JP6699011B2 - Lysophosphatidylserine derivatives containing fatty acid surrogates - Google Patents

Description

Detailed Description of the Invention

  The present invention relates to a lysophosphatidylserine derivative containing a fatty acid surrogate and a salt thereof, and a fatty acid surrogate. More specifically, it relates to a lysophosphatidylserine derivative having a lysophosphatidylserine receptor function-regulating activity and salts thereof, and a fatty acid surrogate that can be used as a synthetic intermediate for these compounds. The present invention also relates to a pharmaceutical composition or a lysophosphatidylserine receptor function modulator, which comprises a lysophosphatidylserine derivative and a salt thereof.

Lysophospholipid is a general term for phospholipids having one acyl group. Lysophospholipids have lower hydrophobicity than diacylphospholipids constituting cell membranes, and have the property that they can be easily released from cell membranes. It has been clarified that some lysophospholipids function as signaling molecules between cells or between membranes and have an important role in the body, and conventionally, when inflammatory reactions such as tissue damage occur, It is known that phospholipids in biological membranes are hydrolyzed to produce lysophospholipids (Patent Document 1). It is known that lysophosphatidylserine (LysoPS), which is a kind of lysophospholipid, is involved in acute inflammation caused by degranulation of mast cells (Non-patent documents 1 and 2). As LysoPS receptor, a G-protein coupled receptor GPR34, P2Y10, A630033H20Rik, and GPR174 has been identified (Non-Patent Document 3), of which, GPR34, P2Y10, and GPR174 is a LPS _1, LPS _2, and LPS ₃ It is called (Non-Patent Document 4). Among them, it has been reported that LPS ₁ is involved in signal transduction that induces or enhances degranulation reaction of mast cells and can be a target for treatment of allergic disease and chronic inflammatory disease (Patent Documents 1 and 2). ). It is also known that a specific lysophosphatidylserine derivative (lysophosphatidylthreonine) strongly promotes the degranulation reaction of mast cells (Patent Documents 3 and 4).

  In addition, it has been reported that a screening method for a compound useful as an autoimmune therapeutic agent and lysophosphatidylserine and its derivatives were found by the screening method (Patent Document 5). Autoimmune disease is a general term for diseases in which the immune system, which is originally a defense mechanism against foreign substances, excessively reacts and attacks the normal cells and tissues of oneself to cause symptoms. Systemic autoimmune diseases that affect the entire body and organ-specific diseases that affect only specific organs are roughly classified into two types. In general, autoimmune diseases often become chronic diseases and intractable diseases, and some of them are designated as research target diseases of the Ministry of Health, Labor and Welfare. Many studies have been carried out on a method for treating an autoimmune disease, for example, a method for treating chronic inflammation caused by an autoimmune disease using a cytokine-specific antibody involved in inflammation (Patent Document 6), and pathogenic autologous disease. A method for treating diseases by neutralizing antibodies (Patent Document 7) and the like have been reported. However, the cause of autoimmune diseases is often unknown, and effective treatment methods have not yet been established for many autoimmune diseases. For autoimmune diseases, drugs that suppress the immune system and anti-inflammatory drugs (steroids or nonsteroidal drugs) that reduce inflammation are used as first-line agents.

JP-A-2007-267601 WO2006/088246 JP 2007-284402A JP, 2010-184867, A WO2012/157746 Special table 2010-502183 Special table 2009-505640

Nature Volume 279, pp. 250-252 (1979) J.C.FEBS Lett. 105, 58-62 (1979) Journal of Health Science Vol. 57, No. 2, pp. 115-128 (2011) Nature Methods, Vol. 9, No. 10, pp. 1021-1029 (2012)

  An object of the present invention is to provide a lysophosphatidylserine derivative or a salt thereof, and a fatty acid surrogate that can be used as a synthetic intermediate for these compounds. Another object of the present invention is to provide a pharmaceutical composition or a lysophosphatidylserine receptor function regulator, which comprises the compound or a salt thereof.

  The present inventors have conducted extensive studies to achieve the above-mentioned object, and have found a compound having a GPR34, P2Y10 and/or GPR174 agonist activity or a salt thereof, and a compound having a lysophosphatidylserine receptor agonist activity or The present invention relating to the salt was completed. In addition, when an alternative structure of the fatty acid structure contained in lysophosphatidylserine and the like was intensively searched, it was found that replacing a part of the chain fatty chain structure with an aromatic ring structure increases the receptor agonist activity, and it is related to the fatty acid surrogate. The present invention has been completed.

That is, the present invention relates to the following compounds, intermediates (fatty acid surrogates), pharmaceutical compositions, and lysophosphatidylserine receptor function regulators.
Formula (I):

[In the formula:
R ¹ is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl, hydroxy C _1-6 alkyl, C _7-14 Aralkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aryloxy, 5-10 membered Selected from heteroaryloxy, cyano, amino, nitro, trifluoromethyl, halogen atom, and hydroxy,
R ² and R ³ are independently selected from C _1-6 alkyl, C _1-6 alkoxy, and halogen atoms,
p is 0 to 5,
q and r are independently 0 to 4,
l and m are independently 0-3;
n is 0-5;
Z ¹ and Z ² are, when m is 0 or 1, one is an oxygen atom and the other is a direct bond, or both are direct bonds, and when m is 2 or 3, Z ¹ and Z ^{2 are} Are independently selected from the group consisting of oxygen atom and direct bond;
Z ³ is selected from the group consisting of an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO ₂ —, difluoromethylene, and a direct bond, wherein R ⁹ is a hydrogen atom or C _{1-. 6} alkyl;
R ⁴ is a hydrogen atom, C _1-6 alkyl, C _7-14 aralkyl, or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is a hydrogen atom or C _1-6 alkyl;
R ⁶ and R ⁷ are independently a hydrogen atom, C _1-6 alkyl, C _7-14 aralkyl, formyl, C _1-6 alkylcarbonyl, C _6-10 arylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkoxy selected from the group consisting of C _1-6 alkyl, and C _7-14 aralkyloxycarbonyl;
R ⁸ is a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, or C _7-14 aralkyl;
X-A-Y is

One group selected from the group consisting of
Wherein R ¹⁰ and R ¹¹ are independently hydrogen atom, halogen atom, C _1-6 alkyl optionally substituted by one or more R ¹² , hydroxy, or C _1-6 alkoxy, R ¹² is derived from hydroxy, C _1-6 alkoxy, C _3-10 cycloalkyloxy, 5-10 membered heterocyclyloxy, C _7-14 aralkyloxy, C _6-10 aryloxy, and 5-10 membered heteroaryloxy. Selected, s is 1-5, X and Y are independently CH ₂ or a direct bond;
B represents an oxygen atom or -NR ¹³ - and is, where, R ¹³ is a hydrogen atom or C _1-6 alkyl;
Any one of Q ¹ , Q ² and Q ³ is a carbon atom or a nitrogen atom, and the remaining two are carbon atoms]
Or a salt thereof.
(2) Formula (II):

[In the formula:
R ¹ is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl, hydroxy C _1-6 alkyl, C _7-14 Aralkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aryloxy, 5-10 membered Selected from heteroaryloxy, cyano, amino, nitro, trifluoromethyl, halogen atom, and hydroxy,
R ³ is independently selected from C _1-6 alkyl, C _1-6 alkoxy, and halogen atoms,
p is 0 to 5,
r is 0 to 4,
m is 3 to 15;
n is 0-5;
Z ¹ and Z ² are independently selected from the group consisting of an oxygen atom and a direct bond;
R ⁴ is a hydrogen atom, C _1-6 alkyl, C _7-14 aralkyl, or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is a hydrogen atom or C _1-6 alkyl;
R ⁶ and R ⁷ are independently a hydrogen atom, C _1-6 alkyl, C _7-14 aralkyl, formyl, C _1-6 alkylcarbonyl, C _6-10 arylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkoxy selected from the group consisting of C _1-6 alkyl, and C _7-14 aralkyloxycarbonyl;
R ⁸ is a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, or C _7-14 aralkyl;
X-A-Y is

One group selected from the group consisting of
Wherein R ¹⁰ and R ¹¹ are independently hydrogen atom, halogen atom, C _1-6 alkyl optionally substituted by one or more R ¹² , hydroxy, or C _1-6 alkoxy, R ¹² is derived from hydroxy, C _1-6 alkoxy, C _3-10 cycloalkyloxy, 5-10 membered heterocyclyloxy, C _7-14 aralkyloxy, C _6-10 aryloxy, and 5-10 membered heteroaryloxy. Selected, s is 1-5, X and Y are independently CH ₂ or a direct bond;
B represents an oxygen atom or -NR ¹³ - and is, where, R ¹³ is a hydrogen atom or C _1-6 alkyl;
Any one of Q ¹ , Q ² and Q ³ is a carbon atom or a nitrogen atom, and the remaining two are carbon atoms]
Or a salt thereof.
(3) Formula (III):

[In the formula:
R ¹ is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl, hydroxy C _1-6 alkyl, C _7-14 Aralkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aryloxy, 5-10 membered Selected from heteroaryloxy, cyano, amino, nitro, trifluoromethyl, halogen atom, and hydroxy;
R ³ is independently selected from C _1-6 alkyl, C _1-6 alkoxy, and halogen atoms;
p and r are independently 0-4;
m is independently 0 to 3;
n is 0-5;
Z ¹ and Z ² are, when m is 0 or 1, one is an oxygen atom and the other is a direct bond, or both are direct bonds, and when m is 2 or 3, Z ¹ and Z ^{2 are} Are independently selected from the group consisting of oxygen atom and direct bond;
Z ³ is selected from the group consisting of an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO ₂ —, difluoromethylene, and a direct bond, wherein R ⁹ is a hydrogen atom or C _{1-. 6} alkyl;
R ⁴ is a hydrogen atom, C _1-6 alkyl, C _7-14 aralkyl, or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is a hydrogen atom or C _1-6 alkyl;
R ⁶ and R ⁷ are independently a hydrogen atom, C _1-6 alkyl, C _7-14 aralkyl, formyl, C _1-6 alkylcarbonyl, C _6-10 arylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkoxy selected from the group consisting of C _1-6 alkyl, and C _7-14 aralkyloxycarbonyl;
R ⁸ is a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, or C _7-14 aralkyl;
X-A-Y is

One group selected from the group consisting of
Wherein R ¹⁰ and R ¹¹ are independently hydrogen atom, halogen atom, C _1-6 alkyl optionally substituted by one or more R ¹² , hydroxy, or C _1-6 alkoxy, R ¹² is derived from hydroxy, C _1-6 alkoxy, C _3-10 cycloalkyloxy, 5-10 membered heterocyclyloxy, C _7-14 aralkyloxy, C _6-10 aryloxy, and 5-10 membered heteroaryloxy. Selected, s is 1-5, X and Y are independently CH ₂ or a direct bond;
B represents an oxygen atom or -NR ¹³ - and is, where, R ¹³ is a hydrogen atom or C _1-6 alkyl;
Any one of Q ¹ , Q ² and Q ³ is a carbon atom or a nitrogen atom, and the remaining two are carbon atoms;
R ¹⁵ is selected from C _3-15 alkyl, C _3-10 cycloalkyl, and 5-10 membered heterocyclyl]
Or a salt thereof.
(4) The compound according to any one of (1) to (3), wherein p is 1 to 3, or a salt thereof.
(5) (1) to (4), wherein R ¹ is independently selected from C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, C _6-10 aryloxy, and halogen atom. 7.) The compound or salt thereof according to any of 1.
(6) Z ³ (CH ₂ ) ₁ is selected from the group consisting of an oxygen atom, —NH—, —CH ₂ —, —OCH ₂ —, and a direct bond, (1), (4), (5 7.) The compound or salt thereof according to any of 1.
(7) The compound according to any one of (1) to (6), wherein R ⁵ is hydrogen atom or methyl, or a salt thereof.
(8) R ⁴ is a hydrogen atom;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ is a hydrogen atom;
The compound according to any one of (1) to (7), or a salt thereof.
(9) X-A-Y is

One group selected from the group consisting of
X and Y are independently CH ₂ or a direct bond;
The compound according to any one of (1) to (8), or a salt thereof.
(10) Formula (IV):

[In the formula:
R ¹ is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl, hydroxy C _1-6 alkyl, C _7-14 Aralkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, cyano, amino, nitro, trifluoromethyl, halogen Selected from an atom and hydroxy,
R ² and R ³ are independently selected from C _1-6 alkyl, C _1-6 alkoxy, and halogen atoms,
p is 0 to 5,
q and r are independently 0 to 4,
l and m are independently 0-3;
n is 0-5;
Z ¹ and Z ² are, when m is 0 or 1, one of them is an oxygen atom and the other is a direct bond, or both are direct bonds, and Z ¹ and Z ² are independently an oxygen atom. And selected from the group consisting of direct binding;
Z ³ is selected from the group consisting of an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO ₂ —, difluoromethylene, and a direct bond, wherein R ⁹ is a hydrogen atom or C _{1-. 6} alkyl;
Any one of Q ¹ , Q ² and Q ³ is a carbon atom or a nitrogen atom, and the remaining two are carbon atoms]
Or a salt thereof.
(11) A pharmaceutical composition comprising the compound or salt thereof according to any one of (1) to (9) for treating an autoimmune disease.
(12) Rhizophosphatidyl which comprises the compound or salt thereof according to any one of (1) to (9) and acts on any one or more lysophosphatidylserine receptors selected from GPR34, P2Y10 and GPR174. Serine receptor function regulator.
(13) The lysophosphatidylserine receptor function regulator according to (12), which has a lysophosphatidylserine receptor agonist activity.
Formula (Ia):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Y, p, q, r, l, m, n, Z ¹ , Z ² , And Z ³ are as defined in (1) above, n is preferably 1-3, more preferably 2, m is preferably 0-3, more preferably 1, and l is , Preferably 0 to 3, more preferably 0, Z ¹ (CH ₂ ) _m Z ² is preferably —OCH ₂ — or —CH ₂ O—, and Z ³ (CH ₂ ) ₁ is preferably Is selected from the group consisting of an oxygen atom, —NH—, —CH ₂ —, —OCH ₂ —, and a direct bond]
The compound according to (1), or a salt thereof, represented by:
Expression (Ib):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , p, q, r, l, m, n, Z ¹ , Z ² , and Z ³ is as defined in (1) above, n is preferably 1 to 3, more preferably 2, m is preferably 0 to 3, more preferably 1, and l is It is preferably 0 to 3, more preferably 0, Z ¹ (CH ₂ ) _m Z ² is preferably —OCH ₂ — or —CH ₂ O—, and Z ³ (CH ₂ ) ₁ is preferably , An oxygen atom, —NH—, —CH ₂ —, —OCH ₂ —, and a direct bond, and R ¹⁰ is preferably C _1-6 optionally substituted by one or more R ¹² . Alkyl, R ¹² is preferably hydroxy, C _1-6 alkoxy, C _3-10 cycloalkyloxy, 5-10 membered heterocyclyloxy, C _7-14 aralkyloxy, C _6-10 aryloxy, and 5 Selected from 10-membered heteroaryloxy]
The compound according to (1), or a salt thereof, represented by:
(16) Formula (Ic):

In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹¹ , p, q, r, l, m, n, Z ¹ , Z ² , and Z ³ is as defined in (1) above, n is preferably 1-3, more preferably 2, m is preferably 0-3, more preferably 1, l is preferably Is 0 to 3, more preferably 0, Z ¹ (CH ₂ ) _m Z ² is preferably —OCH ₂ — or —CH ₂ O—, and Z ³ (CH ₂ ) ₁ is preferably Selected from the group consisting of an oxygen atom, —NH—, —CH ₂ —, —OCH ₂ —, and a direct bond, R ¹¹ is preferably hydroxy or C _1-6 alkoxy]
The compound according to (1), or a salt thereof, represented by:
Formula (17):

In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , p, q, r, l, m, n, Z ¹ , Z ² , and Z ³ are As defined in the above (1), n is preferably 1 to 3, more preferably 2, m is preferably 0 to 3, more preferably 1, l is preferably 0 to 3, more is preferably _{^{0, Z 1 (CH 2)}} m Z 2 is preferably -OCH ₂ - or -CH ₂ is O-, the Z ³ (CH _{2) l,} preferably, an oxygen atom, Selected from the group consisting of —NH—, —CH ₂ —, —OCH ₂ —, and direct bond]
The compound according to (1), or a salt thereof, represented by:
(18) Formula (IIa):

In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Y, n, and m are as defined in the above (2), and n is preferably 1 to 3, more preferably Is 2 and m is preferably 3 to 15, more preferably 3 to 10, still more preferably 3 to 8 and particularly preferably 4 to 6].
The compound according to (2), or a salt thereof, represented by:
(19) Formula (IIb):

In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , n, and m are as defined in the above (2), and n is preferably 1 to 3, and more preferably 2, m is preferably 3 to 15, more preferably 3 to 10, even more preferably 3 to 8, particularly preferably 4 to 6, and R ¹⁰ is preferably substituted by one or more R ¹² . a also C _1-6 alkyl optionally, R ¹² is a hydroxyl, C _1-6 alkoxy, C _3-10 cycloalkyloxy, 5-10 membered heterocyclyloxy, C _{7 - 14} aralkyloxy, C _{6- 10} aryloxy and 5-10 membered heteroaryloxy, n is preferably 1 to 3, more preferably 2, m is preferably 3 to 10, more preferably 3 to 8, and further preferably Is 4-6]
The compound according to (2), or a salt thereof, represented by:
(20) Formula (IIc):

In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹¹ , n, and m are as defined in the above (2), and n is preferably 1 to 3, and more preferably 2, m is preferably 3 to 15, more preferably 3 to 10, still more preferably 3 to 8 and particularly preferably 4 to 6, and R ¹¹ is preferably hydroxy or C _1-6 alkoxy. Is]
The compound according to (2), or a salt thereof, represented by:
(21) Formula (IId):

In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , n, and m are as defined in the above (2), and n is preferably 1 to 3, more preferably 2. , M is preferably 3 to 15, more preferably 3 to 10, still more preferably 3 to 8, and particularly preferably 4 to 6].
The compound according to (2), or a salt thereof, represented by:
(22) Formula (IIIa):

In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Y, n, and m are as defined in the above (3), and n is preferably 1 to 3, more preferably Is 2, m is preferably 0 to 3, more preferably 1, R ¹⁵ is preferably C _3-10 alkyl, more preferably C _3-8 alkyl, and even more preferably C _4-6 alkyl. Is]
The compound according to (3), or a salt thereof, represented by:
(23) Formula (IIIb):

In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , n, and m are as defined in the above (3), and n is preferably 1 to 3, more preferably 2, m is preferably 0 to 3, more preferably 1, R ¹⁵ is preferably C _3-10 alkyl, more preferably C _3-8 alkyl, even more preferably C _4-6 alkyl. And R ¹⁰ is preferably C _1-6 alkyl optionally substituted by one or more R ¹² , wherein R ¹² is hydroxy, C _1-6 alkoxy, C _3-10 cycloalkyloxy, 5 10-membered heterocyclyloxy, C _7-14 aralkyloxy, C _6-10 aryloxy, and 5-10 membered heteroaryloxy]
The compound according to (3), or a salt thereof, represented by:
(24) Formula (IIIc):

In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹¹ , n, and m are as defined in the above (3), and n is preferably 1 to 3, and more preferably 2, m is preferably 0 to 3, more preferably 1, R ¹⁵ is preferably C _3-10 alkyl, more preferably C _3-8 alkyl, even more preferably C _4-6 alkyl. And R ¹¹ is preferably hydroxy, or C _1-6 alkoxy]
The compound according to (3), or a salt thereof, represented by:
(25) Formula (IIId):

In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , n, and m are as defined in the above (3), and n is preferably 1 to 3, more preferably 2. , M is preferably 0 to 3, more preferably 1, and R ¹⁵ is preferably C _3-10 alkyl, more preferably C _3-8 alkyl, still more preferably C _4-6 alkyl].
The compound according to (3), or a salt thereof, represented by:
(26) O-(hydroxy(3-((3-(2-((3-(o-tolyloxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-(hydroxy(3-((3-(2-((3-(m-tolyloxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-(hydroxy(3-((3-(2-((3-(p-tolyloxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-((3-((3-(2-((3-(3-chlorolophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine;
O-((3-((3-(2-((3-(4-chlorolophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine;
O-((3-((3-(2-((3-(3,4-dichlorophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine;
O-((3-((3-(2-((3-(4-bromolophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine;
O-((3-((3-(2-((3-(4-(tert-butyl)phenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine;
O-((3-((3-(2-((3-([1,1'-biphenyl]-4-yloxy)
Benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine;
O-((3-((3-(2-([1,1'-biphenyl]-3-ylmethoxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine;
O-((3-((3-(3-([1,1'-biphenyl]-3-ylmethoxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine;
O-(((R)-3-((3-(2-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)propanoyl)oxy)-2 -Hydroxypropoxy)(hydroxy)phosphoryl)-L-serine;
O-(((R)-3-((3-(3-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenyl)propanoyl)oxy)-2 -Hydroxypropoxy)(hydroxy)phosphoryl)-L-serine;
O-(hydroxy((R)-2-hydroxy-3-((3-(2-((3-(phenylamino)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-(((R)-3-((3-(2-([1,1'-biphenyl]-3-ylmethoxy)phenyl)propanoyl)oxy)-2-hydroxypropoxy)(hydroxy)phosphoryl)-L -Serine;
O-(((R)-3-((3-(3-([1,1'-biphenyl]-3-ylmethoxy)phenyl)propanoyl)oxy)-2-hydroxypropoxy)(hydroxy)phosphoryl)-L -Serine;
O-(hydroxy(3-((3-(2-((3-(4-iodophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-(hydroxy(3-((3-(2-((3-(4-methoxyphenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-((3-((3-(2-((3-benzylbenzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine;
O-((3-((3-(2-((3-(benzyloxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine;
O-(hydroxy(((2R,3R)-2-(((3-(2-((3-(p-tolyloxy)benzyl)oxy)phenyl)propanoyl)oxy)methyl)tetrahydro-2H-pyran-3 -Yl)oxy)phosphoryl)-L-serine;
O-((((2R,3R)-2-(((3-(2-((3-(4-chlororophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)methyl)tetrahydro-2H-pyran- 3-yl)oxy)(hydroxy)phosphoryl)-L-serine;
O-(hydroxy(((2R,3R)-3-((3-(2-((3-(p-tolyloxy)benzyl)oxy)phenyl)propanoyl)oxy)tetrahydro-2H-pyran;
O-((((2R,3R)-3-((3-(2-((3-(4-chlorophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)tetrahydro-2H-pyran-2-yl) Methoxy)(hydroxy)phosphoryl)-L-serine;
O-((((2R,3R)-3-((3-(2-((3-(2-fluorophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)tetrahydro-2H-pyran-2-yl) Methoxy)(hydroxy)phosphoryl)-L-serine;
O-(hydroxy((R)-2-hydroxy-3-((3-(2-(4-phenoxybutoxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-(hydroxy((R)-2-hydroxy-3-((3-(2-((6-phenoxyhexyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-(hydroxy((R)-2-hydroxy-3-((3-(3-(4-phenoxybutoxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-(hydroxy((R)-2-hydroxy-3-((3-(3-((6-phenoxyhexyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-(hydroxy(3-((3-(2-(4-phenoxybutoxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-(hydroxy(3-((3-(2-((6-phenoxyhexyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-(hydroxy(3-((3-(3-(4-phenoxybutoxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-(hydroxy(3-((3-(3-((6-phenoxyhexyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine;
O-(((R)-3-((3-(2-((3-(hexyloxy)benzyl)oxy)phenyl)propanoyl)oxy)-2-hydroxypropoxy)(hydroxy)phosphoryl)-L-serine ;
O-(((R)-3-((3-(3-((3-(hexyloxy)benzyl)oxy)phenyl)propanoyl)oxy)-2-hydroxypropoxy)(hydroxy)phosphoryl)-L-serine ;
O-((3-((3-(2-((3-(hexyloxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine; and O-((3- ((3-(3-((3-(hexyloxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine;
A compound selected from, or a salt thereof.
Expression (V):

[In the formula:
R ¹ is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl, hydroxy C _1-6 alkyl, C _7-14 Aralkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aryloxy, 5-10 membered Selected from heteroaryloxy, cyano, amino, nitro, trifluoromethyl, halogen atom, and hydroxy,
R ³ is independently selected from C _1-6 alkyl, C _1-6 alkoxy, and halogen atoms,
p is 0 to 5,
r is 0 to 4,
m is 3 to 15;
n is 0-5;
Z ¹ and Z ² are independently selected from the group consisting of an oxygen atom and a direct bond;
Any one of Q ¹ , Q ² and Q ³ is a carbon atom or a nitrogen atom, and the remaining two are carbon atoms]
Or a salt thereof.
Expression (VI):

[In the formula:
R ¹ is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl, hydroxy C _1-6 alkyl, C _7-14 Aralkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aryloxy, 5-10 membered Selected from heteroaryloxy, cyano, amino, nitro, trifluoromethyl, halogen atom, and hydroxy;
R ³ is independently selected from C _1-6 alkyl, C _1-6 alkoxy, and halogen atoms;
p and r are independently 0-4;
m is independently 0 to 3;
n is 0-5;
Z ¹ and Z ² are, when m is 0 or 1, one is an oxygen atom and the other is a direct bond, or both are direct bonds, and when m is 2 or 3, Z ¹ and Z ^{2 are} Are independently selected from the group consisting of oxygen atom and direct bond;
Z ³ is selected from the group consisting of an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO ₂ —, difluoromethylene, and a direct bond, wherein R ⁹ is a hydrogen atom or C _{1-. 6} alkyl;
Any one of Q ¹ , Q ² and Q ³ is a carbon atom or a nitrogen atom, and the remaining two are carbon atoms;
R ¹⁵ is selected from C _3-15 alkyl, C _3-10 cycloalkyl, and 5-10 membered heterocyclyl]
Or a salt thereof.

  According to the present invention, there are provided a lysophosphatidylserine derivative or a salt thereof, and a fatty acid surrogate that can be used as a synthetic intermediate for the compound, and a pharmaceutical composition containing the compound or the salt or a lysophosphatidylserine receptor. A body function regulator is provided.

  Hereinafter, the present invention will be described more specifically.

Compound or salt thereof Examples of the compound of the present invention or salt thereof include the compounds of the above formulas (I), (II) and (III) or salts thereof, more specifically, the compounds described in Examples below. Be done.

  Further, the compounds of the above formulas (I), (II), (III), (Ia) to (Id), (IIa) to (IId) and (IIIa) to (IIId) may be substituted with ortho, meta and para. Each body is included.

  The most preferable embodiment of the present invention includes the compounds shown in Tables 1-1 to 1-6 below or salts thereof:

  Fatty acid surrogates that are another aspect of the present invention include the compounds shown in Tables 2-1 to 2-4 below, or salts thereof:

In the present specification, “C _1-6 alkyl” means a linear, branched, cyclic or partially cyclic alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl and n-propyl. , I-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and the like, for example, C _1-4 alkyl. And C _1-3 alkyl and the like.

In the present specification, the “C _1-6 alkylcarbonyl” means an alkylcarbonyl group having a C _1-6 alkyl group already defined as an alkyl moiety, and includes, for example, methylcarbonyl (acetyl), ethylcarbonyl, tert-butylcarbonyl. In addition to, C _1-4 alkylcarbonyl and the like are included.

In the present specification, the “C _1-6 alkylsulfonyl” means a group in which a C _1-6 alkyl group already defined as an alkyl moiety is bonded to a sulfonyl group, and examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl and isopropyl. Sulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like are included.

“Hydroxy C _1-6 alkyl” means a group in which one or more hydroxy groups have been replaced with a hydrogen atom bonded to a carbon atom of a C _1-6 alkyl group previously defined as an alkyl moiety, eg, Hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like are included.

In the present specification, "C _1-6 alkoxy" means an alkyloxy group having an alkyl group having 1 to 6 carbon atoms already defined as an alkyl moiety, and includes, for example, methoxy, ethoxy, n-propoxy, i-propoxy. , N-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpen Toxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy and the like are included, for example, C _1-4 alkoxy and C _{1 -3} Alkoxy and the like are also included. Further, in the present specification, “C _1-4 alkoxy” also includes, for example, C _1-3 alkoxy and the like.

The term “C _1-6 alkoxycarbonyl” as used herein means an alkoxycarbonyl group having a C _1-6 alkoxy group already defined as an alkoxy moiety, and includes, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, C _1-3 alkoxycarbonyl and the like are included.

In the present specification, the “C _1-6 alkoxy C _1-6 alkyl” includes, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 1-methoxyethyl and the like.

In the present specification, the “C _2-6 alkenyl” includes, for example, a straight chain or branched chain alkenyl group having one straight or branched double bond having 2 to 6 carbon atoms. .. The term further includes linear or branched alkenyl groups containing two or more double bonds.

In the present specification, the term “C _2-6 alkynyl” means a straight-chain or branched-chain alkenyl group having 2 to 6 carbon atoms, and a straight-chain or branched-chain alkynyl group containing one triple bond. , And linear or branched alkynyl groups containing two or more triple bonds.

In the present specification, “C _3-10 cycloalkyl” means a cyclic alkyl group having 3 to 10 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. In addition, C _3-10 cycloalkyl is included in the range defined by the above C _1-30 alkyl.

  In the present specification, the “5- to 10-membered heterocyclyl” includes one or more heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom, and has 5 to 10 ring atoms, and is a saturated or partially saturated aliphatic heterocycle. It means a ring group. Specific examples include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl and the like.

The “C _6-10 aryl” in the present specification is, for example, an aromatic carbocyclic group having 6 to 10 carbon atoms and includes, for example, phenyl, naphthyl and the like.

In the present specification, “C _6-10 aryloxy” includes, for example, phenoxy, naphthyloxy and the like.

In the present specification, “C _6-10 arylcarbonyl” includes, for example, benzoyl and the like.

In the present specification, "C _7-14 aralkyl" means an arylalkyl group having a carbon number of 7 to 14 and containing an aryl group, for example, benzyl, 1-phenethyl, 2-phenethyl, 1-naphthylmethyl, 2- Includes naphthylmethyl and the like. The carbon number of the alkyl group portion is, for example, 1 to 4.

In the present specification, "C _7-14 aralkyloxycarbonyl" includes, for example, benzyloxycarbonyl, 1-phenethyloxycarbonyl, 2-phenethyloxycarbonyl, 1-naphthylmethyloxycarbonyl, 2-naphthylmethyloxycarbonyl and the like. Be done.

  In the present specification, the "5- to 10-membered heteroaryl" is a monocyclic aromatic heterocyclic group having 5 to 10 ring atoms, which contains one or more heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom. Means Specific examples include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl and the like.

  In the present specification, "5- to 10-membered heteroaryloxy" includes, for example, pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, pyridyloxy, pyrimidyloxy, pyridazinyloxy, furyloxy, thienyloxy and oxazoli. Include ruoxy, oxadiazolyloxy, thiazolyloxy, thiadiazolyloxy and the like.

  The “halogen atom” in the present specification includes, for example, a chlorine atom, a fluorine atom, an iodine atom and the like.

  In the present specification, when one or more bonds between carbon atoms are double bonds, they may be in cis configuration or trans configuration.

  The present invention relating to the compounds represented by the above formulas (I), (II) and (III) includes various stereoisomers such as tautomers, geometric isomers and optical isomers, and a mixture thereof. Be done.

  The “salt” of the compound of the present invention is not particularly limited as long as it is a salt and is preferably a salt that can be used as a medicine. Examples of the salt formed by the compound of the present invention with a base include salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine. The salt may be an acid addition salt, and specific examples of the salt include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; and formic acid, Acid addition salts with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid Is mentioned.

  As used herein, the term "fatty acid surrogate" refers to an alternative structure of fatty acid. In other words, in one embodiment of the present invention, the “fatty acid surrogate” can be used as a synthetic intermediate for an analog compound having a lysophosphatidyl phosphate structure. In another aspect, the “fatty acid surrogate” can be used as a substitute compound for a substance having a fatty acid structure or as a synthetic intermediate.

  Furthermore, the compounds of the present invention also include hydrates, various solvates, crystalline polymorphs and the like.

The atoms contained in the compound of the present invention (for example, hydrogen atom, carbon atom, oxygen atom, nitrogen atom, sulfur atom and phosphorus atom) are isotope atoms other than the most naturally occurring isotopes. Alternatively, the isotope atom may be a radioactive conductor atom. Thus, according to one aspect of the present invention there is provided a compound of formula (I), (II) and (III), or salt thereof, as hereinbefore defined, which is labeled with an isotope atom. It Here, labeling with isotope atoms, for example, be a labeling with radioactive isotopes (such as ³ H, ¹⁴ C, ³² P), the ease of the side surface of the preparation of the compounds according to the ³ H Labeling is preferred. The ³ H-labeled compound of the present invention can be synthesized, for example, by using a ³ H-labeled fatty acid or its derivative.

In one aspect of the invention, the compounds of formula (I), (II) and (III) are administered as prodrugs and converted in vivo to the active compound. For example, R ⁴ and R ⁸ in formulas (I), (II), and (III) may be groups forming a carboxylic acid ester or a phosphoric acid ester. Specific examples thereof include the groups described in Journal of Medicinal Chemistry, 2008, 51(8), 2337, and the like. C _1-6 alkyl (for example, tert-butyl), C _1-6 alkoxy C _{1- 6} alkyl (eg, methoxymethyl), C _1-6 alkylcarbonyloxy C _1-6 alkyl (eg, pivaloyloxymethyl), C _1-6 alkoxycarbonyloxy C _1-6 alkyl (eg, isopropoxycarbonyloxy) Methyl), optionally substituted phenyl (eg C _1-3 alkoxyphenyl), optionally substituted benzyl (eg C _1-6 alkoxy, hydroxy, C _1-6 alkylcarbonyloxy, nitro, and Benzyl optionally substituted by 1 to 3 groups selected from halogen atoms, phthalidyl (eg, isobenzofuranone optionally substituted by 1 to 4 groups selected from C _1-6 alkoxy) 3-yl), dioxolenonylmethyl (eg, dioxolenone-4-ylmethyl optionally substituted at the 5-position of the dioxolenone ring with a group selected from C _1-6 alkoxy or phenyl), or furylmethyl (eg, 2-furylmethyl in which the 5-position of the furan ring may be substituted with nitro) and the like are included.

Synthesis of compound or its salt The lysophosphatidylserine receptor consists of a hydrophilic site (amino acid site and phosphodiester site), a hydrophobic site (acyl side chain site), and a linking site that links the hydrophilic site and the hydrophobic site. Since it is a modular molecule, each modular structure can be systematically converted according to the following general synthetic method to synthesize the compound of the present invention and a salt thereof. The compounds of the formulas (I), (II), and (III), for example, the compounds having the linking site (deoxytype) of the formula (Id) can be synthesized by the steps shown in the following schemes.

Wherein R ³ is as previously defined herein; the —O-acyl side chain is a carboxylic acid of formula (IV), (V), and (VI) as previously defined herein. Corresponding to the structure; PG ¹ , PG ² , and PG ³ each represent a protecting group, for example PG ¹ , PG ² and PG ³ are tert-butyldimethylsilyl (TBS) or tert-butyl, PG ³ is tert-butoxycarbonyl (Boc)].

  The compound contained in the formula (Id) is obtained by, for example, condensing and oxidizing one of the hydroxy groups of the linking site (deoxy type) and phosphoamidite in step a, and then performing the condensation step with the acyl side chain site in step b. Then, it can be prepared by deprotecting phosphoric acid, carboxylic acid and amine in step c.

  In the condensation reaction in step a, for example, an active derivative of phosphoric acid is used and a suitable condensing agent is used. In the presence of a suitable reaction accelerator (eg, 1H-tetrazole) in a suitable solvent such as methylene chloride, tetrahydrofuran, N,N′-dimethylformamide, toluene, diethyl ether, 1,4-dioxane, etc. It can be carried out. The oxidation step can be performed using a suitable oxidizing agent (eg, tert-butyl hydroperoxide, metachloroperbenzoic acid, iodine-pyridine-water, etc.) in a suitable solvent. The condensation step and the oxidation step may be performed on the product obtained by post-treatment after the condensation reaction, or may be performed as a one-pot reaction without post-treatment.

  The alcohol acylation step of step b may be prepared using an acid chloride, in which case it is in the presence of a suitable base, such as 4-dimethylaminopyridine, or in the absence of a base, in a suitable solvent. You can do it below. Acylation is carried out using a carboxylic acid and a suitable condensing agent (for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), 1,3-diisopropylcarbodiimide (DIC), etc.). You can also

  The deprotection step of step c can be performed by subjecting it to appropriate deprotection conditions, and for example, trifluoroacetic acid (TFA) can be used. By further performing substituent conversion, the target compound included in formula (Id) can be obtained.

  These steps are not particularly limited, but can be carried out at a reaction temperature of, for example, 0 to 70° C., preferably 15 to 30° C., and a reaction time of, for example, 10 minutes to 2 days, preferably 1 to 2 hours.

  In addition, the compound contained in formula (Id) is first condensed with one of the hydroxy groups of the linking site (deoxytype) and the acyl side chain site in step a′, and then condensed/oxidized with phosphoamidite in step b′. And then deprotecting phosphoric acid, carboxylic acid and amine in step c. In this reaction, when hydroxypropylamine is used instead of the starting material 1,3-propanediol, a compound having amide as a linking group instead of ester can be synthesized.

[Wherein R ³ , PG ² and PG ³ are as previously defined herein].

The amino acid moieties used in the synthesis of formulas (I), (II), (III) can be prepared, for example, by protecting the alcoholic carboxylic acid and amine of the amino acid with the appropriate substituents PG ² and PG ³ in step a It can be prepared.

  The protection reaction of the carboxylic acid and amine in step a can be carried out by subjecting them to appropriate protection conditions.

[Wherein R ³ , PG ¹ , PG ² and PG ³ are as previously defined herein].

  The phosphoramidite used for the synthesis of the formulas (I), (II) and (III) is prepared, for example, by reacting the alcohol (amino acid moiety) synthesized in Scheme 2 with bis(diisopropylamino)-tert-butylphosphine. can do. The condensation step of step a can be performed under the same conditions as the condensation step of step a in scheme 1.

[Wherein n and m are as previously defined herein; PG ⁶ means a protecting group, eg PG ⁶ is TBS or C _1-6 alkyl (methyl, ethyl, tert-butyl). Is].

  The side chain moiety having a benzene ring used in the synthesis of the formulas (I), (II), and (III) protects, for example, the carboxylic acid of the phenol having a carboxylic acid group in step a, and the phenol is alkylated in step b. And deprotecting the carboxylic acid in step c.

  The phosphoric acid protection step of step a can be performed by subjecting it to appropriate protection conditions. The alkylation reaction of phenol in step b can be carried out under appropriate conditions, for example, using an alkyl halide as a reactant. The deprotection step of step c can be performed by subjecting it to appropriate deprotection conditions.

Wherein n and m are as previously defined herein; PG ⁷ means a protecting group, eg PG ⁷ is TBS or C _1-6 alkyl (methyl, ethyl, tert-butyl). Is].

  The side chain moiety having a benzene ring used in the synthesis of the formulas (I), (II), and (III) is reduced by, for example, reducing an aldehyde that substitutes the benzene ring to alcohol in step a, and coupling with phenol in step b. And deprotecting the carboxylic acid in step c.

  The aldehyde reduction step of step a can be carried out, for example, by using sodium borohydride as a reducing agent and subjecting it to appropriate protection conditions. The coupling reaction with phenol in step b can be carried out, for example, using DEAD as a reactant under appropriate conditions. The deprotection step of step c can be performed by subjecting it to appropriate deprotection conditions.

Pharmaceutical Composition The pharmaceutical composition of the present invention may be used in various dosage forms, for example, for oral administration, tablets, capsules, powders, granules, pills, solutions, emulsions, suspensions, solutions, and spirits. Agents, syrups, extracts and elixirs. Parenteral agents include, for example, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and the like; transdermal administrations. Or, it can be a patch, ointment or lotion; a sublingual agent for buccal administration, a buccal patch, and an aerosol agent for nasal administration, but is not limited thereto. These formulations can be produced by known methods usually used in the formulation process. The compounds of formula (I), (II), (III) are preferably administered as parenteral agents.

  The pharmaceutical composition may contain various commonly used components, for example, one or more pharmaceutically acceptable excipients, disintegrating agents, diluents, lubricants, flavoring agents, coloring agents. , Sweetening agents, flavoring agents, suspending agents, wetting agents, emulsifying agents, dispersing agents, auxiliary agents, preservatives, buffering agents, binders, stabilizers, coating agents and the like. The pharmaceutical composition of the invention may also be in sustained or sustained release dosage forms.

  The dose of the therapeutic agent, prophylactic agent, or pharmaceutical composition of the present invention can be appropriately selected depending on the administration route, patient's body type, age, physical condition, degree of disease, elapsed time after onset, etc. The pharmaceutical composition of can include a therapeutically and/or prophylactically effective amount of a compound of formula (I), (II), (III) above. In the present invention, the compounds of the above formulas (I), (II) and (III) may be generally used in a dose of 1 to 10000 mg/day/adult. Administration of the pharmaceutical composition may be a single dose or multiple doses, for example, immunosuppressants (cyclosporine, tacrolimus, sirolimus, methotrexate, azathioprine, etc.), steroidal anti-inflammatory drugs (hydrocortisone, prednisolone, dexamethasone, etc.) ), non-steroidal anti-inflammatory drugs (such as loxoprofen sodium, indomethacin, diclofenac sodium) or antibody drugs (such as infliximab, adalimumab, tocilizumab, certolizumab pegol, etanercept)). it can.

  The therapeutic agent or prophylactic agent of the present invention contains, if necessary, conventionally known coloring agents, preservatives, fragrances, flavors, coating agents, antioxidants, vitamins, amino acids, peptides, proteins, and minerals (iron, zinc). , Magnesium, iodine, etc.) and the like. The therapeutic or prophylactic agent of the present invention is in a form suitable for pharmaceutical compositions, functional foods, health foods, beverages, supplements, etc., such as granules (including dry syrup), capsules (soft capsules, hard capsules). Prepared in the form of various solid preparations such as tablets, tablets (including chewable tablets), powders (powder), pills, etc., or liquid preparations for internal use (including solutions, suspensions, syrups) You may. Further, the therapeutic or prophylactic agent of the present invention can be used as it is as a pharmaceutical composition, a functional food, a health food, a supplement or the like.

  Examples of additives for formulation include excipients, lubricants, binders, disintegrants, fluidizers, dispersants, wetting agents, preservatives, thickeners, pH adjusters, colorants, Examples thereof include flavoring agents, surfactants, and solubilizing agents. Further, in the case of a liquid formulation, a thickening agent such as pectin, xanthan gum, guar gum can be added. Further, a coating agent may be used to prepare a coated tablet or a paste-like glue. Furthermore, even when it is prepared in another form, a conventional method may be used.

  The pharmaceutical composition according to one aspect of the present invention is one selected from, for example, GPR34, P2Y10, and GPR174 based on the chemical structures of the compounds represented by formulas (I), (II), and (III). Lysophosphatidylserine receptor function-regulating activity, lysophosphatidylserine receptor agonist activity, mast cell degranulation inhibitory activity, histamine release inhibitory activity, leukotriene production inhibitory activity, prostaglandin production inhibition It has an action, an IL-13 production inhibitory action, a tryptase secretion inhibitory action, an antigen-antibody reaction inhibitory action and the like. Moreover, the pharmaceutical composition of the present invention can be used as a therapeutic or prophylactic agent for diseases such as autoimmune diseases. The autoimmune disease may be any of systemic diseases and organ-specific diseases, for example, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Graves' disease, antiphospholipid antibody syndrome, These include Sjogren's syndrome, primary biliary cirrhosis, polymyositis, and autoimmune hepatitis.

Lysophosphatidylserine receptor function modulator According to one aspect of the present invention, there is provided one or more lysophosphatidylserine receptor function modulators selected from GPR34, P2Y10 and GPR174, which comprises the above compound or a salt thereof. To be done. Further, the lysophosphatidylserine receptor function regulator may be one that selectively regulates any two functions selected from GPR34, P2Y10, and GPR174, or selectively regulates the function of P2Y10. It may be

  The term “lysophosphatidylserine receptor function modulator” used in the present invention refers to an agent that acts on a lysophosphatidylserine receptor such as GPR34, P2Y10 and GPR174 to enhance or suppress the expression of a target receptor, or Refers to an agent used to enhance or suppress the in-vivo function peculiar to the receptor.

Here, the lysophosphatidylserine receptor is a modular type consisting of a hydrophilic site (amino acid site and phosphodiester site), a hydrophobic site (acyl side chain site), and a linking site that links the hydrophilic site and the hydrophobic site. Since it is a molecule, systematically converting each modular structure according to the general synthetic method of the above compound, and examining whether each modular structure is required for biological activity expression It becomes possible to elucidate the required structure and the structural requirement for creating receptor-selective agonists. That is, for example, the lysophosphatidylserine receptor function modulator according to the present invention is a compound having an agonist activity for one or more receptors, a selective agonist activity for two receptors (dual agonist activity), or 1 By incorporating a compound having a selective agonist activity into one of the two receptors, it can be used as a chemical tool for elucidating the unknown physiological function of the lysophosphatidylserine receptor. In addition, the lysophosphatidylserine receptor function regulator of the present invention can also be used as an active ingredient of the above-mentioned pharmaceutical composition.
<GPR34 function regulator>
Since GPR34 is highly expressed in mononuclear cells centering on macrophages, it is assumed that GPR34 is involved in the control of migration, proliferation and activation of macrophages and granulocytes. Further, in lung infection experiments of pathogenic bacteria (Cryptococcus neoformans), it has been found that GPR34 knockout mice have a larger number of pathogenic bacteria than wild-type mice, and that the function of eliminating pathogenic bacteria is abnormal. That is, it has been suggested that GPR34 is involved in a wide range of immune responses via mononuclear cells, and a lysophosphatidylserine receptor function regulator that selectively regulates GPR34 function is associated with mononuclear cells. It can be used to clarify the physiological function of

  In addition, it has been confirmed that the production of cytokines such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) is excessively elevated in GPR34 knockout mice, and the production of cytokine as a function of GPR34 is confirmed. There are reports that suggest suppression. That is, the lysophosphatidylserine receptor function regulator that selectively regulates the function of GPR34 can be used as a chemical tool for elucidating the suppression of cytokine production in vivo.

It is also useful as a medicine such as a prophylactic/therapeutic agent for diseases related to the function of GPR34.
<P2Y10 function regulator>
It has been clarified that P2Y10 is highly expressed in lymphoid organs such as the thymus and spleen, and in particular, its expression is greatly increased in activated lymphocytes. It has also been reported that P2Y10 inhibits the formation of cell aggregates of activated T lymphocytes by controlling the LFA1 function, and as a physiological function of P2Y10, L2-1-ICAM- of activated lymphocytes was reported. 1 may be involved in suppression of cell adhesion by inhibiting interaction. That is, the lysophosphatidylserine receptor function regulator that selectively regulates the function of P2Y10 can be used as a chemical tool for elucidating the physiological function related to the suppression of cell adhesion of activated lymphocytes.

In addition, it is also useful as a drug such as a prophylactic/therapeutic agent for diseases associated with the function of P2Y10.
<GPR174 function regulator>
Like P2Y10, GPR174 is also highly expressed in lymphoid organs such as the thymus and spleen, and its expression is greatly increased especially in activated lymphocytes. Therefore, GPR174 also has some important function in the activation stage of the immune system. there is a possibility. For example, it was revealed that a P2Y10 selective agonist did not suppress IL-2 production of activated lymphocytes, whereas a GPR174 selective agonist suppressed IL-2 production. It has also been reported that the single nucleotide polymorphism of GPR174 is associated with Graves' disease or hyperthyroidism characterized by an autoantibody target antigen specifically expressed in thyroid tissue. That is, the lysophosphatidylserine receptor function regulator that selectively regulates the function of GPR174 can be used as a chemical tool for elucidating the physiological function involved in the suppression of IL-2 production of activated lymphocytes.

  In addition, it is also useful as a drug such as a prophylactic/therapeutic agent for diseases related to the function of GPR174, for example, diseases related to the immune system, particularly Graves' disease and hyperthyroidism.

Method of evaluating compound or salt thereof The agonistic activity of a test compound on the lysophosphatidylserine receptor can be evaluated using GPR34, P2Y10 or GPR174. That is, the method for evaluating or screening the above compound or a salt thereof as a test compound is not particularly limited as long as it uses GPR34, P2Y10 or GPR174, and for example, a gene encoding GPR34, P2Y10 or GPR174 is expressed. Cells, a transgenic non-human mammal overexpressing a gene encoding GPR34, P2Y10 or GPR174, a transgenic non-human mammal expressing a gene encoding human GPR34, human P2Y10 or human GPR174, etc. be able to. Here, the cells used for evaluation or screening are not particularly limited, but include commonly used known cultured cells such as HEK293 cells. In addition, examples of non-human mammals include mice, rats, rabbits, dogs, cats, monkeys and the like. The screen may also use animal tissues and cells. In that case, the test compound can be administered by allowing the test compound to act on the subject, for example, by including the test compound in a solution or medium in which tissues or cells are retained.

  The compound or its salt can be evaluated or screened using a cultured cell expressing a gene encoding GPR34, P2Y10 or GPR174, and the use of the cultured cell is preferable from the viewpoint of screening efficiency. Since GPR34, P2Y10 or GPR174 is a G protein-coupled receptor, it is possible to carry out an assay using calcium response, cAMP production, reporter gene and the like as indicators. The assay can also be performed by expressing the gene encoding the labeled human epidermal growth factor receptor (EGFR) ligand in the cultured cells and quantifying the amount of the labeled compound cleaved. Here, specific examples of the labeled EGFR ligand include a fusion protein of an EGFR ligand and alkaline phosphatase (AP). In addition, examples of the EGFR ligand to be labeled include transforming growth factor α (TGFα). Assay methods using labeled EGFR ligands are performed with reference to, for example, Tokumaru et al., J Cell Biol 151, 209-220 (2000); Inoue et al., Nature Methods 9, 1021-1019 (2012). be able to.

  The GPR34, P2Y10 or GPR174 used in the above evaluation or screening is not particularly limited as long as it is a polypeptide having these receptor activities, and for example, GPR34, P2Y10 or GPR174 derived from a mammal such as human, mouse or rat is used. To be done. As a specific example, a polypeptide having GPR34, P2Y10 or GPR174 activity as disclosed in Patent Documents 2 and 5 can be used.

  Hereinafter, the present invention will be described in more detail by showing Examples, but the present invention is not limited to these Examples.

Reagents and data measurement reagents are from Sigma-Aldrich Chemical Co. The product purchased from Tokyo Kasei Kogyo, Wako Pure Chemical, Kanto Kagaku was used without further purification. ¹ H- and ¹³ C-NMR were measured using a BRUKER AVANCE400 spectrometer (400 MHz), and chemical shifts were deuterated chloroform (7.26 ppm ( ¹ H-NMR), 77.00 ppm ( ¹³ C-NMR)). Is expressed in ppm with respect to. ³¹ P-NMR chemical shifts are expressed in ppm relative to phosphoric acid in water (85% w/w, 0.00 ppm). Mass spectrometry was measured in positive and negative ion mode on a BRUKER microTOF-05 spectrometer (ESI-TOF) or SHIMADZU AXIMA-TOF (MALDI-TOF). Silica gel used for column chromatography was purchased from Kanto Chemical. Elemental analysis was performed using a Yanaco MT-6 CHN CORDER spectrometer.

[Example 1]
Synthesis of O-(hydroxy(3-((3-(2-((3-(o-tolyloxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis of Intermediate 1-1

To remove the contained water, the phosphoramidite (1.2815 g, 2.761 mmol) synthesized in Scheme 6 below was dissolved in dichloromethane (10 mL) and toluene (0.5 mL), and then the solvent was distilled off under vacuum. 1-(tert-Butyldimethylsilyloxy)bropanol (648.4 mg, 3.406 mmol) was added to the obtained residue, dichloromethane (10 mL) and toluene (0.5 mL) were added, and the solvent was evaporated under vacuum. The residue was dissolved in dichloromethane (4 mL), and a solution of 1H-tetrazole (574.2 mg, 8.196 mmol) in THF (8.5 mL) was added at 0°C. Within minutes, a white powder precipitated. The reaction mixture was stirred at room temperature for 4 hours under argon atmosphere. Tert-butyl hydroperoxide (decane solution of TBHP (5.0-6.0 M, 1.100 mL)) was added at room temperature, and the mixture was further stirred at room temperature for 1.7 hr. The reaction mixture was diluted with water (12 mL), the aqueous layer was separated, and extracted three times with dichloromethane (20 mL x 3). The organic layers were collected, washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate=2:1) to give the title compound (1.1918 g, 2.093 mmol, 76%, sticky oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 5.491-5.472 (1H, m), 4.371-4.312 (2H, m), 4.242-4.178 (1H, m), 4.140-4.053 (2H, m), 3.722 -3.683 (2H, m), 1.894-1.821 (2H, m), 1.493-1.478 (18H, m), 1.448 (9H, s), 0.889 (9H, s), 0.050 (6H, d, J=1.2 Hz ).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 168.37, 155.25, 82.58, 79.87, 67.30, 64.52, 58.91, 54.38, 33.37, 33.30, 29.78, 29.74, 28.29, 27.93, 25.86, 18.23, -5.43.
³¹ P NMR (CDCl ₃ ): δ = -5.51, -5.68.
HRMS (ESI-TOF, [M+Na] ⁺ ): C ₂₅ H ₅₂ NNaO ₉ PSi ⁺ : Calculated 592.3041. Found 592.3022.

Synthesis of Intermediate 1-2

HF/pyridine (1.18 mL) dissolved in pyridine (2.9 mL) was added dropwise to a solution of Intermediate 1-1 (1.1397 g, 2.000 mmol) in THF (12 mL) at 0° C., and the mixture was stirred at room temperature for 5 hours. . Ethyl acetate (10 mL) and KHSO ₄ (5% aqueous solution, 10 mL) were added to the obtained solution, the aqueous layer was separated, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic layers were collected, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate=1:1 to 0:1) to give the title compound (567.8 mg, 1.247 mmol, 62%, white solid).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 5.518 (1H, dd, J=7.8 Hz, 3.8 Hz), 4.380-4.309 (2H, m), 4.272-4.226 (1H, m), 4.208-4.141 ( 2H, m), 3.752 (2H, td, J=6.0 Hz, 2.4 Hz), 1.882-1.846 (2H, m), 1.501-1.450 (27H, m).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 168.45, 155.25, 83.86, 83.79, 82.85, 82.80, 80.02, 67.46, 64.20, 58.11, 58.05, 54.48, 54.40, 32.82, 32.77, 29.79, 29.75, 28.30, 27.95. .
³¹ P NMR (CDCl ₃ )): δ = -4.74.
HRMS (ESI-TOF, [M+Na] ⁺ ): C ₁₉ H ₃₈ NNaO ₉ P ⁺ : Calculated value 478.2176. Found 478.2177.
Elemental analysis: C ₁₉ H ₃₈ NO ₉ P: Calculated C, 50.10; H, 8.41; N, 3.08. Found C, 49.84; H, 8.17; N, 3.03.
Mp: 114-115°C (white powder, recrystallized from n-hexane/CH ₂ Cl ₂ ).

Synthesis of Intermediate 1-3

Compound 31 (101.0 mg, 0.2787 mmol) synthesized below and a solution of intermediate 1-2 (91.1 mg, 0.2000 mmol) in dichloromethane (1.5 mL) were added to DMAP (10.4 mg, 0.0851 mmol) and EDCI·HCl (80.3 mg). , 0.4189 mmol) was added at 0° C., and the mixture was stirred under an argon atmosphere at room temperature for 17.2 hours. EDCI·HCl (80.3 mg, 0.4189 mmol) and MeOH (1 mL) were added to the reaction mixture at 0° C., and after stirring at room temperature for 5.7 hours under an argon atmosphere, water (15 mL) was added and dichloromethane (15 mL) was added. x 3). The organic layers were collected, washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate=3:2) to give the title compound (124.1 mg, 0.1551 mmol, 78%, colorless sticky oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.302 (1H, t, J = 7.90 Hz), 7.260-7.238 (1H, m), 7.190-7.140 (3H, m), 7.109-7.057 (2H, m ), 6.937-6.829 (5H, m), 5.494 (1H, d, J = 7.76 Hz), 5.047 (2H, s), 4.368-4.303 (2H, m), 4.224-4.178 (1H, m), 4.162- 4.120 (2H, m), 4.062-3.966 (2H, m), 2.950 (2H, t, J = 7.62 Hz), 2.624-2.586 (2H, m), 2.214 (3H, s), 1.973-1.898 (2H, m), 1.476-1.434 (27H, m).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.01, 168.27, 158.16, 156.28, 155.16, 154.03, 139.11, 131.42, 130.04, 129.76, 128.94, 127.51, 127.12, 124.17, 120.71, 120.58, 119.98, 116.32, 115.36. , 111.50, 83.61, 83.54, 82.58, 82.56, 79.83, 69.25, 67.33, 67.28, 63.99, 63.93, 60.33, 54.40, 54.32, 33.93, 29.71, 29.70, 29.67, 29.50, 29.42, 28.23, 27.87, 26.04, 16.07.
³¹ P NMR (CDCl ₃ ): δ = -5.54, -5.68.
HRMS (ESI-TOF, [M+Na] ⁺ ): C ₄₂ H ₅₈ NNaO ₁₂ P ⁺ : Calculated 822.3589. Found 822.3561.

Synthesis of compound 1

Intermediate 1-3 (115.1 mg, 0.1439 mmol) was dissolved in TFA (1.0 mL) at 0° C., the mixture was stirred at room temperature for 1.5 hr, diluted with dichloromethane (10 mL), and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol:water=9:1:0 to 65:25:4) to give the TFA salt of the title compound (33.0 mg, 0.0562 mmol, 39%, white powder).
¹ H NMR (400 MHz, CDCl ₃ /TFA-d): δ = 7.289-7.219 (2H, m), 7.165-7.126 (2H, m), 7.081-7.047 (3H, m), 6.919-6.802 (5H, m), 5.024 (2H, s), 4.465 (2H, brs), 4.339 (1H, brs), 4.137 (2H, brs), 3.916 (2H, brs), 2.905 (2H, t, J = 7.38 Hz), 2.748 (2H, t, J = 7.40 Hz), 2.178 (3H, s), 1.871 (2H, brs).
³¹ P NMR (CDCl ₃ ): δ = -1.97.
HRMS (ESI-TOF, [MH] ^- ): C ₂₉ H ₃₃ NO ₁₀ P ^- : Calculated value 586.1848. Measured value 586.1878.
Elemental analysis: Calculated value C ₂₉ H ₃₄ NO ₁₀ P・1.4CF ₃ CO ₂ H: C, 51.12; H, 4.78; N, 1.87. Found value C, 50.82; H, 4.76; N, 1.88.

[Example 2]
Synthesis of O-(hydroxy(3-((3-(2-((3-(m-tolyloxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that the compound 32 synthesized below was used instead of the compound 31, and in the final step column chromatography (chloroform:methanol:acetic acid=9:1:0-8: 1:1) and the colorless oil obtained was dissolved in dichloromethane and TFA at 0° C. and then dried under vacuum at 40° C. overnight to give the TFA salt of the title compound (53.5 mg, 0.0911 mmol, final). The yield of the process was 47%, and white powder was obtained.
¹ H NMR (400 MHz, CDCl ₃ /TFA-d): δ = 7.276 (1H, t, J=7.84 Hz), 7.190-7.052 (4H, m), 7.010 (1H, s), 6.905-6.758 (6H , m), 5.005 (2H, s), 4.410 (2H, brs), 4.312 (1H, brs), 4.089 (2H, brs), 3.885 (2H, brs), 2.906 (2H, brs), 2.610 (2H, brs), 2.282 (3H, s), 1.832 (2H, brs).
³¹ P NMR (CDCl ₃ ): δ = -1.73.
HRMS (ESI-TOF, [MH] ^- ): C ₂₉ H ₃₃ NO ₁₀ P ^- : Calculated value 586.1848. Measured value 586.1876.
Elemental _{analysis: C 29 H 34 NO 10 P} · 1.7CF 3 CO 2 H:. Calculated C, 49.80; H, 4.61; N, 1.79 Found C, 49.63; H, 4.75; N, 1.84.

[Example 3]
Synthesis of O-(hydroxy(3-((3-(2-((3-(p-tolyloxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that the compound 33 synthesized below was used instead of the compound 31, and in the final step, column chromatography (chloroform:methanol:water=8:2:0 to 65: 25:4) to give the TFA salt of the title compound (46.9 mg, 0.0798 mmol, 49% yield of the final step, white powder).
¹ H NMR (400 MHz, CDCl ₃ /TFA-d): δ = 7.312 (1H, t, J=7.6 Hz), 7.211-7.052 (6H, m), 6.927-6.886 (5H, m), 5.067 (2H , s), 4.606 (2H, brs), 4.472 (1H, brs), 4.246-4.198 (2H, m), 4.000 (2H, brs), 2.957 (2H, t, J=7.4 Hz), 2.712 (2H, t, J=7.6 Hz), 2.334 (3H, s), 1.948-1.921 (2H, m).
³¹ P NMR (CDCl ₃ ): δ = -1.81.
HRMS (ESI-TOF, [M+Na] ⁺ ): C ₂₉ H ₃₄ NNaO ₁₀ P ⁺ : Calculated value 610.1813. Found 610.1833.
Elemental analysis: C ₂₉ H ₃₄ NO ₁₀ P/1.7 CF ₃ CO ₂ H: Calculated C, 49.80; H, 4.61; N, 1.79. Found C, 49.94; H, 4.59; N, 2.05.
Mp: 190-191°C (white powder).

[Example 4]
Synthesis of O-((3-((3-(2-((3-(3-chlorolophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that the compound 34 synthesized below was used instead of the compound 31, and in the final step, column chromatography (chloroform:methanol:acetic acid=9:1:0-8: 1:1 to 7:2:1) and the resulting colorless oil was dissolved in dichloromethane and TFA at 0° C. and then dried under vacuum at 40° C. overnight to give the TFA salt of the title compound (55.7). mg, 0.0771 mmol, 63% yield of the final step, white powder) was obtained.
¹ H NMR (400 MHz, CDCl ₃ /TFA-d): δ = 7.346 (1H, t, J=7.88 Hz), 7.226 (1H, t, J=8.12 Hz), 7.183-7.145 (2H, m), 7.088-7.053 (3H, m), 6.969-6.939 (2H, m), 6.889-6.851 (3H, m), 5.064 (2H, s), 4.501 (2H, brs), 4.378 (1H, brs), 4.145 ( 2H, t, J=5.90 Hz), 3.961 (2H, brs), 2.944 (2H, t, J=7.44 Hz), 2.683 (2H, t, J=7.44 Hz), 1.897 (2H, t, J=5.42) Hz).
³¹ P NMR (CDCl ₃ ): δ = -1.49.
HRMS (ESI-TOF, [MH] ^- ): C ₂₈ H ₃₀ ClNO ₁₀ P ^- : Calculated value 606.1301. Found 606.1297.
Elemental _{analysis: C 28 H 30 ClNO 10 P} · 0.7CF 3 CO 2 H:. Calculated C, 51.34; H, 4.65; N, 2.04 Found C, 51,42; H, 4.93; N, 2.08.

[Example 5]
Synthesis of O-((3-((3-(2-((3-(4-chlorolophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that the compound 35 synthesized below was used instead of the compound 31, and in the final step, column chromatography (chloroform:methanol:acetic acid=9:1:0-8: 1:1 to 7:1:2, chloroform:methanol:water=65:25:4) to give the TFA salt of the title compound (4.8 mg, 0.0079 mmol, 5% yield of final step, white powder). Obtained.
¹ H NMR (400 MHz, CDCl ₃ /TFA-d): δ = 7.323 (1H, t, J=8.0 Hz), 7.265 (2H, dt, J=9.2 Hz, 2.8 Hz), 7.180-7.127 (2H, m), 7.064 (1H, d, J=6.4 Hz), 7.020 (1H, brs), 6.930-6.841 (5H, m), 5.056 (2H, s), 4.486 (2H, brs), 4.373 (1H, brs) ), 4.195-4.139 (2H, m), 3.920 (2H, brs), 2.930 (2H, t, J=7.4 Hz), 2.674 (2H, t, J=7.4 Hz), 1.877 (2H, brs).
³¹ P NMR (CDCl ₃ ): δ = -2.48.
HRMS (ESI-TOF, [MH] ⁺ ): C ₂₈ H ₃₀ ClNO ₁₀ P ⁺ : Calculated value 606.1301. Found 606.1305.
Elemental analysis: C ₂₈ H ₃₁ ClNO ₁₀ P・2 CF ₃ CO ₂ H: Calculated C, 45.97; H, 3.98; N, 1.68. Found C, 45.60; H, 3.94; N, 1.82.
Mp: 200-203 °C (white powder).

[Example 6]
Synthesis of O-((3-((3-(2-((3-(3,4-dichlorophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that the compound 38 synthesized below was used instead of the compound 31, and column chromatography (chloroform:methanol:water=9:1:0 to 65: 25:4) to obtain the TFA salt of the title compound (20.1 mg, 0.0313 mmol, yield of final step 39%, white powder).
¹ H NMR (400 MHz, CDCl ₃ /TFA-d): δ = 7.396-7.356 (2H, m), 7.212-7.173 (2H, m), 7.097-7.055 (3H, m), 6.970 (1H, dd, J=8.2 Hz, 0.8 Hz), 6.921-6.862 (2H, m), 6.848 (1H, dd, J=8.8 Hz, 1.4 Hz), 5.098 (2H, s), 4.600 (2H, brs), 2.963 (2H , t, J=7.4 Hz), 2.721 (2H, t, J=7.4 Hz), 1.941 (2H, t, J=5.4 Hz).
³¹ P NMR (CDCl ₃ ): δ = -1.85.
HRMS (ESI-TOF, [MH] ^- ): C ₂₈ H ₂₉ Cl ₂ NO ₁₀ P ^- : Calculated value 640.0912. Found value 640.0942.
Elemental analysis: C ₂₈ H ₃₀ Cl ₂ NO ₁₀ P・2.6 CF ₃ CO ₂ H: Calculated C, 42.47; H, 3.50; N, 1.49. Found C, 42.25; H, 3.55; N, 1.59.
Mp: 201-204°C (white powder).

[Example 7]
Synthesis of O-((3-((3-(2-((3-(4-bromolophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was carried out in the same manner as in Example 1 except that the compound 40 synthesized below was used instead of the compound 31, and column chromatography (chloroform:methanol:acetic acid=8:1:1 to 7: 1:2) and the resulting colorless oil was dissolved in dichloromethane and TFA at 0° C. and then dried under vacuum at 40° C. overnight to give the TFA salt of the title compound (44.5 mg, 0.0682 mmol, final). The yield of the process was 85%, and white powder) was obtained.
¹ H NMR (400 MHz, CDCl ₃ /TFA-d)): δ = 7.429 (2H, dt, J=8.92 Hz, 2.62 Hz), 7.350 (1H, t, J=7.88 Hz), 7.210-7.141 (2H , m), 7.097 (1H, d, J=7.28 Hz), 7.045 (1H, s), 6.952 (1H, dd, J=8.08 Hz, 0.96 Hz), 6.923-6.857 (4H, m), 5.088 (2H , s), 4.620 (2H, brs), 4.500 (1H, brs), 4.195 (2H, t, J=6.18 Hz), 4.047 (2H, d, J=4.00 Hz), 2.963 (2H, t, J= 7.42 Hz), 2.717 (2H, t, J=7.46 Hz), 1.972-1.943 (2H, m).
³¹ P NMR (CDCl ₃ ): δ = -1.41
HRMS (ESI-TOF, [MH] ⁺ ): C ₂₈ H ₃₀ ClNO ₁₀ P ⁺ : Calculated value 650.0796, 652.0776. Found value 650.0810, 652.0795.
Elemental analysis: C ₂₈ H ₃₁ BrNO ₁₀ P.0.7CF ₃ CO ₂ H: Calculated C, 48.22; H, 4.36; N, 1.91. Found C, 48.22; H, 4.43; N, 1.85.

[Example 8]
Synthesis of O-((3-((3-(2-((3-(4-(tert-butyl)phenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that the compound 42 synthesized below was used instead of the compound 31, and in the final step, column chromatography (chloroform:methanol:water=9:1:0 to 65: 25:4) to give the TFA salt of the title compound (48.0 mg, 0.0762 mmol, 51% yield in the final step, white powder).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.369-7.298 (3H, m), 7.203-7.065 (4H, m), 6.944-6.875 (5H, m), 5.074 (2H, s), 4.556 (2H) , brs), 4.453 (1H, brs), 4.196 (2H, d, J = 6.00 Hz), 3.952 (2H, brs), 1.910 (2H, brs), 1.318 (9H, s).
³¹ P NMR (CDCl ₃ ): δ = -2.19.
HRMS (ESI-TOF, [MH] ^- ): C ₃₂ H ₃₉ NO ₁₀ P ^- : Calculated value 628.2317. Measured value 628.2324.
Elemental analysis: C ₃₂ H ₄₀ NO ₁₀ P・2.5 CF ₃ CO ₂ H: Calculated value C, 48.58; H, 4.68; N, 1.53. Found value C, 48.46; H, 4.86; N, 1.71.
Mp: 185-187°C (white powder).

[Example 9]
O-((3-((3-(2-((3-([1,1'-biphenyl]-4-yloxy
Synthesis of Si)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that the compound 43 synthesized below was used instead of the compound 31, and in the final step column chromatography (chloroform:methanol:acetic acid=9:1:0-8: 1:1) and the resulting colorless oil was dissolved in dichloromethane and TFA at 0° C. and then dried under vacuum at 40° C. overnight to give the TFA salt of the title compound (41.8 mg, 0.0644 mmol, final). The yield of the process was 56%, and white powder was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.578-7.550 (4H, m), 7.452-7.434 (2H, m), 7.380-7.315 (2H, m), 7.213-7.162 (2H, m), 7.116 -7.056 (4H, m), 7.011 (1H, dd, J=8.08, 0.96 Hz), 6.917-6.883 (2H, m), 5.095 (2H, s), 4.600-4.587 (2H, m), 4.474 (1H , brs), 4.169 (2H, t, J=6.26 Hz), 4.018 (2H, brs), 2.968 (2H, t, J=7.44 Hz), 2.716 (2H, t, J=7.48 Hz), 1.943-1.914 (2H, m).
³¹ P NMR (CDCl ₃ ): δ = -1.36.
HRMS (ESI-TOF, [MH] ^- ): C ₃₄ H ₃₅ NO ₁₀ P ^- : Calculated value 648.2004. Measured value 648.2014.
Elemental analysis: C ₃₄ H ₃₆ NO ₁₀ P・1.5CF ₃ CO ₂ H: Calculated C, 54.15; H, 4.61; N, 1.71. Found C, 54.21; H, 4.86; N, 1.78.

[Example 10]
O-((3-((3-(2-([1,1'-biphenyl]-3-ylmethoxy)phenyl)
Synthesis of phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that the compound 47 synthesized below was used instead of the compound 31, and in the final step column chromatography (chloroform:methanol:acetic acid=9:1:0-8: 1:1 to 7:1:2, chloroform:methanol:acetic acid=8:1:1 to 7:1:2), and the acetate salt of the title compound (18.6 mg, 0.033 mmol, yield of final step 39) %, colorless solid) was obtained. The obtained acetate salt was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (white solid) of the title compound.
¹ H-NMR(CDCl _{3 /} TFA-d): δ=7.633 (1H, s), 7.575 (3H, t, J=6.4Hz), 7.468-7.333 (5H, m), 7.210 (1H, t, J =7.4Hz), 7.104 (1H, d, J=6.8Hz), 6.972 (1H, d, J=8.0Hz), 6.910 (1H, t, J=7.2Hz), 5.161 (2H, s), 4.566- 4.440 (3H, m), 4.130 (2H, brs), 3.969 (2H, brs), 2.988 (2H, t, J=7.2Hz), 2.734 (2H, t, J=7.2Hz), 1.863 (2H, brs) ).
³¹ P-NMR (CDCl ₃ /TFA-d): δ = -1.53.
HRMS (ESI-TOF, [MH] ^- ): C ₂₈ H ₃₁ NO ₉ P ^- : Calcd 556.1742. Found 556.1744. Mp: 134.0℃-137.5℃, colorless cube solid.
Elemental analysis: C ₂₈ H ₃₂ NO ₉ P/0.9CF ₃ COOH: Calculated C, 54.22; H, 5.02; N, 2.12. Found C, 54.06; H, 5.25; N, 2.17.

[Example 11]
O-((3-((3-(3-([1,1'-biphenyl]-3-ylmethoxy)f
Synthesis of phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that the compound 48 synthesized below was used instead of the compound 31, and in the final step, column chromatography (chloroform:methanol:acetic acid=9:1:0-8: 1:1 to 7:1:2, chloroform:methanol:acetic acid=8:1:1 to 7:1:2), and the acetate salt of the title compound (24.3 mg, 0.044 mmol, final step yield 60) %, white solid) was obtained. The obtained acetate salt was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (white solid) of the title compound.
¹ H-NMR(CDCl _{3 /} TFA-d): δ=7.636 (1H, s), 7.582 (2H, d, J=7.2Hz), 7.471-7.333 (6H, m), 7.226 (1H, t, J =7.8Hz), 6.851 (3H, m), 5.161 (2H, s), 4.572-4.453 (3H, m), 4.214 (2H, brs), 4.007 (2H, brs), 2.907 (2H, t, J= 7.4Hz), 2.712 (2H, t, J=7.0Hz), 1.956 (2H, brs).
³¹ P-NMR (CDCl ₃ /TFA-d): δ = -1.60.
HRMS (ESI-TOF, [MH] ^- ): C ₂₈ H ₃₁ NO ₉ P ^- : Calcd 556.1742. Found 556.1761. Mp: 134.0℃-136.0℃, colorless plate solid.
Elemental _{analysis: C 28 H 32 NO 9 P} · 0.6CF 3 COOH:. Calculated C, 56.03; H, 5.25; N, 2.24 Found C, 55.90; H, 5.57; N, 2.13.

[Example 12]
O-(((R)-3-((3-(2-((2',6'-dimethyl-[1,1'-bi
Synthesis of phenyl]-3-yl)methoxy)phenyl)propanoyl)oxy)-2-hydroxypropoxy)(hydroxy)phosphoryl)-L-serine

Synthesis of intermediate 12-1

The compound 37 synthesized below was used instead of the compound 31, and (2S)-2-tert-butylcarbonylamino-3-[((2R)-2-(tert-butyldimethylsilyl) was used instead of the intermediate 1-2. (Oxy)-3-hydroxypropoxy)-tert-butoxyphosphoryloxy]propionic acid tert-butyl ester was used for synthesis in the same manner as in the intermediate 1-3 of Example 1, and column chromatography (final step) was performed. Purification by hexane:ethyl acetate=3:1) gave the title compound (109.8 mg, 0.118 mmol, 70%, colorless oil).
¹ H-NMR(CDCl ₃ ): δ=7.420 (2H, m), 7.152 (4H, m), 7.100 (3H, m), 6.881 (2H, m), 5.495 (1H, m), 5.146 (2H, s), 4.348 (2H, m), 4.216 (1H, m), 4.119 (1H, m), 4.029-3.821 (4H, m), 2.998 (2H, t, J=7.8Hz), 2.662 (2H, m) ), 2.011 (6H, s), 1.460 (27H, m), 0.866 (9H, s), 0.078 (3H, s), 0.056 (3H, s). ¹³ C-NMR(CDCl ₃ ): δ=172.85, 172.84, 168.31, 168.27, 156.48, 155.25, 141.45, 141.27, 137.43, 135.95, 130.06, 129.06, 128.72, 128.51, 127.74, 127.53, 127.29, 127.08, 125.34, 120.75, 111.80, 83.85, 83.78, 82.61, 79.90. 69.15, 69.11, 69.06, 69.02, 67.85, 67.80, 67.51, 67.48, 67.43, 65.12, 65.08, 54.56, 54.42, 54.38, 54.34, 33.97, 29.80, 29.76, 29.73, 28.29, 27.94, 26.07, 25.64, 20.79, 18.00. -4.80, -4.87.
³¹ P-NMR (CDCl ₃ ): δ=-5.61, -5.79.
HRMS (ESI-TOF, [M+Na] ⁺ ): C ₄₉ H ₇₄ NNaO ₁₂ PSi ⁺ : Calculated 950.4610. Found 950.4627.

Synthesis of compound 12

Intermediate 12-1 (105.6 mg, 0.114 mmol) was dissolved in TFA (2 mL) at 0° C., the mixture was stirred at room temperature for 1.5 hr, diluted with dichloromethane (6 mL), and the solvent was evaporated. The residue was subjected to column chromatography (chloroform:methanol:acetic acid=9:1:0 to 8:1:1 to 7:1:2 to 6:1:3, chloroform:methanol:acetic acid=7:1:2 to 6:). Purification by 1:3) gave the acetate salt of the title compound (8.5 mg, 0.014 mmol, 12% yield of final step, white solid). The obtained acetate was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (orange solid) of the title compound.
¹ H-NMR(CDCl ₃ ): δ=7.449 (1H, t, J=7.4Hz), 7.384 (1H, d, J=7.6Hz), 7.213-7.063 (7H, m), 6.951 (2H, m) , 5.176 (2H, s), 4.660-3.704 (8H, m), 2.977 (2H, t, J=7.2Hz), 2.785 (2H, t, J=7.2Hz), 1.981 (6H, s).
³¹ P-NMR (CDCl ₃ ): δ=-1.72.
HRMS (ESI-TOF, [MH] ^- ): C ₃₀ H ₃₅ NO ₁₀ P ^- : Calculated value 600.2004. Found value 600.2029.

[Example 13]
O-(((R)-3-((3-(3-((2',6'-dimethyl-[1,1'-bi
Synthesis of phenyl]-3-yl)methoxy)phenyl)propanoyl)oxy)-2-hydroxypropoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was carried out in the same manner as in Example 12 except that compound 37 synthesized below was used instead of compound 36, and column chromatography (chloroform:methanol:acetic acid=9:1:0 to 8: 1:1-7:1:2-6:1:3) to give the acetate salt of the title compound (77.1 mg, 0.128 mmol, 59% yield of final step, white solid). The obtained acetate was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (brown solid) of the title compound.
¹ H-NMR(CDCl ₃ ): δ=7.454 (1H, t, J=7.6Hz), 7.385 (1H, d, J=7.6Hz), 7.243-6.995 (6H, m), 6.855 (3H, m) , 5.180 (2H, s), 4.658-3.778 (8H, m), 2.918 (2H, t, J=7.2Hz), 2.755 (2H, t, J=7.0Hz), 1.980 (6H, s).
³¹ P-NMR (CDCl ₃ ): δ=-1.42.
HRMS (ESI-TOF, [MH] ^- ): C ₃₀ H ₃₅ NO ₁₀ P ^- : Calculated value 600.2004. Found value 600.2046.
Mp: 49.0℃-52.2℃, colorless solid.
Elemental _{analysis: C 30 H 36 NO 10 P} · 1.5CF 3 COOH:. Calculated C, 51.30; H, 4.89; N, 1.81 Found C, 51.12; H, 5.26; N, 1.88.

[Example 14]
Synthesis of O-(hydroxy((R)-2-hydroxy-3-((3-(2-((3-(phenylamino)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 12 except that the compound 49 synthesized below was used instead of the compound 36, and column chromatography (chloroform:methanol:acetic acid=9:1:0-8: 1:1 to 7:1:2) to obtain the acetate salt of the title compound (54.9 mg, 0.093 mmol, yield of the final step 74%, yellow solid). The obtained acetate was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (orange solid) of the title compound.
¹ H-NMR(CDCl _{3 /} TFA-d): δ=7.767 (1H, m), 7.549 (4H, brs), 7.462 (2H, m), 7.226 (3H, m), 7.169 (1H, brs), 6.970 (1H, brs), 6.909 (1H, d, J=4.0Hz), 5.159 (2H, brs), 4.626-4.377 (5H, m), 4.198-4.084 (3H, m), 3.026 (2H, m) , 2.772 (2H, m).
³¹ P-NMR (CDCl _{3 /} TFA-d): δ = -1.80.
HRMS (ESI-TOF, [MH] ^- ): C ₂₈ H ₃₂ N ₂ O ₁₀ P ^- : Calculated value 587.1800. Found value 587.1797. Mp: 115.0℃-118.0℃, brown cube solid.
Elemental _{analysis: C 28 H 33 N 2 O} 10 P · CF 3 COOH:. Calculated C, 51.29; H, 4.88; N, 3.99 Found C, 51.47; H, 5.05; N, 3.80.

[Example 15]
O-(((R)-3-((3-(2-([1,1'-biphenyl]-3-ylmethoxy
)Phenyl)propanoyl)oxy)-2-hydroxypropoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was carried out in the same manner as in Example 12 except that the compound 47 synthesized below was used instead of the compound 36, and column chromatography (chloroform:methanol:acetic acid=9:1:0-8: Purified by 1:1 to 7:1:2 to 6:1:3, chloroform:methanol:acetic acid=8:1:1 to 7:1:2, and the acetate salt of the title compound (22.6 mg, 0.039 mmol, Yield 27% in the final step, white solid) was obtained. The obtained acetate was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (brown solid) of the title compound.
¹ H-NMR(CDCl ₃ ): δ=7.602 (4H, m), 7.448 (3H, m), 7.355 (2H, m), 7.222 (1H, t, J=7.2Hz), 7.131 (1H, m) , 7.003 (1H, m), 6.936 (1H, m), 4.597 (2H, brs), 4.456 (1H, brs), 4.249 (1H, m), 4.150-3.601 (4H, m), 3.005 (2H, t) , J=7.4Hz), 2.777 (2H, t, J=7.4Hz).
³¹ P-NMR(CDCl ₃ ): δ=-1.64. HRMS (ESI-TOF, [MH] ^- ): C ₂₈ H ₃₁ NO ₁₀ P ^- : Calculated value 572.1691. Found value 572.1738. Mp: 71.0℃-75.0℃ , Colorless solid.
Elemental analysis: C ₂₈ H ₃₂ NO ₁₀ P/1.0CF ₃ COOH/1.0H ₂ O: Calculated C, 51.07; H, 5.00; N, 1.99. Found C, 50.71; H, 5.15; N, 2.05.

[Example 16]
O-(((R)-3-((3-(3-([1,1'-biphenyl]-3-ylmethoxy
)Phenyl)propanoyl)oxy)-2-hydroxypropoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 12 except that the compound 48 synthesized below was used instead of the compound 36, and column chromatography (chloroform:methanol:acetic acid=9:1:0-8: 1:1-7:1:2-6:1:3) to give the acetate salt of the title compound (78.5 mg, 0.137 mmol, 88% yield of final step, white solid). The obtained acetate was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (brown solid) of the title compound.
¹ H-NMR(CDCl ₃ ): δ=7.641-7.313 (8H, m), 7.143 (2H, m), 6.838 (3H, m), 5.197 (2H, s), 4.660-3.784 (8H, m), 2.958 (2H, m), 2.772 (2H, t, J=7.4Hz). ³¹ P-NMR(CDCl ₃ ): δ=-1.39.
HRMS (ESI-TOF, [MH] ^- ): C ₂₈ H ₃₁ NO ₁₀ P ^- : Calculated value 572.1691. Found value 572.1741. Mp: 51.0℃-54.0℃, colorless solid.
Elemental _{analysis: C 28 H 32 NO 10 P} · 2.0CF 3 COOH:. Calculated C, 47.95; H, 4.28; N, 1.75 Found C, 47.59; H, 4.52; N, 2.04.

[Example 17]
Synthesis of O-(hydroxy(3-((3-(2-((3-(4-iodophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that the compound 41 synthesized below was used instead of the compound 31, and in the final step, column chromatography (chloroform:methanol:acetic acid=8:1:1 to 7: 1:2) and the resulting colorless oil was dissolved in dichloromethane and TFA at 0° C. and then dried under vacuum at 40° C. overnight to give the TFA salt of the title compound (36.8 mg, 0.0526 mmol, final). Process yield 48%, white powder) was obtained.
¹ H NMR (400 MHz, CDCl ₃ /TFA-d): δ = 7.609 (2H, d, J=8.76 Hz), 7.340 (1H, t, J=7.88 Hz), 7.197-7.150 (2H, m), 7.090 (1H, d, J=8.76 Hz), 7.037 (1H, s), 6.939 (1H, dd, J=8.04 Hz, 1.00 Hz), 6.911-6.863 (2H, m), 6.751 (2H, d, J =8.76 Hz), 5.073 (2H, s), 4.566 (2H, brs), 4.440 (1H, brs), 4.182 (2H, brs), 3.994 (2H, brs), 2.951 (2H, t, J=7.28 Hz ), 2.701 (2H, t, J=7.32 Hz), 1.932 (2H, brs).
³¹ P NMR (CDCl ₃ ): δ = -1.65
HRMS (ESI-TOF, [MH] ^- ): C ₂₈ H ₃₀ INO ₁₀ P ⁺ : Calc'd 698.0657. Found 698.0673.

[Example 18]
Synthesis of O-(hydroxy(3-((3-(2-((3-(4-methoxyphenoxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that the compound 44 synthesized below was used instead of the compound 31, and in the final step column chromatography (chloroform:methanol:acetic acid=8:1:1 to 7: 1:2, chloroform:methanol:acetic acid=16:2:3 to 7:1:2), and the colorless oil obtained was dissolved in dichloromethane and TFA at 0° C., and then dissolved at 40° C. under vacuum. Drying overnight gave the TFA salt of the title compound (31.7 mg, 0.0523 mmol, 52% yield of final step, white powder).
¹ H NMR (400 MHz, CDCl ₃ /TFA-d): δ = 7.327 (1H, t, J=7.82 Hz), 7.217-7.178 (1H, m), 7.153-7.096 (2H, m), 7.038 (1H , s), 7.019-6.902 (7H, m), 5.083 (2H, s), 4.653 (2H, brs), 4.532 (1H, brs), 4.205 (2H, t, J=6.20 Hz), 4.065 (2H, brs), 3.917 (3H, s), 2.969 (2H, t, J=7.46 Hz), 2.726 (2H, t, J=7.48 Hz), 1.980-1.951 (2H, m).
³¹ P NMR (CDCl ₃ ): δ = -1.31.
HRMS (ESI-TOF, [MH] ^- ): C ₂₉ H ₃₃ NO ₁₁ P ^- : Calculated value 602.1797. Measured value 602.1798.
Elemental _{analysis: C 29 H 34 NO 11 P} · 0.75CF 3 CO 2 H:. Calculated C, 53.16; H, 5.08; N, 2.03 Found C, 53.05; H, 5.30; N, 1.88.

[Example 21]
O-(hydroxy(((2R,3R)-2-(((3-(2-((3-(p-tolyloxy)benzyl)oxy)phenyl)propanoyl)oxy)methyl)tetrahydro-2H-pyran-3 -Yl) Oxy)phosphoryl)-L-serine synthesis

(2R,3R)-2-(tert-butyldimethyl-silyloxymethyl)-tetrahydro-pyran-3-ol was used in place of 1-(tert-butyldimethylsilyloxy)bropanol, and instead of compound 31, Synthesis was performed in the same manner as in Example 1 except that the synthesized compound 33 was used, and in the final step, purification was performed by column chromatography (chloroform:methanol:water=65:25:4) to give the title compound (16.4 mg, 0.0255 mmol, yield of the final step 74.94%, white solid) was obtained.
¹ H NMR (400 MHz, CDCl ₃ /TFA-d): δ = 7.320 (t, 1H, J = 8.0Hz), 7.218-7.064 (m, 6H), 6.931-6.898 (m, 5H), 5.077 (s , 2H), 4.752-4.622 (m, 2H), 4.609-4.457 (m, 2H), 4.297-4.291 (m, 1H), 4.165-4.141 (m, 2H), 3.772-3.708 (m, 1H), 3.623 -3.598 (m, 1H), 2.964-2.957 (m, 2H), 2.754-2.737 (m, 2H), 2.336 (s, 3H), 2.177-2.152 (m, 1H), 2.076-2.014 (m, 1H) , 1.756-1.741 (m, 1H), 1.584-1.527 (m, 1H)
³¹ P NMR (CDCl ₃ ): δ = 2.7
Elemental analysis: Calculated value C, 45.18%; H, 4.02%; N, 1.36% (C ₃₂ H ₃₈ NO ₁₁ P+CF ₃ CO ₂ H × 3.4); Found value C, 45.01%; H, 4.27% ;N , 1.57%.

[Example 22]
O-((((2R,3R)-2-(((3-(2-((3-(4-chlororophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)methyl)tetrahydro-2H-pyran- Synthesis of 3-yl)oxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 21 except that compound 35 synthesized below was used instead of compound 33, and purified by column chromatography (chloroform:methanol:water=65:25:4) in the final step. The TFA salt of the title compound (17.4 mg, 0.0262 mmol, yield of the final step (quantitative), white solid) was obtained.
¹ H NMR (CDCl ₃ ): δ (ppm): δ = 7.364-7.324 (m, 1H), 7.308-7.266 (m, 2H), 7.182-7.129 (m, 3H), 7.039-7.035 (m, 1H) , 6.967-6.829 (m, 5H), 5.642-5.496 (m, 1H), 5.057 (s, 2H), 4.409-4.333, (m, 3H), 4.247-4.100 (m, 3H), 4.018-3.979 (m , 1H), 3.556-3.520 (m, 1H), 3.461-3.402 (m, 1H), 2.995-2.947 (m, 2H), 2.651 (dd, 2H, J = 15.2Hz, 7.2Hz), 2.265-2.168 ( m, 1H), 2.041-1.900 (m, 1H), 1.687-1.600 (m, 1H), 1.488-1.422 (m, 27H), 1.392-1.287 (m, 1H).
¹³ C NMR (CDCl ₃ ): δ (ppm): δ = 173.03, 168.38, 157.29, 156.34, 155.62, 155.26, 139.52, 139.50, 130.17, 130.06, 129.79, 129.12, 129.07, 128.48, 127.56, 127.52, 121.99, 120.87. , 120.35, 117.94, 117.16, 111.57, 83.92, 82.69, 82.67, 79.93, 76.46, 76.39, 76.36, 76.28, 71.64, 71.59, 69.25, 67.81, 67.72, 67.43, 64.54, 64.46, 54.45, 54.36, 33.92, 29.87. , 29.77, 28.76, 28.65, 28.32, 27.95, 26.00, 25.97, 20.05.
³¹ P NMR (CDCl ₃ ): δ (ppm): δ = -5.28, -5.87.
HRMS (ESI-TOF [M+Na] ⁺ ) : C ₄₄ H ₅₉ ClNNaO ₁₃ P ⁺ calculated value 898.3305, measured value 898.3282
Elemental analysis: Calculated C, 42.94% ;H, 3.63%; N, 1.32% (C ₄₄ H ₅₉ ClNO ₁₃ P + CF ₃ CO ₂ H × 3.5); Found C, 42.74%; H, 3.88% ;N , 1.57%.

[Example 23]
Synthesis of O-(hydroxy(((2R,3R)-3-((3-(2-((3-(p-tolyloxy)benzyl)oxy)phenyl)propanoyl)oxy)tetrahydro-2H-pyran

Synthesis was performed in the same manner as in Example 23 except that compound 33 synthesized below was used instead of compound 39, and column chromatography (chloroform:methanol:acetic acid=6:1:2-6:6) was performed in the final step. Purification by 1:3) gave the title compound (6.1 mg, 0.0095 mmol, 54.4% yield of final step, white solid).
¹ H NMR (CDCl ₃ ): δ (ppm): δ = 7.319-7.280 (m, 1H), 7.199-7.030 (m, 6H), 6.908-6.869 (m, 5H), 5.062 (s, 2H), 4.991 (m, 1H), 4.521 (m, 2H), 4.447-4.412 (m, 1H), 4.096-4.071 (m, 1H), 3.979-3.900 (m, 2H), 3.779 (m, 1H), 3.592-3.540 (m, 1H), 3.073-2.917 (m, 2H), 2.873-2.723 (m, 2H), 2.329 (s, 3H), 1.802-1.652 (m, 3H), 1.432-1.406 (m, 1H)
³¹ P NMR (CDCl ₃ ): δ (ppm): δ = -2.58
HRMS (ESI-TOF [MH] -): C 32 H 37 NO 11 P - Calculated 642.2110, found 642.2121
Elemental analysis: Calculated C, 39.80% ;H, 3.34% ;N, 1.05% (C ₃₂ H ₃₈ NO ₁₁ P + CF ₃ CO ₂ H x 6); Found C, 39.72%; H, 3.66% ;N , 1.06%.
Mp 179-189°C.

[Example 24]
O-((((2R,3R)-3-((3-(2-((3-(4-chlorophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)tetrahydro-2H-pyran-2-yl) Synthesis of (methoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 23 except that compound 34 synthesized below was used instead of compound 39, and purified by column chromatography (chloroform:methanol:water=65:25:4) in the final step. The title compound (36.7 mg, 0.0553 mmol, yield of the final step 99.9%, white solid) was obtained.
¹ H NMR (CDCl ₃ ): δ (ppm): δ = 7.361 (t, 1H, J = 8.0Hz), 7.323-7.293 (m, 2H), 7.225-7.173 (m, 2H), 7.106-7.089 (m , 1H), 7.052 (m, 1H), 6.917-6.899 (m, 5H), 5.109 (s, 2H), 5.031(m, 1H), 4.558 (m, 2H), 4.468 (m, 1H), 4.144- 4.117 (m, 1H), 3.981-3.932 (m, 2H), 3.819 (m, 1H), 3.634-3.582 (m, 1H), 3.060-2.945 (m, 2H), 2.847-2.698 (m, 2H), 1.835-1.689 (m, 3H), 1.470-1.422 (m, 1H)
³¹ P NMR (CDCl ₃ ): δ (ppm): δ = -2.69
HRMS (ESI-TOF [MH] ^- ): C ₃₁ H ₃₄ FNO ₁₁ P ^- Calc 662.1563, Found 662.1544.
Elemental analysis: Calculated C, 37.31% ;H, 3.28% ;N, 1.01% (C ₃₁ H ₃₅ FNO ₁₁ P + CF ₃ CO ₂ H × 6 + H ₂ O × 2); Found C, 37.14%; H, 3.42%; N, 1.30%.
Mp 178-189°C.

[Example 25]
O-((((2R,3R)-3-((3-(2-((3-(2-fluorophenoxy)benzyl)oxy)phenyl)propanoyl)oxy)tetrahydro-2H-pyran-2-yl) Synthesis of (methoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 21 except that the compound 39 synthesized below was used instead of the compound 33, and purified by column chromatography (chloroform:methanol:water=65:25:4) in the final step. Thus, a TFA salt of the title compound (46.9 mg, 0.0729 mmol, yield of final step 107.9%, white solid) was obtained.
¹ H NMR (CDCl ₃ ): δ (ppm): δ = 7.311 (t, 1H, J = 0.8Hz), 7.202-7.014 (m, 8H), 6.904-6.869 (m, 3H), 5.067 (s, 2H ), 4.990 (m, 1H), 4.501-4.449 (m, 2H), 4.430-4.404 (m, 1H), 4.095-4.070 (m, 1H), 3.931-3.885 (m, 2H), 3.768 (m, 1H ), 3.584-3.533 (m, 1H), 3.024-2.904 (m, 2H), 2.808-2.658 (m, 2H), 1.787-1.641 (m, 3H), 1.423-1.30 (m, 1H).
³¹ P NMR (CDCl ₃ ): δ (ppm): δ = -2.95.
HRMS (ESI-TOF [MH] ^- ) : C ₃₁ H ₃₄ FNO ₁₁ P ^- calculated value 646.1859, found value 646.1865.
Elemental analysis: Calculated C, 42.88% ;H, 3.59% ;N, 1.30% (C ₃₁ H ₃₅ FNO ₁₁ P + CF ₃ CO ₂ H x 3.8); Found C, 42.91%; H, 3.88% ;N , 1.39%.
Mp 170-190°C.

[Example 30]
Synthesis of 3-(2-((3-phenoxybenzyl)oxy)phenyl)propanoic acid

Synthesis of Intermediate 30-1

To a solution of methyl 3-(2-hydroxyphenyl)propionate (149.8 mg, 0.831 mmol), 3-phenoxybenzyl alcohol (118.2 mg, 0.590 mmol) and triphenylphosphine (198.1 mg, 0.755 mmol) in toluene (5 mL). , DEAD (2M toluene solution, 374.6 μL, 0.749 mmol) was added dropwise at room temperature, and the mixture was stirred at 70° C. for 3 hours. The solvent of the reaction mixture was evaporated, and the residue was purified by column chromatography (hexane:ethyl acetate=15:1) to give the title compound (200.2 mg, 0.552 mmol, 94%, yellow oil).
¹ H NMR (CDCl ₃ ): δ (ppm): δ = 7.340 (3H, m), 7.158 (3H, m), 7.144 (1H, m), 7.075 (1H, m), 7.025 (2H, m), 6.893 (1H, m), 6.864 (1H, m), 5.064 (2H, s), 2.636 (3H, s), 2.972 (2H, t, J = 7.74 Hz), 2.609 (2H, t, J = 7.74Hz ).

Synthesis of compound 30

Intermediate 30-1 (176.0 mg, 0.486 mmol) was dissolved in methanol (2 mL) and THF (2 mL), sodium hydroxide (2N aqueous solution, 2 mL) was added, and the mixture was stirred at room temperature for 1 hr. 2N Hydrochloric acid was added until the pH of the aqueous layer was 2 to acidify the reaction mixture. The solution was extracted 3 times with ethyl acetate (20 mL x 3). The organic layers were collected, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate=1:1) to give the title compound (149.6 mg, 0.429 mmol, 88%, colorless oil).
¹ H NMR (CDCl ₃ ): δ (ppm): δ = 10.932 (1H, brs), 7.341 (3H, m), 7.713 (3H, m), 7.112 (1H, m), 7.067 (1H, m), 7.029 (2H, m), 6.966 (1H, m), 6.911 (1H, m), 6.882 (1H, m), 5.065 (2H, s), 2.975 (2H, t, J = 7.68Hz), 2.651 (2H , t, J = 7.68Hz).
¹³ C NMR (CDCl ₃ ): δ (ppm): δ = 178.82, 157.70, 156.88, 156.37, 139.20, 130.14, 129.93, 129.78, 128.84, 127.68, 123.47, 121.54, 120.88, 119.19, 118.00, 117.04, 111.58, 69.34. , 33.81, 25.86
HRMS (ESI, [MH] ^- : C ₂₂ H ₁₉ O ₄ ^- calculated 347.1289, found 347.1318.

[Example 31]
Synthesis of 3-(2-((3-(o-tolyloxy)benzyl)oxy)phenyl)propanoic acid

Synthesis of Intermediate 31-1

In a 100 ml round bottom flask containing anhydrous dichloromethane (20 mL) solution of copper acetate (452.6 mg, 2.492 mmol), anhydrous pyridine (0.200 mL, 2.483 mmol), 4Å molecular sieve, o-cresol (289.1 mg, 2.673 mmol). ) And 3-formylphenylboronic acid (566.6 mg, 3.779 mmol) were added and the reaction mixture was stirred at room temperature for 17.5 hours. did. The mixture was filtered over Celite® and the solvent was evaporated to give a green solid. The residue was purified by column chromatography (n-hexane:diethyl ether=20:1) and dried under vacuum overnight to give the title compound (298.7 mg, 1.407 mmol, 53%).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 9.938 (1H, s), 7.548 (1H, dt, J = 7.52 Hz, 1.14 Hz), 7.465 (1H, t, J = 7.80 Hz), 7.335 (1H , dd, J = 2.40 Hz, 0.72 Hz), 7.279 (1H, d, J = 7.44 Hz), 7.226-7.183 (2H, m), 7.124 (1H, td, J = 7.42 Hz, 1.16 Hz), 6.942 ( 1H, d, J = 8.00 Hz), 2.214 (3H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 191.71, 158.79, 153.45, 137.98, 131.72, 130.32, 130.21, 127.41, 124.86, 124.02, 123.11, 120.27, 116.46, 16.08.
HRMS (ESI-TOF, [M+Na] ⁺ ): C ₁₄ H ₁₂ NaO ₂ ⁺ : calcd 235.0730. found 235.0703.

Synthesis of Intermediate 31-2

To a solution of intermediate 31-1 (294.8 mg, 1.389 mmol) in methanol (10 mL), sodium borohydride (111.6 mg, 1.389 mmol) was added little by little at 0°C, and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was diluted with dichloromethane (10 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and water (10 mL). The solution was extracted 3 times with dichloromethane (20 mL x 3), the organic layers were combined, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (257.0 mg, 1.199 mmol, 88%, colorless oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.290-7.237 (2H, m), 7.183-7.139 (1H, m), 7.060 (1H, td, J = 10.5 Hz, 1.24 Hz), 7.025 (1H, dd, J = 7.56 Hz, 0.28 Hz), 6.915-6.893 (2H, m), 6.822-6.796 (1H, m), 4.628 (2H, s), 2.228 (3H, s), 1.780 (1H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 158.21, 154.21, 142.82, 131.46, 130.05, 129.78, 127.15, 124.12, 120.67, 119.90, 116.30, 115.54, 64.98, 16.15.
HRMS (ESI-TOF, [M+Na] ⁺ ): C ₁₄ H ₁₄ NaO ₂ ⁺ : Calc'd 237.0886. Found 237.0914.

Synthesis of Intermediate 31-3

To a solution of methyl 3-(2-hydroxyphenyl)propionate (342.6 mg, 1.901 mmol), intermediate 31-2 (238.9 mg, 238.9 mmol), triphenylphosphine (594.5 mg, 2.267 mmol) in toluene (15 mL), DEAD (2M toluene solution, 1.0 mL) was added dropwise at room temperature, and the reaction mixture was stirred at 70° C. for 3.8 hours under an argon atmosphere. The solvent of the reaction mixture was evaporated, and the residue was purified by column chromatography (n-hexane:ethyl acetate=15:1) to obtain the title compound ((375.6 mg, 0.9977 mmol, 89%, pink oil). It was
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.297 (1H, t, J = 7.8 Hz), 7.252-7.237 (1H, m), 7.185-7.133 (3H, m), 7.102-7.052 (2H, m ), 6.946-6.836 (5H, m), 5.033 (2H, s), 3.633 (3H, s), 2.952 (2H, t, J = 7.6 Hz), 2.595 (2H, t, J = 7.6 Hz), 2.215 (3H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.69, 158.22, 156.34, 154.10, 139.15, 131.46, 130.11, 130.09, 129.79, 129.10, 127.53, 127.17, 124.21, 120.77, 120.67, 120.04, 116.39, 115.45, 111.50. , 69.29, 51.43, 33.95, 26.13, 16.12.
HRMS (ESI-TOF, [M+Na] ⁺ ): C ₂₄ H ₂₄ NaO ₄ ⁺ : Calcd 399.1567. Found 399.1566.

Synthesis of compound 31

Intermediate 31-3 (360.9 mg, 0.9587 mmol) was dissolved in methanol (2 mL) and THF (2 mL), sodium hydroxide (2N aqueous solution, 2 mL) was added, and the mixture was stirred at room temperature for 3.5 hr. 2N Hydrochloric acid was added until the pH of the aqueous layer was 2 to acidify the reaction mixture. The solution was extracted 3 times with ethyl acetate (20 mL x 3). The organic layers were collected, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (n-hexane:ethyl acetate=2:1) to give the title compound (335.0 mg, 0.9243 mmol, 96%, colorless oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.298 (1H, t, J = 7.90 Hz), 7.247-7.227 (1H, m), 7.180-7.140 (1H, m), 7.100-7.047 (2H, m) ), 6.936-6.837 (5H, m), 5.032 (2H, s), 2.943 (2H, t, J = 7.66 Hz), 2.628 (2H, t, J = 7.66 Hz), 2.208 (3H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 179.31, 158.26, 156.33, 154.06, 139.07, 131.47, 130.16, 130.10, 129.83, 128.77, 127.64, 127.18, 124.24, 120.80, 120.65, 120.11, 116.46, 115.33, 111.51. , 69.31, 33.82, 25.81, 16.12.
HRMS (ESI-TOF, [MH] ^- ): C ₂₃ H ₂₁ O ₄ ^- : Calculated value 361.1445. Found 361.1469.
Elemental analysis: C ₂₃ H ₂₂ O ₄ .0.1AcOEt: Calculated value C, 75.71; H, 6.19. Found value: C, 75.42; H, 6.41.

[Example 32]
Synthesis of 3-(2-((3-(m-tolyloxy)benzyl)oxy)phenyl)propanoic acid

Synthesis was performed in the same manner as in Example 31 except that m-cresol was used instead of o-cresol, and column chromatography (n-hexane:ethyl acetate=1:1, dichloromethane:methanol=30) was performed in the final step. 1) and the title compound (219.8 mg, 0.6065 mmol, 33%, colorless oily substance) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.326 (1H, t, J=8.0 Hz), 7.224-7.134 (4H, m), 7.042 (1H, s), 6.955-6.800 (6H, m), 5.055 (2H, s), 2.969 (2H, t, J=7.6 Hz), 2.642 (2H, t, J=7.6 Hz), 2.317 (3H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 178.72, 157.79, 156.82, 156.37, 139.96, 139.15, 130.11, 129.87, 129.46, 128.84, 127.65, 124.28, 121.39, 120.85, 119.86, 117.92, 117.00, 116.18, 111.58. 69.35, 33.79, 25.84, 21.33.
HRMS (ESI-TOF, [MH] ^- ): C ₂₃ H ₂₇ O ₄ ^- : Calculated 361.1445. Found 361.1447.

[Example 33]
Synthesis of 3-(2-((3-(p-tolyloxy)benzyl)oxy)phenyl)propanoic acid

Synthesis was performed in the same manner as in Example 31 except that p-cresol was used instead of o-cresol, and column chromatography (n-hexane:ethyl acetate=2:1) was used in the final step, followed by n. Purification by recrystallization with -hexane and dichloromethane gave the title compound (595.5 mg, 1.643 mmol, 73%, white powder).
¹ H NMR (CDCl ₃ ): δ=7.311 (1H, t, J=4.0 Hz), 7.186-7.108 (5H, m), 7.016 (1H, s), 6.935-6.846 (5H, m), 5.042 (2H) , s), 2.962 (2H, t, J=3.8 Hz), 2.641 (2H, t, J=3.8 Hz), 2.328 (3H, s).
¹³ C NMR (CDCl ₃ ): δ=179.06, 158.25, 156.36, 154.30, 139.07, 133.19, 130.28, 130.12, 129.83, 128.80, 127.66, 121.12, 120.82, 119.41, 117.45, 116.47, 111.53, 69.33, 33.82, 25.85, 20.69.
HRMS (ESI-TOF, [MH] ^- ): C ₂₃ H ₂₁ O ₄ ^- : Calculated value 361.1445. Found 361.1433.
Elemental analysis C ₂₃ H ₂₂ O ₄ : Calculated value C, 76.22; H, 6.12. Measured value C, 76.00; H, 6.29.
Mp: 104.5-106.0°C (recrystallized from n-hexane/CH ₂ Cl ₂ , colorless powder).

Example 34
Synthesis of 3-(2-((3-(3-chlorolophenoxy)benzyl)oxy)phenyl)propanoic acid

Synthesis was carried out in the same manner as in Example 31 except that m-chlorophenol was used instead of o-cresol, and purified by column chromatography (n-hexane:ethyl acetate=2:1) in the final step, The title compound (466.4 mg, 1.218 mmol, 99%, white powder) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.357 (1H, t, J=7.86 Hz), 7.245-7.152 (4H, m), 7.081-7.046 (2H, m), 6.999 (1H, t, J =2.12 Hz), 6.969 (1H, dd, J=2.42 Hz, 0.40 Hz), 6.915-6.848 (3H, m), 5.065 (2H, s), 2.977 (2H, t, J=7.66 Hz), 2.657 ( 2H, t, J=7.68 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 179.49, 157.96, 156.73, 156.28, 139.46, 135.03, 130.50, 130.13, 130.12, 128.78, 127.69, 123.41, 122.29, 120.93, 119.09, 118.47, 117.59, 116.92, 111.53. , 69.19, 33.91, 25.83.
HRMS (ESI-TOF, [MH] ^- ): C ₂₂ H ₁₈ ClO ₄ ^- : Calculated value 381.0899. Found 381.0913.
Elemental analysis C ₂₂ H ₁₉ ClO _4:. Calculated C, 69.02; H, 5.00 Found C, 68.72; H, 5.14.

Example 35
Synthesis of 3-(2-((3-(4-chlororophenoxy)benzyl)oxy)phenyl)propanoic acid

Synthesis was carried out in the same manner as in Example 31 except that p-chlorophenol was used in place of o-cresol, and purified by column chromatography (n-hexane:ethyl acetate=1:1) in the final step, The title compound (349.5 mg, 0.9129 mmol, 94%, white powder) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.356 (1H, t, J=7.8 Hz), 7.289 (2H, dt, J=8.8 Hz, 2.8 Hz), 7.205-7.165 (3H, m), 7.060 (1H, s), 6.974-6.862 (5H, m), 5.071 (2H, s), 2.984 (2H, t, J=7.6 Hz), 2.662 (2H, t, J=7.6 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 179.22, 157.29, 156.28, 155.58, 139.37, 130.12, 130.04, 129.74, 128.80, 128.44, 127.67, 121.94, 120.92, 120.31, 118.01, 117.12, 111.55, 69.22, 33.87. , 25.83.
HRMS (ESI-TOF, [MH] ^- ): C ₂₂ H ₁₈ ClO ₄ ^- : Calculated value 381.0899. Found value 381.0892.
Elemental _{analysis: C 22 H 19 ClO 4:} . Calculated C, 69.02; H, 5.00 Found C, 68.79; H, 5.13.

Example 36
3-(2-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy
Si) Phenyl) Propanic acid synthesis

Synthesis of intermediate 36-1

3-Bromobenzaldehyde (370.4 mg, 2.002 mmol), 2,6-dimethylphenylboronic acid (420.5 mg, 2.804 mmol), saturated aqueous sodium hydrogen carbonate solution (1 M solution, 4 mL, 4.001 mmol) in ethanol (2.2 mL) and Tetrakis(triphenylphosphine)palladium(0) (114.9 mg, 0.099 mmol) was added to a mixed solution of toluene (4 mL), and the mixture was stirred at 80° C. for 22 hours under an argon atmosphere. After cooling the reaction mixture, water (5 mL) and ethyl acetate (10 mL) were added, and the mixture was filtered over Celite (registered trademark). The aqueous layer and the organic layer were separated, the aqueous layer was extracted twice with ethyl acetate (20 mL), the organic layers were combined and extracted with brine (30 mL), and the remaining aqueous layer was extracted with ethyl acetate (20 mL). It was extracted with (mL). The organic layers were collected, dried over sodium sulfate, the solvent was evaporated, and the residue was purified by column chromatography (hexane:diethyl ether=60:1-50:1) to give the title compound (347.8 mg, 1.655 mmol, 83). %, colorless oily substance) was obtained.
¹ H-NMR(CDCl ₃ ): δ = 10.067 (1H, s), 7.889 (1H, dt, J=1.4, 7.7Hz), 7.698 (1H, dt, J=0.4, 1.8Hz), 7.618 (1H, t, J=7.6Hz), 7.450 (1H, dt, J=1.6, 7.6Hz), 7.209 (1H, m), 7.136 (2H, m), 2.029 (6H, s). ¹³ C-NMR(CDCl ₃ ): δ=192.31, 142.11, 140.22, 136.73, 135.80, 135.30, 130.50, 129.23, 128.01, 127.51, 127.48, 20.79.

Synthesis of intermediate 36-2

Synthesis was performed in the same manner as in Example 31 except that Intermediate 36-1 was used instead of Intermediate 31-1, and column chromatography (n-hexane:ethyl acetate=1:0 to 4 was performed in the final step). : 1-2:1) to give the title compound (229.1 mg, 0.636 mmol, 83%, white solid).
¹ H-NMR(CDCl ₃ ): δ =7.431 (2H, m), 7.210-7.097 (7H, m), 6.908 (2H, m), 5.148 (2H, s), 3.008 (2H, t, J=7.8 Hz), 2.695 (2H, m), 2.025 (6H, s). ¹³ C-NMR(CDCl ₃ ): δ=178.93, 156.52, 141.47, 141.34, 137.34, 136.00, 130.08, 128.85, 128.72, 128.57, 127.85, 127.64, 127.29, 127.08, 125.42, 120.79, 111.73, 69.89, 33.82, 25.97, 20.80.
HRMS (ESI-TOF, [MH] ^- ): C ₂₄ H ₂₃ O ₃ ^- : Calculated value 359.1653. Found value 359.1673. Elemental analysis: C ₁₇ H ₂₆ O ₃ :Calculated value C, 79.97; H, 6.71; N, 0.00. Found C, 79.59; H, 6.84; N, 0.00. Mp: 117.5-120.0°C, colorless solid.

[Example 37]
3-(3-((2',6'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy
Si) Phenyl) Propanic acid synthesis

Synthesis was performed in the same manner as in Example 36 except that methyl 3-(3-hydroxyphenyl)propionate was used instead of methyl 3-(2-hydroxyphenyl)propionate, and column chromatography ( The mixture was purified by hexane:ethyl acetate=1:0-4:1-2:1) to give the title compound (366.2 mg, 1.016 mmol, 98%, colorless oil).
¹ H-NMR(CDCl ₃ ): δ =7.423 (2H, m), 7.228-7.099 (6H, m), 6.825 (3H, m), 5.109 (2H, s), 2.928 (1H, t, J=7.8 Hz), 2.670 (1H, m), 2.022 (6H, s). ¹³ C-NMR(CDCl ₃ ): δ =178.33, 158.89, 141.73, 141.49, 141.31, 137.25, 136.00, 129.53, 128.67, 128.56, 127.98, 127.28, 127.07, 125.57, 120.85, 115.15, 112.74, 69.90, 35.31, 30.57, 20.82.
HRMS (ESI-TOF, [MH] ^- ): C ₂₄ H ₂₃ O ₃ ^- : Calculated value 359.1653. Found value 359.1685. Elemental analysis: C ₂₄ H ₂₄ O ₃・0.1H ₂ O: Calculated value C, 79.57; H , 6.73; N, 0.00. Found C, 79.49; H, 6.81; N, 0.00.

[Example 38]
Synthesis of 3-(2-((3-(3,4-dichlorophenoxy)benzyl)oxy)phenyl)propanoic acid

Synthesis was carried out in the same manner as in Example 31 except that 3,4-dichlorophenol was used instead of o-cresol, and purified by column chromatography (n-hexane:ethyl acetate=1:1) in the final step. The title compound (486.3 mg, 1.165 mmol, 92%, white solid) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.369 (1H, t, J=8.0 Hz), 7.356 (1H, d, J=8.8 Hz), 7.244-7.156 (3H, m), 7.095 (1H, d, J=2.4 Hz), 7.076 (1H, s), 6.950 (1H, dd, J=2.7 Hz, 0.8 Hz), 6.903 (1H, td, J=7.2 Hz, 0.8 Hz), 6.862 (1H, d , J=8.4 Hz), 6.848 (1H, dd, J=2.9 Hz, 1.4 Hz), 5.073 (2H, s), 2.980 (2H, t, J=7.6 Hz), 2.658 (2H, t, J=7.6 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ =179.33, 156.48, 156.32, 156.24, 139.63, 133.20, 131.02, 130.23, 130.15, 128.78, 127.71, 126.64, 122.61, 120.99, 120.55, 118.46, 118.15, 117.65, 111.54. , 69.15, 33.90, 25.85.
HRMS (ESI-TOF, [MH] ^- ): C ₂₂ H ₁₇ Cl ₂ O ₄ ^- : Calculated value 415.0509. Found 415.0525.
Elemental _{analysis: C 22 H 18 Cl 2 O} 4:. Calculated C, 63.32; H, 4.35 Found C, 63.05; H, 4.57.

[Example 39]
Synthesis of 3-(2-((3-(2-fluorophenoxy)benzyl)oxy)phenyl)propanoic acid

Synthesis was performed in the same manner as in Example 31 except that 2-fluorophenol was used instead of o-cresol, and purified by column chromatography (hexane:ethyl acetate=2:1 to 1:2) in the final step. The title compound (278.2 mg, 0.7602 mmol, 93.55%, colorless oil) was obtained.
¹ H NMR (CDCl ₃ ): δ (ppm): δ = 10.718 (brs, 1H), 7.431-7.392 (m, 1H), 7.283-7.132 (m, 8H), 7.043-6.936 (m, 3H), 5.126 (s, 2H), 3.064 (t, 2H, J = 7.6Hz), 2.741 (t, 2H, J = 7.6Hz).
¹³ C NMR (CDCl ₃ ): δ (ppm): δ = 179.87, 157.89, 156.44, 155.80, 153.32, 143.55, 143.43, 139.34, 130.22, 120.02, 128.90, 127.80, 125.22, 125.15, 124.88, 124.84, 122.34, 122.33. , 121.57, 121.00, 117.31, 117.13, 116.59, 115.52, 111.68, 69.34, 34.05, 25.91.
HRMS (ESI-TOF [MH] ^- ): C ₂₂ H ₁₈ FNaO ₄ ^- calculated 365.1195, found 365.1223.
Calcd C, 71.72%; H, 5.28 %; N, 0.00% (C 22 H 19 FNaO 4 + ethyl acetate × 0.1); Found C, 71.42%; H, 5.27 %; N, 0.00%.

[Example 40]
Synthesis of 3-(2-((3-(4-bromolophenoxy)benzyl)oxy)phenyl)propanoic acid

Synthesis was performed in the same manner as in Example 31 except that 4-bromophenol was used instead of o-cresol, and column chromatography (n-hexane:ethyl acetate=6:1 to 2:1) was used in the final step. To give the title compound (130.0 mg, 0.3042 mmol, 92%, white powder).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.420 (2H, dt, J=8.88 Hz, 2.70 Hz), 7.346 (1H, t, J=7.88 Hz), 7.193-7.153 (3H, m), 7.047 (1H, s), 6.952-6.848 (5H, m), 5.060 (2H, s), 2.970 (2H, t, J=7.70 Hz), 2.649 (2H, t, J=7.72 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 178.98, 157.15, 156.28, 156.19, 139.39, 132.72, 130.14, 130.07, 128.80, 127.69, 122.03, 120.93, 120.72, 118.11, 117.22, 115.89, 111.54, 69.21, 33.83. , 25.85.
HRMS (ESI-TOF, [MH] ^- ): C ₂₂ H ₁₈ BrO ₄ ^- : Calculated 425.0394, 427.0373. Found 425.0420, 427.0401.
Elemental _{analysis: C 22 H 19 BrO 4:} . Calculated C, 61.84; H, 4.48 Found C, 61.54; H, 4.59.

Example 41
Synthesis of 3-(2-((3-(4-iodophenoxy)benzyl)oxy)phenyl)propanoic acid

Synthesis was performed in the same manner as in Example 31 except that 4-iodophenol was used instead of o-cresol, and column chromatography (n-hexane:ethyl acetate=6:1 to 4:1 to 1) was performed in the final step. 2:1) and the title compound (216.7 mg, 0.4569 mmol, 90%, pale greenish white powder) was obtained.
HRMS (ESI-TOF, [MH] ^- ): C ₂₂ H ₁₈ IO ₄ ^- : Calculated value 473.0255. Found 473.0283.

Example 42
Synthesis of 3-(2-((3-(4-(tert-butyl)phenoxy)benzyl)oxy)phenyl)propanoic acid

Synthesis was performed in the same manner as in Example 31 except that 3-(4-tert-butylphenoxy)benzaldehyde was used instead of Intermediate 31-1, and the final step was performed by column chromatography (n-hexane:ethyl acetate). =2:1) to give the title compound (632.9 mg, 1.565 mmol, 85%, white powder).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.341 (2H, dt, J=8.8 Hz, 2.6 Hz), 7.320 (1H, t, J=7.8 Hz), 7.186-7.119 (3H, m), 7.041 (1H, s), 6.965-6.850 (5H, m), 5.052 (2H, s), 2.963 (2H, t, J=7.6 Hz), 2.643 (2H, t, J=7.6 Hz), 1.317 (9H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 178.12, 158.02, 156.38, 154.31, 146.39, 139.09, 130.15, 129.85, 128.82, 127.68, 126.58, 121.24, 120.83, 118.75, 117.72, 116.76, 111.57, 69.37, 34.31. , 33.68, 31.47, 25.90.
HRMS (ESI-TOF, [MH] ^- ): C ₂₆ H ₂₇ O ₄ ^- : Calculated 403.1915. Found 403.1900.
Elemental _{analysis: C 26 H 28 O 4:} . Calculated C, 77.20; H, 6.98 Found C, 77.05; H, 7.01.
Mp: 111.1-112.5°C (colorless cube-shaped solid, recrystallized from n-hexane/CH ₂ Cl ₂ ).

[Example 43]
3-(2-((3-([1,1'-biphenyl]-4-yloxy)benzyl)oxy
)Phenyl)propanoic acid synthesis

Synthesis was performed in the same manner as in Example 31 except that 4-phenylphenol was used instead of o-cresol, and column chromatography (n-hexane:ethyl acetate=6:1 to 2:1) was performed in the final step. To give the title compound (189.5 mg, 0.4464 mmol, 84%, white solid).
¹ H NMR (400 MHz, CDCl ₃ ): (= 7.429-7.391 (2H, m), 7.365-7.287 (2H, m), 7.186-7.147 (3H, m), 7.104-7.057 (3H, m), 6.994 (1H, dd, J=8.08 Hz, 0.92 Hz), 6.903-6.849 (2H, m), 5.056 (2H, s), 2.965 (2H, t, J=7.68 Hz), 2.638 (2H, t, J= 7.68 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): (= 179.28, 157.56, 156.44, 156.33, 140.46, 139.25, 136.49, 130.12, 129.98, 128.80, 128.74, 128.44, 127.66, 127.02, 126.87, 121.69, 120.86, 119.32, 118.07. , 117.19, 111.55, 69.29, 33.86, 25.84.
HRMS (ESI-TOF, [MH] ^- ): Calcd for C ₂₈ H ₂₃ O ₄ ^- : 423.1602. Found: 423.1631.

[Example 44]
Synthesis of 3-(2-((3-(4-methoxyphenoxy)benzyl)oxy)phenyl)propanoic acid

The title compound was purified by the same method as in Example 31 except that 4-methoxyphenol was used instead of o-cresol, and recrystallization was performed using n-hexane and dichloromethane in the final step. (217.5 mg, 0.5748 mmol, 56%, pale pink solid) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.294 (1H, t, J=7.88 Hz), 7.181-7.146 (2H, m), 7.086 (1H, d, J=7.48 Hz), 6.993-6.971 ( 3H, m), 6.903-6.842 (5H, m), 5.032 (2H, s), 3.788 (3H, s), 2.955 (2H, t, J=7.64 Hz), 2.635 (2H, t, J=7.66 Hz ).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 178.95, 158.93, 156.37, 156.04, 149.77, 139.04, 130.11, 129.80, 128.81, 127.66, 121.06, 120.83, 120.79, 116.80, 115.76, 114.91, 111.55, 69.37, 55.61. , 33.80, 25.84.
HRMS (ESI-TOF, [MH] ^- ): C ₂₃ H ₂₁ O ₅ ^- : Calculated value 377.1394. Found 377.1400.

[Example 45]
Synthesis of 3-(2-((3-benzylbenzyl)oxy)phenyl)propanoic acid

Synthesis was carried out basically in the same manner as in Example 31 except that m-benzylbenzyl alcohol was used instead of intermediate 31-2, and column chromatography (n-hexane:ethyl acetate=2) was carried out in the final step. 1, n-hexane:ethyl acetate=3:1 to 2:1) and further recrystallized with n-hexane/dichloromethane to purify the title compound (413.6 mg, 1.194 mmol, 55%, white). (Solid) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.309-7.127 (11H, m), 6.896-6.857 (2H, m), 5.031 (2H, s), 3.987 (2H, s), 2.967 (2H, t) , J=7.70 Hz), 2.653 (2H, t, J=7.70 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 179.45, 156.51, 141.49, 140.84, 137.34, 130.08, 128.93, 128.79, 128.67, 128.47, 128.38, 127.65, 127.55, 126.10, 124.78, 120.72, 69.70, 41.83, 33.89. , 25.91.
HRMS (ESI-TOF, [MH] ^- ): C ₂₃ H ₂₁ O ₃ ^- : Calc'd 345.1496. Found 345.1504.

[Example 46]
Synthesis of 3-(2-((3-(benzyloxy)benzyl)oxy)phenyl)propanoic acid

Synthesis was carried out basically in the same manner as in Example 31 except that benzyl bromide was used instead of o-cresol and m-hydroxybenzaldehyde was used instead of 3-formylphenylboronic acid, and column chromatography was performed in the final step. Purification by chromatography (n-hexane:ethyl acetate=2:1 to 0:1) gave the title compound (701.3 mg, 1.935 mmol, 87%, white solid).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.435-7.232 (6H, m), 7.184-7.144 (2H, m), 7.058 (1H, s), 7.006 (1H, d, J=7.56 Hz), 6.934-6.861 (3H, m), 5.062 (2H, s), 5.058 (2H, s), 2.993 (2H, t, J=7.72 Hz), 2.681 (2H, t, J=7.74 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 179.31, 159.02, 156.46, 138.83, 136.89, 130.07, 129.63, 128.76, 128.54, 127.91, 127.67, 127.46, 120.78, 119.42, 114.37, 113.20, 119.59, 69.93, 69.60. , 33.91, 25.91.
HRMS (ESI-TOF, [MH] ^- ): C ₂₃ H ₂₁ O ₄ ^- : Calculated 361.1445. Found 361.1445.

[Example 47]
Of 3-(2-([1,1′-biphenyl]-3-ylmethoxy)phenyl)propanoic acid
Synthesis

Synthesis was carried out in the same manner as in Example 31 except that 3-hydroxymethylbiphenyl was used instead of intermediate 31-2, and the final step was carried out by column chromatography (n-hexane:ethyl acetate=3:1). Purification gave the title compound (211.7 mg, 0.637 mmol, 95%, white solid).
¹ H-NMR(CDCl ₃ ): δ =11.572 (1H, brs), 7.686 (1H, m), 7.636 (1H, t, J=1.6Hz), 7.617 (1H, m), 7.574 (1H, dt, 1.6, 7.6Hz), 7.453 (4H, m), 7.362 (1H, m), 7.221 (2H, m), 6.944 (2H, m), 5.180 (2H, s), 3.064 (2H, m), 2.748 ( 2H, m). ¹³ C-NMR(CDCl ₃ ): δ = 179.45, 156.54, 141.56, 140.87, 137.73, 130.12, 129.03, 128.84, 128.78, 127.73, 127.40, 127.16, 126.64, 125.88, 125.77, 120.86, 111.64, 69.79, 33.99, 25.95.
HRMS (ESI-TOF, [MH] ^- ): C ₂₂ H ₁₉ O ₃ ^- : Calculated value 331.1340. Found value 331.1389. Elemental analysis: C ₂₂ H ₂₀ O ₃ :Calculated value C, 79.50; H, 6.06; N, 0.00. Found C, 79.26; H, 6.23; N, 0.00. Mp: 87.8°C-88.8°C, colorless plate solid, (recrystallized from hexane-CH ₂ Cl ₂ ).

[Example 48]
Of 3-(3-([1,1′-biphenyl]-3-ylmethoxy)phenyl)propanoic acid
Synthesis

Synthesis was carried out in the same manner as in Example 47 except that methyl 3-(3-hydroxyphenyl)propionate was used instead of methyl 3-(2-hydroxyphenyl)propionate, and column chromatography ( Purification by n-hexane:ethyl acetate=3:1) gave the title compound (185.0 mg, 0.557 mmol, 91%, white solid).
¹ H-NMR(CDCl ₃ ): δ = 11.302 (1H, brs), 7.677 (1H, m), 7.614 (2H, m), 7.569 (1H, dt, J=1.6, 7.6Hz), 7.451 (4H, m), 7.365 (1H, m), 7.231 (1H, m), 6.855 (3H, m), 5.120 (2H, s), 2.952 (2H, m), 2.694 (2H, m). ¹³ C-NMR( CDCl ₃ ): δ=178.74, 158.97, 141.81, 141.60, 140.91, 137.51, 129.60, 129.02, 128.76, 127.40, 127.20, 126.80, 126.40, 126.33, 120.93, 115.07, 112.59, 69.97, 35.39, 30.58. HRMS (ESI- TOF, [MH] ^- ): C ₂₂ H ₁₉ O ₃ ^- : Calculated value 331.1340. Measured value 331.1369. Elemental analysis: C ₂₂ H ₂₀ O ₃ :Calculated value C, 79.50; H, 6.06; N, 0.00. Measured value C, 79.44; H, 6.10; N, 0.00. Mp: 90.0°C-91.0°C, colorless plate-like solid, (recrystallized from hexane-CH ₂ Cl ₂ ).

Example 49
Synthesis of 3-(2-((3-(phenylamino)benzyl)oxy)phenyl)propanoic acid

Synthesis was performed in the same manner as in Example 31, except that the combination of ethyl 3-aminobenzoate and phenylboronic acid was used in place of the combination of o-cresol and 3-formylphenylboronic acid, and column chromatography was performed in the final step. Purification by (n-hexane:ethyl acetate=2:1 to 0:1) gave the title compound (227.0 mg, 0.653 mmol, 75% (2 steps), colorless oil).
¹ H-NMR(CDCl ₃ ): δ=7.298 (3H, m), 7.231 (2H, m), 7.182 (1H, t, J=1.8Hz), 7.111 (2H, m), 7.056 (1H, ddd, J=8.0Hz, 2.4Hz, 0.8Hz), 7.002-6.920 (4H, m), 5.085 (2H, s), 3.061 (2H, t, J=7.8z), 2.736 (2H, m). ¹³ C- NMR (CDCl ₃ ): δ=179.67, 156.41, 143.55, 142.70, 138.50, 130.06, 129.46, 129.29, 128.73, 127.67, 121.20, 120.73, 119.09, 118.15, 116.52, 115.74, 111.61, 69.50, 34.02, 25.95, 20.99. HRMS (ESI-TOF, [MH] ^- ): C ₂₂ H ₂₀ NO ₃ ^- : Calculated value 346.1449. Found 346.1458. Elemental analysis: C ₂₂ H ₂₁ NO ₃ : Found C, 76.23 H, 6.21; N, 4.09 Calculated C, 76.06; H,6.09; N, 4.03.

[Example 50]
Synthesis of 3-(3-((3-phenoxyphenoxy)methyl)phenyl)propanoic acid

Synthesis of intermediate 50-1

Lithium chloride (1.1906 g, 1.56 eq) in acetonitrile (20 mL), 3-hydroxymethylbenzaldehyde (2.4528 g) in acetonitrile (10 mL), trimethylphosphonoacetate (5.1150 g, 1.56 eq) in acetonitrile (10 mL). (mL) solution was mixed at room temperature, and the resulting mixed solution was mixed with DBU (1,8-diazabicyclo[5.4.0]-7-undecene) (4.2682 g, 1.56 equivalents) in acetonitrile (10 mL) at 0°C. The solution was added over 2 minutes and stirred at 0° C. for 20 minutes and at room temperature for 17 hours. Water (50 mL) was added, the mixture was extracted with ethyl acetate (250 mL), the organic layer was washed with brine (100 mL), and dried over magnesium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (2.5720 g, 74%, colorless oil).
¹ H-NMR (400MHz, CDCl ₃ ): 7.679 (1H, d, J=16.0Hz), 7.523 (1H, s), 7.449-7.426 (1H, m), 7.383-7.370 (2H, d-like m) , 6.444 (1H, d, J=16.0Hz), 4.713 (2H, s), 3.800 (3H, s). ¹³ C-NMR (100MHz, CDCl ₃ ): 167.42, 144.65, 141.62, 134.60, 129.06, 128.75, 127.30, 126.35, 118.00, 64.79, 51.71.
Elemental _{analysis: C 11 H 12 O 3:} . Calculated C, 68.74; H, 6.29; N, 0.00 Found C, 68.52; H, 6.30; N, 0.00.

Synthesis of intermediate 50-2

2. To a solution of intermediate 50-1 (2.2627 g) in methanol (100 mL) was added shaving-like magnesium (Magnesium turning) (2.8676 g, 10 equivalents of intermediate 50-1) at 8°C, and the mixture was heated at 12°C for 3 minutes. Stir for 5 hours. After cooling to 0° C., 10% aqueous hydrochloric acid was added, the mixture was extracted with ethyl acetate (600 mL), the organic layer was washed with brine (250 mL), and dried over magnesium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (ethyl acetate:n-hexane=3:4) to give the title compound (2.3038 g, 80%, colorless oil).
¹ H-NMR (400MHz, CDCl ₃ ): 7.291 (1H, t, J=8.0Hz), 7.219-7.202 (2H, brd m), 7.137 (1H, d, J=7.6Hz), 4.678 (2H, s) ), 3.674 (1H,s), 2.963 (2H, t, J=8.0Hz), 2.641 (2H, t, J=7.6Hz), 1.619 (1H, OH). ¹³ C-NMR (100MHz, CDCl ₃ ). : 173.32, 141.14, 140.78, 128.67, 127.48, 126.86, 124.89, 65.16, 51.60, 35.57, 30.79.
Elemental analysis: C ₁₁ H ₁₄ O ₃ +0.2H ₂ O: Calculated C, 66.78; H, 7.34; N, 0.00. Found C, 66.95; H, 7.16; N, 0.00. HRMS (ESI-TOF, [ M+Na] ⁺ ): C ₁₁ H ₁₄ NaO ₃ ⁺ : calculated for 217.08352. found for 217.08637.

Synthesis of Intermediate 50-3

To a solution of intermediate 50-2 (189.3 mg), 3-phenoxyphenol (202.9 mg, 1.2 equivalents), triphenylphosphine (303.4 mg, 1.3 equivalents) in toluene (5 mL), DEAD (40% (w/ w) Toluene solution, 0.7 mL, 1.3 eq) was added at room temperature over 5 minutes. The reaction mixture was stirred at 69-75°C for 21 hr, and then purified by column chromatography (ethyl acetate:n-hexane=1:4, ethyl acetate:n-hexane=3:80) to give the title compound (286.2 mg, 81%, colorless sticky oil) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ): 7.325 (1H, t, d, J=7.2 Hz, 1.2 Hz), 7.291 (1H, t, J=7.2Hz), 7.246 (1H, m), 7.216 (1H , t, J=8.4 Hz), 7.154 (1H, br d, J=7.6 Hz), 7.100 (1H, t, t J=7.6 Hz, 1.2 Hz), 7.013 (1H, d, d, J=8.6Hz) , 1.2 Hz), 6.713 (1H, d, d, d, J=8.4 Hz, 2.4 Hz, 0.8 Hz), 6.630 (1H, t, J=2,4 Hz), 6.603 (1H, d, d, d , J=8.0Hz, 2.2 Hz, 1.2 Hz), 4.981 (2H, s), 3.657 (3H, s), 2.958 (2H, t, J=7.6 Hz), 2.627 (2H, t, J=8.0 Hz) ^{. 13 C-NMR (100MHz,} CDCl 3): 173.20, 160.08, 158.53, 156.85, 140.91, 136.93, 130.12, 129.70, 128.75, 127.96, 127.45, 125.52, 123.39, 119.15, 111.20, 109.59, 105.65, 70.07, 51.58, 35.57, 30.83.
Elemental _{analysis: C 23 H 22 O 4:} .. Calcd C, 76.22; H, 6.12; N, 0.00 Found C, 76.02; H, 6.18; N, 0.00 HRMS (ESI-TOF, [M + Na] + ): C ₂₃ H ₂₂ NaO ₄ ⁺ : calcd 385.14103. found 385.14221.

Synthesis of compound 50

Intermediate 50-3 (272.8 mg) was dissolved in methanol (3 mL) and THF (4 mL), sodium hydroxide (2N aqueous solution, 3 mL) was added, and the mixture was stirred at room temperature for 2 hr. It was diluted with water (100 mL) and 2N hydrochloric acid (5 mL) was added to acidify the reaction mixture. The solution was extracted with ethyl acetate (125 mL), the organic layers were collected, dried over magnesium sulfate, and the solvent was evaporated to give the title compound (257.0 mg, 98%, white solid).
¹ H-NMR (400MHz, CDCl ₃ ): 7.323 (1H, d, d, J=8.2Hz, 1.2 Hz), 7.289 (1H, d, J=7.6 Hz), 7.252 (1H, m), 7.215 (1H , t, J=8.4Hz), 7.163 (1H, brd d, J=7.6 Hz), 7.098 (1H, t, t, J=7.6 Hz, 1.2 Hz), 7.011 (2H, d, d, J=8.2 Hz, 1.2 Hz), 6.713 (1H, d, d, d, J= 8.4 Hz, 2.4 Hz, 0.8 Hz), 6.633 (1H, t, J=2.4 Hz), 6.601 (1H, d, d, d, J=7.4 Hz, 2.0 Hz, 0.8 Hz), 4.984 (2H, s), 2.963 (2H, t, J=8.0Hz), 2.676 (2H, t, J=7.6 Hz).
¹³ C-NMR (100MHz, CDCl ₃ ): 178.23, 160.07, 158.53, 156.86, 140.55, 137.01, 130.14, 129,72, 128.83, 127.96, 127.46, 125.64, 123.41, 119.16, 111.23, 109.64, 105.69, 70.06, 35.35. , 30.49. HRMS (ESI-TOF, [MH] ^- ): C ₂₂ H ₁₉ O ₄ ^- : Calculated value 347.12888. Actual value 347.13222. HRMS (ESI-TOF, [M+Na] ⁺ ): C ₂₂ H ₁₉ O ₄ +Na ⁺ : Calculated value 371.12538. Found value 371.12633. Elemental analysis: C ₂₂ H ₂₀ O ₄ : Calculated value C, 75.84; H, 5.79; N, 0.00. Found value C, 75.52; H, 6.05; N, 0.00 .
Mp 68-69 °C (colorless cube-shaped solid, recrystallized from CH ₂ Cl ₂ /n-hexane).

Example 71
Synthesis of O-(hydroxy((R)-2-hydroxy-3-((3-(2-(4-phenoxybutoxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 12 except that compound 51 was used instead of compound 37, and column chromatography (chloroform:methanol:acetic acid=8:1:1 to 7:1:2) was used in the final step. To give the acetate salt of the title compound (36.2 mg, 0.065 mmol, yield of the final step 26%, white solid). The obtained acetate salt was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (white solid) of the title compound.
¹ H-NMR(CDCl ₃ /TFA-d): δ =7.292 (2H, m), 7.195 (1H, m), 7.069 (1H, dd, J=1.4Hz, 7.4Hz), 7.003 (1H, m) , 6.935 (2H, d, J=8.0Hz), 6.877 (2H, m), 4.567 (2H, brs), 4.433 (1H, brs), 4.301-3.977 (9H, m), 2.933 (2H, t, J =7.4Hz), 2.742 (2H, t, J=7.4Hz), 1.973 (4H, quintet, J=2.9Hz). ³¹ P-NMR(CDCl ₃ /TFA-d): δ =-2.00. HRMS (ESI -TOF, [MH] ^- ): C ₂₅ H ₃₃ NO ₁₁ P ^- : Calculated value 554.1797. Found value 554.1824. Mp: 145.5℃-147.0℃, colorless cube solid. Elemental analysis: C ₂₅ H ₃₄ NO ₁₁ P・0.7CF ₃ COOH: Calculated C, 49.91; H, 5.51; N, 2.20. Found C, 50.14; H, 5.79; N, 2.21.

Example 72
Synthesis of O-(hydroxy((R)-2-hydroxy-3-((3-(2-((6-phenoxyhexyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 12 except that compound 52 was used in place of compound 37, and column chromatography (chloroform:methanol:acetic acid=9:1:0 to 8:1:1) was performed in the final step. 7:1:2) to give the acetate salt of the title compound (75.0 mg, 0.128 mmol, 75% yield of final step, white solid). The obtained acetate was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (brown solid) of the title compound.
¹ H-NMR(CDCl ₃ /TFA-d): δ =7.296 (2H, t, J=8.0Hz), 7.192 (1H, m), 7.071 (1H, d, J=6.4Hz), 6.998 (1H, t, J=7.4Hz), 6.942 (2H, d, J=8.0Hz), 6.878 (2H, m), 4.487 (3H, m), 4.281-3.979 (7H, m), 2.938 (2H, t, J =7.2Hz), 2.746 (2H, t, J=7.2Hz), 1.823 (4H, quintet, J=6.4Hz), 1.526 (4H, m, J=3.5Hz). ³¹ P-NMR(CDCl ₃ /TFA -d): δ = -1.83. HRMS (ESI-TOF, [MH] ^- ):Calcd for C ₂₇ H ₃₇ NO ₁₁ P ^- : 582.2110. Found: 582.2107. Mp: 129.5℃-131.5℃, colorless cube solid Elemental analysis: C ₂₇ H ₃₈ NO ₁₁ P・0.5CF ₃ COOH: Calculated C, 52.50; H, 6.06; N, 2.20. Found C, 52.10; H, 6.31; N, 2.19.

Example 73
Synthesis of O-(hydroxy((R)-2-hydroxy-3-((3-(3-(4-phenoxybutoxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 12 except that compound 53 was used in place of compound 37, and column chromatography (chloroform:methanol:acetic acid=9:1:0 to 8:1:1) was performed in the final step. 7:1:2-6:1:3) to give the acetate salt of the title compound (67.6 mg, 0.122 mmol, 71% yield of final step, yellow solid). The obtained acetate was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (brown solid) of the title compound.
¹ H-NMR(CDCl ₃ /TFA-d): δ =7.309 (1H, m), 7.228 (1H, t, J=7.8Hz), 7.023 (1H, t, J=7.4Hz), 6.957 (2H, d, J=8.0 Hz), 6.814 (3H, m), 4.617 (2H, brs), 4.484 (1H, brs), 4.329-4.047 (9H, m), 2.919 (2H, t, J=7.6Hz), 2.756 (2H, t, J=7.4Hz), 1.967 (4H, m). ³¹ P-NMR(CDCl ₃ /TFA-d): δ =-1.70. HRMS (ESI-TOF, [MH] ^- ): C ₂₅ H ₃₆ NO ₁₀ P ^- : Calculated value 554.1797. Found value 554.1825. Mp: 140.5℃-144.0℃, colorless cube solid. Elemental analysis: C ₂₆ H ₃₄ NO ₁₁ P・0.5CF ₃ COOH: Calculated value C, 50.98. H, 5.68; N, 2.29. Found C, 51.02; H, 5.48; N, 2.32.

Example 74
Synthesis of O-(hydroxy((R)-2-hydroxy-3-((3-(3-((6-phenoxyhexyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 12 except that compound 54 was used in place of compound 37, and column chromatography (chloroform:methanol:acetic acid=9:1:0 to 8:1:1) was performed in the final step. 7:1:2 to 6:1:3) to give the acetate salt of the title compound (69.1 mg, 0.118 mmol, 69% yield of final step, white solid). The obtained acetate salt was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (white solid) of the title compound.
¹ H-NMR(CDCl ₃ /TFA-d): δ =7.297 (2H, m), 7.211 (1H, t, J=8.0Hz), 6.998 (1H, tt, J=7.4Hz, 1.1Hz), 6.946 (2H, m), 6.793 (3H, m), 4.560 (2H, brs), 4.431 (1H, brs), 4.269-3.957 (9H, m), 2.897 (2H, t, J=7.6Hz), 2.727 ( 2H, t, J=7.6Hz), 1.808 (4H, m), 1.509 (4H, m).
³¹ P-NMR(CDCl ₃ /TFA-d): δ = -1.91. HRMS (ESI-TOF, [MH] ^- ): C ₂₇ H ₃₇ NO ₁₁ P ^- : Calculated 582.2110. Found 582.2122. Mp: 138.0 ℃ -141.5 ℃, colorless cube solid. Elemental analysis: C ₂₇ H ₃₈ NO ₁₁ P・0.5CF ₃ COOH: Calculated value C, 52.50; H, 6.06; N, 2.19. Found value C, 52.60; H, 6.06; N, 2.27.

Example 75
Synthesis of O-(hydroxy(3-((3-(2-(4-phenoxybutoxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that compound 51 was used instead of compound 31, and was purified by column chromatography (chloroform:methanol:acetic acid=7:1:2) in the final step to give the title compound. Acetate (35.3 mg, 0.065 mmol, 66% yield of the final step, white solid) was obtained. The obtained acetate was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (brown solid) of the title compound.
¹ H-NMR(CDCl ₃ /TFA-d): δ =7.297 (2H, t, J=8.0Hz), 7.195 (1H, t, J=7.4Hz), 7.069 (1H, d, J=6.8Hz) , 7.009 (1H, t, J=7.4Hz), 6.945 (2H, d, J=8.0Hz), 6.876 (2H, t, J=7.2Hz), 4.576 (2H, brs), 4.467 (1H, brs) , 4.179 (4H, m), 4.039 (4H, m), 2.929 (2H, t, J=7.2Hz), 2.714 (2H, t, J=7.0Hz), 1.965 (6H, m). ³¹ P-NMR (CDCl ₃ /TFA-d): δ = -1.64. HRMS (ESI-TOF, [MH] ^- ): C ₂₅ H ₃₃ NO ₁₀ P ^- : Calculated 538.1848. Found 538.1875. Mp: 124.0℃-128.0℃ , Colorless cube-shaped solid. Elemental analysis: C ₂₅ H ₃₃ NO ₁₀ P・0.8CF ₃ COOH: Calculated C, 50.65; H, 5.56; N, 2.22. Found C, 50.58; H, 5.59; N, 2.23.

Example 76
Synthesis of O-(hydroxy(3-((3-(2-((6-phenoxyhexyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that compound 52 was used in place of compound 31, and column chromatography (chloroform:methanol:acetic acid=9:1:0 to 8:1:1) was performed in the final step. 7:1:2 to 6:1:3) to obtain the acetate salt of the title compound (50.1 mg, 0.088 mmol, 90% yield in the final step, colorless solid). The obtained acetate was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (brown solid) of the title compound.
¹ H-NMR(CDCl ₃ /TFA-d): δ =7.298 (2H, t, J=7.8Hz), 7.191 (1H, t, J=7.6Hz), 7.067 (1H, d, J=6.8Hz) , 7.011 (1H, d, J=7.2Hz), 6.953 (2H, d, J=8.0Hz), 6.876 (2H, m), 4.578-4.471 (3H, m), 4.205 (2H, brs), 4.104 ( 2H, t, J=6.6Hz), 4.003 (4H, m), 2.933 (2H, t, J=6.6Hz), 2.721 (2H, t, J=6.8Hz), 1.950 (2H, brs), 1.827 ( 4H, m), 1.521 (4H, m). ³¹ P-NMR(CDCl ₃ /TFA-d): δ = -1.65.
HRMS (ESI-TOF, [MH] ^- ): C ₂₇ H ₃₇ NO ₁₀ P ^- : Calculated 566.2161. Found 566.2187. Mp: 131.5℃-133.0℃, colorless cube solid. Elemental analysis: C ₂₇ H ₃₈ NO ₁₀ P・0.3CF ₃ COOH: Calculated value C, 55.09; H, 6.42; N, 2.33. Found value C, 54.79; H, 6.41; N, 2.23.

Example 77
Synthesis of O-(hydroxy(3-((3-(3-(4-phenoxybutoxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that compound 53 was used in place of compound 31, and column chromatography (chloroform:methanol:acetic acid=9:1:0 to 8:1:1) was performed in the final step. 7:1:2) to give the acetate salt of the title compound (37.1 mg, 0.069 mmol, yield of final step 76%, white solid). The obtained acetate was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (brown solid) of the title compound.
¹ H-NMR(CDCl ₃ /TFA-d): δ =7.299 (2H, t, J=8.0Hz), 7.214 (1H, t, J=8.0Hz), 7.006 (1H, t, J=7.4Hz) , 6.945 (2H, d, J=8.4Hz), 6.803 (2H, m), 6.762 (1H, brs), 4.582-4.478 (3H, m), 4.226 (2H, m), 4.138-4.037 (6H, m ), 2.908 (2H, t, J=7.4Hz), 2.715 (2H, t, J=7.4Hz), 1.998 (6H, m). ³¹ P-NMR(CDCl ₃ /TFA-d): δ = -1.68 . HRMS (ESI-TOF, [MH] ^- ): C ₂₅ H ₃₃ NO ₁₀ P ^- : Calculated value 538.1848. Found: 538.1858. Mp: 122.5℃-124.0℃, brown cube solid. Elemental analysis: C ₂₅ H ₃₄ NO ₁₀ P・0.5CF ₃ COOH: Calculated C, 52.35; H, 5.83; N, 2.35. Found C, 52.35; H, 5.92; N, 2.33.

Example 78
Synthesis of O-(hydroxy(3-((3-(3-((6-phenoxyhexyl)oxy)phenyl)propanoyl)oxy)propoxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that compound 54 was used instead of compound 31, and column chromatography (chloroform:methanol:acetic acid=9:1:0 to 8:1:1) was performed in the final step. 7:1:2) to obtain the acetate salt of the title compound (39.9 mg, 0.070 mmol, 85% yield in the final step, white solid). The obtained acetate salt was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (white solid) of the title compound.
¹ H-NMR(CDCl ₃ /TFA-d): δ =7.299 (2H, t, J=8.0Hz), 7.213 (1H, t, J=7.8Hz), 7.005 (1H, t, J=7.4Hz) , 6.950 (2H, d, J=8.0Hz), 6.798 (3H, m), 4.581 (2H, brs), 4.469 (1H, brs), 4.223 (2H, t, J=5.8Hz), 4.070 (6H, m), 2.902 (2H, t, J=7.6Hz), 2.713 (2H, t, J=7.4Hz), 1.973 (2H, t, J=5.2Hz), 1.812 (4H, quartet, J=6.3Hz) , 1.512 (4H, quartet, J=3.6Hz). ³¹ P-NMR(CDCl ₃ /TFA-d): δ = -1.51.
HRMS (ESI-TOF, [MH] ^- ): C ₂₇ H ₃₇ NO ₁₀ P ^- : Calculated value 566.2161. Found value 566.2204. Mp: 120.0℃-123.0℃, colorless cube solid. Elemental analysis: C ₂₇ H ₃₈ NO ₁₀ P・0.2CF ₃ COOH: Calculated C, 55.74; H, 6.52; N, 2.37. Found C, 55.44; H, 6.45; N, 2.23.

Example 79
O-(((R)-3-((3-(2-((3-(hexyloxy)benzyl)oxy)phenyl)propanoyl)oxy)-2-hydroxypropoxy)(hydroxy)phosphoryl)-L-serine Synthesis of

Synthesis was performed in the same manner as in Example 12 except that compound 59 was used in place of compound 37, and column chromatography (chloroform:methanol:acetic acid=9:1:0 to 8:1:1) was performed in the final step. 7:1:2) to obtain the acetate salt of the title compound (26.5 mg, 0.044 mmol, 33% yield in the final step, colorless solid). The obtained acetate was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (brown solid) of the title compound.
¹ H-NMR(CDCl ₃ /TFA-d): δ =7.291 (1H, t, J=7.8Hz), 7.181 (1H, m), 7.090 (1H, d, J=7.2Hz), 7.018 (1H, d, J=7.6Hz), 6.976 (1H, brs), 6.904 (3H, m), 5.054 (2H, s), 4.535-4.394 (3H, m), 4.279 -3.723 (7H, m), 2.976 (2H) , t, J=7.2Hz), 2.744 (2H, t, J=7.4Hz), 1.766 (2H, quintet, J=7.1Hz), 1.424 (2H, m), 1.320 (4H, m), 0.887 (3H , t, J=7.0Hz). ³¹ P-NMR(CDCl ₃ /TFA-d): δ = -1.81. HRMS (ESI-TOF, [MH] ^- ): C ₂₈ H ₃₉ NO ₁₁ P ^- : Calculated value 596.2266. Found 596.2306. Mp: 128.0℃-132.0℃, colorless cube solid. Elemental analysis: C ₂₈ H ₄₀ NO ₁₁ P・CF ₃ COOH: Calculated C, 50.64; H, 5.81; N, 1.97. C, 50.89; H, 5.85; N, 1.95.

Example 80
O-(((R)-3-((3-(3-((3-(hexyloxy)benzyl)oxy)phenyl)propanoyl)oxy)-2-hydroxypropoxy)(hydroxy)phosphoryl)-L-serine Synthesis of

Synthesis was performed in the same manner as in Example 12 except that compound 60 was used instead of compound 37, and column chromatography (chloroform:methanol:acetic acid=9:1:0 to 8:1:1) was performed in the final step. 7:1:2) to obtain the acetate salt of the title compound (21.3 mg, 0.036 mmol, yield of the final step 38%, white solid). The obtained acetate salt was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (orange solid) of the title compound.
¹ H-NMR(CDCl ₃ /TFA-d): δ =7.316 (1H, t, J=8.0Hz), 7.230 (1H, t, J=8.0Hz), 7.040 (2H, m), 6.945 (1H, dd, J=2.2Hz, 8.2Hz), 5.084 (2H, s), 4.616 (2H, brs), 4.457 (1H, brs), 4.330-4.014 (7H, m), 2.922 (2H, t, J=7.2 Hz), 2.756 (2H, t, J=7.2Hz), 1.767 (2H, m), 1.473-1.275 (6H, m), 0.885 (3H, m). ³¹ P-NMR(CDCl ₃ /TFA-d) : δ = -1.74. HRMS (ESI-TOF, [MH] ^- ): C ₂₈ H ₃₉ NO ₁₁ P ^- : Calculated value 596.2285. Found value 596.2266. Mp: 121.0℃-124.0℃, colorless cube solid. Elemental analysis : C ₂₈ H ₄₀ NO ₁₁ P・0.5CF ₃ COOH: Calculated value C, 53.21; H, 6.24; N, 2.14. Measured value C, 53.50; H, 6.48; N, 2.15.

Example 81
Synthesis of O-((3-((3-(2-((3-(hexyloxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that compound 59 was used instead of compound 31, and column chromatography (chloroform:methanol:acetic acid=9:1:0 to 8:1:1 to 1) was performed in the final step. 7:1:2 to 6:1:3) to obtain the acetate salt of the title compound (20.8 mg, 0.036 mmol, 55% yield in the final step, colorless solid). The obtained acetate was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (brown solid) of the title compound.
¹ H-NMR(CDCl ₃ /TFA-d): δ =7.310 (1H, t, J=7.8Hz), 7.194 (1H, t, J=7.6Hz), 7.103 (1H, m), 7.056 (1H, d, J=7.6Hz), 7.003 (1H, s), 6.909 (3H, m), 5.075 (2H, s), 4.588-4.475 (3H, m), 4.185 (2H, m), 4.101-3.971 (4H , m), 2.986 (2H, t, J=7.0Hz), 2.738 (2H, t, J=6.8Hz), 1.937 (2H, brs), 1.783 (2H, quintet, J=7.1Hz), 1.434 (2H , quintet, J=7.1Hz), 1.338 (4H, m), 0.894 (3H, t, J=6.8Hz). ³¹ P-NMR(CDCl ₃ /TFA-d): δ = -1.46. HRMS (ESI- TOF, [MH] ^- ): C ₂₈ H ₃₉ NO ₁₀ P ^- : Calculated 580.2317. Found 580.2304. Mp: 124.5℃-127.0℃, colorless cube solid. Elemental analysis: C ₂₈ H ₄₀ NO ₁₀ P・0.5. CF ₃ COOH: Calculated C, 54.54; H, 6.39; N, 2.19. Found C, 54.40; H, 6.49; N, 2.30.

Example 82
Synthesis of O-((3-((3-(3-((3-(hexyloxy)benzyl)oxy)phenyl)propanoyl)oxy)propoxy)(hydroxy)phosphoryl)-L-serine

Synthesis was performed in the same manner as in Example 1 except that compound 60 was used in place of compound 31, and column chromatography (chloroform:methanol:acetic acid=9:1:0 to 8:1:1 to 1) was performed in the final step. 7:1:2) to obtain the acetate salt of the title compound (34.4 mg, 0.059 mmol, yield of the final step 60%, colorless solid). The obtained acetate salt was dissolved in TFA, and then the solvent was distilled off to obtain a TFA salt (white solid) of the title compound.
¹ H-NMR(CDCl ₃ /TFA-d): δ =7.311 (1H, t, J=7.8Hz), 7.221 (1H, t, J=7.8Hz), 7.043 (2H, d, J=8.0Hz) , 6.937 (1H, dd, J=2.2Hz, 8.2Hz), 6.838 (3H, m), 5.081 (2H, s), 4.584 (2H, brs), 4.467 (1H, brs), 4.231 (2H, m) , 4.102-4.004 (4H, m), 2.910 (2H, t, J=7.4Hz), 2.720 (2H, t, J=7.4Hz), 1.970 (2H, brs), 1.769 (2H, m), 1.474- 1.292 (6H, m), 0.891 (3H, m). ³¹ P-NMR(CDCl ₃ /TFA-d): δ = -1.75. HRMS (ESI-TOF, [MH] ^- ): C ₂₈ H ₃₉ NO ₁₀ P ^- : Calculated 580.2317. Found 580.2356. Mp: 139.0℃-141.5℃, colorless plate solid. Elemental analysis: C ₂₈ H ₄₀ NO ₁₀ P・0.7CF ₃ COOH: Calculated C, 53.39; H, 6.20; N, 2.12. Found C, 53.39; H, 6.43; N, 2.15.

  The following scheme shows a method for synthesizing a phosphate moiety (phosphoamidite) in which amino acid moieties used in the present invention are linked.

Evaluation of agonist activity of GPR34, P2Y10 and GPR174 [Test Example 1] Evaluation of agonist activity by TGFα cleavage assay
HEK293 cells were suspended in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS) at 2.0×10 ⁵ cells/mL, and seeded in 60 mL dishes at 4 mL each. After culturing for 24 hours in the presence of 5% CO ₂ , various expression vectors were transfected using LipofectAMINE 2000 (Invitrogen). 1 μg of AP-labeled TGFα plasmid vector and 1 μg of mouse GPR34, P2Y10 or GPR174 pCAGGS plasmid vector were used per 60 mm dish. The plasmid vector was prepared by the method disclosed in Patent Documents 2 and 5. AP-labeled TGFα is a protein in which human placental alkaline phosphatase is fused to the N-terminal side of membrane-bound pro-TGFα, and the plasmid vector for AP-labeled TGFα is Tokumaru et al., J Cell Biol. It can be prepared based on the description in 151, 209-220 (2000). Twenty-four hours after transfection, cells were detached using trypsin/EDTA, resuspended in culture medium to give 2.0×10 ⁴ cells/well, and seeded on a 96-well plate. When stimulating with a compound, Hanks balanced salt solution (HBSS, containing 5 mM HEPES) was used for resuspension. After standing for 30 minutes, various concentrations of test compounds were added, and the mixture was allowed to stand for another 1 hour in the presence of 5% CO ₂ . The 96-well plate was centrifuged (190 xg, 3 minutes), and 80 µL of the supernatant was transferred to another 96-well plate. 80 μL of a reaction buffer (40 mM Tris-HCl (pH 9.5)) containing 10 mM p-nitrophenyl phosphate (p-NPP) was added to the supernatant and cells. OD405 was measured with a microplate reader (background) and after heating at 37°C for 1 hour, OD405 was measured again. For each well, AP activity was calculated by applying the value obtained by subtracting the background from the second absorbance to the following formula.

  Furthermore, a graph was created using the value obtained by subtracting the AP activity (%) of the unstimulated group as the vertical axis. The EC50 value calculated for each test compound of Examples 1 to 5, 5, 6, 8, 10 to 16, 21 to 25, 71, 72, 75, 76, 79, 81, 82 is the EC50 value of the following reference compound 1. The results of calculating the agonist activity of each compound in comparison with the above are shown in Table 3 below. The activity was calculated by plotting the compound concentration and the AP activity (%), and the activity of the reference compound 1 (LPS18:1) was +++, and the activity of the reference compound 1 was 10 times that of the +++, 100 times the activity of the reference compound 1. Is shown as ++++++, 1/10 of the activity is shown as ++, 1/100 of the activity is shown as +, and less than that is shown as −. The EC50 value of each compound is also shown in parentheses.

  In addition, for comparison, the agonist activity was also measured for compounds (compounds A to D, reference compound 2) having no substituent on the benzene ring and no modification of the linker portion between the rings. The results are shown in Table 3 below.

  As shown in Table 3, it was confirmed that all the compounds have strong agonistic activity against GPR34, P2Y10, and/or GPR174. For example, it was confirmed that the compounds of Examples 21 to 25 are agonists having selectivity for GPR34. In addition, it was confirmed that the compounds of Examples 3, 5, 6, 21, 22, 23, and 24 have higher activity against GPR34 as compared with the compounds having no substituent on the benzene ring, respectively. It was

Claims (13)

Formula (I):

[In the formula:
R ¹ is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl, hydroxy C _1-6 alkyl, C _7-14 Aralkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aryloxy, 5-10 membered Selected from heteroaryloxy, cyano, amino, nitro, trifluoromethyl, halogen atom, and hydroxy,
R ² and R ³ are independently selected from C _1-6 alkyl, C _1-6 alkoxy, and halogen atoms,
p is 0 to 5,
q and r are independently 0 to 4,
l and m are independently 0-3;
n is 0-5;
Z ¹ and Z ² are, when m is 0 or 1, one is an oxygen atom and the other is a direct bond, or both are direct bonds, and when m is 2 or 3, Z ¹ and Z ^{2 are} Are independently selected from the group consisting of oxygen atom and direct bond;
Z ³ is selected from the group consisting of an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO ₂ —, difluoromethylene, and a direct bond, wherein R ⁹ is a hydrogen atom or C _{1-. 6} alkyl (provided that when Z ³ is a direct bond, l is not 0);
R ⁴ is a hydrogen atom, C _1-6 alkyl, C _7-14 aralkyl, or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is a hydrogen atom or C _1-6 alkyl;
R ⁶ and R ⁷ are independently a hydrogen atom, C _1-6 alkyl, C _7-14 aralkyl, formyl, C _1-6 alkylcarbonyl, C _6-10 arylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkoxy selected from the group consisting of C _1-6 alkyl, and C _7-14 aralkyloxycarbonyl;
R ⁸ is a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, or C _7-14 aralkyl;
X-A-Y is

One group selected from the group consisting of
Wherein R ¹⁰ and R ¹¹ are independently hydrogen atom, halogen atom, C _1-6 alkyl optionally substituted by one or more R ¹² , hydroxy, or C _1-6 alkoxy, R ¹² is derived from hydroxy, C _1-6 alkoxy, C _3-10 cycloalkyloxy, 5-10 membered heterocyclyloxy, C _7-14 aralkyloxy, C _6-10 aryloxy, and 5-10 membered heteroaryloxy. Selected, s is 1-5, X and Y are independently CH ₂ or a direct bond;
B represents an oxygen atom or -NR ¹³ - and is, where, R ¹³ is a hydrogen atom or C _1-6 alkyl;
Any one of Q ¹ , Q ² and Q ³ is a carbon atom or a nitrogen atom, and the remaining two are carbon atoms]
Or a salt thereof (provided that (2S)-2-amino-3-[hydroxy-((2R,3S)-3-{3-[2-(3-phenoxy-benzyloxy)-phenyl]. -Propionyloxy}-tetrahydro-pyran-2-ylmethoxy)-phosphoryloxy]-propionic acid, (2S)-2-amino-3-[hydroxy-((2R,3R)-2-{3-[2-( 3-phenoxy-benzyloxy)-phenyl]-propionylmethoxy}-tetrahydro-pyran-3-yloxy)-phosphoryloxy]-propionic acid, (2S)-2-amino-3-[hydroxy-((2R,3R) -3-{3-[2-(3-phenoxy-benzyloxy)-phenyl]-propionyloxy}-tetrahydro-pyran-2-ylmethoxy)-phosphoryloxy]-propionic acid, (2S)-2-amino-3 -[Hydroxy-((2R,3S)-2-{3-[2-(3-phenoxy-benzyloxy)-phenyl]-propionyloxymethyl}-tetrahydro-pyran-3-yloxy)-phosphoryloxy]-propion Acid, (2S)-2-amino-3-[hydroxy-((2R,3S)-2-{3-[2-(3-phenoxy-benzyloxy)-phenyl]-propionyloxymethyl}-3,6 -Dihydro-2H-pyran-3-yloxy)-phosphoryloxy]-propionic acid, (2S)-2-amino-3-[hydroxy-((2R,3R)-2-{3-[2-(3- Phenoxy-benzyloxy)-phenyl]-propionyloxymethyl}-3,6-dihydro-2H-pyran-3-yloxy)-phosphoryloxy]-propionic acid, (2S,3S)-2-amino-3-[hydroxy] -((2R,3S)-3-{3-[2-(3-phenoxy-benzyloxy)-phenyl]-propionyloxy}-tetrahydro-pyran-2-ylmethoxy)-phosphoryloxy]-butyric acid, (2S, 3S)-2-Amino-3-[hydroxy-((2R,3R)-3-{3-[2-(3-phenoxy-benzyloxy)-phenyl]-propionyloxy}-tetrahydro-pyran-2-ylmethoxy )-Phosphoryloxy]-butyric acid, (2S,3S)-2-amino-3-[hydroxy-((2R,3S)-2-{3-[2-(3-phenoxy-benzyloxy)-phenyl]- Propionyloxymethyl}-tetrahydro -Pyran-3-yloxy)-phosphoryloxy]-butyric acid, (2S,3S)-2-amino-3-[hydroxy-((2R,3R)-2-{3-[2-(3-phenoxy-benzyl) (Oxy)-phenyl]-propionyloxymethyl}-tetrahydro-pyran-3-yloxy)-phosphoryloxy]-butyric acid and (2S)-2-amino-3-[hydroxy-((1R)-1-methoxymethyl-2. -{3-[2-(3-phenoxy-benzyloxy)-phenyl]-propionyloxy}-ethoxy)-phosphoryloxy]-propionic acid). Formula (II-1) or Formula (II-2) :

[In the formula:
R ¹ is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl, hydroxy C _1-6 alkyl, C _7-14 Aralkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aryloxy, 5-10 membered Selected from heteroaryloxy, cyano, amino, nitro, trifluoromethyl, halogen atom, and hydroxy,
R ³ is independently selected from C _1-6 alkyl, C _1-6 alkoxy, and halogen atoms,
p is 0 to 5,
r is 0 to 4,
m is 3 to 15;
n is 0-5;
Z ¹ and Z ² are independently selected from the group consisting of an oxygen atom and a direct bond;
R ⁴ is a hydrogen atom, C _1-6 alkyl, C _7-14 aralkyl, or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is a hydrogen atom or C _1-6 alkyl;
R ⁶ and R ⁷ are independently a hydrogen atom, C _1-6 alkyl, C _7-14 aralkyl, formyl, C _1-6 alkylcarbonyl, C _6-10 arylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkoxy selected from the group consisting of C _1-6 alkyl, and C _7-14 aralkyloxycarbonyl;
R ⁸ is a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, or C _7-14 aralkyl;
X-A-Y is

One group selected from the group consisting of
Wherein R ¹⁰ and R ¹¹ are independently hydrogen atom, halogen atom, C _1-6 alkyl optionally substituted by one or more R ¹² , hydroxy, or C _1-6 alkoxy, R ¹² is derived from hydroxy, C _1-6 alkoxy, C _3-10 cycloalkyloxy, 5-10 membered heterocyclyloxy, C _7-14 aralkyloxy, C _6-10 aryloxy, and 5-10 membered heteroaryloxy. Selected, s is 1-5, X and Y are independently CH ₂ or a direct bond;
B represents an oxygen atom or -NR ¹³ - and is, where, R ¹³ is a hydrogen atom or C _1-6 alkyl;
Any one of Q ¹ , Q ² and Q ³ is a carbon atom or a nitrogen atom, and the remaining two are carbon atoms]
Or a salt thereof. Formula (III-1) or Formula (III-2) :

[In the formula:
R ¹ is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl, hydroxy C _1-6 alkyl, C _7-14 Aralkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aryloxy, 5-10 membered Selected from heteroaryloxy, cyano, amino, nitro, trifluoromethyl, halogen atom, and hydroxy;
R ³ is independently selected from C _1-6 alkyl, C _1-6 alkoxy, and halogen atoms;
p and r are independently 0-4;
m is independently 0 to 3;
n is 0-5;
Z ¹ and Z ² are, when m is 0 or 1, one is an oxygen atom and the other is a direct bond, or both are direct bonds, and when m is 2 or 3, Z ¹ and Z ^{2 are} Are independently selected from the group consisting of oxygen atom and direct bond;
Z ³ is selected from the group consisting of an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO ₂ —, difluoromethylene, and a direct bond, wherein R ⁹ is a hydrogen atom or C _{1-. 6} alkyl;
R ⁴ is a hydrogen atom, C _1-6 alkyl, C _7-14 aralkyl, or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is a hydrogen atom or C _1-6 alkyl;
R ⁶ and R ⁷ are independently a hydrogen atom, C _1-6 alkyl, C _7-14 aralkyl, formyl, C _1-6 alkylcarbonyl, C _6-10 arylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkoxy selected from the group consisting of C _1-6 alkyl, and C _7-14 aralkyloxycarbonyl;
R ⁸ is a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, or C _7-14 aralkyl;
X-A-Y is

One group selected from the group consisting of
Wherein R ¹⁰ and R ¹¹ are independently hydrogen atom, halogen atom, C _1-6 alkyl optionally substituted by one or more R ¹² , hydroxy, or C _1-6 alkoxy, R ¹² is derived from hydroxy, C _1-6 alkoxy, C _3-10 cycloalkyloxy, 5-10 membered heterocyclyloxy, C _7-14 aralkyloxy, C _6-10 aryloxy, and 5-10 membered heteroaryloxy. Selected, s is 1-5, X and Y are independently CH ₂ or a direct bond;
B represents an oxygen atom or -NR ¹³ - and is, where, R ¹³ is a hydrogen atom or C _1-6 alkyl;
Any one of Q ¹ , Q ² and Q ³ is a carbon atom or a nitrogen atom, and the remaining two are carbon atoms;
R ¹⁵ is selected from C _3-15 alkyl, C _3-10 cycloalkyl, and 5-10 membered heterocyclyl]
Or a salt thereof.   The compound according to any one of claims 1 to 3, wherein p is 1 to 3, or a salt thereof. R ¹ is independently selected from C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, C _6-10 aryloxy, and halogen atoms. The compound or its salt as described in the item. Z ³ (CH ₂ ) _l is selected from the group consisting of an oxygen atom, —NH—, —CH ₂ —, —OCH ₂ —, and a direct bond. The described compound, or a salt thereof. The compound according to any one of claims 1 to 6, wherein R ⁵ is hydrogen atom or methyl, or a salt thereof. R ⁴ is a hydrogen atom;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ is a hydrogen atom;
The compound according to claim 1, or a salt thereof. X-A-Y

One group selected from the group consisting of
X and Y are independently CH ₂ or a direct bond;
The compound according to claim 1, or a salt thereof. Formula (IV):

[In the formula:
R ¹ is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl, hydroxy C _1-6 alkyl, C _7-14 Aralkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, cyano, amino, nitro, trifluoromethyl, halogen Selected from an atom and hydroxy,
p is 0 or 1,
Z ³ is selected from the group consisting of an oxygen atom and a direct bond]
Or a salt thereof.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a salt thereof for treating an autoimmune disease.   A lysophosphatidylserine receptor which comprises the compound or a salt thereof according to any one of claims 1 to 9 and acts on any one or more lysophosphatidylserine receptors selected from GPR34, P2Y10, and GPR174. Function regulator.   The lysophosphatidylserine receptor function regulator according to claim 12, which has a lysophosphatidylserine receptor agonist activity.