method, for example, recrystallization, reprecipitation, or chromatography, and eluting with an appropriate eluent.

Step E4 is a step for producing a compound having the general formula (XLVIII) and is carried out in an inert solvent,
It is carried out by hydrolyzing compound (XLVII) in the presence of a base.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but alcohols such as methanol and ethanol, benzene, toluene and xylene are preferable. Aromatic hydrocarbons, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Diethyl ether, tetrahydrofuran, dioxane,
Examples thereof include ethers such as dimethoxyethane and diethylene glycol dimethyl ether, mixed solvents of these solvents, and mixed solvents of these solvents and water, and alcohols and ethers are more preferable.

The base used is not particularly limited as long as it can be used as a base in a usual reaction, but sodium hydroxide, potassium hydroxide,
Examples thereof include alkali metal hydroxides such as lithium hydroxide and barium hydroxide.

The reaction temperature will differ depending on the starting compounds, the solvent, the type of base, etc., but is usually -20 ° C to 200 ° C, and preferably 0 ° C to 20 ° C.

The reaction time will differ depending on the raw material compounds, reaction temperature, solvent and type of base, but is usually 30 minutes to 48 hours, and preferably 1 hour to 24 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction solution is neutralized with dilute hydrochloric acid, etc., and if insoluble matter is present, it is removed by filtration, and then concentrated or added with an immiscible organic solvent such as water and ethyl acetate to separate the organic layer containing the target compound. After drying over anhydrous sodium sulfate, anhydrous magnesium sulfate and the like, the solvent is distilled off.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. The obtained target product is
If necessary, separation and purification can be carried out by applying a conventional method such as recrystallization, reprecipitation, or chromatography and eluting with a suitable eluent.

Step E5 is a step for producing a compound having the general formula (IL), which is a step for converting compound (XLVIII) into compound (IL) in the presence of a base in an inert solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but is preferably diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane or diethylene glycol dimethyl ether. Ethers such as: N,
N-dimethylformamide, N, N-dimethylacetamide,
Amides such as N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphorotriamide; aromatic hydrocarbons such as benzene, toluene and xylene, more preferably ethers and amides Is.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but preferably lithium hydride, sodium hydride,
Alkali metal hydrides such as potassium hydride; Inorganic bases such as sodium fluoride, alkali metal fluorides such as potassium fluoride; Sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium Alkali metal alkoxides such as t-butoxide, lithium methoxide; or butyllithium,
Examples thereof include organic metal bases such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide. More preferred are alkali metal alkoxides and alkali metal hydrides.

The reaction temperature will differ depending on the starting compounds, solvent, type of base, etc., but it is usually -80 ° C to 100 ° C, and preferably 0 ° C to 50 ° C.

The reaction time will differ depending on the starting compounds, reaction temperature, solvent and type of base, but it is usually 5 minutes to 4 minutes.
8 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction solution is neutralized with dilute hydrochloric acid, etc., and if insoluble matter is present, it is removed by filtration, and then concentrated or added with an immiscible organic solvent such as water and ethyl acetate to separate the organic layer containing the target compound. After drying over anhydrous sodium sulfate, anhydrous magnesium sulfate and the like, the solvent is distilled off.

The obtained desired product can be separated and purified, if necessary, by applying a conventional method, for example, recrystallization, reprecipitation, or chromatography, and eluting with an appropriate eluent.

The step E6 is the step of converting the compound (La) to
R ¹ is a hydrogen atom, and R ² and R ^3a are taken together to form a compound having the formula (-(C = O)-) group (La-
1) is a step of producing, which is a step of converting the compound (IL) into the target compound (La-1) in the presence of a reducing agent in an inert solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but alcohols such as methanol, ethanol and isopropanol; diethyl ether are preferred. Ethers such as diisopropyl ether, t-butyl methyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane; ethyl acetate, propyl acetate And the like, and more preferably alcohols.

The reducing agent used is not particularly limited as long as it is usually used in a catalytic reduction reaction.
Palladium carbon, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride (Wilkinson complex), palladium-barium sulfate, and Raney nickel are preferably used. More preferably, it is palladium carbon.

The pressure is not particularly limited, but is usually 1 to 1
It is carried out at 0 atm.

The reaction temperature will differ depending on the types of starting compounds, solvent, base, etc., but is usually 0 ° C. to 100 ° C.

The reaction time will differ depending on the starting compounds, reaction temperature, solvent and type of base, but it is usually 5 minutes to 4 minutes.
8 hours.

For example, after removing the catalyst by filtration, the organic layer containing the target compound is concentrated or added with water and an immiscible organic solvent such as ethyl acetate, and dried over anhydrous sodium sulfate, anhydrous magnesium sulfate or the like. , Obtained by distilling off the solvent.

The desired product thus obtained can be separated and purified, if necessary, by applying a conventional method, for example, recrystallization, reprecipitation, or chromatography, and eluting with an appropriate eluent.

Step E7 is a step for producing a compound having the general formula (LI), which is a step for converting compound (XLVII) into compound (LI) in the presence of a reducing agent in an inert solvent, This step can be carried out according to the above-mentioned E method, step E6.

Step E8 is a step wherein R is the compound (La).
^3a is a step of producing a compound having a compound (La-2) in which a hydrogen atom is present, in an inert solvent in the presence of a base,
This is a step of producing a compound (La-2) by hydrolyzing a compound (LI), and this step can be performed according to the E method, step E4.

The step E9 is a step for producing the compound (La-1), which is a step for producing the object compound (La-1) from the compound (La-2) in the presence of a base in an inert solvent. Yes, this step can be performed according to the above-mentioned E method, step E5.

Step E10 is a compound (La) wherein R ² and R ^3a are taken together to form a compound of formula (-(C = O)-).
This is a step for producing a compound (La-3) in which R ^3a does not represent a group and is a hydroxy-protecting group, and is carried out by protecting the hydroxy group of the compound (La-2), if desired. , A method which is usually carried out depending on the protecting group of the hydroxy group, for example, Protective Groups
in Organic Synthesis (Third Edition, 1999, John Wiley
& Sons, Inc.).

Also, instead of the compound (XLIVa), the compound (XLIVb) was used, and the above E method Nos. E2 to E10 were used.
Compound (Lb) can be produced by performing the steps.

Method F is a method for producing compound (XLVI).

[0399]

[Chemical 34]

In the above formula, m, Ph, Ar and Z have the same meanings as described above.

Step F1 is a step for producing compound (XLVI) and is carried out by reacting a compound having general formula (LII) with triphenylphosphine in an inert solvent.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction,
For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as toluene, benzene, xylene; methylene chloride,
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and preferably aromatic Hydrocarbons (most preferably benzene).

The reaction temperature will differ depending on the starting compounds, the type of solvent, etc., but it is usually room temperature to 200 ° C., preferably 0 ° C. to 150 ° C. (most preferably around 110 ° C.).
Is.

The reaction time mainly depends on the reaction temperature, the starting compound,
The time is usually 5 minutes to 96 hours, preferably 15 minutes to 48 hours (most preferably around 24 hours), though varying depending on the type of solvent used and the like.

If necessary, the object compound of Method F may be prepared according to a conventional method,
For example, recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, for example, adsorption column chromatography using a carrier such as silica gel, alumina, or magnesium-silica gel florisil; Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas),
A method using a synthetic adsorbent such as partition column chromatography using a carrier such as Diaion HP-20 (manufactured by Mitsubishi Kasei), a method using ion exchange chromatography, or a normal phase using silica gel or alkylated silica gel. Reversed-phase column chromatography (preferably high performance liquid chromatography) may be appropriately combined and eluted with a suitable eluent to perform separation and purification.

When the isomers need to be separated, the separation and purification means can be used after the reaction in each of the above steps or at an appropriate time after the end of the desired step.

Starting compounds (XXVIII), (XXXI
V), (XLII), (XLIII) and (LII)
Are easily manufactured according to known or known methods or methods analogous thereto.

The amino alcohol derivative having the general formula (I), the pharmacologically acceptable salt thereof, the ester or the other derivative thereof, which is the active ingredient of the pharmaceutical composition of the present invention, has low toxicity and excellent immunosuppressive action. The pharmaceutical composition of the present invention has, in particular, systemic lupus erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, Behcet's disease, Chron's disease, ulcerative colitis, autoimmune hepatitis, poor regeneration. Anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullous disease, psoriasis vulgaris, vascular inflammation group, Wegener's granuloma, uveitis, idiopathic interstitial Pneumonia, Goodpasture syndrome, sarcoidosis,
Allergic granulomatous vasculitis, bronchial asthma, myocarditis, cardiomyopathy, aortitis syndrome, post-myocardial infarction syndrome, primary pulmonary hypertension, minimal change nephrosis, membranous nephropathy, membranous proliferative nephritis, focal Glomerulosclerosis, crescentic nephritis, myasthenia gravis, inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, acute polyarthritis, Syndham's chorea, systemic sclerosis, adult-onset diabetes, insulin Dependent diabetes mellitus, juvenile diabetes, atherosclerosis, glomerulonephritis, tubular interstitial nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatitis, viral hepatitis, GVHD,
It is useful as a prophylactic or therapeutic agent for suppressing rejection in various organ transplants, autoimmune diseases such as contact dermatitis, sepsis, and other immune-related diseases.

Further, the novel optically active amino alcohol compounds (La) and (Lb) of the present invention are useful as intermediates for the production of pharmaceuticals.

As a synthetic intermediate of the optically active amino alcohol compounds (La) and (Lb), an optically active 2-substituted-2-amino-1,3-propanediol is used.
Monoester derivative (XLIVa) or (XLIVb)
Is preferred, and such optically active 2-substituted-2-amino-
1,3-Propanediol Monoester derivative (XL
IVa) and (XLIVb) are obtained by using a 2-substituted-2-amino-1,3-propanediol derivative (XLII) as a raw material and using a carboxylic acid vinyl ester derivative (XLIII) in the presence of lipase. By the selective acylation of only one hydroxyl group, it can be produced easily and easily with a high yield.

When the compound having the general formula (I), the pharmaceutically acceptable salt or the ester thereof, which is the active ingredient of the pharmaceutical composition of the present invention, is used as the above-mentioned therapeutic agent or prophylactic agent, it itself Or an appropriate pharmacologically acceptable,
It can be mixed with excipients, diluents and the like and administered orally, for example, by tablets, capsules, granules, powders, syrups, etc. or parenterally by injections, suppositories, etc.

These formulations include excipients such as lactose,
Sugar derivatives such as white sugar, glucose, mannitol, sorbitol; corn starch, potato starch,
α-starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan: and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, aluminometasilicate. Inorganic excipients such as silicate derivatives such as magnesium; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. ), Lubricants (eg metal stearates such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as bee gum and gay wax; boric acid; adipic acid; sodium sulfate) Sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid anhydride such as silicic acid anhydride and silicic acid hydrate; Derivatives can be mentioned), binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients), and disintegrants (for example). Low substituted hydroxypropylse (Such as cellulose derivatives such as sucrose, carboxymethyl cellulose, carboxymethyl cellulose calcium, internally crosslinked sodium carboxymethyl cellulose; and chemically modified starch / celluloses such as carboxymethyl starch, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone can be mentioned.) Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid And sorbic acid), flavoring agents (for example, commonly used sweeteners, acidulants, and flavors). Can be mentioned.), It is prepared in a known manner by using additives such as diluents.

The amount used varies depending on the symptoms, age, etc., but in the case of oral administration, the lower limit of the daily dose is 0.05 m
g (preferably 5 mg), upper limit 200 mg (preferably
40 mg), in the case of intravenous administration, the daily lower limit is 0.01 mg (preferably 1 mg) and the upper limit is 100 mg per dose.
It is desirable to administer (preferably 10 mg) to an adult 1 to 6 times daily depending on the condition.

[0414]

EXAMPLES The present invention will be described in more detail below by showing Examples and Test Examples, but the scope of the present invention is not limited to these.

Example 1 (2R) -Amino -2-methyl-4- [5- (5-cyclohexylpent-
1-Inyl) thiophen-2- yl] butan-1-ol (Exemplified Compound No. 1-770) Example 1 (a) 2-methyl-2- (2-thienyl) ethylmalonic acid diethyl s
Ether Sodium hydride (55%) 18.8 g (0.43 mol) was suspended in dimethylformamide (200 ml), under ice-cooling, methyl malonic acid diethyl ester 50.0 g (0.29 mol) 3
Slowly added over 0 minutes and stirred for an additional 30 minutes. Then, a solution prepared by dissolving 75.2 g (0.32 mol) of 2- (2-iodoethyl) thiophene in dimethylformamide (200 ml) was added over 15 minutes under a nitrogen atmosphere, and the mixture was further stirred at room temperature for 4 hours. The reaction mixture was poured into ice-cooled 10% hydrochloric acid (500 ml) and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was subjected to flash silica gel column chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 1).
Purification was performed at 5: 1) to obtain 53.1 g (65%) of the title compound as a colorless oily substance. Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 2986, 1726,
1271, 1252 Mass spectrum (FAB) m / z: 285 ((M + H) ⁺ ).

Example 1 (b) 2-Methyl-2- (2-thienyl) ethylmalonic acid monoethyl
Obtained was dissolved in ester Example 1 (a) 2-Methyl-2- (2-thienyl) ethyl malonate diethyl ester 52.7 g of (0.19 mol) in ethanol (240 ml) and water (80 ml), Under ice cooling, 11.4 g (0.20 mol) of potassium hydroxide was added, and the mixture was stirred for 2 hours.
Further, add 5.7 g (0.1 mol) of potassium hydroxide to each 3 hours.
The mixture was added once and stirred for a total of 6 hours. Water (300 ml) and ice-cooled 10
% Hydrochloric acid (500 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 0: 1) to give the title compound as a pale yellow oil, 28.6 g (60%). )Obtained. Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 2987, 1732,
1712, 1251, 1109 Mass spectrum (FAB) m / z: 257 ((M + H) ⁺ ).

Example 1 (c) 2-Methoxycarbonylamino-2-methyl-4- (2-thienyl)
Butanoic acid ethyl ester 2-methyl-2- (2-thienyl) ethylmalonic acid monoethyl ester obtained in Example 1 (b) 19.0 g (74.3 mmol)
Was dissolved in benzene (450 ml) and triethylamine 11.4
ml (81.7 mmol) and diphenylphosphoric acid azide 17.6 m
l (81.7 mmol) was added, and the mixture was stirred at room temperature for 10 minutes and further at 80 ° C. for 1 hour and a half. Then 60.3 ml of methanol
(1.49 mol) slowly added dropwise at the same temperature over 30 minutes,
Stirred for an additional 8 hours. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was subjected to flash silica gel column chromatography (elution solvent; hexane: ethyl acetate = 8: 1 to 4: 4).
Purification was carried out in 1) to give the title compound as a colorless oil,
Obtained 14.7 g (69%). Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.11
(1H, d, J = 5.1 Hz), 6.90 (1H, dd, J = 5.1, 3.5 H
z), 6.77 (1H, d, J = 3.5 Hz), 5.69 (1H, brs), 4.19
(2H, q. J = 7.3 Hz), 3.66 (3H, s), 2.84 (2H, dd, J
= 10.5, 10.5 Hz), 2.64 (2H, m), 2.20 (2H, dd, J =
10.5, 8.4 Hz), 1.61 (3H, s), 1.28 (3H, t, J = 7.3
Hz) Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 3417, 2987,
1719, 1503, 1453, 1081 Mass spectrum (FAB) m / z: 286 ((M + H) ⁺ ).

Example 1 (d) 2-methoxycarbonylamino-2-methyl-4- (2-thienyl)
Butan-1-ol 2-methoxycarbonylamino-2-obtained in Example 1 (c)
Methyl-4- (2-thienyl) butanoic acid ethyl ester 14.7
g (51.6 mmol) was dissolved in ethanol (150 ml) and tetrahydrofuran (100 ml) and sodium borohydride was added.
5.07 g (0.13 mol) and lithium chloride 5.68 g (0.13 mol)
Was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Next morning, similarly, sodium borohydride 5.07 g (0.13 mol)
And 5.68 g (0.13 mol) of lithium chloride were added, and the mixture was further stirred overnight at room temperature under a nitrogen atmosphere. The same operation was performed for another 2 days. The reaction mixture was ice-cooled with 10% hydrochloric acid (500
ml) and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was subjected to flash silica gel column chromatography (elution solvent; hexane: ethyl acetate =).
The purification was performed at 2: 1 to 1: 5) to obtain 11.7 g (93%) of the title compound as white crystals. Infrared absorption spectrum ν _max cm ^-1 (KBr): 3406, 3244, 1
687, 1562, 1264, 1089 Mass spectrum (FAB) m / z: 244 ((M + H) ⁺ ) Elemental analysis value; (% as C ₁₁ H ₁₇ NO ₃ S) Calculated value: C: 54.30, H: 7.04 , N: 5.76, S: 13.18 Found: C: 54.18, H: 6.98, N: 5.78, S: 13.34.

Example 1 (e) 2-Methoxycarbonylamino-2-methyl-4- (5-bromothio)
Offen-2-yl) butan-1-ol 2-methoxycarbonylamino-2-obtained in Example 1 (d)
Methyl-4- (2-thienyl) butan-1-ol 11.7 g (48.0 mmol) was dissolved in dimethylformamide (120 ml),
10.8 g (60.8 mmol) of N-bromosuccinimide under ice cooling
Was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 4 hours. The reaction mixture was poured into ice-cooled 10% hydrochloric acid (300 ml) and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; hexane: ethyl acetate = 4: 1 to 1: 3) to give the title compound as a pale yellow oil, 12.4 g (80%). )
Obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 6.84
(1H, d, J = 3.7 Hz), 6.57 (1H, d, J = 3.7 Hz), 4.8
0 (1H, brs), 3.68 (2H, m), 3.64 (3H, s), 2.80 (2H,
m), 1.9-2.2 (2H, m), 1.24 (3H, s) infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 3627, 3436,
2956, 1722, 1711, 1513, 1259, 1087, 1048 Mass spectrum (FAB) m / z: 322 ((M + H) ⁺ ).

Example 1 (f) 4- [2- (5-Bromothiophen-2-yl)] ethyl-4-methylo
Xazolidin-2-one 2-methoxycarbonylamino-2-obtained in Example 1 (e)
Methyl-4- (5-bromothiophen-2-yl) butan-1-ol 12.4 g (38.6 mmol) was added to dimethylformamide (125
ml), potassium t-butoxide (6.50 g, 57.9 mmol) was added under nitrogen atmosphere under ice cooling, and the mixture was further stirred at the same temperature for 3 hours. The reaction mixture was ice-cooled with 10% hydrochloric acid (300 m
It was poured into l) and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was subjected to flash silica gel column chromatography (elution solvent; hexane: ethyl acetate = 4 :).
1: 1: 2) to obtain 10.7 g (95%) of the title compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 6.86
(1H, d, J = 3.7 Hz), 6.58 (1H, d, J = 3.7 Hz), 5.7
3 (1H, brs), 4.18 (1H, d, J = 8.6 Hz), 4.08 (1H,
d, J = 8.6 Hz), 2.84 (2H, m), 1.94 (2H, m), 1.41
(3H, s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3211, 1749, 1
399, 1037, 798 Mass spectrum (FAB) m / z: 290 ((M + H) +) Elemental _{analysis; (C 10 H 12 NO 2} % as SBr) Calculated: C: 41.39, H: 4.17 , N : 4.83, S: 11.05, Br: 27.54 Found: C: 41.36, H: 4.04, N: 4.82, S: 11.08, Br: 27.29.

Example 1 (g) (4R)-[2- (5-Bromothiophen-2-yl)] ethyl-4-methyi
Luoxazolidin-2-one and (4S)-[2- (5-bromothiof
En-2-yl)] ethyl-4-methyloxazolidin-2-one 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidine obtained in Example 1 (f) The 2-one was optically resolved with a preparative optically active HPLC column (ChiralCel OD, Daicel) (column, ChiralCel OD (2 cmφ x 25 cm);
Elution solvent, hexane: 2-propanol = 70: 30; flow rate,
5 ml / min). The one eluted first (55 min) was the 4S form, and the one eluted later (77 min) was the 4R form. The absolute configuration was determined by X-ray crystal structure analysis. (4S) form; [α] _D ²⁴ −4.2 (c 1.03, methanol) (4R) form; [α] _D ²⁴ +4.2 (c 1.00, methanol).

Example 1 (h) (4R)-[2- [5- (5-cyclohexylpent-1-ynyl) thiof
En-2-yl]] ethyl-4-methyloxazolidin-2-one The (4R)-[2- (5-bromothiophen-2-one obtained in Example 1 (g).
Il)] Ethyl-4-methyloxazolidin-2-one 450 mg
(1.55 mmol) was dissolved in 4.5 ml of dimethylformamide, and 5-cyclohexylpent-1-yne (50% xylene solution) 1.40 g (4.65 mmol), triethylamine 2.16 ml
(15.5 mmol), copper (I) iodide 30 mg (0.16 mmol)
And dichlorobis (triphenylphosphine) palladium (109 mg, 0.16 mmol) were added, and the mixture was heated at 80 ° C under nitrogen atmosphere to 2
Stir for hours. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is chromatographed on silica gel (eluting solvent;
Hexane: ethyl acetate = 4: 1 to 3: 2),
456 mg (82%) of the title compound were obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 6.92
(1H, d, J = 3.6 Hz), 6.63 (1H, d, J = 3.6 Hz), 5.4
5 (1H, brs), 4.18 (1H, d, J = 8.6 Hz), 4.07 (1H, d,
J = 8.6 Hz), 2.78-2.90 (2H, m), 2.38 (2H, t, J =
7.2 Hz), 1.92-2.00 (2H, m), 1.55-1.75 (7H, m), 1.4
0 (3H, s), 1.10-1.35 (6H, m), 0.83-0.95 (2H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3450, 2926,
2852, 1758, 1382, 1046.

Example 1 (i) (2R) -amino-2-methyl-4- [5- (5-cyclohexylpento-
1-Inyl) thiophen-2-yl] butan-1-ol (4R)-[2- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl obtained in Example 1 (h) ]] Ethyl-4-methyloxazolidin-2-one 456 mg (1.27 mmol) was dissolved in tetrahydrofuran 1 ml and methanol 2 ml, and the mixture was cooled with ice.
2 ml of 5N potassium hydroxide aqueous solution was added, and the mixture was heated under reflux for 18 hours. Water was added to the reaction solution, which was extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is chromatographed on silica gel (elution solvent; methylene chloride: methanol = 20: 1-).
Methylene chloride: methanol: ammonia water = 10: 1: 0.
Purification by 1) yielded 353 mg (83%) of the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 6.92
(1H, d, J = 3.5 Hz), 6.62 (1H, d, J = 3.5 Hz), 3.3
7 (1H, d, J = 10.5 Hz), 3.32 (1H, d, J = 10.5 Hz),
2.75-2.90 (2H, m), 2.38 (2H, t, J = 7.1 Hz), 1.52
-1.79 (9H, m), 1.12-1.33 (6H, m), 1.11 (3H, s), 0.
81-0.96 (2H, m) Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 2925, 285
2, 1449, 1041 Mass spectrum (FAB) m / z: 334 ((M + H) ⁺ ) Elemental analysis value; (% as C ₂₀ H ₃₁ NOS ・ 0.3H ₂ O) Calculated value: C: 70.87, H: 9.40, N: 4.13, S: 9.46 Found: C: 70.83, H: 9.21 , N: 4.22, S: 9.64 [α] D 24 -2.0 (c 0.60, methanol).

Example 2 (2R) -Amino -2-methyl-4- [5- (6-cyclohexylhexyl-
1-Inyl) thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1-882) The title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 6.91
(1H, d, J = 3.6 Hz), 6.62 (1H, d, J = 3.6 Hz), 3.3
9 (1H, d, J = 10.7 Hz), 3.34 (1H, d, J = 10.7 Hz),
2.82 (2H, t, J = 8.5 Hz), 2.40 (2H, t, J = 6.9 H
z), 2.18-1.92 (4H, m), 1.88-1.51 (8H, m), 1.47-1.38
(2H, m), 1.28-1.07 (9H, m), 0.93-0.78 (2H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3327, 3275, 2
922, 2850, 1611, 1563, 1539, 1447, 1065, 1040, 803,
521 Example 3 2-Amino-2-methyl-4- [5- (5-phenylpent-1-ynyl)
Thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1
-824) Racemic 4- [2- (5-bromothiophen-2-yl)] ethyl-
Using 4-methyloxazolidin-2-one as a starting material, the title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.32-
7.26 (2H, m), 7.25-7.16 (3H, m), 6.94 (1H, d, J =
3.6 Hz), 6.93 (1H, d, J = 3.6 Hz), 3.37 (1H, d, J =
10.8 Hz), 3.31 (1H, d, J = 10.4 Hz), 2.83 (2H, t,
J = 8.4 Hz), 2.77 (2H, t, J = 7.6 Hz), 2.42 (2H,
t, J = 7.2 Hz), 1.96-1.85 (2H, m), 1.84-1.64 (2H,
m), 1.50 (3H, brs), 1.11 (3H, s) infrared absorption spectrum ν _max cm ^-1 (liquid film): 293
1, 2859, 1748, 1602, 1584, 1538, 1496, 1455, 1191,
1053, 908, 804, 747, 700, 573.

Example 4 2-Amino-2-methyl-4- [5- [5- (4-methoxyphenyl) pen
To-1-ynyl] thiophen-2-yl] butan-1-ol salt
Acid salt (Exemplified Compound No. 1-849) racemic 4- [2- (5-bromothiophen-2-yl)] ethyl-
Using 4-methyloxazolidin-2-one as a starting material, the title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 8.07
(3H, brs), 7.10 (2H, d, J = 8.6 Hz), 6.89 (1H, d,
J = 3.5 Hz), 6.81 (2H, d, J = 8.6 Hz), 6.65 (1H, d,
J = 3.5 Hz), 4.72 (1H, brs), 3.77 (3H, s), 3.65
(2H, s), 2.78-2.97 (2H, m), 2.66 (2H, t, J = 7.5 H
z), 2.36 (2H, t, J = 7.1 Hz), 1.77-2.20 (4H, m),
1.36 (3H, s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3370, 3009,
2932, 1589, 1511, 1245, 1070, 1036.

Example 5 2-Amino-2-methyl-4- [5- [5- (4-fluorophenyl) pen
To-1-ynyl] thiophen-2-yl] butan-1-olma
Rain salt (Exemplified Compound No. 1-833) Racemic 4- [2- (5-bromothiophen-2-yl)] ethyl-
Using 4-methyloxazolidin-2-one as a starting material, the title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δppm: 7.18-
7.25 (2H, m), 6.95-7.03 (2H, m), 6.94 (1H, d, J =
3.6 Hz), 6.73 (1H, d, J = 3.6 Hz), 6.25 (2H, s), 3.
61 (1H, d, J = 11.6 Hz), 3.52 (1H, d, J = 11.6 H
z), 2.80-2.95 (2H, m), 2.74 (2H, t, J = 7.6 Hz),
2.40 (2H, t, J = 7.0 Hz), 1.80-2.10 (4H, m), 1.31
(3H, s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3352, 2940,
1578, 1509, 1385, 1367, 1221, 1194.

Example 6 2-Amino-2-methyl-4- [5- (biphenyl-4-yl) ethynyl
Thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1
-742) Racemic 4- [2- (5-bromothiophen-2-yl)] ethyl-
Using 4-methyloxazolidin-2-one as a starting material, the title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.55-
7.65 (6H, m), 7.43-7.50 (2H, m), 7.33-7.40 (1H,
m), 7.11 (1H, d, J = 3.6 Hz), 6.72 (1H, d, J = 3.6
Hz), 3.39 (1H, d, J = 10.4 Hz), 3.34 (1H, d, J = 1
0.4 Hz), 2.80-2.95 (2H, m), 1.70-1.90 (2H, m), 1.1
3 (3H, s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3335, 3075,
2924, 1485, 1463, 1051, 837, 809, 764, 698.

Example 7 2-Amino-2-methyl-4- [5- (4-butylphenyl) ethynyl
Thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1
-737) Racemic 4- [2- (5-bromothiophen-2-yl)] ethyl-
Using 4-methyloxazolidin-2-one as a starting material, the title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.42
(2H, d, J = 8.1 Hz), 7.36-7.15 (5H, m), 7.16 (2H,
d, J = 8.1 Hz), 7.07 (1H, d, J = 3.3 Hz), 6.70 (1
H, d, J = 3.3 Hz), 3.99 (2H, s), 3.36-3.24 (2H,
m), 2.92-2.81 (2H, m), 2.01-1.95 (2H, m), 2.65-2.2
6 (3H, m), 1.11 (3H, s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3326, 3264, 2
926, 2904, 1603, 1541, 1468, 1454, 1211, 1063, 103
3, 803, 701.

Example 8 2-Amino-2-methyl-4- [5- (4-cyclohexylphenyl)
Ethynylthiophen -2-yl] butan-1-ol (Exemplified Compound No. 1-741) Racemic 4- [2- (5-bromothiophen-2-yl)] ethyl-
Using 4-methyloxazolidin-2-one as a starting material, the title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δppm: 7.42
(2H, d, J = 8.2 Hz), 7.26 (2H, d, J = 8.2 Hz), 7.2
0 (1H, d, J = 3.6 Hz), 6.83 (1H, d, J = 3.6 Hz), 3.
56-3.24 (5H, m), 2.88-2.70 (2H, m), 1.89-1.52 (7H,
m), 1.43-1.21 (6H, m), 0.97 (3H, s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3326, 3279, 2
924, 2850, 1645, 1567,1539, 1448, 1385, 1055, 826,
547.

Example 9 2-Amino-2-methyl-4- [5- (4-propylphenyl) ethini
Luthiophen-2-yl] butan-1-ol (Exemplified Compound No. 1-736) Racemic 4- [2- (5-bromothiophen-2-yl)] ethyl-
Using 4-methyloxazolidin-2-one as a starting material, the title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δppm: 7.36
(2H, d, J = 8.2 Hz), 7.18 (2H, d, J = 8.2 Hz), 7.06
(1H, d, J = 3.5 Hz), 6.76 (1H, d, J = 3.5 Hz), 3.
39 (1H, d, J = 10.7 Hz), 3.38 (1H, d, J = 10.7 H
z), 2.93-2.80 (2H, m), 2.69-2.58 (2H, m), 1.83-1.59
(4H, m), 1.10 (3H, s), 0.94 (3H, t, J = 7.3 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3323, 3267, 2
959, 2929, 2869, 1611,1540, 1510, 1468, 1213, 106
6, 1035, 816, 804, 510.

Example 10 2-Amino-2-methyl-4- [5- (4-propyloxyphenyl)
Ethynylthiophen -2-yl] butan-1-ol (Exemplified Compound No. 1-740) Racemic 4- [2- (5-bromothiophen-2-yl)] ethyl-
Using 4-methyloxazolidin-2-one as a starting material, the title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δppm: 7.37
(2H, d, J = 8.9 Hz), 7.03 (1H, d, J = 3.6 Hz), 6.8
9 (2H, d, J = 8.9 Hz), 6.75 (1H, d, J = 3.6 Hz),
3.95 (2H, t, J = 6.3 Hz), 3.39 (1H, d, J = 10.7 H
z), 3.35 (1H, d, J = 10.7 Hz), 2.92-2.78 (2H, m),
1.86-1.72 (4H, m), 1.09 (3H, s), 1.04 (3H, t, J =
7.6 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3329, 3275, 2
964, 2936, 1604, 1509,1466, 1249, 1065, 975, 832,
807.

Example 11 (2R) -Amino -2-methyl-4- [5- (5-cyclohexylpentyl)
(L ) Thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1-98) (2R) -amino-2-methyl-4- [5- (5-cyclohexylpent-1) obtained in Example 1 -Inyl) thiophen-2-yl] butane
175 mg (0.53 mmol) of 1-ol was dissolved in 9 ml of ethanol, 90 mg of 10% palladium-carbon was added, and the mixture was stirred under a hydrogen atmosphere for 2 days. After filtering palladium-carbon with Celite, the filtrate was evaporated under reduced pressure to give 150 mg of the title compound (85
%). Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 6.58
(1H, d, J = 3.2 Hz), 6.55 (1H, d, J = 3.2 Hz), 3.36
(1H, d, J = 10.5 Hz), 3.31 (1H, d, J = 10.5 Hz),
2.75-2.90 (2H, m), 2.73 (2H, t, J = 7.6 Hz), 1.59
-1.83 (9H, m), 1.12-1.32 (10H, m), 1.11 (3H, s), 0.
81-0.89 (2H, m) Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 2926, 2853,
1440, 1042 Mass spectrum (FAB) m / z: 338 ((M + H) ⁺ ) Elemental analysis value; (% as C ₂₀ H ₃₅ NOS ・ H ₂ O) Calculated value: C: 67.56, H: 10.49, N : 3.94, S: 9.01 Found: C: 67.11, H: 10.03 , N: 3.93, S: 8.88 [α] D 24 -0.7 (c 3.03, methanol).

Example 12 (2R) -Amino -2-methyl-4- [5- (6-cyclohexylhexyl
(L ) Thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1-210) (2R) -amino-2-methyl-4- [5- (6-cyclohexylhexy-) obtained in Example 2 1-Inyl) thiophen-2-yl] butane
The title compound was obtained in the same manner as in Example 11 using 1-ol. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 6.58
(1H, d, J = 3.3 Hz), 6.55 (1H, d, J = 3.3 Hz), 3.3
7 (1H, d, J = 10.4 Hz), 3.32 (1H, d, J = 10.4 Hz),
2.68-2.93 (4H, m), 1.05-1.85 (24H, m), 0.77-0.93
(2H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3334, 3269, 3
159, 2922, 2850, 1465,1448, 1060 Mass spectrum (EI) m / z: 351 (M ⁺ ) Elemental analysis value; (% as C ₂₁ H ₃₇ NOS) Calculated value: C: 71.74, H: 10.61, N : 3.98, S: 9.12 Found: C: 71.47, H: 10.48, N: 3.98, S: 9.37 [α] _D ²⁴ -1.3 (c 1.15, methanol).

Example 13 2-Amino-2-methyl-4- [5- (5-phenylpentyl) thiof
En -2-yl] butan-1-ol (Exemplified Compound No. 1-152) 2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) obtained in Example 3 The title compound was obtained in the same manner as in Example 11 by using thiophen-2-yl] butan-1-ol. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.31-
7.24 (2H, m), 7.20-7.14 (3H, m), 6.58 (1H, d, J =
2.8 Hz), 6.54 (1H, d, J = 3.6 Hz), 3.36 (1H, d, J =
10.8 Hz), 3.31 (1H, d, J = 10.4 Hz), 2.81 (2H, t,
J = 8.4 Hz), 2.74 (2H, t, J = 7.6 Hz), 2.61 (2H,
t, J = 7.6 Hz), 1.84-1.56 (6H, m), 1.52 (3H, brs),
1.46-1.37 (2H, m), 1.11 (3H, s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3333, 3263,
2927, 2852, 1496, 1453, 1059, 969, 928, 798, 747,
699, 569.

Example 14 2-Amino-2-methyl-4- [5- [5- (4-methoxyphenyl) pen
Cyl ] thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1-177) 2-amino-2-methyl-4- [5- [5- (4-methoxyphenyl) obtained in Example 4 The title compound was obtained in the same manner as in Example 11 using pento-1-ynyl] thiophen-2-yl] butan-1-ol. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.08
(2H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 6.5
8 (1H, d, J = 3.3 Hz), 6.54 (1H, d, J = 3.3 Hz), 3.
79 (3H, s), 3.36 (1H, d, J = 10.5 Hz), 3.31 (1H,
d, J = 10.5 Hz), 2.70-2.85 (4H, m), 2.55 (2H, t, J
= 7.7 Hz), 1.55-1.85 (6H, m), 1.35-1.45 (2H, m),
1.11 (3H, s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3333, 3263,
3103, 2926, 2852, 1514, 1247, 1061, 1029.

Example 15 2-Amino-2-methyl-4- [5- [5- (4-fluorophenyl) pen
Cyl] thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1-161) 2-amino-2-methyl-4- [5- [5- (4-fluorophenyl) obtained in Example 5 The title compound was obtained in the same manner as in Example 11 using pento-1-ynyl] thiophen-2-yl] butan-1-ol. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δppm: 7.12-
7.18 (2H, m), 6.92-6.98 (2H, m), 6.63 (1H, d, J =
3.5 Hz), 6.56 (1H, d, J = 3.5 Hz), 6.25 (2H, s), 3.
61 (1H, d, J = 11.6 Hz), 3.51 (1H, d, J = 11.6 H
z), 2.70-2.90 (4H, m), 2.58 (2H, t, J = 7.6 Hz),
1.88-2.03 (2H, m), 1.57-1.70 (4H, m), 1.28-1.42 (5
H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 2929, 2854,
1578, 1509, 1464, 1387, 1356, 1223.

Example 16 2-Amino-2-methyl-4- [5- [2- (biphenyl-4-yl) ethyl]
Lu] thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1-44) 2-amino-2-methyl-4- [5- (biphenyl-4-yl) ethynylthiophene obtained in Example 6 The title compound was obtained in the same manner as in Example 11 by using 2-yl] butan-1-ol. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.25-
7.65 (9H, m), 6.60 (1H, d, J = 3.5 Hz), 6.59 (1H,
d, J = 3.5 Hz), 3.37 (1H, d, J = 10.5 Hz), 3.32 (1
H, d, J = 10.5 Hz), 3.06-3.15 (2H, m), 2.95-3.04
(2H, m), 2.75-2.90 (2H, m), 1.65-1.85 (2H, m), 1.1
2 (3H, s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3333, 3265,
2924, 2852, 1598, 1486, 1448, 1059, 798, 695.

Example 17 (2R) -Amino -2-methyl-4- [5- (5-cyclohexylpentapenta
Noyl ) thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1-1331) (2R) -amino-2-methyl-4- [5- (5-cyclohexylpent-1) obtained in Example 1 -Inyl) thiophen-2-yl] butane
126 mg (0.41 mmol) of 1-ol was dissolved in 2 ml of methanol, 2 ml of 6N sulfuric acid was added, and the mixture was heated under reflux for 4 hours. The reaction solution was made alkaline with 1N aqueous sodium hydroxide solution and then extracted with methylene chloride. After drying the methylene chloride layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure,
130 mg (91%) of the title compound were obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.54
(1H, d, J = 3.7 Hz), 6.84 (1H, d, J = 3.7 Hz), 3.3
9 (1H, d, J = 10.4 Hz), 3.34 (1H, d, J = 10.4 Hz),
2.78-2.98 (4H, m), 1.13 (3H, brs), 0.8-1.9 (19H,
m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3332, 3267, 3
134, 2922, 2851, 1647, 1457, 1057 Mass spectrum (EI) m / z: 351 (M ⁺ ) Elemental analysis value; (% as C ₂₀ H ₃₃ NO ₂ S) Calculated value: C: 68.33, H: 9.46 , N: 3.98, S: 9.12 Found: C: 67.99, H: 9.48, N: 3.92, S: 9.11 [α] _D ²⁴ -2.1 (c 1.03, methanol).

Example 18 (2R) -Amino -2-methyl-4- [5- (6-cyclohexylhexa
Noyl ) thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1-1357) (2R) -amino-2-methyl-4- [5- (6-cyclohexylhexy-) obtained in Example 2 1-Inyl) thiophen-2-yl] butane
The title compound was obtained in the same manner as in Example 17 using 1-ol. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.53
(1H, d, J = 3.9 Hz), 6.63 (1H, d, J = 3.9 Hz), 3.3
9 (1H, d, J = 10.5 Hz), 3.34 (1H, d, J = 10.5 Hz),
2.80-2.95 (4H, m), 1.33 (3H, brs), 0.8-1.9 (21H,
m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3149, 2922, 2
851, 1654, 1460, 1059,922 Mass spectrum (EI) m / z: 365 (M ⁺ ) Elemental analysis value; (% as C ₂₁ H ₃₅ NO ₂ S) Calculated value: C: 69.00, H: 9.65, N : 3.83, S: 8.77 Found: C: 68.74, H: 9.50, N: 3.83, S: 8.85 [α] _D ²⁴ -1.3 (c 1.15, methanol).

Example 19 2-Amino-2-methyl-4- [5- (5-phenylpentanoyl) thio
Ofen-2-yl] butan- 1-ol hydrochloride (Exemplified Compound No. 1-1344) 2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) obtained in Example 3 Using) thiophen-2-yl] butan-1-ol, the title compound was obtained in the same manner as in Example 17. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δppm: 7.71
(1H, d, J = 4.0 Hz), 7.28-7.20 (2H, m), 7.20-7.10
(3H, m), 6.98 (1H, d, J = 3.6 Hz), 3.62 (1H, d, J =
7.6 Hz), 3.53 (1H, d, J = 12.0 Hz), 3.04-2.88 (4
H, m), 2.64 (2H, t, J = 7.2 Hz), 2.15-2.04 (1H, m),
2.04-1.92 (1H, m), 1.78-1.62 (4H, m), 1.32 (3H,
s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3378, 2927,
1648, 1588, 1562, 1504, 1456, 1230, 1067, 827, 74
8, 698, 578.

Example 20 2-Amino-2-methyl-4- [5- [5- (4-fluorophenyl) pen
Tanoyl] thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1-1348) 2-amino-2-methyl-4- [5- [5- (4-fluorophenyl) obtained in Example 5 The title compound was obtained in the same manner as in Example 17 using pent-1-ynyl] thiophen-2-yl] butan-1-ol. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.51
(1H, d, J = 3.7 Hz), 7.08-7.17 (2H, m), 6.90-7.00
(2H, m), 6.83 (1H, d, J = 3.7 Hz), 3.39 (1H, d, J =
10.4 Hz), 3.33 (1H, d, J = 10.4 Hz), 2.80-2.98 (4
H, m), 2.62 (2H, t, J = 7.5 Hz), 1.60-1.90 (6H,
m), 1.12 (3H, s) infrared absorption spectrum ν _max cm ^-1 (KBr): 3178, 2935,
2858, 1645, 1455, 1218, 1058.

Example 21 2-Amino-2-methyl-4- [5- (biphenyl-4-yl) acetyl
Thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1
-1326) Using 2-amino-2-methyl-4- [5- (biphenyl-4-yl) ethynylthiophen-2-yl] butan-1-ol obtained in Example 6 to obtain Example 17 The title compound was obtained in the same manner. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.64
(1H, d, J = 3.7 Hz), 7.52-7.60 (4H, m), 7.30-7.47
(5H, m), 6.86 (1H, d, J = 3.7 Hz), 4.18 (2H, s), 3.
38 (1H, d, J = 10.3 Hz), 3.33 (1H, d, J = 10.3 H
z), 2.84-2.98 (2H, m), 1.70-1.87 (2H, m), 1.12 (3
H, s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3420, 2927,
1654, 1488, 1455, 1234, 1058, 751.

Example 222-amino-2-methyl-4- [5- (5-phenylpent-1-enyl)
Thiophen-2-yl] butan-1-ol maleate
(Exemplified Compound No. 1-670) Example 22 (a)4-methyl-4- [2- [5- (5-phenylpent-1-enyl) thiof
En-2-yl]] ethyloxazolidin-2-one 5-phenylpent-1-yne 0.38 ml (2.58 mmol)
Add catechol borane 500 mg (1.72 mmol) at warm temperature
Then, the mixture was stirred at 60 ° C for 3 hours. Cool the reaction mixture to room temperature
After discarding, add 5.0 ml of toluene to this reaction solution,
Synthesized 4- [2- (5-bromothiophen-2-yl)] ethyl-4-
Methyloxazolidin-2-one 500 mg (1.72 mmol),
Bis (triphenylphosphine) palladium chloride 119 mg
 (0.17 mmol), sodium ethoxide 0.83 ml (20%
(Ethanol solution) was added at room temperature. This at 60 ℃ for 2 hours
It was stirred. After cooling the reaction solution to room temperature, 1N sodium hydroxide was added.
Umm was added. It is extracted with ethyl acetate, saturated with water
Washed with brine. Ethyl acetate layer is anhydrous sodium sulfate
After drying with, the solvent was distilled off under reduced pressure. Preparative thin layer
Chromatography (eluting solvent; hexane: ethyl acetate =
1: 1) to give 378 mg (68%) of the title compound.
It was

Example 22 (b) 2-Amino-2-methyl-4- [5- (5-phenylpent-1-enyl)
Thiophen-2-yl] butan-1-ol maleate 4-methyl-4- [2- [5- (5-phenylpent-1-enyl) thiophene-2-obtained in Example 22 (a) Yl]] Ethyloxazolidin-2-one (370 mg, 1.15 mmol) was hydrolyzed in the same manner as in Example 1 (i) to give 2-amino-2-methyl-4- [5
205 mg (0.69 mmol) of-(5-phenylpent-1-enyl) thiophen-2-yl] butan-1-ol were obtained. 160 mg (34%) of the title compound was obtained as a maleate according to the general method for producing a maleate. Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δppm: 7.83
-7.70 (2H, m), 7.38-7.12 (5H, m), 6.78 (1H, d, J =
3.5 Hz), 6.71 (1H, d, J = 3.5 Hz), 6.50 (1H, d, J
= 15.6 Hz), 6.02 (2H, s), 5.96-5.83 (1H, m), 5.52
(2H, brs), 5.36-5.10 (1H, m), 3.51-3.38 (2H, m),
2.83-2.58 (4H, m), 2.28-2.15 (2H, m), 1.88-1.63 (4
H, m), 1.18 (3H, s) infrared absorption spectrum ν _max cm ^-1 (KBr): 3026, 2932, 1
579, 1497, 1386, 1357, 1194, 1075, 1012, 865, 699,
570.

Example 23 2-Amino-2-methyl-4- [5- (5-cyclohexylpent-1-
(Enyl ) thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1-657) The title compound was obtained in the same manner as in Example 22. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 6.64
(1H, d, J = 3.5 Hz), 6.61 (1H, d, J = 3.5 Hz), 6.4
1 (1H, d, J = 15.7 Hz), 5.95-5.88 (1H, m), 3.36 (1
H, d, J = 10.5 Hz), 3.31 (1H, d, J = 10.5 Hz), 2.8
6-2.73 (2H, m), 2.29-2.08 (2H, m), 1.83-1.55 (8H,
m), 1.52-1.33 (4H, m), 1.30-1.12 (6H, m), 1.11 (3
H, s), 0.92-0.79 (2H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3328, 3275, 2
921, 2850, 1610, 1447,1225, 1066, 1038, 957, 804,
504.

Example 24 2-Amino-2-methyl-4- [5- (6-cyclohexylhex-1-
(Enyl) thiophen-2-yl] butan-1-ol malein
Acid salt (Exemplified Compound No. 1-683) The title compound was obtained in the same manner as in Example 22. Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δppm: 7.90
-7.69 (2H, m), 6.77 (1H, d, J = 3.4 Hz), 6.70 (1H,
d, J = 3.4 Hz), 6.47 (1H, d, J = 15.8 Hz), 6.04 (2
H, s), 5.92-5.84 (1H, m), 5.55 (1H, brs), 3.49-3.3
2 (2H, m), 2.85-2.71 (2H, m), 2.18-2.06 (2H, m),
1.96-1.53 (8H, m), 1.42-1.03 (14H, m), 0.93-0.78 (2
H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3042, 2924, 2
851, 1695, 1577, 1533,1493, 1477, 1387, 1362, 135
1, 1210, 1074, 866.

Example 25 2-Amino-2-methyl-4- [4- (5-phenylpent-1-ynyl)
Thiophen-2-yl] butan-1-ol hydrochloride (Exemplified Compound No. 2-185) Example 25 (a) 4- (5-phenylpent-1-ynyl) thiophene-2-carboa
Rudehydr 5-phenylpent-1-yne 18.1 g (126 mmol) was dissolved in tetrahydrofuran 100 ml, and 4-bromothiophene-2-carbaldehyde 18.7 g (98 mmol) and triethylamine 1 were dissolved in tetrahydrofuran 200 ml.
50 ml (1.07 mol), copper (I) iodide 962 mg (5.05 mmol) and dichlorobis (triphenylphosphine) palladium 3.54 g (5.04 mmol) were added, and the mixture was heated to 50 ° C. under a nitrogen atmosphere.
And stirred for 4 hours. After filtering the reaction solution, the filtrate was evaporated under reduced pressure. Ether was added to the residue, and the mixture was washed with water and saturated brine. The ether layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (elution solvent; hexane: ethyl acetate = 100: 1-10:
Purification by 1) yielded 19.4 g (78%) of the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 9.88
(1H, s), 7.72 (1H, s), 7.71 (1H, s), 7.35-7.27 (2H,
m), 7.24-7.16 (3H, m), 2.78 (2H, t, J = 7.2 Hz),
2.41 (2H, t, J = 7.2 Hz), 1.98-1.88 (2H, m) Infrared absorption spectrum ν _max cm ^-1 (liquid film): 223
8, 1679, 1440, 1234, 1157, 858, 748, 700, 665, 620 Mass spectrum (FAB) m / z: 255 ((M + H) ⁺ ).

Example 25 (b) [4- (5-phenylpent-1-ynyl) thiophen-2-yl] me
Tanol 4- (5-phenylpent-1-ynyl) obtained in Example 25 (a)
Thiophene-2-carbaldehyde 15.0 g (59.0 mmol)
Was dissolved in 150 ml of methanol, and 2.29 g (60.5 mmol) of sodium borohydride was added under ice cooling. below freezing,
After stirring for 25 minutes, the solvent was distilled off under reduced pressure. Water was added to the residue, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. After drying the ethyl acetate layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 15.2 g of the title compound.
(99%) was obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.34-
7.27 (3H, m), 7.24-7.17 (3H, m), 6.98 (1H, s), 4.7
8 (2H, d, J = 5.6 Hz), 2.77 (2H, t, J = 7.6 Hz), 2.
39 (2H, t, J = 7.2 Hz), 1.96-1.85 (2H, m), 1.77 (1
H, t, J = 5.6 Hz) Infrared absorption spectrum ν _max cm ^-1 (liquid film): 334
6, 3026, 2940, 2861, 2235, 1602, 1496, 1455, 1355,
1182, 1141, 1013, 844, 748, 700, 626 Mass spectrum (FAB) m / z: 256 (M ⁺ ).

Example 25 (c) [4- (5-phenylpent-1-ynyl) thiophen-2-yl] a
Cetonitrile [4- (5-phenylpent-1-ynyl) thiophen-2-yl] methanol (4.68 g, 18.3 mmol) synthesized in Example 25 (b) was dissolved in tetrahydrofuran (70 ml), and ice-cooled to give a triodor. 20 ml of tetrahydrofuran in which 0.69 ml (7.30 mmol) of phosphorus chloride was dissolved was added dropwise. After completion of the dropping, the mixture was stirred for 10 minutes under a nitrogen atmosphere with ice cooling. Ice water was added to the reaction mixture, extraction was performed with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 120 ml of acetonitrile, 2.85 g (18.3 mmol) of tetraethylammonium cyanide was added under ice cooling, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Reaction mixture 5
% Aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluting solvent: hexane: ethyl acetate = 20: 1 to 15: 1) to obtain 3.21 g (66%) of the title compound. Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 7.15-
7.35 (6H, m), 7.03 (1H, s), 3.86 (2H, s), 2.77 (2
H, t, J = 7.5 Hz), 2.39 (2H, t, J = 7.0 Hz), 1.83-
1.98 (2H, m) Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 3691, 294
6, 2236, 1603, 1497, 1454, 1416, 1361.

Example 25 (d) 2- [4- (5-phenylpent-1-ynyl) thiophen-2-yl]
Ethanol Example 3.2 (g) [4- (5-phenylpent-1-ynyl) thiophen-2-yl] acetonitrile 3.21 g (12.1 mmol) obtained in Example 25 (c) was dissolved in 15 ml of ethanol, and water was added under ice cooling. 15 m
1.70 g (30.2 mmol) of potassium hydroxide dissolved in 1 was added, and the mixture was heated under reflux for 2 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran 15 ml,
Triethylamine 1.69 ml (12.1 mmol) was added. After that, 1.21 ml of ethyl chloroformate (12.
15 ml of tetrahydrofuran in which 7 mmol) was dissolved was added dropwise, and the mixture was stirred for 30 minutes while cooling with ice under a nitrogen atmosphere. After the reaction solution was filtered, the resulting filtrate was slowly added to an aqueous solution of sodium borohydride (2.29 g, 60.5 mmol) (10 ml) under ice cooling, and the mixture was stirred at room temperature for 3 days. The reaction mixture was cooled, acidified with 1N hydrochloric acid, extracted with ethyl acetate,
The ethyl acetate layer was washed with 1N aqueous sodium hydroxide solution and saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 4: 1) to give 2.74 g (8%) of the title compound.
4%). Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.15-
7.30 (6H, m), 6.86 (1H, s), 3.85 (2H, t, J = 6.2 H
z), 3.02 (2H, t, J = 6.2 Hz), 2.77 (2H, t, J = 7.6
Hz), 2.39 (2H, t, J = 7.1 Hz), 1.85-1.95 (2H, m) Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 3620, 294
7, 1732, 1603, 1497, 1454, 1359, 1250, 1046.

Example 25 (e) 2- (2-iodoethyl) -4- (5-phenylpent-1-ynyl) thio
2- [4- (5-phenylpent-1-ynyl) thiophen-2-yl] ethanol 2.69 g (9.95 mmol) obtained in Offen Example 25 (d) was used as Example 1 (g). Similarly, the title compound 3.4
Obtained 5 g (91%). Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.15-
7.30 (6H, m), 6.84 (1H, s), 3.30-3.35 (4H, m), 2.7
7 (2H, t, J = 7.6 Hz), 2.39 (2H, t, J = 7.0Hz), 1.
85-1.95 (2H, m) Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 2946, 286
3, 1603, 1497, 1454, 1429, 1360, 1172.

Example 25 (f) 2-Methyl-2- [4- (5-phenylpent-1-ynyl) thiophene
2- (2-yl) ethylmalonic acid monoethyl ester methylmalonic acid diethyl ester (1.57 g, 9.02 mmol) was dissolved in dimethylformamide (30 ml), and the mixture was cooled with ice.
Sodium hydride (0.38 g, 9.47 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Then, under ice cooling to the reaction solution, 2- (2-iodoethyl) -obtained in Example 25 (e).
30 ml of dimethylformamide in which 4- (5-phenylpent-1-ynyl) thiophene was dissolved was added dropwise, and the mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled, acidified with 1N hydrochloric acid, extracted with ethyl acetate, and the ethyl acetate layer was washed with 1N aqueous sodium hydroxide solution and saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (eluting solvent; hexane: ethyl acetate = 50: 1-20:
Partially purified by 1). The resulting mixture was mixed with ethanol 9
ml, dissolved in 1 ml of water, potassium hydroxide 0.80 under ice cooling
g (14.3 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Silica gel chromatography of the residue (elution solvent; methylene chloride: methanol = 50: 1)
Was purified by to give 1.02 g (28%) of the title compound. Nuclear magnetic resonance spectrum (500MHz, CDCl ₃ ) δppm: 7.15-
7.30 (6H, m), 6.79 (1H, s), 4.23 (2H, q, J = 7.1 H
z), 2.60-2.85 (4H, m), 2.38 (2H, t, J = 7.0Hz), 2.
20-2.32 (2H, m), 1.86-1.94 (2H, m), 1.53 (3H, s),
1.29 (3H, t, J = 7.1 Hz) Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 3509, 294
4, 1732, 1713, 1455, 1377, 1254, 1181, 1113.

Example 25 (g) 2-methoxycarbonylamino-2-methyl-4- [4- (5-phenyl )
Lupent-1-ynyl) thiophen-2-yl] butanoic acid ethi
Glycol ester Example 25 using a obtained in (f) 2-methyl-2- [4- (5-phenyl-pent-1-ynyl) thiophen-2-yl] ethyl malonate monoethyl ester of 0.99 g (2.48 mmol) Then, in the same manner as in Example 1 (j), 0.85 g (80%) of the title compound was obtained. Nuclear magnetic resonance spectrum (500MHz, CDCl ₃ ) δppm: 7.15-
7.30 (5H, m), 7.13 (1H, s), 6.75 (1H, s), 5.69 (1
H, brs), 4.15-4.33 (2H, m), 3.66 (3H, s), 2.50-2.8
0 (5H, m), 2.38 (2H, t, J = 7.0 Hz), 2.15-2.23 (1
H, m), 1.87-1.93 (2H, m), 1.60 (3H, s), 1.25-1.30
(3H, m) Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 3417, 298
7, 2945, 1719, 1504, 1453, 1323, 1077.

Example 25 (h) 4-Methyl-4- [2- [4- (5-phenylpent-1-ynyl) thiof
En-2-yl]] ethyloxazolidin-2-one 2-methoxycarbonylamino-2-obtained in Example 25 (g)
Methyl-4- [4- (5-phenylpent-1-ynyl) thiophene-
2-yl] butanoic acid ethyl ester 0.82 g (1.92 mmol) was dissolved in ethanol 15 ml and tetrahydrofuran 10 ml, and under ice cooling, lithium chloride 0.24 g (5.75 mmol),
Sodium borohydride 0.22 g (5.75 mmol) was added,
The mixture was stirred at 70 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled, acidified with 1N hydrochloric acid, extracted with ethyl acetate,
The ethyl acetate layer was washed with saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel chromatography (eluting solvent; hexane: ethyl acetate = 4: 1 to 1: 1) to obtain 0.65 g (96%) of the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.15-
7.35 (6H, m), 6.79 (1H, s), 5.38 (1H, brs), 4.18
(1H, d, J = 8.6 Hz), 4.08 (1H, d, J = 8.6 Hz), 2.8
0-2.90 (2H, m), 2.77 (2H, t, J = 7.6 Hz), 2.38 (2
H, t, J = 7.0 Hz), 1.85-2.00 (4H, m), 1.41 (3H, s) Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 3450, 297
8, 2945, 1757, 1497, 1401, 1382, 1249, 1046.

Example 25 (i) 2-Amino-2-methyl-4- [4- (5-phenylpent-1-ynyl)
Thiophen-2-yl] butan-1-ol Hydrochloride 4-Methyl-4- [2- [4- [5- (phenylpent-1-ynyl) thiophen-2-yl obtained in Example 25 (h) ]] 200 mg (0.57 mmol) of ethyloxazolidin-2-one was dissolved in 1 ml of tetrahydrofuran and 2 ml of methanol, 2 ml of 5N potassium hydroxide aqueous solution was added under ice cooling, and the mixture was heated under reflux for 18 hours. Water was added to the reaction solution, which was extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Dissolve the residue in 2 ml of 1,4-dioxane,
Under ice cooling, 4N hydrochloric acid dioxane solution was added, the solvent was evaporated, and the obtained white solid was washed with ether and dried to obtain 165 mg (80%) of the title compound. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δppm: 7.15-
7.30 (6H, m), 6.84 (1H, s), 3.61 (1H, d, J = 11.5
Hz), 3.52 (1H, d, J = 11.5 Hz), 2.80-2.95 (2H, m),
2.75 (2H, t, J = 7.5 Hz), 2.35 (2H, t, J = 7.0 H
z), 1.82-2.10 (4H, m), 1.32 (3H, s) infrared absorption spectrum ν _max cm ^-1 (KBr): 3351, 3027,
2928, 1594, 1509, 1455, 1389, 1062.

Example 26 2-Amino-2-methyl-4- [4- (5-phenylpentyl) thiof
En-2-yl] butan-1-ol hydrochloride (Exemplified Compound No. 2-39) Example 26 (a) 4-methyl-4- [2- [4- (5-phenylpentyl) thiophene-2-
[Ill]] ethyloxazolidin-2-one 4-methyl-4- [2- [4- [5- (phenylpent-1-ynyl) thiophen-2-yl]] ethyloxazolidine obtained in Example 25 (h) -2-one 174 mg (0.49 mmol) in ethanol 9 ml
In 90%, 5% palladium-carbon (90 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 4 hours. After filtering the catalyst with Celite,
The filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluting solvent; hexane: ethyl acetate = 1: 1) to obtain 164 mg (93%) of the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.25-
7.30 (2H, m), 7.15-7.20 (3H, m), 6.70 (1H, s), 6.6
3 (1H, s), 5.33 (1H, brs), 4.18 (1H, d, J = 8.6 H
z), 4.07 (1H, d, J = 8.6 Hz), 2.80-2.90 (2H, m),
2.61 (2H, t, J = 7.8 Hz), 2.53 (2H, t, J = 7.7 H
z), 1.93-2.02 (2H, m), 1.55-1.70 (4H, m), 1.35-1.45
(5H, m) Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 3451, 297
7, 2934, 2858, 1757, 1400, 1382, 1045.

Example 26 (b) 2-Amino-2-methyl-4- [4- (5-phenylpentyl) thiof
En-2-yl] butan-1-ol hydrochloride 4-Methyl-4- [2- [4- (5-phenylpentyl) thiophen-2-yl]] ethyl obtained in Example 26 (a) Oxazolidine-2
In the same manner as in Example 25 (i), using 136 mg (0.38 mmol) of -one, 107 mg (76%) of the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.10-
7.30 (5H, m), 6.63 (1H, s), 6.61 (1H, s), 3.66 (2
H, s), 2.80-2.95 (2H, m), 2.58 (2H, t, J = 7.7 H
z), 2.47 (2H, t, J = 7.7 Hz), 2.00-2.18 (2H, m),
1.52-1.67 (4H, m), 1.25-1.45 (5H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3223, 2929, 2
887, 1606, 1525, 1455, 1400, 1054.

Example 27 2-Amino-2-methyl-4- [4- (5-phenylpentanoyl) thio
Ofen-2-yl] butan-1-ol hydrochloride (Exemplary Compound No. 2-343) 2-amino-2-methyl-4- [4- (5-phenylpento-obtained in Example 26 (i) 1-Inyl) thiophen-2-yl] butane-1-
178 mg of all hydrochloride (0.49 mmol) was added to methanol 2
This was dissolved in ml, 6 ml of 6N sulfuric acid was added, and the mixture was heated under reflux for 4 hours. The reaction solution was made alkaline with 1N aqueous sodium hydroxide solution and then extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 1,4-dioxane 2 ml, 4N hydrochloric acid dioxane solution was added under ice cooling, the solvent was evaporated, and the obtained white solid was washed with ether and dried to give 100 mg of the title compound. (53%) was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δppm: 8.14
(1H, s), 7.29 (1H, s), 7.10-7.27 (5H, m), 3.63 (1H,
d, J = 11.6 Hz), 3.53 (1H, d, J = 11.6 Hz), 2.85-
3.00 (4H, m), 2.64 (2H, t, J = 7.0 Hz), 1.92-2.13
(2H, m), 1.67-1.75 (4H, m), 1.33 (3H, s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3361, 3026,
2939, 1666, 1591, 1456, 1154, 1072.

Example 28 2-Amino-2-ethyl-4- [5- (5-cyclohexylpent-1-
(Inyl) thiophen-2-yl] butan-1-ol malein
Acid salt (Exemplified Compound No. 1-1909) racemic 4- [2- (5-bromothiophen-2-yl)] ethyl-
Using 4-ethyloxazolidin-2-one as a starting material and in the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 6.90
(1H, d, J = 3.6 Hz), 6.72 (1H, d, J = 3.6 Hz), 6.2
5 (2H, s), 3.61 (1H, d, J = 11.7 Hz), 3.57 (1H, d,
J = 11.7 Hz), 2.75-2.90 (2H, m), 2.38 (2H, t, J =
7.0 Hz), 1.88-2.06 (2H, m), 1.52-1.82 (9H, m), 1.1
2-1.37 (6H, m), 0.85-1.04 (5H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3191, 2922,
2851, 1576, 1521, 1386, 1362, 1193, 1068.

Example 292-amino-2-ethyl-4- [5- (5-cyclohexylpentyl)
Thiophen-2-yl] butan-1-ol maleate
(Exemplified compound number 1-1764) 2-amino-2-ethyl-4- [5- (5-cyclo
Hexylpent-1-ynyl) thiophen-2-yl] butane-1
The title compound was prepared in the same manner as in Example 11 using -ol.
Obtained. Nuclear magnetic resonance spectrum (400MHz, CD₃OD) δ ppm: 6.64
 (1H, d, J = 3.7 Hz), 6.57 (1H, d, J = 3.7 Hz), 6.2
5 (2H, s), 3.61 (1H, d, J = 11.8 Hz), 3.57 (1H, d,
J = 11.8 Hz), 2.70-2.87 (4H, m), 1.88-2.05 (2H,
m), 1.56-1.82 (9H, m), 1.10-1.38 (10H, m), 0.99 (3
H, t, J = 7.5 Hz), 0.81-0.93 (2H, m) Infrared absorption spectrum ν_max cm^-1 (KBr): 3196, 2923,
2852, 1581, 1523, 1385, 1368, 1193, 1067, 1016.

Example 30 2-Amino-2-ethyl-4- [5- (5-cyclohexylpentanoi
Le) thiophen-2-yl] butan-1-ol maleate (Exemplified Compound No. 1-2097) 2-amino-2-ethyl-4- [5- (5-cyclohexylpento-obtained in Example 28) 1-Inyl) thiophen-2-yl] butane-1
The title compound was obtained in the same manner as in Example 17 by using -ol. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.72
(1H, d, J = 3.7 Hz), 6.99 (1H, d, J = 3.7 Hz), 6.2
5 (2H, s), 3.63 (1H, d, J = 11.6 Hz), 3.59 (1H, d,
J = 11.6 Hz), 2.85-3.02 (4H, m), 1.94-2.12 (2H,
m), 1.60-1.83 (9H, m), 1.10-1.42 (8H, m), 1.01 (3
H, t, J = 7.5 Hz), 0.82-0.96 (2H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3395, 2922,
2851, 1654, 1582, 1520, 1458, 1385, 1370, 1203, 10
67.

Example 31 (2R) -Amino -2-methyl-4- [5- (4-cyclohexyloxy
But-1-ynyl) thiophen-2-yl] butan-1-ol
Maleate (Exemplified Compound No. 1-1072) (4R)-[2- (5-Bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one was used as a starting material and the same as in Example 1. To give the title compound. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 6.93
(1H, d, J = 3.6 Hz), 6.73 (1H, d, J = 3.6 Hz), 6.2
5 (2H, s), 3.57-3.67 (3H, m), 3.51 (1H, d, J = 11.6
Hz), 3.32-3.42 (1H, m), 2.78-2.95 (2H, m), 2.63
(2H, t, J = 6.7Hz), 1.50-2.10 (7H, m), 1.17-1.37
(8H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3394, 2932,
2858, 1583, 1506, 1386, 1367, 1194, 1104.

Example 32 2-Amino-2-methyl-4- [5- (4-cyclohexylmethoxyphenol)
(Phenyl ) thiophen-2-yl] butan-1-ol (Exemplified compound number 1-1729) 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as a starting material The title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.45
(2H, d, J = 8.7 Hz), 7.02 (1H, d, J = 3.6 Hz), 6.8
8 (2H, d, J = 8.7 Hz), 6.76 (1H, d, J = 3.6Hz), 3.
77 (2H, d, J = 6.3 Hz), 3.40 (1H, d, J = 10.9 Hz),
3.36 (1H, d, J = 10.9 Hz), 2.91-2.79 (2H, m), 1.90
-1.68 (8H, m), 1.41-1.08 (5H, m), 1.11 (3H, s).

Example 33 2-Amino-2-methyl-4- [5- (4-benzyloxyphenyl)
Thiophen-2-yl] butan-1-ol (Exemplified Compound No. 1
-1744) The title compound was obtained in the same manner as in Example 1 using 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as a starting material. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 7.51
-7.27 (7H, m), 7.07 (1H, d, J = 3.6 Hz), 6.98 (2H,
d, J = 8.7 Hz), 6.76 (1H, d, J = 3.6 Hz), 5.06 (2
H, s), 3.44-3.38 (2H, m), 2.91-2.80 (2H, m), 1.86-
1.74 (2H, m), 1.11 (3H, s).

Example 34 (2R) -Amino -2-methyl-4- {5- [3- (4
-Methylphenoxy) propynyl] thiophen-2-i
Ru} butan-1-ol maleate (Exemplified Compound No. 1-1063) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.31
(3H, s), 1.88-2.10 (2H, m), 2.27 (3H, s), 2.80-2.95
(2H, m), 3.51 (1H, d, J = 11.6 Hz), 3.60 (1H, d, J = 1
1.6 Hz), 4.89 (2H, s), 6.25 (2H, s), 6.77 (1H, d,
J = 3.6 Hz), 6.88 (2H, d, J = 8.6 Hz), 7.05 (1H, d, J =
3.6 Hz), 7.09 (2H, d, J = 8.6 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3338, 3211, 3
006, 2923, 2229, 1583, 1511, 1372, 1228, 1018.

Example 35 (2R) -Amino -2-methyl-4- {5- [3- (4
-Methylphenoxy) propyl] thiophen-2-i
Ru} butan-1-ol maleate (Exemplified Compound No. 1-391) (2R) -amino-2-methyl-4 obtained in Example 34.
The title compound was obtained in the same manner as in Example 11 by using-{5- [3- (4-methylphenoxy) propynyl] thiophen-2-yl} butan-1-ol maleate. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.31
(3H, s), 1.88-2.10 (4H, m), 2.25 (3H, s), 2.77-2.92
(2H, m), 2.94 (2H, t, J = 7.5 Hz), 3.51 (1H, d, J = 1
1.6 Hz), 3.60 (1H, d, J = 11.6 Hz), 3.93 (2H, t, J =
6.2 Hz), 6.25 (2H, s), 6.62 (1H, d, J = 3.3 Hz), 6.6
5 (1H, d, J = 3.3 Hz), 6.77 (2H, d, J = 8.5Hz), 7.04
(2H, d, J = 8.5 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3412, 3028, 2
947, 2926, 1577, 1513, 1387, 1357, 1239, 1055.

Example 36 (2R) -Amino -2-methyl-4- {5- [3- (3
-Methylphenoxy) propynyl] thiophen-2-i
Ru} butan-1-ol oxalate (Exemplified compound number
1-2276) The title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.31
(3H, s), 1.90-2.10 (2H, m), 2.31 (3H, s), 2.82-2.96
(2H, m), 3.52 (1H, d, J = 11.7 Hz), 3.60 (1H, d, J = 1
1.7 Hz), 4.90 (2H, s), 6.73-6.85 (4H, m), 7.05 (1
H, d, J = 3.6 Hz), 7.16 (1H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 2923, 2575, 2
226, 1621, 1583, 1559, 1489, 1290, 1255, 1154, 104
Five.

Example 37 (2R) -Amino -2-methyl-4- {5- [3- (4
-Ethylphenoxy) propynyl] thiophen-2-i
Ru} butan-1-ol maleate (Exemplified Compound No. 1-1064) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.20
(3H, t, J = 7.6 Hz), 1.31 (3H, s), 1.88-2.10 (2H, m),
2.58 (2H, q, J = 7.6 Hz), 2.80-2.95 (2H, m), 3.51 (1
H, d, J = 11.5 Hz), 3.60 (1H, d, J = 11.5 Hz), 4.89 (2
H, s), 6.25 (2H, s), 6.77 (1H, d, J = 3.6 Hz), 6.90
(2H, d, J = 8.6 Hz), 7.05 (1H, d, J = 3.6Hz), 7.12 (2
H, d, J = 8.6 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3385, 2959, 2
928, 2226, 1581, 1510, 1384, 1232, 1020.

Example 38 (2R) -Amino -2-methyl-4- {5- [3- (4
-Methylthiophenoxy) propynyl] thiophene-2
-Yl } butan-1-ol maleate (Exemplified Compound No. 1-1068) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.31
(3H, s), 1.88-2.10 (2H, m), 2.42 (3H, s), 2.81-2.96
(2H, m), 3.51 (1H, d, J = 11.5 Hz), 3.60 (1H, d, J = 1
1.5 Hz), 4.92 (2H, s), 6.25 (2H, s), 6.78 (1H, d,
J = 3.6 Hz), 6.96 (2H, d, J = 8.9 Hz), 7.06 (1H, d, J =
3.6 Hz), 7.27 (2H, d, J = 8.9 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3401, 2984, 2
918, 2227, 1575, 1492, 1376, 1237, 1011.

Example 39 (2R) -Amino -2-methyl-4- {5- [3-
(3,5-Dimethoxyphenoxy) propynyl] thiof
En -2-yl} butan-1-ol fumarate (Exemplified compound No. 1-2285) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.31
(3H, s), 1.90-2.10 (2H, m), 2.82-2.96 (2H, m), 3.51
(1H, d, J = 11.6 Hz), 3.61 (1H, d, J = 11.6 Hz), 3.75
(6H, s), 4.89 (2H, s), 6.13 (1H, dd, J = 2.2, 2.2 H
z), 6.43 (2H, d, J = 2.2 Hz), 6.69 (2H, s), 6.78 (1H,
d, J = 3.6 Hz), 7.07 (1H, d, J = 3.6 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3382, 2936, 2
222, 1682, 1601, 1476, 1205, 1152, 1066.

Example 40 (2R) -Amino -2-methyl-4- {5- [3-
(3,4-Dimethoxyphenoxy) propynyl] thiof
En -2-yl} butan-1-ol maleic acid salt (Exemplified Compound No. 1-2284) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.31
(3H, s), 1.88-2.10 (2H, m), 2.81-2.95 (2H, m), 3.51
(1H, d, J = 11.4 Hz), 3.61 (1H, d, J = 11.4 Hz), 3.78
(3H, s), 3.81 (3H, s), 4.88 (2H, s), 6.25 (2H,
s), 6.54 (1H, dd, J = 8.7, 2.7 Hz), 6.66 (1H, d, J = 2.
7 Hz), 6.78 (1H, d, J = 3.6 Hz), 6.87 (1H, d, J = 8.7
Hz), 7.05 (1H, d, J = 3.6 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3361, 2934, 2
221, 1581, 1512, 1385, 1369, 1228, 1196, 1023.

Example 41 (2R) -Amino -2-methyl-4- {5- [3- (4
-Acetylphenoxy) propynyl] thiophene-2-
Il} butan-1-ol (Exemplified Compound No. 1-2288) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.07
(3H, s), 1.68-1.82 (2H, m), 2.56 (3H, s), 2.77-2.91
(2H, m), 3.33 (1H, d, J = 11.0 Hz), 3.36 (1H, d, J = 1
1.0 Hz), 5.05 (2H, s), 6.73 (1H, d, J = 3.6 Hz), 7.0
4 (1H, d, J = 3.6Hz), 7.10 (2H, d, J = 9.0 Hz), 8.00
(2H, d, J = 9.0Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3351, 3315, 3
287, 2916, 2878, 2734, 2229, 1673, 1599, 1376, 136
4, 1253, 1174.

Example 42 (2R) -Amino -2-methyl-4- {5- [3- (4
-Carboxyphenoxy) propynyl] thiophene-2
-Yl} butan-1-ol hydrochloride (Exemplified compound number
1-2289) The title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.31
(3H, s), 1.90-2.10 (2H, m), 2.82-2.96 (2H, m), 3.51
(1H, d, J = 11.5 Hz), 3.61 (1H, d, J = 11.5 Hz), 5.04
(2H, s), 6.79 (1H, d, J = 3.7 Hz), 7.05-7.11 (3H,
m), 7.99 (2H, d, J = 8.8 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3383, 3064, 2
226, 1699, 1604, 1508, 1379, 1233, 1170, 1002.

Example 43 (2R) -Amino -2-methyl-4- [5- [3- (3-methoxy)
Phenoxy) propynyl] thiophen-2-yl] butane-1
-All Maleate (Exemplified Compound No. 1-2283) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.31
(3H, s), 1.88-2.10 (2H, m), 2.80-2.96 (2H, m), 3.51
(1H, d, J = 11.6 Hz), 3.60 (1H, d, J = 11.6Hz), 3.77
(3H, s), 4.91 (2H, s), 6.25 (2H, s), 6.52-6.61 (3
H, m), 6.78 (1H, d, J = 3.6Hz), 7.06 (1H, d, J = 3.6H
z), 7.18 (1H, t, J = 8.4Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3005, 2940, 2
223, 1583, 1493, 1387, 1362, 1284, 1191, 1153, 108
0, 1045, 1020, 866, 813, 758, 687, 565.

Example 44 (2R) -Amino-2-methyl-4- [5- [4- (4-methylphenoxy)
Enoxy) but-1-ynyl] thiophen-2-yl] butane-
1-ol maleate (Exemplified Compound No. 1-1139) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.31
(3H, s), 1.87-2.10 (2H, m), 2.26 (3H, s), 2.85 (2H,
t, J = 6.8Hz), 2.78-2.95 (2H, m), 3.51 (1H, d, J = 1
1.6 Hz), 3.61 (1H, d, J = 11.6Hz), 4.09 (2H, t, J = 6.
8Hz), 6.25 (2H, s), 6.73 (1H, d, J = 3.6Hz), 6.82 (2
H, d, J = 8.4Hz), 6.96 (1H, d, J = 3.6Hz), 7.07 (2H, d,
J = 8.4Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3032, 2925, 2
596, 1578, 1513, 1388, 1359, 1293, 1244, 1205, 117
6, 1079, 1039, 867, 812, 509.

Example 45 (2R) -Amino -2-methyl-4- [5- [4- (4-fluoro
Phenoxy) but-1-ynyl] thiophen-2-yl] buta
N-1-ol (Exemplified Compound No. 1-1135) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.15
(3H, s), 1.72-1.89 (2H, m), 2.22 (3H, brs), 2.88 (2
H, t, J = 6.8Hz), 2.76-2.93 (2H, m), 3.37 (1H, d, J = 1
0.8 Hz), 3.42 (1H, d, J = 10.8Hz), 4.11 (2H, t, J = 6.
8Hz), 6.64 (1H, d, J = 3.6Hz), 6.84-6.90 (2H, m), 6.9
3-7.03 (3H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3356, 3296, 3
090, 2971, 2950, 2916, 2896, 2877, 2812, 2735, 158
9, 1506, 1465, 1389, 1289, 1245, 1219, 1203, 1154,
1065, 1039, 974, 923, 831, 819, 742, 568, 523, 50
9.

Example 46 (2R) -Amino -2-methyl-4- {5- [3-
(3,4-Dimethylphenoxy) propynyl] thiophe
N-2-yl} butan-1-ol maleate (Exemplified compound No. 1-2278) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.31
(3H, s), 1.90-2.09 (2H, m), 2.19 (3H, s), 2.23 (3H,
s), 2.81-2.94 (2H, m), 3.31 (1H, s), 3.51 (1H, d,
J = 11.6 Hz), 3.61 (1H, d, J = 11.6 Hz), 4.87 (2H,
s), 6.25 (2H, s), 6.70-6.78 (3H, m), 7.01-7.04 (2H,
m) Infrared absorption spectrum ν _max cm ^-1 (Liquid Film): 3353,
3022, 2971, 2923, 2226, 1579, 1500, 1385, 1368, 1
287, 1249, 1205, 1165, 1120, 1077, 1039, 930, 865,
806, 713, 573, 446.

Example 47 (2R) -2-Amino-2-methyl-4- [2- (3-
Phenylpropyloxy) thiophen-5-yl] buta
N-1-ol tartaric acid salt (Exemplified Compound No. 1-2395) Example 47 (a) (2R) -amino-2-methyl-4-thiophene-2-
Irbutan-1-ol 1 / 2D-(−)-tartrate salt 85% ee of (4R) -methyl-4- [2 obtained in Example 66.
-(Thiophen-2-yl)] ethyloxazolidine-
2-one 7.30 g (34.6 mmol) of tetrahydrofuran
It was dissolved in 35 ml and 70 ml of methanol, 70 ml of 5N potassium hydroxide aqueous solution was added under ice cooling, and the mixture was stirred at 80 ° C. for 2 days. Methylene chloride was added to the reaction solution, which was washed with water.
The methylene chloride layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 6.20 g of the obtained residue was added to ethanol 60
After dissolving in ml, a solution of 5.19 g (34.6 mmol) of D-(-)-tartaric acid in 50 ml of ethanol was added, and the deposited precipitate was collected by filtration to obtain 7.56 g of the crude title compound. The obtained crude target compound (7.54 g) was recrystallized using 75 ml of ethanol and 50 ml of water to obtain 5.89 g (98% ee) of the title compound. Again, 5.88 g of the obtained target compound was added to 60 m of ethanol.
1 and 54 ml of water were used for recrystallization to give the title compound 5.11
g (57%, 99.7% ee) was obtained. Infrared absorption spectrum ν _max cm ^-1 (KBr): 3400, 3218, 31
26, 2937, 2596, 1599,1530, 1400, 1124, 1077, 715 Elemental analysis value; (% as C ₉ H ₁₅ NOS ・ 0.5C ₄ H ₄ O ₆ ) Calculated value : C, 50.95; H, 6.61; N, 5.40; S, 12.36 Found: C, 50.68; H, 6.91; N, 5.38; S, 12.48 [α] _D ²⁴ -14 (c 1.00, H ₂ O).

Example 47 (b) Acetic acid (2R) -acetylamino-2-methyl-4-
(Thiophen-2-yl) butyl (2R) -amino-2-methyl-4-thiophen-2-ylbutan-1-ol 1 / obtained in Example 47 (a)
2D-(-)-tartaric acid salt 5.11 g (19.6 mmol) was cooled with ice,
After adding 30 ml of a 1N aqueous sodium hydroxide solution to give a free form, the mixture was extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give (2R) -amino-2-methyl-4-thiophen-2-ylbutan-1-ol 3.55 g (98%). It was 1.51 g (8.15) of (2R) -amino-2-methyl-4- (thiophen-2-yl) butan-1-ol obtained.
30 ml of pyridine was added to the
Acetic anhydride (1.95 ml, 20.7 mmol) and 4- (dimethylamino) pyridine (200 mg, 1.64 mmol) were added.
The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and a half. The reaction solution was poured into 150 ml of 1N hydrochloric acid under ice cooling, extracted with ethyl acetate, and the ethyl acetate layer was washed successively with 1N hydrochloric acid and saturated brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (eluting solvent; hexane: ethyl acetate = 3: 1-1:
Purification according to 2) gave 2.15 g (98%) of the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 1.37 (3H,
s), 1.93 (3H, s), 1.94-2.10 (1H, m), 2.10 (3H, s),
2.24-2.38 (1H, m), 2.85 (2H, t, J = 8.0 Hz), 4.18 (1
H, d, J = 11.6 Hz), 4.32 (1H, d, J = 11.6 Hz), 5.39 (1
H, brs), 6.81 (1H, dd, J = 1.2, 3.6 Hz), 6.92 (1H, d
d, J = 3.6, 5.2 Hz), 7.12 (1H, dd, J = 1.2, 5.2 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3265, 3079, 29
33, 2862, 1735, 1638, 1559, 1472, 1441, 1374, 1318,
1241, 1179, 1039, 701, 616.

Example 47 (c) Acetic acid (2R) -acetylamino-2-methyl-4-
(5-Bromothiophen-2-yl) butyl Acetic acid (2R) -acetylamino-2-methyl-4- (thiophen-2-yl) butyl obtained in Example 47 (b)
1.81 g (6.70 mmol) of dimethylformamide 20 ml
Dissolved in N-bromosuccinimide under ice cooling 1.27 g
(7.11 mmol) was added, and the mixture was stirred under a nitrogen atmosphere under ice cooling for 10 minutes and at room temperature overnight. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline.
The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (elution solvent; hexane: ethyl acetate = 3: 1-1: 2).
Purification was carried out to give 2.32 g (99%) of the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 1.35 (3H,
s), 1.95 (3H, s), 1.95-2.08 (1H, m), 2.10 (3H, s),
2.24-2.37 (1H, m), 2.76 (2H, t, J = 8.4 Hz), 4.15 (1
H, d, J = 11.2 Hz), 4.30 (1H, d, J = 11.2 Hz), 5.39 (1
H, brs), 6.57 (1H, d, J = 3.6 Hz), 6.84 (1H, d, J = 3.
6 Hz) Infrared absorption spectrum ν _max cm ^-1 (liquid film): 3300,
3076, 2980, 2937, 1740, 1657, 1544, 1466, 1446, 1
373, 1242, 1045, 794, 604.

Example 47 (d) (2R) -2-amino-2-methyl-4- [2- (3-
Phenylpropyloxy) thiophen-5-yl] buta
Sodium (0.06 g, 2.6 mmol) was added to 3 -n-1-ol tartrate 3-phenyl-1-propanol (1 ml), the temperature was gradually raised, and the mixture was stirred at 80 to 90 ° C. for 3 hours. Allowed to cool, to which (2R) -acetylamino-2-methyl-4- (5-bromothiophen-2-yl) butyl acetate (0.177 g, 0.51 mmol) obtained in Example 47 (c). , Potassium iodide (0.8 mg, 0.005 mmol) and copper (II) oxide (21.0 mg, 0.26 mmol) were added, and the mixture was stirred at 90 ° C. for 19 hours. After cooling, the reaction solution was subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol: triethylamine, 10: 1: 0).
100: 10: 1, V / V / V) and basic silica gel column chromatography (elution solvent; dichloromethane: methanol, 100: 1, V / V) to purify (2R) -2-amino-2-. Methyl-4- [2- (3-phenylpropyloxy) thiophen-5-yl] butan-1-ol (9.1 mg, yield 6%) was obtained. The obtained (2R) -2-amino-2-methyl-4- [2- (3-
Phenylpropyloxy) thiophen-5-yl] butan-1-ol (15.2 mg, 0.048 mmol)
Is dissolved in methanol (1 ml) and tartaric acid (4.5 m
g, 0.049 mmol) was added and the mixture was stirred at room temperature for 1 hour and 30 minutes. The mixture was concentrated under reduced pressure, ethyl acetate was added thereto, and the precipitated crystals were collected by filtration, washed with ethyl acetate and dried to give the title object compound (18.5 mg, 95%). Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 1.30 (3
H, s), 1.86-2.07 (4H, m), 2.68-2.79 (4H, m), 3.51 (1
H, d, J = 11.6Hz), 3.59 (1H, d, J = 11.6Hz), 3.97 (2H,
t, J = 6.5Hz), 6.00 (1H, d, J = 3.7Hz), 6.44 (1H, d, J =
3.7Hz), 7.14-7.28 (5H, m) Mass spectrum (ESI) m / z: 342 (M + Na) ⁺ , 320 (M + H) ⁺ .

Example 48 (2R) -Amino -2-methyl-4- {5- [3- (3
-Acetylphenoxy) propynyl] thiophene-2-
Il} butan-1-ol oxalate (Exemplified compound No. 1-2287) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 1.31 (3H,
s), 1.88-2.10 (2H, m), 2.60 (3H, s), 2.82-2.95 (2
H, m), 3.51 (1H, d, J = 11.6 Hz), 3.60 (1H, d, J = 11.6 Hz)
Hz), 5.02 (2H, s), 6.78 (1H, d, J = 3.6 Hz), 7.06
(1H, d, J = 3.6 Hz), 7.26 (1H, m), 7.44 (1H, m), 7.6
1-7.67 (2H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3346, 3213, 29
29, 2224, 1679, 1595, 1582, 1277, 1205, 721.

Example 49 (2R) -Amino -2-methyl-4- [5- (5-phen)
Nylpent-1-ynyl) thiophen-2-yl] buta
N-1-ol oxalate (Exemplified Compound No. 1-824) Example 49 (a) Acetic acid (2R) -acetylamino-2-methyl-4-
[5- (5-phenylpent-1-ynyl) thiophene
2-yl] butyl (2R) -acetylamino-2-methyl-4- (5-bromothiophen-2-yl) butyl acetate 1.60 g (4.59 mmol) synthesized in Example 47 (c) was added to dimethylformamide 16 ml. Dissolved in 5-phenylpent-1-yne 1.99
g (13.8 mmol), triethylamine 6.40 ml (45.9
), Copper (I) iodide 175 mg (0.92 mmol)
And 322 mg (0.46 mmol) of dichlorobis (triphenylphosphine) palladium were added, and the temperature was 80 ° C under nitrogen atmosphere.
It was stirred for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (elution solvent; hexane: ethyl acetate = 2: 1 to 1).
Purification by 2: 3) gave 1.41 g (75%) of the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 1.36 (3H,
s), 1.85-2.05 (3H, m), 1.94 (3H, s), 2.10 (3H,
s), 2.25-2.35 (1H, m), 2.43 (2H, t, J = 7.0 Hz), 3.70
-3.80 (4H, m), 4.17 (1H, d, J = 11.2 Hz), 4.31 (1H,
d, J = 11.2 Hz), 5.38 (1H, brs), 6.64 (1H, d, J = 3.6
Hz), 6.94 (1H, d, J = 3.6 Hz), 7.15-7.42 (5H, m) Infrared absorption spectrum ν _max cm ^-1 (CHCl ₃ ): 3443, 2946,
2862, 1737, 1681, 1511, 1374, 1251, 1042.

Example 49 (b) (2R) -amino-2-methyl-4- [5- (5-phene)
Nylpent-1-ynyl) thiophen-2-yl] buta
N-1-ol oxalate The acetic acid (2R) -acetylamino-2-methyl-4- [5- (5-phenylpent-1) obtained in Example 49 (a).
-Inyl) thiophen-2-yl] butyl 1.40 g (3.40
Tetrahydrofuran: methanol: water =
It was dissolved in 14 ml of a 1: 1: 1 solution, 1.43 g (34.0 mmol) of lithium hydroxide monohydrate was added, and the mixture was stirred at 50 ° C. for 4 hours. The reaction solution was poured into water and extracted with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; methylene chloride: methanol: aqueous ammonia = 20: 1: 0 to 10: 1: 0.1) to obtain (2
R) -Amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butane-
1-ol 1.11 g (100%) was obtained. Obtained (2R)
-Amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-
All 360 mg (1.10 mmol) was dissolved in methanol, oxalic acid 99 mg (1.10 mmol) was added, and the precipitated crystals were recrystallized from methanol to obtain 394 mg (86%) of the title compound as white crystals. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 1.31 (3H,
s), 1.82-2.10 (4H, m), 2.40 (2H, t, J = 7.0 Hz), 2.
75 (2H, t, J = 7.5 Hz), 2.80-2.95 (2H, m), 3.52 (1H,
d, J = 11.5 Hz), 3.61 (1H, d, J = 11.5 Hz), 6.73 (1H,
d, J = 3.6 Hz), 6.94 (1H, d, J = 3.6 Hz), 7.13-7.30
(5H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3383, 3106, 3
026, 2980, 2942, 2622, 2514, 1721, 1609, 1539, 119
8, 699 Mass spectrum (FAB) m / z: 328 (M + H) + (Free form) Elemental _{analysis; (C 20 H 25 NOS ·} C 2 H 2 O 4 · 0.2H% as ₂ O) Calculated : C, 62.75; H, 6.55; N, 3.32; S, 7.61 Found: C, 62.50; H, 6.29; N, 3.39; S, 7.70 [α] _D ²⁵ -0.9 (c 1.00, methanol).

Example 50 (2R) -Amino -2-methyl-4- [5- (5-phene)
Nylpentanoyl) thiophen-2-yl] butane-1
-All oxalate salt (Exemplified Compound No. 1-1344) (2R) -amino-2-methyl-4 obtained in Example 49
387 mg (1.18 mmol) of-[5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol was dissolved in 4 ml of methanol and 4 ml of 6N sulfuric acid was added.
Was added and the mixture was heated under reflux for 4 hours. After cooling the reaction mixture to 0 ° C, 1
Alkaline with specified sodium hydroxide solution (pH 14)
After that, it was extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel chromatography (Chromatorex NH (1
(00-200 mesh)) (elution solvent; methylene chloride: methanol = 1: 0 to 50: 1) and purify (2R) -amino-2-methyl-4- [5- (5-phenylpentanoyl) Thiophen-2-yl] butan-1-ol 336 mg
(82%) obtained. Dissolve this in methanol and add 88 oxalic acid.
mg (0.97 mmol) was added, and the obtained crystals were recrystallized from methanol to give the title compound as white crystals.
2 mg (78%) was obtained. Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ): δ 1.19 (3
H, s), 1.55-1.67 (4H, m), 1.80-1.98 (2H, m), 2.60
(2H, t, J = 6.7 Hz), 2.83-2.96 (4H, m), 3.40 (1H, d,
J = 11.3 Hz), 3.47 (1H, d, J = 11.3 Hz), 7.00 (1H, d,
J = 3.7 Hz), 7.13-7.22 (3H, m), 7.23-7.31 (2H, m),
7.80 (1H, d, J = 3.7 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3126, 2942, 26
57, 1915, 1718, 1649, 1609, 1547, 1445, 1205, 700 Mass spectrum (FAB) m / z: 346 (M + H) ⁺ (Free form) Elemental analysis value; (C ₂₀ H ₂₇ NO ₂ S ・ _{C 2 H 2 O 4 · 0.5H} 2 O as a%) calculated: C, 59.44; H, 6.80 ; N, 3.15; S, 7.21 Found: C, 59.62; H, 6.53 ; N, 3.31; S, 7.43 .

Example 51 (2R) -Amino -2-methyl-4- [5- (5-phen)
Nylpentyl) thiophen-2-yl] butan-1-o
Oxalate (Exemplified Compound No. 1-152) The acetic acid (2R) -acetylamino-2-methyl-4- [5- (5-phenylpent-1) obtained in Example 49 (a).
-Inyl) thiophen-2-yl] butyl 337 mg (0.82
Mmol) was dissolved in 17 ml of methanol, 170 mg of 10% palladium-carbon was added, and the mixture was stirred under a hydrogen atmosphere for 16 hours. After the catalyst was filtered off with Celite, the filtrate was evaporated under reduced pressure,
Acetic acid (2R) -acetylamino-2-methyl-4-
[5- (5-phenylpentyl) thiophen-2-yl]
Obtained 318 mg (93%) of butyl. Acetic acid obtained (2
R) -Acetylamino-2-methyl-4- [5- (5-
Phenylpentyl) thiophen-2-yl] butyl 298m
g (0.72 mmol) was dissolved in 6 ml of a solution of tetrahydrofuran: methanol: water = 1: 1: 1, 301 mg (7.17 mmol) of lithium hydroxide monohydrate was added, and the mixture was heated to 50 ° C.
And stirred for 6 hours. The reaction solution was poured into water and extracted with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (243 mg) was dissolved in methanol, oxalic acid (65 mg, 0.72 mmol) was added, and the precipitated crystals were collected by filtration to give the title compound as white crystals.
Obtained mg (83%). Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 1.31 (3H,
s), 1.32-1.42 (2H, m), 1.58-1.70 (4H, m), 1.88-2.
08 (2H, m), 2.59 (2H, t, J = 7.6 Hz), 2.74 (2H, t, J
= 7.4 Hz), 2.75-2.91 (2H, m), 3.52 (1H, d, J = 11.6 H
z), 3.61 (1H, d, J = 11.6 Hz), 6.56 (1H, d, J = 3.3 H
z), 6.63 (1H, d, J = 3.3 Hz), 7.09-7.17 (3H, m), 7.1
9-7.27 (2H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3458, 3134, 29
29, 2855, 2595, 1724, 1642, 1543, 1219, 710 cm ^-1 .

Example 52 (2R) -Amino -2-methyl-4- [5- [3- (4-chlorophenoxy)
Ci) Propinyl] thiophen-2-yl] butan-1-ol
Oxalate (Exemplified Compound No. 1-2273) Example 52 (a) Acetic acid (2R) -acetylamino-2-methyl-4- [5- (3-hi)
Droxypropynyl) thiophen-2-yl] butyl acetate (2R) -acetylamino acetate synthesized in Example 47 (c)
-2-Methyl-4- (5-bromothiophen-2-yl) butyl 1.38
g (3.95 mmol) was dissolved in 20 ml of dimethylformamide, and propargyl alcohol 0.69 ml (11.9 mmol), triethylamine 5.60 ml (40.1 mmol),
76 mg (0.40 mmol) of copper (I) iodide and 276 mg (0.39 of dichlorobis (triphenylphosphine) palladium)
Was added and the mixture was stirred at 80 ° C. for 1 hour under a nitrogen atmosphere. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1 to 1: 3) to obtain 685 mg (54%) of the title compound as white crystals. Nuclear magnetic resonance spectrum (500MHz, CDCl ₃ ): δ 1.35 (3H,
s), 1.91 (1H, brs), 1.94 (3H, s), 1.97-2.05 (1H,
m), 2.10 (3H, s), 2.27-2.35 (1H, m), 2.75-2.82 (2
H, m), 4.16 (1H, d, J = 11.2 Hz), 4.31 (1H, d, J = 11.
2 Hz), 4.49 (2H, s), 5.43 (1H, brs), 6.66 (1H, d, J
= 3.6 Hz), 7.02 (1H, d, J = 3.6 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3295, 3077, 2
981, 2217, 1740, 1644, 1556, 1373, 1251, 1028.

Example 52 (b) (2R) -amino-2-methyl-4- [5- [3- (4-chlorophenoxy)
Ci) Propinyl] thiophen-2-yl] butan-1-ol
Oxalate salt Acetic acid (2R) -acetylamino synthesized in Example 52 (a)
-2-Methyl-4- [5- (3-hydroxypropynyl) thiophene
-2-yl] butyl 285 mg (0.88 mmol) and 4-chlorophenol 136 mg (1.06 mmol) were dissolved in anhydrous tetrahydrofuran 5 ml, and under ice cooling, azodicarboxylic acid diethyl ester 230 mg (1.32 mmol) and triphenylphosphine 346 mg ( 1.32 mmol),
The mixture was stirred at room temperature for 4 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel chromatography (eluting solvent; hexane: ethyl acetate =).
2: 1 to 1: 3) and purified with (2R) -acetylamino-2-methyl-4- [5- [3- (4-chlorophenoxy) propynyl] thiophen-2-yl] butyl acetate. 195 as a yellow oil
Obtained mg (51%). This was dissolved in 6 ml of a solution of tetrahydrofuran: methanol: water = 1: 1: 1, and 370 mg (8.82 mmol) of lithium hydroxide monohydrate was added,
The mixture was stirred at 0 ° C for 6 hours. The reaction solution was poured into water and extracted with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 175 mg (0.50 mmol) of the residue was dissolved in 5 ml of ethyl acetate, and 45 mg of oxalic acid (0.
(50 mmol) was added, and the precipitated crystals were collected by filtration to give the title compound as white crystals (198 mg, 86%). Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ): δ 1.18 (3
H, s), 1.7-2.0 (2H, m), 2.84 (2H, t, J = 8.7Hz), 3.4
3 (2H, m), 5.07 (2H, s), 6.83 (1H, d, J = 3.6Hz), 7.
05 (2H, d, J = 9.0Hz), 7.19 (1H, d, J = 3.6Hz), 7.37
(2H, d, J = 9.0Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3416, 1719, 15
97, 1490, 1375, 1241,1201,1092, 1006,830 Mass spectrum (FAB) m / z: 350 (M + H) ⁺ (Free form) Elemental analysis value; (C ₂₀ H ₂₇ NO ₂ S ・ C ₂ H ₂ O ₄ as a%) calculated: C, 54.61; H, 5.04 ; N, 3.18; S, 7.29; Cl, 8.06 Found: C, 54.61; H, 5.04 ; N, 3.01; S, 7.16; Cl, 7.7
7.

Example 53 (2R) -Amino -2-methyl-4- [5- (1-hydr)
Roxy-5-phenylpentyl) thiophen-2-i
Lu] butan-1-ol oxalate (Exemplary Compound No. 1
-1686) (2R) -amino-2-methyl-4 obtained in Example 50
-[5- (5-phenylpentanoyl) thiophene-2
130 mg (0.38 mmol) of -yl] butan-1-ol was dissolved in 3 ml of methanol, 17 mg (0.45 mmol) of sodium borohydride was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution under ice cooling, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol and oxalic acid 34 mg (0.38
Mmol) was added and the solvent was evaporated under reduced pressure. To this, 3 ml of ethanol was added, and the precipitate was collected by filtration to give the title compound (95 m).
g (58%) was obtained as white crystals. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 1.25-1.50
(2H, m), 1.30 (3H, s), 1.58-1.68 (2H, m), 1.70-2.
08 (4H, m), 2.52-2.64 (2H, m), 2.80-2.94 (2H, m),
3.53 (1H, d, J = 11.7 Hz), 3.59 (1H, d, J = 11.7 Hz),
4.74 (1H, t, J = 6.8 Hz), 6.69 (1H, d, J = 3.6 Hz), 6.
74 (1H, d, J = 3.6 Hz), 7.08-7.27 (5H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3357, 2933, 28
57, 1579, 1496, 1454, 1310, 1070, 699.

Example 54 (2R) -Amino -2-methyl-4- [5- (4-phen)
Nilbut-1-ynyl) thiophen-2-yl] butane
-1-ol oxalate (Exemplified Compound No. 1-756) Acetate (2R) -acetylamino-
2-methyl-4- (5-bromothiophen-2-yl)
The title compound was obtained using butyl and 4-phenylbut-1-yne. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 1.31 (3
H, s), 1.88-2.09 (2H, m), 2.68 (2H, t, J = 7.3 Hz),
2.78-2.93 (4H, m), 3.52 (1H, d, J = 11.6 Hz), 3.61
(1H, d, J = 11.6 Hz), 6.72 (1H, d, J = 3.6Hz), 6.88 (1
H, d, J = 3.6Hz), 7.16-7.31 (5H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3204, 3110, 30
26, 2981, 2929, 2887, 1719, 1608, 1541, 1202, 699.

Example 55 (2R) -Amino -2-methyl-4- [5- (4-phen)
Nylbutanoyl) thiophen-2-yl] butane-1-
All oxalate salt (Exemplified Compound 1-1330) In the same manner as in Example 50, (2R) -amino-2-methyl-4- [5- (4-phenylbut-1-) obtained in Example 54.
The title compound was obtained using inyl) thiophen-2-yl] butan-1-ol. Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ): δ 1.19 (3
H, s), 1.82-1.98 (4H, m), 2.62 (2H, t, J = 7.7 Hz),
2.85-2.97 (4H, m), 3.39 (1H, d, J = 11.7 Hz), 3.45 (1
H, d, J = 11.7 Hz), 7.00 (1H, d, J = 3.8Hz), 7.15-7.33
(5H, m), 7.76 (1H, d, J = 3.8Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3410, 3210, 29
41, 2653, 2576, 1665, 1641, 1530, 1452, 1325.

Example 56 (2R) -Amino -2-methyl-4- [5- (4-cyclo)
Lohexylbut-1-ynyl) thiophen-2-yl]
Butan -1-ol (Exemplified Compound No. 1-743) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 0.87-0.99
(2H, m), 1.08 (3H, s), 1.11-1.50 (6H, m), 1.62-1.
81 (7H, m), 2.41 (2H, t, J = 7.2 Hz), 2.74-2.88 (2H,
m), 3.34 (1H, d, J = 11.0 Hz), 3.37 (1H, d, J = 11.0
Hz), 6.66 (1H, d, J = 3.6 Hz), 6.87 (1H, d, J = 3.6 H
z) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3334, 3269, 3
153, 2922, 2851, 1618, 1449, 1060, 804.

Example 57 (2R) -Amino -2-methyl-4- [5- (4-cyclo)
Rohexylbutyl) thiophen-2-yl] butane-1
- ol (Compound No. 1-71) obtained in Example 56 (2R) - amino-2-methyl-4
The title compound was obtained in the same manner as in Example 11 by using-[5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 0.80-0.95
(2H, m), 1.08 (3H, s), 1.10-1.40 (8H, m), 1.54-1.
81 (9H, m), 2.68-2.87 (4H, m), 3.34 (1H, d, J = 10.9
Hz), 3.37 (1H, d, J = 10.9 Hz), 6.53 (1H, d, J = 3.2 H
z), 6.58 (1H, d, J = 3.2 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3333, 3269, 3
170, 2923, 2850, 1619,1461, 1447, 1059, 801.

Example 58 (2R) -Amino -2-methyl-4- [5- (4-cyclo)
Lohexylbutanoyl) thiophen-2-yl] butane
-1-ol (Exemplified Compound No. 1-1329) (2R) -amino-2-methyl-4 obtained in Example 56
The title compound was obtained in the same manner as in Example 17 by using-[5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 0.83-0.97
(2H, m), 1.09 (3H, s), 1.10-1.33 (6H, m), 1.61-1.
86 (9H, m), 2.82-3.00 (4H, m), 3.35 (1H, d, J = 10.9
Hz), 3.39 (1H, d, J = 10.9 Hz), 6.94 (1H, d, J = 3.7 H
z), 7.69 (1H, d, J = 3.7 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3333, 3268, 3
142, 2921, 2849, 1648, 1457, 1208, 1057, 923, 816.

Example 59 2-Amino-2-methyl-4- [5- (3-cyclohexyl
Silmethoxypropynyl) thiophen-2-yl] buta
N-1-ol maleate (Exemplified Compound No. 1-118
5) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 0.92-1.04
(2H, m), 1.13-1.37 (3H, m), 1.31 (3H, s), 1.53-1.
82 (6H, m), 1.89-2.11 (2H, m), 2.82-2.96 (2H, m),
3.35 (2H, d, J = 6.4 Hz), 3.51 (1H, d, J = 11.5 Hz),
3.61 (1H, d, J = 11.5 Hz), 4.87 (2H, s), 6.25 (2H,
s), 6.78 (1H, d, J = 3.6 Hz), 7.05 (1H, d, J = 3.6 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 2924, 2852, 2
218, 1577, 1496, 1386, 1356, 1195, 1089, 866.

Example 60 (2R) -Amino -2-methyl-4- [5- (4-cyclo)
Lohexyloxybutyl) thiophen-2-yl] buta
N-1-ol maleate (Exemplified compound No. 1-40
0) (2R) -amino-2-methyl-4 obtained in Example 31
The title compound was obtained in the same manner as in Example 11 by using-[5- (4-cyclohexyloxybut-1-yl) thiophen-2-yl] butan-1-ol. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 1.15-1.35
(5H, m), 1.31 (3H, s), 1.50-1.80 (7H, m), 1.85-2.
08 (4H, m), 2.73-2.92 (4H, m), 3.20-3.30 (1H, m),
3.45-3.55 (3H, m), 3.60 (1H, d, J = 11.6 Hz), 6.25
(2H, s), 6.59 (1H, d, J = 3.3 Hz), 6.64 (1H, d, J = 3.
3 Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 2931, 2856, 1
577, 1490, 1471, 1459, 1388, 1357, 1108, 1081, 86
8.

Example 61 (2R) -Amino -2-methyl-4- {5- [4- (4
-Fluorophenoxy) butyl] thiophen-2-i
Ru} butan-1-ol (Exemplified Compound No. 1-463) (2R) -amino-2-methyl-4- [5 obtained in Example 45.
The title compound was obtained in the same manner as in Example 11 by using-[4- (4-fluorophenoxy) but-1-ynyl] thiophen-2-yl] butan-1-ol. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 1.08 (3H,
s), 1.70-1.85 (6H, m), 2.73-2.88 (4H, m), 3.34 (1
H, d, J = 10.9 Hz), 3.38 (1H, d, J = 10.9 Hz), 3.94 (2
H, t, J = 5.9 Hz), 6.58 (1H, d, J = 3.7 Hz), 6.60 (1H,
d, J = 3.7 Hz), 6.83-6.90 (2H, m), 6.93-7.00 (2H,
m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3333, 3268, 3
162, 2940, 2865, 1509, 1474, 1244, 1220, 1060, 830,
763.

Example 62 (2R) -Amino -2-methyl-4- {5- [4- (4
-Methoxyphenoxy) butyl] thiophen-2-i
Ru} butan-1-ol (Exemplified Compound No. 1-479) (4R) -methyl-4- [2- was obtained in the same manner as in Example 1h.
[4- (4-Methoxyphenoxy) but-1-ynyl]] ethyloxazolidine was obtained according to the procedure of Example 26 to give the title compound. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 1.08 (3H,
s), 1.68-1.84 (6H, m), 2.73-2.87 (4H, m), 3.34 (1
H, d, J = 10.8 Hz), 3.38 (1H, d, J = 10.8 Hz), 3.72 (3
H, s), 3.91 (2H, t, J = 6.0 Hz), 6.58 (1H, d, J = 3.1
Hz), 6.60 (1H, d, J = 3.1 Hz), 6.81 (4H, s) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3335, 3273, 3
183, 2945, 2868, 1514, 1473, 1233, 1045, 825, 735.

Example 63 (2R) -Amino -2-methyl-4- [5- (4-ben
Diloxybut-1-ynyl) thiophen-2-yl] bu
Tan-1-ol oxalate (Exemplified compound number 1-126
6) The title compound was obtained in the same manner as in Example 1. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 1.31 (3H,
s), 1.89-2.10 (2H, m), 2.70 (2H, t, J = 6.8 Hz), 2.
80-2.94 (2H, m), 3.52 (1H, d, J = 11.6 Hz), 3.61 (1
H, d, J = 11.6 Hz), 3.64 (2H, t, J = 6.8 Hz), 4.57 (2
H, s), 6.74 (1H, d, J = 3.6Hz), 6.94 (1H, d, J = 3.6 H
z), 7.23-7.39 (5H, m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 3358, 3028, 29
26, 2544, 1719, 1702, 1605, 1496, 1468, 1454, 1402,
1279, 1204, 1105, 806, 739, 720, 699, 500 Mass spectrum (FAB) m / z: 344 (M + H) ⁺ (Free body).

Example 64 (2R) -Amino -2-methyl-4- [5- (4-ben
Ziroxybutyl) thiophen-2-yl] butane-1
-All maleate (Exemplified Compound No. 1-594) obtained in Example 63, (2R) -amino-2-methyl-
The title compound was obtained in the same manner as in Example 11 by using 4- [5- (4-benzyloxybut-1-ynyl) thiophen-2-yl] butan-1-ol. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 1.31 (3H,
s), 1.59-1.76 (4H, m), 1.88-2.08 (2H, m), 2.76 (2
H, t, J = 7.2 Hz), 2.79-2.91 (2H, m), 3.49 (2H, t, J
= 6.4 Hz), 3.51 (1H, d, J = 11.6 Hz), 3.60 (1H, d, J =
11.6 Hz), 4.48 (2H, s), 6.25 (2H, s), 6.58 (1H, d,
J = 3.6Hz), 6.64 (1H, d, J = 3.6 Hz), 7.23-7.38 (5H,
m) Infrared absorption spectrum ν _max cm ^-1 (KBr): 2935, 2862, 15
79, 1496, 1386, 1363, 1195, 1104, 1077, 1012, 875,
866, 804, 737, 698, 569 Mass spectrum (FAB) m / z: 348 (M + H) ⁺ (Free body).

Example 65 (2R) -Amino -2-methyl-4- {5- [3- (4
-Methylcyclohexyloxy) propynyl] thiophe
N-2-yl} butan-1-ol maleate (Exemplified Compound No. 1-1050) In the same manner as in Example 1, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD): δ 0.89, 0.9
0 (total 3H, d, J = 6.4 Hz), 1.31 (3H, s), 0.92-1.56, 1.7
0-2.12 (total 11H, m), 2.81-2.96 (2H, m), 3.40-3.49,
3.73-3.79 (total 1H, m), 3.52 (1H, d, J = 11.2 Hz), 3.61
(1H, d, J = 11.2Hz), 4.36, 4.39 (total 2H, s), 6.25 (2
H, s), 6.78 (1H, d, J = 3.6 Hz), 7.04 (1H, d, J = 3.6
Hz) Infrared absorption spectrum ν _max cm ^-1 (KBr): 2927, 2864, 22
19, 1579, 1508, 1386,1366, 1193, 1093, 1077, 876,
865, 807, 717, 568 Mass spectrum (FAB) m / z: 336 (M + H) ⁺ (Free form).

Example 66 (4R) -Methyl -4- [2- (thiophen-2-yl) ethyl] oxa
Zolidin-2-one (Exemplified Compound No. 4-4) Example 66 (a) (2R) -t-butoxycarbonylamino-3-n-hexanoylo
Xy-2- methyl-1-propanol 2-t-butoxycarbonylamino-2-methyl-1,3-propanediol 20.0 g (97.4 mmol) of diisopropyl ether 2
Suspended in 00 ml, n-hexanoic acid vinyl ester 16.3 ml
(0.10 mol) and lipase [Immobilized lipase from Ps
0.8 g of eudomonas sp. (TOYOBO; 0.67 U / mg)] was added, and the mixture was vigorously stirred at room temperature for 2 hours. After filtering the reaction solution, the filtrate was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; hexane: ethyl acetate = 10:
1 to 2: 1) and 25.0 g (85%) of the title compound.
Was obtained as a colorless oil.

The obtained (2R) -t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol was used as an optically active HPLC column for analysis (ChiralCel OF (Daicel), (0.46 cm x 25 cm), elution solvent; n-hexane: 2-
The optical purity was determined with propanol = 70: 30, flow rate; 0.5 ml / min).

It was confirmed that the one eluted earlier (8.2 min) was the 2S form and the one eluted later (10.5 min) was the 2R form, and the optical purity in this reaction was 85% ee. [α] ^D ₂₅ -8.5 (c 1.86, CHCl ₃ ) Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 4.86
(s, 1H), 4.25 (d, 1H, J = 11.2 Hz), 4.19 (d, 1H, J
= 11.2 Hz), 3.86 (brs, 1H), 3.70-3.55 (m, 2H), 2.3
6 (t, 2H, J = 7.4 Hz), 1.68-1.58 (m, 2H), 1.44 (s,
9H), 1.40-1.30 (m, 4H), 1.25 (s, 3H), 0.90 (t, 3H,
J = 7.0 Hz) Infrared absorption spectrum ν max cm ^-1 (Liquid Film): 3415,
3380, 2961, 2935, 2874, 1721, 1505, 1458, 1392, 1
368, 1293, 1248, 1168, 1076 Mass spectrum (FAB) m / z: 304 ((M + H) ⁺ ).

Example 66 (b) (2R) -t-butoxycarbonylamino-3-n-hexanoylo
Xy-2-methyl-1-propanal (2R) -t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol obtained in Example 66 (a) 30.7 g (0.10 mol ) In 600 ml of methylene chloride,
220 g of molecular sieves and 43.6 g (0.20 mol) of pyridinium chlorochromate were added under ice cooling, and then stirred at room temperature for 2 hours. The reaction solution was diluted with ether and then filtered. The filtrate was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate =).
10: 1-5: 1) and the title compound 28.8 g
(95%) was obtained as a colorless oil. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 9.45
(s, 1H), 5.26 (brs, 1H), 4.44 (d, 1H, J = 11.2 H
z), 4.32 (d, 1H, J = 11.2 Hz), 2.32 (t, 2H, J = 7.6
Hz), 1.70-1.55 (m, 2H), 1.45 (s, 9H), 1.38 (s, 3
H), 1.40-1.25 (m, 4H), 0.90 (t, 3H, J = 7.0 Hz) Infrared absorption spectrum νmax cm ^-1 (Liquid Film): 3367,
2961, 2935, 2874, 1742, 1707, 1509, 1458, 1392, 1
369, 1290, 1274, 1254, 1166, 1100, 1078 Mass spectrum (FAB) m / z: 302 ((M + H) ⁺ ).

Example 66 (c) (2R) -t-butoxycarbonylamino-1-n-hexanoylo
Xy-2-methyl-4- (thiophen-2-yl) -3-butene 2-thienylmethyltriphenylphosphonium salt 67.
1 g (0.15 mol) was suspended in 750 ml of tetrahydrofuran,
17.2 g (0.15 mol) of potassium t-butoxide was added thereto,
The mixture was stirred at room temperature under a nitrogen atmosphere for 20 minutes. 23.0 g (7R) -t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal obtained in Example 66 (b) dissolved in 250 ml of tetrahydrofuran was added to the reaction solution. mmo
l) was added dropwise under ice cooling, and after completion of the addition, the mixture was stirred under ice cooling for 30 minutes. After that, water was added to the reaction solution and extracted with ethyl acetate,
The ethyl acetate layer was washed with saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (eluting solvent; n-hexane: ethyl acetate = 20: 1) to obtain 27.8 g (96%) of the title compound as a colorless oily substance. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.32-
7.26, 7.16-7.14 (m, total 1H), 7.04-7.01, 7.01-6.93
(m, total 2H), 6.63 (d, 0.5 H, J = 16.0 Hz), 6.60 (d,
0.5 H, J = 13.6 Hz), 6.10 (d, 0.5 H, J = 16.0 Hz),
5.58 (d, 0.5 H, J = 13.6 Hz), 4.94, 4.93 (brs, total 1
H), 4.40-4.10 (m, 2H), 2.34 (t, 2H, J = 7.4 Hz), 1.
70-1.55 (m, 2H), 1.57, 1.50, 1.44 (s, total 9H), 1.40-
1.25 (m, 7H), 0.88 (t, 3H, J = 7.0 Hz) Infrared absorption spectrum νmax cm ^-1 (Liquid Film): 3370,
2961, 2933, 1725, 1495, 1456, 1391, 1367, 1247, 1
167, 1109, 1100, 1072, 697 Mass spectrum (FAB) m / z: 381 (M ⁺ ).

Example 66 (d) (4R) -methyl-4- [2- (thiophen-2-yl) ethenyl] oxy
Sazolidin-2-one (2R) -t-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (thiophene obtained in Example 66 (c)
2-yl) -3-butene 40.5 g (0.11 mol) was dissolved in 150 ml of tetrahydrofuran and 150 ml of methanol, and 530 ml of 1N sodium hydroxide aqueous solution was added thereto under ice cooling, and 30 minutes under ice cooling. It was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with methylene chloride, and the methylene chloride layer was washed with saturated brine. The methylene chloride layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product 35.0
got g. This crude product was dissolved in 300 ml of tetrahydrofuran, 17.8 g (0.16 mol) of potassium t-butoxide was added under ice cooling, and the mixture was stirred under ice cooling for 10 minutes and at room temperature for 40 minutes. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the ethyl acetate layer was washed with saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1 to 1: 1) to give the title compound 1
8.0 g (81%) was obtained as a white solid. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.34
(d, 0.5H, J = 5.1 Hz), 7.19 (d, 0.5H, J = 5.0Hz), 7.0
7-6.91 (m, 2H), 6.74 (d, 0.5H, J = 16.0Hz), 6.59 (d,
0.5H, J = 12.5), 6.17 (brs, 1H), 6.06 (d, 0.5H, J = 1
6.0Hz), 5.65 (d, 0.5H, J = 12.5Hz), 4.41 (d, 0.5H, J
= 8.6Hz), 4.31-4.16 (m, 1.5H), 1.60 (s, 1.5H), 1.55
(s, 1.5H) Infrared absorption spectrum ν max cm ^-1 (KBr): 3275, 3110, 2
974, 1752, 1391, 1376, 1281, 1169, 1039, 960, 704 Mass spectrum (FAB) m / z: 209 (M ⁺ ).

Example 66 (e) (4R) -Methyl-4- [2- (thiophen-2-yl) ethyl] oxa
Zolidine-2-one (4R) -methyl-4- [2- (thiophen-2-yl) ethenyl] oxazolidin-2-one obtained in Example 66 (d) 18.0 g (8
6.0 mmol) was dissolved in 150 ml of methanol, 4.5 g of 10% palladium-carbon was added, and the mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere. Palladium-carbon in the reaction solution was filtered using a Kiriyama funnel thinly laid with silica gel, and the filtrate was evaporated under reduced pressure. The obtained solid was washed with diethyl ether and dried to give the title compound (16.5 g, 91%) as a white solid.

The obtained (4R) -methyl-4- [2- (thiophene-2)
-Yl) ethyl] oxazolidin-2-one is an optically active HPLC column for analysis (ChiralCel OD-H (Daicel), (0.46 cm x
25 cm), elution solvent; n-hexane: 2-propanol = 6
The optical purity was determined at 0:40, flow rate; 0.5 ml / min).

It was confirmed that the one eluted first (16.8 min) was the 2S form, and the one eluted later (17.6 min) was the 2R form, and the optical purity in this reaction was 85% ee. [α] ^D ₂₅ +5.1 (c 2.4, CHCl ₃ ) Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.15
(d, 1H, J = 5.2 Hz), 6.93 (dd, 1H, J = 5.2, 3.6 H
z), 6.81 (d, 1H, J = 3.6 Hz), 5.39 (brs, 1H), 4.19
(d, 1H, J = 8.4 Hz), 4.08 (d, 1H, J = 8.4 Hz), 3.0
0-2.84 (m, 2H), 2.08-1.92 (m, 2H), 1.42 (s, 3H) Infrared absorption spectrum νmax cm ^-1 (KBr): 3283, 1770, 1
399, 1244, 1043, 941,846, 775, 706, 691 Mass spectrum (EI) m / z: 211 (M ⁺ ) (4R) -methyl-4- [2- (thiophene-2) with 85% ee optical purity.
-Yl) ethyl] oxazolidin-2-one 11 g ethyl acetate
After adding 25 ml and 5.0 ml of n-hexane and heating to dissolve,
It was left at room temperature for 2 hours. The precipitated white crystals were collected by filtration and dried to obtain 4.0 g of the title compound having an optical purity of 99% ee. [α] ^D ₂₅ +7.8 (c 2.0, CHCl ₃ ).

Example 67 (4R) -Methyl -4- [2- (thiophen-2-yl) ethyl] oxa
Zolidine-2-one (Exemplified Compound No. 4-4) Example 67 (a) (2R) -t-butoxycarbonylamino-1-n-hexanoylo
Xy-2-methyl-4- (thiophen-2-yl) butane (2R) -t-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-obtained in Example 66 (c) (Thiophene
2-yl) -3-butene 27.6 g (72.4 mmol) in ethanol 450
It was dissolved in ml, 10% palladium-carbon (14.0 g) was added, and the mixture was stirred at room temperature for 4 days in a hydrogen atmosphere. The palladium-carbon in the reaction solution was filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent;
Purification by hexane: ethyl acetate = 20: 1 to 10: 1) gave 22.1 g (80%) of the title compound as a colorless oil. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.02
(d, 1H, J = 5.2 Hz), 6.91 (dd, 1H, J = 5.2, 3.6 H
z), 6.80 (d, 1H, J = 3.6 Hz), 4.53 (brs, 1H), 4.26-
4.12 (m, 2H), 2.85 (t, 2H, J = 8.4 Hz), 2.34 (t, 2
H, J = 7.6 Hz), 2.26-2.16 (m, 1H), 2.01-1.90 (m, 1
H), 1.68-1.56 (m, 2H), 1.44 (s, 9H), 1.31 (s, 3H),
1.40-1.26 (m, 4H), 0.89 (t, 3H, J = 7.6Hz) Infrared absorption spectrum νmax cm ^-1 (Liquid Film): 3371,
2961, 2933, 2872, 2864, 1721, 1502, 1466, 1455, 1
392, 1367, 1246, 1168, 1074, 694, mass spectrum (FAB) m / z: 384 ((M + H) ⁺ ).

Example 67 (b) (2R) -t-butoxycarbonylamino-2-methyl-4- (thiof
E emission-2-yl) -1 obtained in butanol Example 67 (a) (2R)-t-butoxycarbonylamino -1-n-hexanoyloxy-2-methyl-4- (thiophen
2-yl) butane 22.0 g (57.4 mmol) was dissolved in a mixed solution of 140 ml of tetrahydrofuran and 280 ml of methanol, and 280 ml of 1N sodium hydroxide aqueous solution was added thereto under ice cooling,
The mixture was stirred under ice cooling for 30 minutes and at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with methylene chloride, and the methylene chloride layer was washed with saturated brine. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (15.5 g, 95%) as a white solid. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.11
(d, 1H, J = 5.2 Hz), 6.92 (dd, 1H, J = 5.2, 3.6 H
z), 6.81 (d, 1H, J = 3.6 Hz), 4.64 (brs, 1H), 4.08
(brs, 1H), 3.74-3.60 (m, 2H), 2.98-2.76 (m, 2H),
2.20-2.10 (m, 1H), 2.03-1.90 (m, 1H), 1.44 (s, 9
H), 1.22 (s, 3H) Infrared absorption spectrum νmax cm ^-1 (KBr): 3279, 3250, 3
067, 2973, 2929, 2908, 2857, 1679, 1552, 1367, 129
1, 1245, 1167, 1076, 1064, 1009, 861, 851, 701 Mass spectrum (FAB) m / z: 286 ((M + H) ⁺ ).

Example 67 (c) (4R) -methyl-4- [2- (thiophen-2-yl) ethyl] oxa
Zolidine-2-one (2R) -t-butoxycarbonylamino-2-methyl-4- (thiophen-2-yl) -1-butanol 1 obtained in Example 67 (b)
5.4 g (53.9 mmol) of N, N-dimethylformamide 200 ml
Was dissolved in, and 9.07 g (80.8 mmol) of potassium t-butoxide was added under ice cooling, and the mixture was stirred under ice cooling for 10 minutes and at room temperature for 40 minutes. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the ethyl acetate layer was washed with saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: hexane: ethyl acetate = 3: 1 to 1: 1) to obtain 11.5 g (100%) of the title compound as a white solid. Various instrument data were in agreement with those obtained in Example 1.

Example 68 (4R)-[2- (Benzo [b] thiophen-6-yl) ethyl] -4-methyi
Luoxazolidin-2-one (Exemplified Compound No. 4-17) Example 68 (a) (2R) -t-butoxycarbonylamino-1-n-hexanoylo
Xy-2-methyl-4- (benzo [b] thiophen-6-yl) -3-bu
Synthesized in ten Example 66 (b) (2R) -t- butoxycarbonylamino -3-n-hexanoyloxy-2-methyl-1-propanal 28.2 g (93.6 mmol) and 6-bromo-triphenyl phosphonium 45.8 g (93.6 mmol) of ammonium benzo [b] thiophene was suspended in 700 ml of tetrahydrofuran, 11.6 g (0.10 mol) of potassium t-butoxide was added thereto, and the mixture was stirred at room temperature for 30 minutes. Then, water was added to the reaction solution, extraction was performed with ethyl acetate, and the ethyl acetate layer was washed with saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: hexane: ethyl acetate = 10: 1) to obtain 28.0 g (69%) of the title compound as a colorless oily substance. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.82
(d, 1H, J = 9.7 Hz), 7.75 (d, 1H, J = 8.2 Hz), 7.4
4-7.39 (m, 1H), 7.32-7.26 (m, 2H), 6.74, 5.73 (d,
1H, J = 12.6Hz), 6.61, 6.34 (d, 1H total, J = 16.2H
z), 4.87, 4.69 (br s, total 1H), 4.34-4.16, (m, 2H),
2.37-2.32 (m, 2H), 1.67-1.15 (m, 20H), 0.91-0.84
(m, 3H). Infrared absorption spectrum ν max cm ^-1 (Liquid Film): 3440,
3373, 2961, 2932, 2872, 1724, 1597, 1498, 1457, 1
390, 1367, 1247, 1167, 1099, 1073. Mass spectrum (FAB) m / z: 431 (M ⁺ ).

Example 68 (b) (2R) -t-butoxycarbonylamino-1-n-hexanoylo
Xy-2-methyl-4- (benzo [b] thiophen-6-yl) butane (2R) -t-butoxycarbonylamino-1-n-hexanoyloxy-2-obtained in Example 68 (a) Methyl-4- (benzo [b]
28.0 g (64.9 mmol) of thiophen-6-yl) -3-butene was dissolved in 700 ml of methanol to obtain 10% palladium-carbon 14.0 g.
Was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 days. The palladium-carbon in the reaction solution was filtered through Celite, and the filtrate was evaporated under reduced pressure. Silica gel column chromatography of the residue
(Elution solvent; hexane: ethyl acetate = 15: 1 to 10:
Purification according to 1) gave 24.30 g (87%) of the title compound as a colorless oil. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.73
(d, 1H, J = 8.2 Hz), 7.69 (s, 1H), 7.36 (d, 1H, J
= 5.2 Hz), 7.28 (d, 1H, J = 5.6 Hz), 7.19 (d, 1H,
J = 8.1 Hz), 4.56 (br s, 1H), 4.28 (d, 1H, J = 11.
0 Hz), 4.14 (d, 1H, J = 11.0 Hz), 2.73 (t, 2H, J =
8.7 Hz), 2.34 (t, 2H, J = 7.5 Hz), 1.68-1.61 (m,
2H), 1.45 (s, 9H), 1.41-1.38 (m, 8H), 0.89 (t, 3H,
J = 6.7Hz). Infrared absorption spectrum νmax cm ^-1 (Liquid Film): 3371,
2960, 2933, 2870, 1720, 1604, 1501, 1466, 1392, 1
367, 1248, 1167, 1074. Mass spectrum (FAB) m / z: 456 ((M + Na) ⁺ ).

Example 68 (c) (4R)-[2- (benzo [b] thiophen-6-yl) ethyl] -4-methyi
Luoxazolidin-2-one (2R) -t-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (benzo [b] obtained in Example 68 (b)
24.3 g (56.0 mmol) of thiophen-6-yl) butane was dissolved in 220 ml of tetrahydrofuran and 110 ml of methanol, and 110 ml of a 1N aqueous sodium hydroxide solution was added thereto under ice cooling, and further under ice cooling for 15 minutes. The mixture was stirred at room temperature for 2 hours.
The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with methylene chloride, and the methylene chloride layer was washed with saturated brine. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (18.8 g, 100%). The obtained crude product was dissolved in 380 ml of dimethylformamide, 9.43 g (84.1 mmol) of potassium t-butoxide was added under ice cooling, and the mixture was cooled to 5 under ice cooling.
The mixture was stirred for 1 minute at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the ethyl acetate layer was washed with saturated saline.
The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent; hexane: ethyl acetate = 3: 2-2:
Purification by 1) yielded 13.8 g (94%) of the title compound as a white solid.

The obtained (4R)-[2- (benzo [b] thiophene-6
-Yl) ethyl] -4-methyloxazolidin-2-one is an optically active HPLC column for analysis (ChiralCel AD (Daicel),
(0.46 cm x 25 cm), elution solvent; n-hexane: 2-propanol = 70:30, flow rate; 0.5 ml / min) to determine the optical purity.

It was confirmed that the one eluted first (15.9 min) was the 4S form, and the one eluted later (17.6 min) was the 4R form, and the optical purity in this reaction was 80% ee. [α] ^D ₂₄ +2.3 (c 0.6, CHCl ₃ ) Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 7.73
(d, 1H, J = 8.2 Hz), 7.68 (s, 1H), 7.38 (d, 1H, J
= 5.7 Hz), 7.29 (d, 1H, J = 13.0 Hz), 7.18 (d, 1H,
J = 13.6 Hz), 5.91 (br s, 1H), 4.21 (d, 1H, J = 8.
7 Hz), 4.09 (d, 1H, J = 8.7 Hz), 2.84-2.76 (m, 2H),
1.97 (t, J = 8.5 Hz, 3H). Infrared absorption spectrum ν max cm ^-1 (KBr): 3292, 2970, 2
930, 1749, 1722, 1601,1479, 1461, 1397, 1277, 104
5. Mass spectrum (EI) m / z: 261 (M ⁺ ).

Example 69 (2R) -t-butoxycarbonylamino-3-n-hexyl
Xanoyloxy-2-methyl-1-propanol 2-t-butoxycarbonylamino-2-methyl-1,
200 mg (0.97 mmol) of 3-propanediol
Was dissolved in 2 ml of diisopropyl ether, and 0.16 ml (1.02 mmol) of n-hexanoic acid vinyl ester and lipase [Immobilized lipase from Pseudomo
nas sp. (TOYOBO; 0.67U / mg)] 20m
g was added, and the mixture was stirred at room temperature for 4 hours.

After removing the insoluble matter of the reaction mixture by filtration, the residue was concentrated under reduced pressure, and the residue was subjected to flash silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1).
Purification was performed at 0: 1 to 7: 3) to obtain 258 mg (87%) of the title compound as a colorless oily substance.

The obtained (2R) -t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-
1-Propanol is an optically active HPLC column for analysis (ChiralCel OF, Daicel, 0.46 cm (x25c
m, elution solvent; hexane: 2-propanol = 70: 3
0; flow rate: 0.5 ml / min) to determine the optical purity.

The one eluted first (8.2 minutes) was 2S.
The body, and the one that was eluted later (10.5 minutes) was the 2R body. It was confirmed that the optical purity in this reaction was 89% ee.

[0523] The absolute configuration can be easily synthesized from this compound (Tetrahedron Asymme).
try 10 (1999) 4653-4661) Specific rotation of (2R) -t-butoxycarbonylamino-2-methyl-3-buten-1-ol, which is a known compound and produced in Reference Example 1 (a). It was decided by carrying out a comparative examination. Nuclear magnetic resonance spectrum _{(400MHz, CD 3 CL 3)} δ ppm: 4.89
(1H, br.s), 4.24 (1H, d, J = 11.2Hz), 4.19 (1H, d, J = 11.2H
z), 3.66-3.54 (2H, m), 2.36 (2H, t, J = 7.4Hz), 1.69-1.57
(2H, m), 1.44 (9H, s), 1.39-1.22 (4H, m), 1.25 (3H, s),
0.90 (3H, t, J = 6.6Hz) Infrared absorption spectrum ν _max cm ^-1 (C
HCL ₃ ): 3411,3380,2961,2934,1722,1504,1459,1392,136
8,1292,1248,1168,1077,1015 Optical rotation [α] ²⁴ _D : -1.1 ° (c = 0.81, methanol).

Example 70 (2R) -t-Butoxycarbonylamino-3-n- h
Xanoyloxy-2-ethyl-1-propanol 2-t-butoxycarbonylamino-2-ethyl-1,
200 mg (0.91 mmol) of 3-propanediol
In the same manner as in Example 69, 252 mg (87%) of the title compound was obtained as a colorless oil.

The obtained (2R) -t-butoxycarbonylamino-3-n-hexanoyloxy-2-ethyl-
1-Propanol is an optically active HPLC column for analysis (ChiralCel OF, Daicel, 0.46 cm (x25c
m, elution solvent; hexane: 2-propanol = 70: 3
0; flow rate: 0.5 ml / min) to determine the optical purity.

The one eluted first (8.5 minutes) is 2S.
The 2R body was the body that was eluted later (10.7 minutes). It was confirmed that the optical purity in this reaction was 95% ee.

Regarding the absolute configuration, it can be easily synthesized from this compound (Helvetica Chimica).
Acta 69 (1986) 1365-1377) A known compound, (+)-(R) -α-ethyl-, produced in Reference Example 5 (f).
It was determined by comparatively examining the specific optical rotation of α-vinylglycine. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 4.78 (1H, b
rs), 4.28 (1H, d, J = 11.1Hz), 4.13 (1H, d, J = 11.1Hz), 3.
72-3.57 (2H, m), 2.35 (2H, t, J = 7.6Hz), 1.83-1.54 (4H,
m), 1.44 (9H, s), 1.38-1.24 (4H, m), 0.95-0.86 (6H, m) infrared absorption spectrum ν _max (CHCl ₃ ) cm ^-1 : 3371,2966,293
5,1722,1503,1460,1368,1249,1168,1086,1028,866,781 Optical rotation [α] ²⁴ _D : -2.4 ° (c = 0.72, methanol) Using the compound synthesized in Example 69 or Example 70 , A known useful compound, (−)-(R) -α-methyl-
α-Vinylglycine (Reference Example 1), (+)-(S) -α
This led to -methyl-α-ethynylglycine (Reference Example 2) and (+)-(R) -α-ethyl-α-vinylglycine (Reference Example 3).

Reference Example 1 (-)-(R) -α-methyl-α-vinylglycine Reference Example 1 (a) (2R) -t-butoxycarbonylamino-2-methyl
-3-Buten-1-ol (2R) -t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-prepared in Example 69.
A solution of 1.5 g (4.9 mmol) of 1-propanol in methylene chloride (18 ml) was charged with molecular sieves 4A.
(10.5 g) was added, and the mixture was stirred at room temperature for 10 minutes, 2.1 g (9.8 mmol) of pyridinium chlorochromate was added, and the mixture was stirred for 1 hour. Diethyl ether was added to the reaction solution, and the insoluble material was removed by filtration using a silica gel short column (eluent: diethyl ether). By distilling off the organic solvent under reduced pressure, 1.5 g of the obtained residue was used in the next reaction.

To a tetrahydrofuran suspension (10 ml) containing 4.5 g (12.5 mmol) of methyltriphenylphosphonium bromide, 1.3 g (11.5 mmol) of potassium t-butoxide was added at 0 ° C. and the mixture was stirred for 1 hour. .
To this reaction solution was added dropwise a tetrahydrofuran solution (10 ml) of the residue obtained in the previous reaction.

The reaction solution was stirred at 0 ° C. for 30 minutes, distilled water was added, and the mixture was extracted with ethyl acetate. This with distilled water,
It was washed with saturated saline in this order and dried over magnesium sulfate. After the solvent was distilled off, the insoluble matter was removed using a silica gel short column (eluent: hexane: ethyl acetate = 10: 1). After concentrating the solvent, 1.2 g of the obtained residue
In methanol solution (20 ml), 1N aqueous sodium hydroxide solution (20 ml) was added, and the mixture was stirred at room temperature for 30 min. After adding diethyl ether to this reaction solution,
It was washed with distilled water and saturated saline in this order, and dried over magnesium sulfate.

After distilling off the solvent, the residue was purified by preparative thin layer chromatography (eluent; hexane: ethyl acetate = 1: 1) to obtain 180 mg (0.894 mmol, yield 18%) of the title compound. . Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 5.89 (1H, d
dd, J = 11.0,6.6,1.5Hz), 5.21 (1H, d, J = 1.5Hz), 5.17 (1H,
d, J = 6.6Hz), 4.84 (1H, br.s), 3.76 (1H, br.s), 3.62 (2H,
m), 1.44 (9H, s), 1.32 (3H, s) infrared absorption spectrum ν _max (CHCl ₃ ) cm ^-1 : 3418,3348,297
9,1692,1499,1455,1393,1368,1283,1253,1170,1074,918 Optical rotation [α] ²⁴ _D : + 10.4 ° (c = 0.51, methanol).

Reference Example 1 (b) (2R) -t-butoxycarbonylamino-2-methyl
-3-Butenal (2R) -t-butoxycarbonylamino-2-methyl-3-buten-1-ol 18 obtained in Reference Example 1 (a)
0 mg (0.894 mmol) of methylene chloride 5.0 m
Dissolve in 1, and under ice cooling, Molecular Sieves 4A 2.0
g, pyridinium chlorochromate 386 mg (1.79)
(Mmol) and added and stirred at room temperature for 1 hour. Ether was added to the reaction solution, the insoluble matter of the reaction mixture was filtered off, and the residue was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 10: 1) to obtain 160 mg (90%) of the title compound as a colorless oil. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 9.26 (1H,
s), 5.83 (1H, dd, J = 17.5,10.6Hz), 5.35 (1H, d, J = 10.6H)
z), 5.32 (1H, d, J = 17.5Hz), 5.22 (1H, br.s), 1.48 (3H,
s), 1.45 (9H, s) infrared absorption spectrum ν _max (CHCl ₃ ) cm ^-1 : 3350,2980,173
7,1707,1505,1455,1369,1279,1256,1168,1069,925,86
7.

Reference Example 1 (c) (2R) -t-butoxycarbonylamino-2-methyl
-3-Butenoic acid 160 mg of (2R) -t-butoxycarbonylamino-2-methyl-3-butenal obtained in Reference Example 1 (b)
(0.803 mmol) of t-butanol 8.0 m
1, dissolved in 2.0 ml of water, 0.38 ml (3.61 mmol) of 2-methyl-2-butene, 96 mg (0.803 mmol) of sodium dihydrogen phosphate dihydrate, 254 mg of sodium chlorite ( (2.81 mmol) was added and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, and the ethyl acetate layer was washed with saturated saline. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to flash silica gel column chromatography (eluting solvent; n-hexane: ethyl acetate = 20:
Purification was performed in 1 to 1: 1) to obtain 130 mg (75%) of the title compound as a colorless oily substance. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 5.07 (1H, b
rs), 5.68 (1H, br.s), 5.12 (1H, d, J = 17.4Hz), 5.05 (1H,
d, J = 10.6Hz), 1.48 (3H, s), 1.40 (9H, s) infrared absorption spectrum ν _max (CHCl ₃ ) cm ^-1 : 3394,2980,169
1,1602,1483,1455,1368,1253,1172,1066,756.

Reference Example 1 (d) (−)-(R) -α-methyl-α-vinylglycine hydrochloride
Salt (2R) -t-butoxycarbonylamino-2-methyl-3-butenoic acid 120 mg obtained in Reference Example 1 (c)
(0.557 mmol) was dissolved in 1.5 ml of ethanol, 1.5 ml of a 4N hydrochloric acid dioxane solution was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, washed with ether and dried to give 72 mg (85%) as a white solid.
Got Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 6.07 (1H, d
d, J = 17.6,11.0Hz), 5.48 (1H, d, J = 11.1Hz), 5.47 (1H, d, J
= 17.6Hz), 1.66 (3H, s) Infrared absorption spectrum ν _max (KBr) cm ^-1 : 3349,3029,1751,
1524,1200,954 Optical rotation [α] ²⁵ _D : -18.7 ° (c = 0.70, H ₂ O).

Reference Example 1 (e) (-)-(R) -α-methyl-α- vinylglycine (-)-(R) -α-methyl- obtained in Reference Example 1 (d)
60 mg (0.40 milligram) of α-vinylglycine hydrochloride was dissolved in 1.5 ml of ethanol, 1.5 ml of propylene oxide was added, and the mixture was heated under reflux for 2 hours. The white solid in the reaction solution was filtered to obtain 32 mg (70%) of the title compound as a white solid. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 6.17 (1H, d
d, J = 17.2,10.6Hz), 5.56 (1H, d, J = 10.6Hz), 5.54 (1H, d, J
= 17.2Hz), 1.43 (3H, s) IR absorption spectrum ν _max (KBr) cm ^-1 : 3600-2500,1605,
1535,1455,1415,1385,1360,1280,1235,1150,1000,940 Optical rotation [α] ²⁵ _D : -27.6 ° (c = 0.62, H ₂ O).

Reference Example 2 (+)-(S) -α-methyl-α-ethynylglycine Reference Example 2 (a) 3-t-butoxycarbonyl-2,2-dimethyl- (4
R) -n-Hexanoyloxymethyl-4-methyloxy
Sazolidine (2R) -t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-obtained in Example 69
10.1 g (33.3 mmol) of 1-propanol was dissolved in 152 ml of methylene chloride, 16.4 ml (133 mmol) of acetone dimethyl acetal and 172 mg (1.00 mmol) of p-toluenesulfonic acid were added, and the mixture was stirred at room temperature for 12 hours. It was stirred.

The reaction mixture was concentrated, and the residue was purified by flash silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 10: 1) to give the title compound as a colorless oil (5.72 g, 50%). )Obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 4.29 (1H,
s), 4.18 (1H, s), 3.99 (1H, m), 3.64 (1H, m), 2.28-2.34
(2H, m), 1.26-1.25 (24H, m), 0.89 (3H, t) Optical rotation [α] ²⁵ _D : + 17.2 ° (c = 1.50, CHCl ₃ ).

Reference Example 2 (b) 3-t-butoxycarbonyl-2,2-dimethyl- (4
S) -Hydroxymethyl-4-methyloxazolidine 3-t-butoxycarbonyl-obtained in Reference Example 2 (a)
1,2-dimethyl- (4R) -n-hexanoyloxymethyl-4-methyloxazolidine 13.7 g (39.
9 mmol) was dissolved in 200 ml of methylene chloride, and -7
Diisobutylaluminum hydride (1.0M
Hexane solution) 99 ml (99.7 mmol) was added dropwise. After stirring at -78 ° C for 30 minutes, return to room temperature and 10 wt
200% aqueous sodium-potassium tartrate solution (200 ml) was added, and the mixture was vigorously stirred for 30 minutes. The reaction solution was extracted with diethyl ether, the ether layer was dried over anhydrous sodium sulfate,
The residue was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 5: 2) to obtain 10.5 g (100%) of the title compound as a white crystal. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 4.49 (1H, b
rs), 3.55-3.71 (4H, m), 1.56 (3H, s), 1.49 (12H, s), 1.4
2 (3H, s) Optical rotation [α] ²⁵ _D : -1.67 ° (c = 1.45, CHCl ₃ ).

Reference Example 2 (c) 3-t-Butoxycarbonyl-2,2-dimethyl- (4
R) -formyl-4-methyloxazolidine 3-t-butoxycarbonyl-obtained in Reference Example 2 (b)
2,2-Dimethyl- (4S) -hydroxymethyl-4-
Methyl oxazolidine 9.79 g (39.9 mmol)
Was dissolved in 150 ml of methylene chloride, 13.0 g (59.8 mmol) of pyridinium chlorochromate and 65.0 g of molecular sieves 4A were added under ice cooling, and the mixture was stirred at room temperature for 1 hour.

After adding diethyl ether to the reaction solution, the reaction solution was filtered using a silica gel column, the filtrate was concentrated under reduced pressure, and flash silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 8 :).
Purification was performed in 1), and the title compound was obtained as white crystals.
07 g (88%) was obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 9.40-9.48
(1H, s), 3.91 (1H, d, J = 9.2Hz), 3.67 (1H, d, J = 9.2Hz), 1.
14-1.66 (18H, m) Optical rotation [α] ²⁵ _D + 20.6 ° (c = 1.25, CHCl ₃ ).

Reference Example 2 (d) 3-t-butoxycarbonyl-2,2-dimethyl- (4
S)-(2,2-Dibromo) ethenyl-4-methyloxy
Sazolidine 17.3 g (65.8 mmol) of triphenylphosphine was dissolved in 25 ml of methylene chloride, and 10.9 g (32.9 mmol) of carbon tetrabromide was dissolved in 1 ml of methylene chloride under ice cooling.
The solution dissolved in 5 ml was added dropwise, and the mixture was stirred under ice cooling for 5 minutes. To the reaction solution, 4.00 g (16.4 mm) of 3-t-butoxycarbonyl-2,2-dimethyl- (4S) -formyl-4-methyloxazolidine obtained in Reference Example 2 (c) was obtained.
solution) dissolved in 40 ml of methylene chloride and stirred at room temperature for 14 hours, the insoluble matter of the reaction mixture was removed by filtration, and the residue was concentrated under reduced pressure to give the crude title compound as a colorless oil (4.70 g). (71.2%) was obtained.

Reference Example 2 (e) 3-t-Butoxycarbonyl-2,2-dimethyl- (4
S) -Ethynyl-4-methyloxazolidine 3-t-butoxycarbonyl-obtained in Reference Example 2 (d)
2,2-Dimethyl- (4S)-(2,2-dibromo) ethenyl-4-methyloxazolidine 4.70 g (11.
(8 mmol) was dissolved in 94 ml of tetrahydrofuran, and n-butyllithium (1.6
N hexane solution) was added dropwise, and the mixture was stirred at -78 ° C for 3.5 hours. 100m saturated aqueous ammonium chloride solution
1 was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, the residue was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 15: 1) to give the title compound as white crystals. As 2.21 g (78
%)Obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 4.13 (1H,
d, J = 8.4Hz), 3.84 (1H, d, J = 8.4Hz), 2.32 (1H, s), 1.49-
1.69 (18H, m) Optical rotation [α] ²⁵ _D : + 65.6 ° (c = 1.10, CHCl ₃ ).

Reference Example 2 (f) (2S) -Amino-2-methyl-3-butyn-1-o
Obtained in Le Reference Example 2 (e), 3-t- butoxycarbonyl -
2,2-Dimethyl- (4S) -ethynyl-4-methyloxazolidine 350 mg (1.46 mmol) and hydrochloric acid 1
0 ml was added, the mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure to give the crude title compound as a yellow oily substance 127
mg was obtained.

Reference Example 2 (g) (2S) -t-butoxycarbonylamino-2-methyl
-3- Butyn-1-ol 127 mg (1.28 ml) of (2S) -amino-2-methyl-3-butyn-1-ol obtained in Reference Example 2 (f)
Was dissolved in 1 ml of water and 5 ml of tetrahydrofuran to give 380 mg of di-t-butyl carbonate (1.74).
Mmol) and 385 mg of anhydrous sodium carbonate (3.6
(3 mmol) was added, and the mixture was stirred at room temperature for 14 hours.

[0545] A saturated ammonium chloride aqueous solution 6 m was added to the reaction solution.
1 was added and the mixture was extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1: 1) to give 154 mg (53%) of the title compound as white crystals.
Obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 5.00 (1H, b
rs), 3.78 (1H, dd, J = 6.0 and 11.2Hz), 3.67 (1H, dd, J = 7.
9 and 11.2Hz), 3.20 (1H, br.s), 2.40 (1H, s), 1.55 (3H,
s), 1.46 (9H, s) Optical rotation [α] ²⁵ _D : + 1.89 ° (c = 0.70, CHCl ₃ ).

Reference Example 2 (h) (2S) -t-butoxycarbonylamino-2-methyl
-3-butyric acid (2S) -t-butoxycarbonylamino-2-methyl-3-butyn-1-ol 1. obtained in Reference Example 2 (g).
20 g (6.02 mmol) was dissolved in 30 ml of acetone, and under ice cooling, 3.48 ml (9.03 of Jones reagent).
Was added and the mixture was stirred for 2 hours under ice cooling. Further, 3.48 ml (9.03 mmol) of Jones reagent was added, and the mixture was stirred at room temperature for 14 hours. 5 ml of 2-propanol and 30 ml of water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure to obtain 1.38 g of the crude title compound as a yellow oily substance.

Reference Example 2 (i) (+)-(S) -α-methyl-α-ethynylglycine salt
Obtained in salt Reference Example 2 (h), (2S) -t- butoxycarbonylamino-2-methyl-3-butyn acid 1.38g
(6.02 mmol) was dissolved in 20 ml of tetrahydrofuran, 10 ml of hydrochloric acid was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, 20 ml of water and 1 of ethyl acetate.
0 ml was added and the water tank was concentrated under reduced pressure to obtain 0.24 g (27%) of the crude title compound as yellow crystals.

Reference Example 2 (j) (+)-(S) -α-methyl-α-ethynylglycine (+)-(S) -α-methyl- obtained in Reference Example 2 (i)
To 0.24 g (6.02 mmol) of α-ethynylglycine hydrochloride, 9 ml of ethanol and 3 ml of propylene oxide were added, and the mixture was heated under reflux for 2 hours. The reaction mixture was filtered and the solid was washed with ether to give the title compound as white crystals (108 mg, 60%). Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 3.06 (1H,
s), 1.77 (3H, s) Optical rotation [α] ²⁵ _D : + 41.7 ° (c = 0.96, H ₂ O).

Reference Example 3 (+)-(R) -α-ethyl-α-vinylglycine Reference Example 3 (a) (2S) -t-butoxycarbonylamino-2-ethyl
-3-n-Hexanoyloxy-1-propanal (2R) -t-butoxycarbonylamino-3-n-hexanoyloxy-2-ethyl-obtained in Example 70.
3 g (9.45 mmol) of 1-propanol was dissolved in 60 ml of methylene chloride, and under the cooling with ice, molecular sieves 4 was added.
A 20 g, pyridinium chlorochromate 4.07 g (1
8.9 mmol) was added and the mixture was stirred at room temperature for 1 hour. Ether was added to the reaction solution, the insoluble matter of the reaction mixture was filtered off, and the residue was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 10: 1) to obtain 2.79 g (94%) of the title compound as a colorless oil. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 9.34 (1H,
s), 5.29 (1H, br.s), 4.60 (1H, d, J = 11.5Hz), 4.40 (1H, d,
J = 11.5Hz), 2.28 (2H, t, J = 7.5Hz), 2.05-2.20 (1H, m), 1.7
0-1.80 (1H, m), 1.55-1.65 (2H, m), 1.45 (9H, s), 1.25-1.
40 (4H, m), 0.90 (3H, t, J = 7.0Hz), 0.81 (3H, t, J = 7.5Hz) Infrared absorption spectrum ν _max (CHCl ₃ ) cm ^-1 : 3418,2979,293
4,2873,1737,1710,1496,1369,1251,1160 Mass spectrum (FAB) m / z: 316 ((M + H) ⁺ ).

Reference Example 3 (b) (2R) -t-butoxycarbonylamino-2-ethyl
-3-Butene-1-ol-n-hexanoic acid ester methyltriphenylphosphonium bromide 7.90 g
(22.0 mmol) was suspended in 25 ml of tetrahydrofuran, and under ice cooling, potassium t-butoxide (2.28 g) was added.
(20.3 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour.

Then, obtained in Reference Example 3 (a), (2S)
-T-butoxycarbonylamino-2-ethyl-3-n
-Hexanoyloxy-1-bropanal 2.79 g
(8.85 mmol) was dissolved in 25 ml of tetrahydrofuran, and the mixture was added dropwise to the reaction solution under ice cooling and stirred for 15 minutes. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated saline, the ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to flash silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 40: 1 to 2).
Purification was performed at 0: 1) to obtain 1.30 g (47%) of the title compound as a colorless oily substance. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 5.78 (1H, d
d, J = 17.6,11.0Hz), 5.22 (1H, d, J = 11.0Hz), 5.12 (1H, d, J
= 17.6Hz), 4.62 (1H, br.s), 4.29 (2H, s), 2.31 (2H, t, J =
7.5Hz), 1.83-1.95 (1H, m), 1.55-1.75 (3H, m), 1.44 (9H,
s), 1.25-1.35 (4H, m), 0.83-0.93 (6H, m) infrared absorption spectrum ν _max (CHCl ₃ ) cm ^-1 : 3448,2972,293
4,2873,1721,1494,1368,1249,1163 Mass spectrum (FAB) m / z: 314 ((M + H) ⁺ ).

Reference Example 3 (c) (2R) -t-butoxycarbonylamino-2-ethyl
-3-Buten-1-ol (2R) -t-butoxycarbonylamino-2-ethyl-3-buten-1-ol-n obtained in Reference Example 3 (b)
Hexanoic acid ester (1.30 g, 4.15 mmol) was dissolved in methanol (20 ml), 1N sodium hydroxide (40 ml) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extraction was performed with diethyl ether, the ether layer was washed with saturated brine, the ether layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to flash silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 9: 1 to 4 :).
Purification was carried out in 1), and the title compound was obtained as a white solid.
Obtained 85 g (95%). Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 5.77 (1H, d
d, J = 17.0,10.7Hz), 5.25 (1H, d, J = 10.7Hz), 5.16 (1H, d, J
= 17.0Hz), 4.77 (1H, br.s), 4.10 (1H, br.s), 3.65-3.75
(2H, m), 1.58-1.83 (2H, m), 1.45 (9H, s), 0.87 (3H, t, J =
7.5Hz) Infrared absorption spectrum ν _max (CHCl ₃ ) cm ^-1 : 3348,3275,298
7,2969,2935,1685,1541,1277,1170,1053 Mass spectrum (FAB) m / z: 216 ((M + H) ⁺ ) Optical rotation [α] ²⁴ _D : + 2.8 ° (c = 1.03, methanol ).

Reference Example 3 (d) (2R) -t-butoxycarbonylamino-2-ethyl
-3-Butenal (2R) -t-butoxycarbonylamino-2-ethyl-3-buten-1-ol 0. obtained in Reference Example 3 (c).
Using 79 g (3.67 mmol) and in the same manner as in Reference Example 3 (a), 0.63 g (80%) of the title compound as a white solid.
%). Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 9.24 (1H,
s), 5.83 (1H, dd, J = 17.5,10.7Hz), 5.39 (1H, d, J = 10.7Hz),
5.31 (1H, d, J = 17.5Hz), 5.29 (1H, br.s), 1.85-2.15 (2H,
m), 1.57 (9H, s), 0.85 (3H, t, J = 7.5Hz) Infrared absorption spectrum ν _max (CHCl ₃ ) cm ^-1 : 3443,3416,298
0,1712,1489,1369,1249,1162 Mass spectrum (FAB) m / z: 214 ((M + H) ⁺ ) Optical rotation [α] ²⁵ _D : + 69 ° (c = 1.00, methanol).

Reference Example 3 (e) (2R) -t-butoxycarbonylamino-2-ethyl
-3-butenoic acid (2R) -t-butoxycarbonylamino-2-ethyl-3-butenal obtained in Reference Example 3 (d) 0.60 g
(2.81 mmol) of t-butanol 8 ml and water 2
Dissolve in 1.3 ml, 2-methyl-2-butene 1.34 ml
(12.7 mmol), sodium dihydrogen phosphate dihydrate 0.44 g (2.81 mmol), and sodium chlorite 0.89 g (9.85 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, and the ethyl acetate layer was washed with saturated saline. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to flash silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 20: 1).
Purification was performed at ~ 1: 1) to obtain 0.42 g (65%) of the title compound as a white solid. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 6.05 (1H, d
d, J = 17.3,10.7Hz), 5.25-5.35 (3H, m), 1.95-2.20 (2H,
m), 1.44 (9H, s), 0.90 (3H, t, J = 7.4Hz) Infrared absorption spectrum ν _max (CHCl ₃ ) cm ^-1 : 3430,2981,171
3,1493,1369,1252,1166 Mass spectrum (FAB) m / z: 230 ((M + H) ⁺ ) Optical rotation [α] ²⁵ _D : + 19.4 ° (c = 1.00, methanol).

Reference Example 3 (f) (+)-(R) -α-Ethyl-α-vinylglycine (5R) -t-butoxycarbonylamino-2-ethyl-obtained in Reference Example 3 (e). 3-butenoic acid 379 mg
(1.65 mmol) was dissolved in 2 ml of ethanol,
2 ml of a 4N hydrochloric acid dioxane solution was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, washed with ether,
Dried. The obtained white solid was dissolved in 6 ml of ethanol, 2 ml of propylene oxide was added, the mixture was heated under reflux for 2 hours, and the white solid in the reaction solution was filtered to obtain 83 mg of the title compound as a white solid. After the filtrate was concentrated under reduced pressure, the residue was dissolved in water, and Bond Elute HF
After filtration with (C ₁₈ ), concentration under reduced pressure was performed to give the title compound 6
1 mg was obtained (144 mg in total, 75% yield). Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 6.08 (1H, d
d, J = 17.7,11.1Hz), 5.41 (1H, d, J = 11.1Hz), 5.34 (1H, d, J
= 17.7Hz), 1.82-2.12 (2H, m), 0.95 (3H, t, J = 7.6Hz) Infrared absorption spectrum ν _max (KBr) cm ^-1 : 3200-2400,1623,
1605,1511,1369 Mass spectrum (FAB) m / z: 130 ((M + H) ⁺ ) Optical rotation [α] ²⁵ _D : + 20.6 ° (c = 1.00, H ₂ O).

Reference Example 4 2.11 g (48.4 mmol) of sodium 5- (4-fluorophenyl) pent-1- yne hydride was suspended in 60 ml of anhydrous tetrahydrofuran, and 10.84 g of diethylphosphonoacetic acid ethyl ester was cooled under ice cooling. (48.4 mmol) was added dropwise and stirred for 10 minutes. Then, a solution of 5.00 g (40.3 mmol) of 4-fluorobenzaldehyde dissolved in 60 ml of anhydrous tetrahydrofuran was added dropwise at the same temperature.
The reaction solution was stirred for 3 hours, poured into 150 ml of ice water, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by flash silica gel column chromatography (eluting solvent: hexane: ethyl acetate = 10: 1 to 3: 1) to give 4-fluorocinnamic acid. Acid ethyl ester as a colorless oil, 6.69 g (86
%)Obtained. 6.52 g (33.6 mmol) of this ester was dissolved in 100 ml of ethyl acetate to obtain 5% rhodium / alumina 1.30.
g was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 30 ml of anhydrous tetrahydrofuran. This solution was added dropwise under ice cooling to a suspension of 1.26 g (33.2 mmol) of lithium aluminum hydride in 60 ml of anhydrous tetrahydrofuran. After stirring the reaction mixture at the same temperature for 30 minutes,
A saturated aqueous sodium sulfate solution was added, and the mixture was further stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (eluting solvent: hexane: ethyl acetate = 5: 1 to 1: 1) and 4
4.86 g (95%) of -fluorophenylpropan-1-ol was obtained as a colorless oily substance.

The obtained 4-fluorophenylpropane-
1-ol 4.83 g (31.3 mmol) was added to methylene chloride 50 m.
It was dissolved in 1 l and 6.55 ml of triethylamine (4
7.0 mmol) and methanesulfonyl chloride 2.91 ml
(37.6 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. The reaction mixture was diluted with 50 ml of methylene chloride, washed successively with ice-cooled 10% hydrochloric acid and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with acetone 10
Dissolved in 0 ml. Then sodium iodide 9.39 g (62.
6 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hours under a nitrogen atmosphere. 10% after diluting the reaction mixture with 250 ml of ethyl acetate
After washing sequentially with aqueous sodium thiosulfate solution and saturated saline solution,
It was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (eluting solvent: hexane: ethyl acetate = 5: 1 to 2: 1) to give 4-fluorophenyl-1-iodopropane as a pale yellow oil. As a product, 7.12 g (86%) was obtained.

[0558] 50 ml of sodium acetylide (18% xylene suspension) was added to 20 ml of hexamethylphosphoramide, and 4-fluorophenyl-1-previously obtained under ice cooling.
A solution of 7.00 g (26.5 mmol) of iodopropane in 20 ml of anhydrous dimethylformamide was added. The reaction mixture was stirred at room temperature for 2 hours. Ice water was carefully poured under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (eluting solvent: hexane),
2.67 g (62%) of the title compound was obtained as a colorless oil. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 1.82 (2H,
m), 1.99 (1H, t, J = 2.6 Hz), 2.19 (2H, m), 2.71 (2
H, t, J = 7.5 Hz), 6.97 (2H, m), 7.14 (2H, m) mass spectrum (EI) m / z: 162 (M ⁺ ).

Reference Example 5 5- (4-Methoxyphenyl) pent-1-yne In the same manner as in Reference Example 4, 3- (4-methoxyphenyl) -1
-Using iodopropane and sodium acetylide,
The title compound was obtained. Nuclear magnetic resonance spectrum (500MHz, CDCl ₃ ): δ 1.78-1.88
(2H, m), 1.98 (1H, t, J = 2.6 Hz), 2.15-2.22 (2H,
m), 2.67 (2H, t, J = 7.5 Hz), 3.79 (3H, s), 6.83 (2
H, d, J = 8.6 Hz), 7.11 (2H, d, J = 8.6 Hz) Mass spectrum (EI) m / z: 174 (M ⁺ ).

Reference Example 6 5-Phenylpent-1-yne In the same manner as in Reference Example 4, 3-phenyl-1-iodopropane and sodium acetylide were used to obtain the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 1.81-1.89
(2H, m), 1.99 (1H, t, J = 2.8 Hz), 2.21 (2H, dt, J =
2.8, 7.6 Hz), 2.74 (2H, t, J = 7.6 Hz), 7.16-7.23 (3
H, m), 7.26-7.32 (2H, m) mass spectrum (EI) m / z: 144 (M ⁺ ).

Reference Example 7 5-Cyclohexylpent-1-yne In the same manner as in Reference Example 4, using 3-cyclohexyl-1-iodopropane and sodium acetylide, the title compound was obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 0.75-1.38
(13H, m), 1.48-1.59 (2H, m), 1.94 (1H, t, J = 2.8 H
z), 2.16 (2H, dt, J = 2.8, 7.2 Hz) Mass spectrum (EI) m / z: 150 (M ⁺ ).

Reference Example 8 4- (4-fluorophenyloxy) but-1- yne 4-fluorophenol 5.00 g (44.6 mmol), 3-
Butyn-1-ol (3.38 ml, 44.6 mmol) and triphenylphosphine (17.5 g, 66.9 mmol) were dissolved in tetrahydrofuran (100 ml), and azodicarboxylic acid diethyl ester (11.7 g, 66.9 mmol) was added under ice-cooling at room temperature for 18 hours. It was stirred. After the solvent was concentrated under reduced pressure, 200 ml of hexane and 20 ml of ethyl acetate were added, the deposited precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by flash silica gel column chromatography (elution solvent; hexane: ethyl acetate = 1: 0) to obtain the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 2.05 (1H,
t, J = 2.7 Hz), 2.63-2.70 (2H, m), 4.07 (2H, t, J =
7.0 Hz), 6.82-6.90 (2H, m), 6.94-7.02 (2H, m) Mass spectrum (EI) m / z: 164 (M ⁺ ).

Reference Example 9 3- (4-Methylphenyloxy) -1-propyne In the same manner as in Reference Example 8, 4-methylphenol and propargyl alcohol were used to obtain the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 2.29 (3H,
s), 2.50 (1H, t, J = 2.4 Hz), 4.67 (2H, d, J = 2.4 H
z), 6.88 (2H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.4 Hz) Mass spectrum (EI) m / z: 146 (M ⁺ ).

Reference Example 10 3-[(4-methylthio) phenyloxy] -1-propyi
In the same manner as in Reference Example 8, the title compound was obtained using 4- (methylthio) phenol and propargyl alcohol. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 2.45 (3
H, s), 2.52 (1H, t, J = 2.4 Hz), 4.68 (2H, d, J = 2.4)
Hz), 6.93 (2H, d, J = 8.9 Hz), 7.27 (2H, d, J = 8.9 H
z) Mass spectrum (EI) m / z: 178 (M ⁺ ).

Reference Example 11 3- (3-Methoxyphenyloxy) -1-propyne In the same manner as in Reference Example 8, 3-methoxyphenol and propargyl alcohol were used to obtain the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 2.52 (1
H, t, J = 2.4 Hz), 3.79 (3H, s), 4.67 (2H, d, J = 2.4
Hz), 6.53-6.60 (3H, m), 7.16-7.23 (1H, m) Mass spectrum (EI) m / z: 162 (M ⁺ ).

Reference Example 12 3- (3,4-Dimethylphenyloxy) -1-propyi
In the same manner as in Reference Example 8, the title compound was obtained using 3,4-dimethylphenol and propargyl alcohol. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 2.20 (3H,
s), 2.24 (3H, s), 2.49 (1H, t, J = 2.4 Hz), 4.65 (2
H, d, J = 2.4 Hz), 6.72 (1H, dd, J = 2.4, 8.0 Hz), 6.7
8 (1H, d, J = 2.4 Hz), 7.04 (1H, d, J = 8.0 Hz) Mass spectrum (EI) m / z: 160 (M ⁺ ).

Reference Example 13 4- (4-Methylphenyloxy) but-1-yne In the same manner as in Reference Example 8, 4-methylphenol and 3-butyn-1-ol were used to obtain the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 2.03 (1
H, t, J = 2.8 Hz), 2.28 (3H, s), 2.66 (2H, dt, J = 2.
8, 7.2 Hz), 4.07 (2H, t, J = 7.2 Hz), 6.81 (2H, d, J =
8.8 Hz), 7.08 (2H, d, J = 8.8 Hz) Mass spectrum (EI) m / z: 160 (M ⁺ ).

Reference Example 14 4-Cyclohexyloxybut-1- yne Into 950 ml of anhydrous methylene chloride, 32 ml of cyclohexanone was added.
(0.31 mol), 1,3-propanediol 33.5 ml (0.
46 mol), 51.5 ml (0.31 mol) of triethyl orthoformate and 1.44 g (6.18 mmol) of zirconium chloride were added, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Ice cold 1
1.5 L of a normal sodium hydroxide aqueous solution was added, the mixture was extracted with methylene chloride, and the methylene chloride layer was washed with water. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by vacuum distillation and cyclohexanone
26.8 g (55%) of trimethyl ketal was obtained. Zirconium chloride 24.9g suspended in tetrahydrofuran 500ml
(0.11 mole), sodium borohydride 20.5g (0.54
Was added slowly under a nitrogen atmosphere, and the mixture was stirred at room temperature for 20 minutes. A 170 ml solution of tetrahydrofuran containing 16.9 g (0.11 mol) of cyclohexanone trimethyl ketal obtained above was added dropwise thereto under ice cooling under a nitrogen atmosphere, and after completion of the dropwise addition, the mixture was stirred at room temperature overnight. below freezing,
The reaction was terminated by adding 600 ml of ice-cooled 2N hydrochloric acid, and tetrahydrofuran was distilled off under reduced pressure. The remaining aqueous phase was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (elution solvent; hexane: ethyl acetate = 10 :).
1-5: 2) to give 3-cyclohexyloxypropan-1-ol (13.4 g, 78%).

11.5 g (72.9 mmol) of the obtained 3-cyclohexyloxypropan-1-ol was methylene chloride.
Dissolve in 240 ml and under ice cooling, molecular sieve 4A5
8 g and 23.8 g (0.11 mol) of pyridinium chlorochromate were added, and the mixture was stirred under a nitrogen atmosphere for 1 hour and 40 minutes. Diethyl ether was added to the reaction solution, and the mixture was filtered through Celite. The celite was washed with diethyl ether, the filtrates were combined, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (elution solvent; hexane: ethyl acetate = 20: 1 to 10 :).
Crude purification by 1) yielded 8.60 g of crude 3-cyclohexyloxypropionaldehyde.

To 120 ml of methylene chloride containing 36.5 g (0.11 mol) of carbon tetrabromide, 57.7 g of triphenylphosphine
120 ml of methylene chloride containing (0.22 mol) was added dropwise under a nitrogen atmosphere under ice cooling, and after completion of the addition, the mixture was further stirred for 5 minutes.
90 ml of methylene chloride containing 8.60 g of the obtained crude 3-cyclohexyloxypropionaldehyde was added dropwise thereto under a nitrogen atmosphere under ice cooling, and after completion of the dropwise addition, the mixture was stirred for 25 minutes. The reaction solution was diluted with methylene chloride, and the reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (elution solvent; hexane: ethyl acetate = 100: 1 to 33: 1).
Purification was carried out to obtain 12.6 g (55%, 2 steps) of 4-cyclohexyloxy-1,1-dibromobut-1-ene.

The obtained 4-cyclohexyloxy-1,
12.6 g (40.4 mmol) of 1-dibromobut-1-ene was added to 130 ml of tetrahydrofuran under a nitrogen atmosphere,
At 78 ° C., 54 ml (81.0 mmol) of a 1.5N n-butyllithium hexane solution was added dropwise. After completion of the dropping, the mixture was stirred for 1 hour, and then the temperature was slowly raised to room temperature. After stirring at room temperature for 50 minutes, water was added under ice cooling to terminate the reaction. Extracted with diethyl ether,
The diethyl ether layer was washed with saturated saline. The diethyl ether layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (eluting solvent; hexane: ethyl acetate = 100: 1-50:
Purification according to 1) gave 4.35 g (71%) of the title compound. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ): δ 1.13-1.3
6 (5H, m), 1.48-1.58 (1H, m), 1.67-1.81 (2H, m),
1.85-1.95 (2H, m), 1.97 (1H, t, J = 2.8 Hz), 2.45 (2
H, dt, J = 2.8, 7.2 Hz), 3.23-3.32 (1H, m), 3.59 (2
H, t, J = 7.2 Hz) Mass spectrum (EI) m / z: 153 (M + H) ⁺ .

Test Example 1 Suppression of rat HvGR (Host versus Graft Reaction)
Measurement of anti -activity (1) Two strains of rats [Lewis (male, 6 weeks old, Charles River Japan) and WKAH / Hkm (male, 7 weeks old) Japan SLC, Inc.] were used. Five rats (host) per group were used. (2) Induction of HvGR Spleen cells were isolated from the spleens of WKAH / Hkm rats or Lewis rats, and RPMI1640 medium (LIFE TECHNOLOGIES, Rockvill
e MD USA) and suspended at a concentration of 1 × 10 ⁸ cells / ml. WKAH / Hkm rat or Le under the skin of both hind limbs of Lewis rat
100 μl of spleen cell suspension from wis rat (1
x10 ⁷ ) was injected. (3) Administration of compound The compound was suspended in 0.5% Tragant's solution. The suspended compound was administered to the compound-administered group (Lewis rat to which WKAH / Hkm rat spleen cells were injected and the sample was administered) at a rate of 5 ml / kg once a day for 4 consecutive days from the day of spleen cell injection. Orally administered to rats. For the syngeneic group (Lewis rat group injected with Lewis rat spleen cells) and the control group (Lewis rat injected with WKAH / Hkm rat spleen cells and no sample administered), 0.5% tragacanth solution was used instead of the sample. It was orally administered. (4) Method for measuring inhibitory activity against HvGR From the weight of popliteal lymph nodes of each individual, the average popli of the same group
Subtract the teal lymph node weight (“HvGR popliteal lymph node weight”), and calculate the inhibition rate from the “HvGR popliteal lymph node weight” of each individual compound-administered group relative to the control group average “HvGR popliteal lymph node weight” did.
The inhibitory activity of a compound was expressed as an ID50 value (mg / kg) calculated from the dose of the compound and the inhibitory rate using the least squares method.
As a result of this test, the compound of the present invention showed excellent inhibitory activity.

[0573]

[Table 5] Compound HvGR ID50 value (mg / kg) Example 1 0.0843 Example 11 0.0844 Example 40 0.0683 Example 43 0.0730 Example 46 0.0454. ． ． ． ． ． ． ． ． ． ． ． ． ． Comparative compound 1 0.354 In the above table, Comparative Compound 1 is WO94 / 0894.
It is the compound described in Example 29 of Japanese Patent Laid-Open No. 3 publication.

Test Example 2 Measurement of inhibitory activity against development of adjuvant arthritis 1. Preparation of Adjuvant Mycobacterium butyricum killed bacteria in liquid paraffin 2 m
It was suspended at a ratio of g / ml and sonicated to prepare. 2. Preparation of test compound The test compound was suspended or dissolved in 0.5% Tragant's solution. 3. Induction of Adjuvant Arthritis 1. 0.05 ml of the adjuvant prepared in
(Is system) into the footpad of the right hind leg. The number of animals in one group was usually 5. In addition, one group was prepared in which no adjuvant was injected (normal group). 4. Administration of compound 2. The compound prepared in 1. was orally administered at a rate of 5 ml per 1 kg of rat body weight once a day for 21 days from the day of adjuvant injection. In addition, 0.5% tragacanth solution was administered to one group to which adjuvant was administered (control group) and a group to which no adjuvant was injected. 5. Method for calculating the onset suppressing activity of the compound One day after the final administration, the volume of the right hind limb was measured with a footpad measuring device, and the average value of the normal group was subtracted from the value of each individual, and the value was taken as the swelling volume. The inhibition rate was calculated from the swelling volume of each individual administered with the compound with respect to the average swelling volume of the control group. ID50 from the compound dose and the inhibition rate of each (mean of group)
The value was calculated. As a result of this test, the compound of the present invention showed excellent inhibitory activity.

[0575]

[Table 6] Compound ID50 value (mg / kg) Example 1 0.0897 Example 34 0.0470. ． ． ． ． ． ． ． ． ． ． ． ． ． Comparative compound 1 0.166 In the above table, Comparative Compound 1 is WO94 / 0894.
It is the compound described in Example 29 of Japanese Patent Laid-Open No. 3 publication.

[0576]

INDUSTRIAL APPLICABILITY A pharmaceutical composition containing an aminoalcohol derivative having the general formula (I) of the present invention, a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof as an active ingredient has low toxicity and excellent immunity. It has an inhibitory action and is useful as a preventive or therapeutic agent for autoimmune diseases or other immune-related diseases.

Further, the novel optically active amino alcohol compounds (La) and (Lb) of the present invention are useful as intermediates for the production of pharmaceuticals.

As an intermediate for the synthesis of the optically active amino alcohol compounds (La) and (Lb), an optically active 2-substituted-2-amino-1,3-propanediol is used.
Monoester derivative (XLIVa) or (XLIVb)
Is preferred, and such optically active 2-substituted-2-amino-
1,3-Propanediol Monoester derivative (XL
IVa) and (XLIVb) are obtained by using a 2-substituted-2-amino-1,3-propanediol derivative (XLII) as a raw material and using a carboxylic acid vinyl ester derivative (XLIII) in the presence of lipase. By the selective acylation of only one hydroxyl group, it can be produced easily and easily with a high yield.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 29/00 A61P 29/00 101 101 37/02 37/02 C07D 333/22 C07D 333/22 413/06 413/06 (72) Inventor, Futoshi Nara Sankyo, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor, Ryuichi Shimosato 1-2-58, Hiromachi, Shinagawa-ku, Tokyo In-house F-term (reference) 4C023 CA01 DA02 4C063 AA01 BB03 CC92 CC94 DD52 EE01 4C086 AA01 AA02 AA03 BB02 BC69 GA04 GA09 MA01 MA04 NA14 ZA81 ZB07 ZB11 ZB15 ZC35

Claims (68)

[Claims] 1. A compound represented by the general formula (I): [In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or an amino group-protecting group, R ³ represents a hydrogen atom or a hydroxy group-protecting group, and R ⁴ represents a lower alkyl group. , N represents an integer of 1 to 6, X represents an ethylene group, a vinylene group, an ethynylene group, or a formula-D.
A group having —CH ₂ — (wherein D represents a carbonyl group, a group having —CH (OH) —, an oxygen atom, a sulfur atom or a nitrogen atom), an aryl group or a substituent group a. Represents an aryl group substituted with 1 to 3 groups, Y is a single bond, C ₁ -C ₁₀ alkylene group, 1 to 3 substituted with a group selected from the substituent groups a and b. _1- C
₁₀ alkylene groups, C ₁ -C ₁₀ alkylene groups having an oxygen atom or a sulfur atom in the carbon chain or at the chain end, or in a carbon chain substituted with 1 to 3 groups selected from the substituent groups a and b Or a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom at the chain end, and R ⁵ is a group selected from a hydrogen atom, a cycloalkyl group, an aryl group, a heterocyclic group, and the substituent groups a and b. 1 to 3
An optionally substituted cycloalkyl group, an aryl group substituted with 1 to 3 groups selected from the substituent groups a and b, or 1 to 3 substituted groups with a group selected from the substituent groups a and b Represents a heterocyclic group, R ⁶ and R ⁷ are the same or different and represent a hydrogen atom or a group selected from the substituent group a, provided that when R ⁵ is a hydrogen atom, Y is a single bond or a direct bond; Shows a group other than a C ₁ -C ₁₀ alkylene group of the chain, the substituent group a is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a carboxyl group, a lower alkoxycarbonyl group,
Hydroxy group, lower aliphatic acyl group, amino group, mono-
Shows a group consisting of a lower alkylamino group, a di-lower alkylamino group, a lower aliphatic acylamino group, a cyano group and a nitro group, and the substituent group b is a cycloalkyl group, an aryl group, a heterocyclic group or a substituent group a. A cycloalkyl group which is substituted with 1 to 3 groups selected from the group 1 and a group selected from the group a of substituents
A group consisting of an aryl group substituted with 3 to 3 and a heterocyclic group substituted with 1 to 3 with a group selected from the substituent group a is shown. ] The compound which has these, its pharmacologically acceptable salt, its ester, or other derivative (s) as an active ingredient. 2. The compound according to claim 1, which has the formula (I), a pharmacologically acceptable salt thereof, an ester or other derivative thereof, is represented by the formula (Ia): A pharmaceutical composition comprising: 3. The compound according to claim 1, wherein the compound having the formula (I), a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof has the formula (Ib): A pharmaceutical composition comprising: 4. Any one selected from claims 1 to 3.
Wherein R ¹ and R ² are the same or different and are ^{1 to} 3 aralkyloxycarbonyl groups substituted with a hydrogen atom, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group or a group selected from the substituent group a. A pharmaceutical composition. 5. Any one selected from claims 1 to 3.
Paragraph 3, wherein R ¹ and R ² are hydrogen atoms. 6. Any one selected from claims 1 to 5.
Wherein R ³ is a hydrogen atom, a lower alkyl group, a lower aliphatic acyl group, an aromatic acyl group or an aromatic acyl group substituted with 1 to 3 groups selected from the substituent group a. object. 7. Any one selected from claims 1 to 5.
Paragraph ³ , wherein R ³ is a hydrogen atom. 8. Any one selected from claims 1 to 7.
In the paragraph, R ⁴ is a C ₁ -C ₄ alkyl group. 9. Any one selected from claims 1 to 7.
In the paragraph above, R ⁴ is a C ₁ -C ₂ alkyl group. 10. The pharmaceutical composition according to claim 1, wherein R ⁴ is a methyl group. 11. The pharmaceutical composition according to any one of claims 1 to 10, wherein n is 2 or 3. 12. The pharmaceutical composition according to any one of claims 1 to 10, wherein n is 2. 13. The aryl substituted with 1 to 3 groups as defined in any one of claims 1 to 12, wherein X is an ethylene group, an ethynylene group, an aryl group or a group selected from the substituent group a. The underlying pharmaceutical composition. 14. A pharmaceutical composition according to any one of claims 1 to 12, wherein X is an ethylene group. 15. The pharmaceutical composition according to any one of claims 1 to 12, wherein X is an ethynylene group. 16. A any one selected from claims 1 to 12, X is the formula -D-CH ₂ - Pharmaceutical compositions is a group having a. 17. The method according to claim 1, wherein X is a group having the formula —D—CH ₂ — (wherein D is a carbonyl group or the formula —CH (OH) —. Represents a group having
A pharmaceutical composition which is 18. In any one of claims 1 to 17, Y is substituted with 1 to 3 by a C ₁ -C ₁₀ alkylene group or a group selected from the substituent groups a and b. C ₁ -C ₁₀ pharmaceutical composition is an alkylene group. 19. In any one of claims 1 to 17, Y is substituted with 1 to 3 by a C ₁ -C ₆ alkylene group or a group selected from the substituent groups a and b. A pharmaceutical composition having a C ₁ -C ₆ alkylene group. 20. In any one of claims 1 to 17, Y is an ethylene group, a trimethylene group, a tetramethylene group, or a group selected from the substituent groups a and b, 1 to 3
A pharmaceutical composition having an individually substituted ethylene, trimethylene or tetramethylene group. 21. The pharmaceutical composition according to any one of claims 1 to 17, wherein Y is an ethylene group, a trimethylene group or a tetramethylene group. 22. The pharmaceutical composition according to any one of claims 1 to 17, wherein Y is an ethylene group or a trimethylene group. 23. In any one of claims 1 to 17, Y is a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in the carbon chain or at the chain end, or the substituent group a. C having an oxygen atom or a sulfur atom in the carbon chain or at the chain end, which is substituted with 1 to 3 groups selected from b and b
₁ -C ₁₀ pharmaceutical composition is an alkylene group. 24. The pharmaceutical composition according to any one of claims 1 to 17, wherein Y is a C ₁ -C ₁₀ alkylene group having an oxygen atom or a sulfur atom in the carbon chain or at the chain end. 25. In any one of claims 1 to 17, Y is C _1- having an oxygen atom in the carbon chain or at the chain end.
A pharmaceutical composition which is a C ₁₀ alkylene group. 26. In any one of claims 1 to 17, Y is C _1- having an oxygen atom in the carbon chain or at the chain end.
A pharmaceutical composition which is a C ₆ alkylene group. 27. The any one selected from claims 1 to 17, Y _{is, -O-CH 2 -, -} O- (CH 2) 2 -, - O-
A pharmaceutical composition which is a group having (CH ₂ ) ₃ —, —CH ₂ —O—, — (CH ₂ ) ₂ —O— or — (CH ₂ ) ₃ —O—. 28. A any one selected from claims 1 to 17, Y is a pharmaceutical composition is a group having a -CH ₂ -O-. 29. The any one selected from claims 1 to 17, Y is, -O- (CH _{2) 2} - or - (CH ₂₎ a pharmaceutical composition is a group having ₂ -O- . 30. The pharmaceutical composition according to any one of claims 1 to 29, wherein R ⁵ is a hydrogen atom. 31. In any one of claims 1 to 29, R ⁵ is substituted with 1 to 3 by a group selected from a cycloalkyl group, a heterocyclic group, and substituent groups a and b. A pharmaceutical composition which is a heterocyclic group substituted with 1 to 3 cycloalkyl groups or groups selected from the substituent groups a and b. 32. The cycloalkyl group as defined in any one of claims 1 to 29, wherein R ⁵ is substituted with 1 to 3 cycloalkyl groups or groups selected from the substituent groups a and b. A pharmaceutical composition which is 33. The pharmaceutical composition according to any one of claims 1 to 29, wherein R ⁵ is a cycloalkyl group. 34. The pharmaceutical composition according to any one of claims 1 to 29, wherein R ⁵ is a cyclohexyl group. 35. In any one of claims 1 to 29, R ⁵ is an aryl group or an aryl group substituted by 1 to 3 groups selected from the substituent groups a and b. Pharmaceutical composition. 36. In any one of claims 1 to 29, R ⁵ is an aryl group or an aryl group having 1 to 3 substituents (wherein the substituent is a halogen atom, a lower alkyl group or a halogeno group). A lower alkyl group, a lower alkoxy group, a lower alkylthio group and a lower aliphatic acyl group). 37. In any one of claims 1 to 29, R ⁵ is an aryl group or an aryl group having 1 to 3 substituents (wherein the substituent is a halogen atom, a lower alkyl group or a halogeno group). Which is a group selected from the group consisting of a lower alkyl group, a lower alkoxy group and a lower aliphatic acyl group). 38. In any one of claims 1 to 29, R ⁵ is a phenyl group or a 1 to 3 substituted phenyl group (wherein the substituent is a halogen atom, a lower alkyl group or a halogeno group). Which is a group selected from the group consisting of a lower alkyl group, a lower alkoxy group and a lower aliphatic acyl group). 39. In any one of claims 1 to 29, R ⁵ is a phenyl group or a phenyl group substituted with 1 to 3 (wherein the substituent is a fluorine atom, a chlorine atom, methyl, Which is a group selected from the group consisting of trifluoromethyl, methoxy and acetyl groups.). 40. In any one of claims 1 to 29, R ⁵ is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-methylphenyl, 4-methylphenyl,
3,4-dimethylphenyl, 3,5-dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 3-methoxyphenyl , 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,
A pharmaceutical composition having a 4,5-trimethoxyphenyl, 3-acetylphenyl or 4-acetylphenyl group. 41. In any one of claims 1 to 40, R ⁶ and R ⁷ are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a halogeno lower alkyl group or a lower alkoxy group. Or a pharmaceutical composition having a lower alkylthio group. 42. A pharmaceutical composition according to any one of claims 1 to 40, wherein R ⁶ and R ⁷ are hydrogen atoms. 43. A pharmaceutical composition according to claim 1, which comprises, as an active ingredient, any one compound selected from the following, a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof. 2-amino-2-methyl-4- [5- (6-cyclohexylhexyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpentyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl -4- [5- (6-cyclohexylhex-1-
(Inyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpent-1-)
(Inyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol, 2 -Amino-2-methyl-4- [5- (6-cyclohexylhexanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpentanoyl) ) Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2 -Ethyl-4- [5- (6-cyclohexylhexyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpentyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl -4- [5- (6-cyclohexylhex-1-
(Inyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpent-1-
(Inyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol, 2 -Amino-2-ethyl-4- [5- (6-cyclohexylhexanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpentanoyl) ) Thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2 -Methyl-4- [5- (6-phenylhexyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl ] Butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenylbutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5 -(6-Phenylhex-1-ynyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenylbut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino- 2-Methyl-4- [5- (6-phenylhexanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophene- 2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenylbutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl- 4- [5- (5-cyclohexyloxypent-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexyloxybuto
-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexyloxypropynyl) thiophen-2-yl] butan-1-ol, 2 -Amino-2-methyl-4- [5- (5-cyclohexyloxypentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexyloxybutyl) ) Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexyloxypropyl) thiophen-2-yl] butan-1-ol, 2-amino-2 -Methyl-4- [5- (5-cyclohexyloxypentanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexyloxybutanoyl) thiophene -2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexyloxypropanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2- Methyl-4- [5- (5-phenoxy Pento-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenoxybut-1-ynyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-phenoxypropynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl -4- [5- (5-phenoxypentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenoxybutyl) thiophen-2-yl] butane -1-ol, 2-amino-2-methyl-4- [5- (3-phenoxypropyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- ( 5-phenoxypentanoyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenoxybutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2- Methyl-4- [5- (3-phenoxypropanoyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-benzyloxyphenyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylmethoxyphenyl) thiophen-2-yl] butan-1-ol, 2-amino-2- Methyl-4- [5- (4-cyclohexylethoxyphenyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropynyl) thiophene-2- Ill] butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropyl) thiophen-2-yl] butan-1-ol and 2-amino-2-methyl-4- [5- (3-Cyclohexylmethoxypropanoyl) thiophen-2-yl] butan-1-ol. 44. A pharmaceutical composition according to claim 1, which comprises, as an active ingredient, any one compound selected from the following, a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof. 2-Amino-2-methyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpentyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl -4- [5- (4-cyclohexyloxybutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [4- (4-fluorophenoxy) butyl] thiophene -2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [4- (4-methoxyphenoxy) butyl] thiophen-2-yl] butan-1-ol, 2-amino -2-Methyl-4- [5- (4-benzyloxybutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylbut-1- (Inyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenylbut-1-ynyl) thiophen-2-yl] butan-1-ol, 2- Amino-2-methyl-4- [5- (5-cyclohexylpent-1-
(Inyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [5- (4-fluorophenyl) pent-1-ynyl] thiophen-2-yl] butan-1- All, 2-amino-2-methyl-4- [5- [5- (4-methoxyphenyl) pent-1-ynyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl- 4- [5- [3- (4-methylcyclohexyloxy) propynyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [3- (4-methylphenoxy ) Propinyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [3- (4-ethylphenoxy) propynyl] thiophen-2-yl] butan-1-ol , 2-amino-2-methyl-4- [5- [3- (4-methylthiophenoxy)
Propinyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexyloxybut
-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [4- (4-fluorophenoxy) but-1-ynyl] thiophen-2-yl ] Butan-1-ol, 2-amino-2-methyl-4- [5- [4- (4-methylphenoxy) but
-1-ynyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropynyl) thiophen-2-yl] butan-1-ol, 2 -Amino-2-methyl-4- [5- (4-phenylmethoxybut-1-
(Inyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol, 2-amino- 2-Methyl-4- [5- (4-phenylbutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpentanoyl) thiophene- 2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl- 4- [5- [5- (4-fluorophenyl) pentanoyl] thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpentyl)
Thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpent-1-
(Inyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol, 2-amino- 2-Methyl-4- [5- [3- (4-chlorophenoxy) propynyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [3- (3 -Methylphenoxy) propynyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [3- (3,4-dimethylphenoxy)
Propinyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [3- (3-methoxyphenoxy) propynyl] thiophen-2-yl] butan-1-ol, 2-Amino-2-methyl-4- [5- [3- (3,4-dimethoxyphenoxy) propynyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5 -[3- (3,5-Dimethoxyphenoxy) propynyl] thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- [3- (3-acetylphenoxy) propynyl] Thiophen-2-yl] butan-1-ol and 2-amino-2-methyl-4- [5- [3- (4-acetylphenoxy) propynyl] thiophen-2-yl] butan-1-ol. 45. The pharmaceutical composition according to any one of claims 1 to 44, which is used as an immunity suppressing agent. 46. A pharmaceutical composition according to any one of claims 1 to 44, for preventing or treating an autoimmune disease. 47. The pharmaceutical composition according to any one of claims 1 to 44, for preventing or treating rheumatoid arthritis. [48] The pharmaceutical composition according to any one of [1] to [44], which is for suppressing rejection in various organ transplants. 49. A general formula (La) or (Lb) [Chemical 4] [In the formula, R¹And R²Are the same or different and are hydrogen atom or amino
Represents a protecting group for the group, R^3aIs a hydrogen atom or a hydroxy-protecting group,
Alternatively, R¹Is a hydrogen atom, and R²And R^3aBut together
Represents a group of formula (-(C = O)-), R^4aIs C₁-C₂₀Alkyl group, heteroatom intervening
C₂-C₂₀Alkyl group, aryl group or aromatic hetero group
C substituted with a ring group₁-C₂₀Alkyl group, C₂-C ₂₀Al
Quinyl group, C intervening hetero atom₃-C₂₀Alkynyl
C substituted with a group, an aryl group or an aromatic heterocyclic group
₂-C₂₀Alkynyl group, C₂-C₂₀Alkenyl group, hetero
C with an atom₃-C₂₀Alkenyl group, aryl group
C substituted with an aromatic heterocyclic group₂-C₂₀Archeni
Substituted with an aryl group, an aryl group or an aromatic heterocyclic group
C with a heteroatom₂-C₂₀Alkyl group or
Represents a chloroalkyl group, m represents an integer of 0 to 4, Ar is an aryl group, an aromatic heterocyclic group, or a substituent group a.
Aryl group substituted with 1 to 5 groups selected, Substitution
Aromatic substituted with 1 to 5 groups selected from the group a
Indicates a heterocyclic group. However, when Ar is an aryl group,
R¹Does not represent a hydrogen atom and R²And / or R^3aIs hydrogen
Show no children. ] The compound represented by. <Substituent group a> halogen atom, lower alkyl group, halogen
Lower alkyl group, lower alkoxy group, lower alkyl group
O group, carboxyl group, lower alkoxycarbonyl group,
Hydroxy group, lower aliphatic acyl group, amino group, mono-
Lower alkylamino group, di-lower alkylamino group, low
-Grade aliphatic acylamino groups, cyano groups and nitro groups. 50. The compound according to claim 49, having the general formula (La). 51. The method according to claim 49 or 50, wherein R ¹ is
A compound that is a hydrogen atom. 52. In any one of claims 49 to 51, R ² and R ^3a together are of the formula (-(C = O)-)
A compound that is a group. 53. The compound according to any one of claims 49 to 51, wherein R ^3a is a hydrogen atom. 54. In any one of claims 49 to 53, R ^4a represents a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group with a heteroatom interposed, an aryl group or an aromatic group. A C ₁ -C ₁₀ alkyl group substituted with a heterocyclic group, a C ₂ -C ₁₀ alkynyl group, a C ₃ -C ₁₀ alkynyl group with a heteroatom intervening,
C ₂ -C ₁₀ substituted with an aryl group or an aromatic heterocyclic group
Alkynyl group, C ₂ -C ₁₀ alkenyl group, C ₃ -C ₁₀ alkenyl group which heteroatom is interposed, C ₂ -C ₁₀ alkenyl group substituted with an aryl group or an aromatic heterocyclic group, an aryl group or an aromatic heterocyclic C ₂ -C ₁₀ alkyl group hetero atom substituted with a cyclic group is interposed, or the compound is a C ₅ -C ₁₀ cycloalkyl group. 55. In any one of claims 49 to 53, R ^4a is a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group with an intervening heteroatom, an aryl group or an aromatic group. heterocycle C ₁ -C ₁₀ alkyl group substituted with a group, C ₂ -C ₁₀ alkynyl group, C ₂ -C ₁₀ alkenyl group, or a compound which is a C ₅ -C ₁₀ cycloalkyl group. 56. The compound according to any one of claims 49 to 53, wherein R ^4a is a C ₁ -C ₁₀ alkyl group. 57. The compound according to any one of claims 49 to 53, wherein R ^4a is a C ₁ -C ₆ alkyl group. 58. The compound according to any one of claims 49 to 53, wherein R ^4a is a methyl or ethyl group. 59. In any one of claims 49 to 58, Ar is substituted with 1 to 4 by a group selected from phenyl, furyl, thienyl, benzothienyl group or the above substituent group a. A compound which is a phenyl, furyl, thienyl or benzothienyl group. 60. The compound according to any one of claims 49 to 58, wherein Ar is a thienyl group or a thienyl group substituted with 1 to 4 groups selected from the substituent group a. 61. In any one of claims 49 through 58, Ar is a benzothienyl group or a benzothienyl group substituted with 1 to 4 groups selected from the above substituent group a. Compound. 62. The compound according to any one of claims 49 to 61, wherein m is 0. 63. The substituent group a according to any one of claims 49 to 62, wherein the substituent group a is a halogen atom, a hydroxyl group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a carboxy group or a lower aliphatic group. A compound which is an acyl group, a lower aliphatic acylamino group, an amino group, a cyano group or a nitro group. 64. A compound represented by the general formula (XLII): [Chemical 5] [In the formula, R¹And R²Are the same or different and are hydrogen atom or amino
Represents a protecting group for the group, R^4aIs C₁-C₂₀Alkyl group, heteroatom intervening
C₂-C₂₀Alkyl group, aryl group or aromatic hetero group
C substituted with a ring group₁-C₂₀Alkyl group, C₂-C ₂₀Al
Quinyl group, C intervening hetero atom₃-C₂₀Alkynyl
C substituted with a group, an aryl group or an aromatic heterocyclic group
₂-C₂₀Alkynyl group, C₂-C₂₀Alkenyl group, hetero
C with an atom₃-C₂₀Alkenyl group, aryl group
C substituted with an aromatic heterocyclic group₂-C₂₀Archeni
Substituted with an aryl group, an aryl group or an aromatic heterocyclic group
C with a heteroatom₂-C₂₀Alkyl group or
A chloroalkyl group is shown. ] 2-Substitution-2-a represented by
Hydro of one of the mino-1,3-propanediol derivatives
Only the xy group was treated with the formula (XLIII) in the presence of lipase. R¹¹COOCH = CH₂      (XLIII) Carboxylic acid vinyl ester derivative having¹¹
Is R^4aThe same group as in the definition of is shown. ) Is used
Of the general formula (X
2-substituted-, represented by LIVa) or (XLIVb)
2-amino-1,3-propanediol monoester
Derivative [Chemical 6] [In the formula, R¹, R², R^4aAnd R¹¹Is synonymous with the above
You ] Manufacturing method. 65. The process according to claim 64, wherein ^one of R ¹ and R ² is a hydrogen atom and the other is a protecting group for an amino group. 66. The carbon atom according to claim 64 or 65, wherein R ^4a is substituted with a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group with an intervening hetero atom, an aryl group or an aromatic heterocyclic group. ₁ -C ₁₀ alkyl group, C ₂ -C ₁₀ alkynyl group, C ₃ -C ₁₀ alkynyl group heteroatoms are interposed,
C ₂ -C ₁₀ substituted with an aryl group or an aromatic heterocyclic group
Alkynyl group, C ₂ -C ₁₀ alkenyl group, C ₃ -C ₁₀ alkenyl group which heteroatom is interposed, C ₂ -C ₁₀ alkenyl group substituted with an aryl group or an aromatic heterocyclic group, an aryl group or an aromatic heterocyclic C ₂ -C ₁₀ alkyl group hetero atom substituted with a cyclic group is interposed, or method is C ₅ -C ₁₀ cycloalkyl group. 67. The C according to claim 64 or 65, wherein R ^4a is substituted with a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group with an intervening hetero atom, an aryl group or an aromatic heterocyclic group. ₁ -C ₁₀ alkyl group, C ₂ -C ₁₀ alkynyl group, C ₂ -C ₁₀ alkenyl group, or a method is C ₅ -C ₁₀ cycloalkyl group. In 68. any one selected from claims 64 to 67, R ¹¹ is, C ₁ -C ₂₀ alkyl group, or, C ₁ -C ₂₀ substituted with an aryl or heteroaryl group A manufacturing method which is an alkyl group.