JP2016179959A - Polycyclic lysophosphatidylserine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a polycyclic lysophosphatidylserine derivative having lysophosphatidylserine receptor agonist activity or salt thereof, a fatty acid surrogate which can be used as a synthetic intermediate for these compounds, and a pharmaceutical composition or lysophosphatidylserine receptor function regulator comprising the lysophosphatidylserine derivative and salt thereof.SOLUTION: The present invention provides a polycyclic lysophosphatidylserine derivative represented by formula (I), or salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to a polycyclic lysophosphatidylserine derivative and a salt thereof. More particularly, the present invention relates to polycyclic lysophosphatidylserine derivatives having lysophosphatidylserine receptor function-regulating activity and salts thereof, and fatty acid surrogates that can be used as synthetic intermediates of these compounds. The present invention also relates to a pharmaceutical composition or a lysophosphatidylserine receptor function regulator comprising a lysophosphatidylserine derivative and a salt thereof.

Lysophospholipid is a general term for phospholipids having one acyl group. The lysophospholipid has a property that it is less hydrophobic than the diacylphospholipid constituting the cell membrane and can be easily released from the cell membrane. Some lysophospholipids function as signal molecules between cells or between membranes and have been found to have an important role in vivo. Traditionally, 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 mast cell degranulation (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 (Non-Patent Document 4). Among these, LPS ₁ has been reported to be involved in signal transduction that induces or enhances degranulation of mast cells and can be a target for the treatment of allergic diseases and chronic inflammatory diseases (Patent Documents 1 and 2). ). In addition, it is 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 screening methods for compounds useful as autoimmune therapeutic agents and lysophosphatidylserine and derivatives thereof have been found by screening methods (Patent Document 5). Autoimmune disease is a general term for diseases that cause symptoms when the immune system, which is originally a defense mechanism against foreign substances, reacts excessively and attacks even normal cells and tissues of itself. There are two broad categories: systemic autoimmune diseases that affect the whole body and organ-specific diseases that affect only specific organs. In general, autoimmune diseases often become chronic diseases or intractable diseases, and some of them are designated as diseases for which specific diseases are researched by the Ministry of Health, Labor and Welfare. Much research has been conducted on methods for treating autoimmune diseases, for example, methods for treating chronic inflammation caused by autoimmune diseases using cytokine-specific antibodies involved in inflammation (Patent Document 6), and pathogenic self. A method for treating a disease by neutralizing an antibody (Patent Document 7) has been reported. However, many causes of autoimmune diseases have not been elucidated, and effective treatments have not yet been established for many autoimmune diseases. For autoimmune diseases, drugs that suppress the immune system and anti-inflammatory drugs (steroids or non-steroid drugs) that relieve inflammation are used as the first selection agent.

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

Nature 279, 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 polycyclic lysophosphatidylserine derivative or a salt thereof, and a fatty acid surrogate that can be used as a synthetic intermediate of these compounds. Another object of the present invention is to provide a pharmaceutical composition or a lysophosphatidylserine receptor function regulator comprising the compound or a salt thereof.

  As a result of diligent research to achieve the above-mentioned problems, the present inventors have found a compound having an agonist activity of GPR34, P2Y10 and / or GPR174 or a salt thereof, and a compound having a lysophosphatidylserine receptor agonist activity or The present invention relating to the salt has been completed. In addition, as a result of diligent search for an alternative structure of the fatty acid structure contained in lysophosphatidylserine, etc., it was found that the receptor agonist activity is increased by replacing a part of the chain fatty chain structure with a polycyclic structure. The present invention relating to lysophosphatidylserine derivatives has been completed.

That is, the present invention relates to, but is not limited to, the following polycyclic compounds, intermediates (fatty acid surrogates), pharmaceutical compositions, and lysophosphatidylserine receptor function regulators.
(1) Formula (I):

[Where:
R ¹ , R ² and R ³ are independently selected from C _1-6 alkyl, C _1-6 alkoxy, and a halogen atom;
p, q and r are independently 0-4,
l and m are independently 0-3;
n is 0-5;
Z ¹ and Z ² , when m is 0 or 1, either 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 independently selected from the group consisting of oxygen atoms and direct bonds;
Z ³ and Z ⁴ are groups in which when l is 0 or 1, one is a direct bond and the other is an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO ₂ —, and difluoromethylene. Or both are direct bonds and when l is 2 or 3, Z ³ and Z ⁴ are independently an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO _2. Selected from the group consisting of-, 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 alkyl) carbonyl, (C _6-10 aryl) carbonyl, (C _1- Selected from the group consisting of ₆ alkoxy) carbonyl, C _1-6 alkoxy C _1-6 alkyl, and (C _7-14 aralkyloxy) carbonyl;
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 ¹ -Y is

A group selected from the group consisting of:
Wherein R ¹⁰ and R ¹¹ are independently a hydrogen atom, a halogen atom, C _1-6 alkyl, hydroxy, or C _1-6 alkoxy optionally substituted by one or more R ¹² , R ¹² is 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;
A ² is an oxygen atom or —NR ¹³ —, wherein 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;
A ³ is,

A group selected from the group consisting of:
Wherein B ¹ and B ² are independently selected from C _3-10 cycloalkylene, 5-10 membered heterocyclylene, C _6-10 arylene, and 5-10 membered heteroarylene,
R ¹⁴ and R ¹⁵ are 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 Selected from 10-membered heteroaryloxy, cyano, amino, nitro, trifluoromethyl, halogen atoms, and hydroxy;
R ¹⁶ is C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 Selected from membered heteroaryl, C _6-10 aryloxy, and 5-10 membered heteroaryloxy;
t is 1-5,
u is 1 to 5]
Or a salt thereof.
(2) A ³ is

And
Here, R ¹⁴ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aryl. The compound or a salt thereof according to (1), selected from oxy, 5- to 10-membered heteroaryloxy, cyano, trifluoromethyl, a halogen atom, and hydroxy.
(3) A ³ is

And
Here, R ¹⁵ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aryl. The compound or a salt thereof according to (1), selected from oxy, 5- to 10-membered heteroaryloxy, cyano, trifluoromethyl, a halogen atom, and hydroxy.
(4) A ³ is

And
Here, the compound according to (1), or a salt thereof, wherein R ¹⁶ is selected from C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl.
(5) The compound or salt thereof according to any one of (1) to (4), wherein p, q and r are 0.
(6) Z ³ (CH ₂ ) ₁ Z ⁴ is selected from the group consisting of an oxygen atom, —NH—, —CH ₂ —, —OCH ₂ —, —CH ₂ O—, and a direct bond, (1 ) To (5) or a salt thereof.
(7) The compound according to any one of (1) to (6) or a salt thereof, wherein R ⁵ is a hydrogen atom or methyl.
(8) R ⁴ is a hydrogen atom;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ is a hydrogen atom;
(1)-The compound in any one of (7), or its salt.
(9) X-A ¹ -Y is

One group selected from the group consisting of:
X and Y are direct bonds;
(1)-The compound in any one of (8), or its salt.
(10) Formula (IV):

[Where:
R ¹ , R ² and R ³ are independently selected from C _1-6 alkyl, C _1-6 alkoxy, and a halogen atom;
p, q and r are independently 0-4,
l and m are independently 0-3;
n is 0-5;
Z ¹ and Z ² , when m is 0 or 1, either one is an oxygen atom and the other is a direct bond, or both are direct bonds, and Z ¹ and Z ² are independently oxygen atoms And selected from the group consisting of direct bonds;
Z ³ and Z ⁴ are groups in which when l is 0 or 1, one is a direct bond and the other is an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO ₂ —, and difluoromethylene. Or both are direct bonds and when l is 2 or 3, Z ³ and Z ⁴ are independently an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO _2. Selected from the group consisting of-, 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;
A ³ is,

A group selected from the group consisting of:
Wherein B ¹ and B ² are independently selected from C _3-10 cycloalkylene, 5-10 membered heterocyclylene, C _6-10 arylene, and 5-10 membered heteroarylene,
R ¹⁴ and R ¹⁵ are 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 Selected from 10-membered heteroaryloxy, cyano, amino, nitro, trifluoromethyl, halogen atoms, and hydroxy;
R ¹⁶ is C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 Selected from membered heteroaryl, C _6-10 aryloxy, and 5-10 membered heteroaryloxy;
t is 1-5,
u is 1 to 5]
Or a salt thereof.
(11) A pharmaceutical composition for treating an autoimmune disease, comprising the compound according to any one of (1) to (9) or a salt thereof.
(12) The compound or salt thereof according to any one of (1) to (9), which acts on any one or more lysophosphatidylserine receptors selected from GPR34, P2Y10, and GPR174, Lysophosphatidylserine receptor function regulator.
(13) The lysophosphatidylserine receptor function regulator according to (12), which has lysophosphatidylserine receptor agonist activity.
(14) 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 , Z ³ , Z ⁴ , and A ³ are as defined in (1) above, n is preferably 1 to 3, more preferably 2, and m is preferably 0 to 3, more preferably. 1, 1 is preferably 0-3, more preferably 0, Z ¹ (CH ₂ ) _m Z ² is preferably —OCH ₂ — or —CH ₂ O—, and Z ³ (CH _{2) l} Z ⁴ is, preferably, oxygen _{atom, -NH -, - CH 2 -} , - OCH 2 -, - CH 2 O-, and is selected from the group consisting of direct bond]
The compound or its salt as described in (1) shown by these.
(15) Formula (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 , Z ³ , Z ⁴ , and A ³ are as defined in (1) above, n is preferably 1 to 3, more preferably 2, and m is preferably 0 to 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 LZ} ⁴ is preferably selected from the group consisting of an oxygen atom, —NH—, —CH ₂ —, —OCH ₂ —, —CH ₂ O—, and a direct bond, and R ¹⁰ is preferably 1 or more a of C _1-6 alkyl optionally substituted by R ^12, R ¹² is preferably a hydroxyl, C _1-6 alkoxy, C _3-10 cycloalkyloxy, 5 0-membered heterocyclyloxy, C _{7 - 14} aralkyloxy, is selected from C _6-10 aryloxy, and 5-10 membered heteroaryloxy]
The compound or its salt as described in (1) shown by these.
(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 , Z ³ , Z ⁴ , and A ³ are as defined in (1) above, n is preferably 1 to 3, more preferably 2, and m is preferably 0 to 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 ) _l Z ⁴ is preferably selected from the group consisting of an oxygen atom, —NH—, —CH ₂ —, —OCH ₂ —, —CH ₂ O—, and a direct bond, R ¹¹ is preferably hydroxy, Or C _1-6 alkoxy]
The compound or its salt as described in (1) shown by these.
(17) Formula (Id):

^{Wherein, 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, Z 3, Z 4 , And A ³ are as defined in (1) above, n is preferably 1 to 3, more preferably 2, m is preferably 0 to 3, more preferably 1, Is preferably 0 to 3, more preferably 0, and Z ¹ (CH ₂ ) _m Z ² is preferably —OCH ₂ — or —CH ₂ O—, and Z ³ (CH ₂ ) ₁ Z ⁴ Is preferably selected from the group consisting of an oxygen atom, —NH—, —CH ₂ —, —OCH ₂ —, —CH ₂ O—, and a direct bond]
The compound or its salt as described in (1) shown by these.
(18) O-((3-((3- (2-((3-((4 '-(tert-butyl)-[1,1'-biphenyl] -4-yl) oxy) benzyl) oxy) Phenyl) propanoyl) oxy) propoxy) (hydroxy) phosphoryl) -L-serine;
O-((3-((3- (2-((3-((3 '-(tert-butyl)-[1,1'-biphenyl] -4-yl) oxy) benzyl) oxy) phenyl) propanoyl) ) Oxy) propoxy) (hydroxy) phosphoryl) -L-serine;
O- (hydroxy (3-((3- (2-((3-((2'-methyl- [1,1'-biphenyl] -4-yl) oxy) benzyl) oxy) phenyl) propanoyl) oxy) Propoxy) phosphoryl) -L-serine;
O-((3-((3- (2-((3-([1,1 ′: 4 ′, 1 ″ -terphenyl] -4-yloxy) benzyl) oxy) phenyl) propanoyl) oxy) propoxy) (Hydroxy) phosphoryl) -L-serine;
O- (hydroxy (3-((3- (2-((3-((4 ′-(phenylethynyl)-[1,1′-biphenyl] -4-yl) oxy) benzyl) oxy) phenyl) propanoyl) ) Oxy) propoxy) phosphoryl) -L-serine; and O-((3-((3- (2-((3-((4 '-((4- (tert-butyl) phenyl) ethynyl)-[ 1,1′-biphenyl] -4-yl) oxy) benzyl) oxy) phenyl) propanoyl) oxy) propoxy) (hydroxy) phosphoryl) -L-serine;
Or a salt thereof.
(19) 3- (2-((3-((4 '-(tert-butyl)-[1,1'-biphenyl] -4-yl) oxy) benzyl) oxy) phenyl) propanoic acid;
3- (2-((3-((3 ′-(tert-butyl)-[1,1′-biphenyl] -4-yl) oxy) benzyl) oxy) phenyl) propanoic acid;
3- (2-((3-((2′-methyl- [1,1′-biphenyl] -4-yl) oxy) benzyl) oxy) phenyl) propanoic acid;
3- (2-((3-([1,1 ′: 4 ′, 1 ″ -terphenyl] -4-yloxy) benzyl) oxy) phenyl) propanoic acid;
3- (2-((3-((4 ′-(phenylethynyl)-[1,1′-biphenyl] -4-yl) oxy) benzyl) oxy) phenyl) propanoic acid; and 3- (2- ( (3-((4 ′-((4- (tert-butyl) phenyl) ethynyl)-[1,1′-biphenyl] -4-yl) oxy) benzyl) oxy) phenyl) propanoic acid;
Or a salt thereof.

  According to the present invention, a polycyclic lysophosphatidylserine derivative or a salt thereof, and a fatty acid surrogate that can be used as a synthetic intermediate of the compound are provided, and a pharmaceutical composition or a lysosome containing the compound or a salt thereof is provided. A phosphatidylserine receptor function modulator is provided.

  Hereinafter, the present invention will be described more specifically.

Compound or salt thereof The compound of the present invention or a salt thereof includes the compound of the above formula (I) or a salt thereof, more specifically, the compounds described in the examples described later.

  In addition, the compounds of the above formulas (I), (Ia) to (Id), and (IV) include ortho, meta, and para substituents, respectively.

  The most preferred embodiments of the present invention include the compounds shown in Table 1 below or salts thereof:

  The fatty acid surrogate which is another embodiment of the present invention includes compounds shown in Table 2 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, such as methyl, ethyl, 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 are also included.

As used herein, “(C _1-6 alkyl) carbonyl” means an alkylcarbonyl group having a C _1-6 alkyl group already defined as the alkyl moiety, such as methylcarbonyl (acetyl), ethylcarbonyl, tert- In addition to butylcarbonyl, (C _1-4 alkyl) carbonyl and the like are included.

As used herein, “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, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropyl Examples include sulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like.

“Hydroxy C _1-6 alkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of a C _1-6 alkyl group already defined as an alkyl moiety, for example, 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 a C _1-6 alkyl group which has already been 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 Toxic, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy, etc. 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” includes, for example, C _1-3 alkoxy and the like.

As used herein, “(C _1-6 alkoxy) carbonyl” means an alkoxycarbonyl group having a C _1-6 alkoxy group already defined as an alkoxy moiety, such as methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. In addition, (C _1-3 alkoxy) carbonyl and the like are included.

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

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

In the present specification, “C _2-6 alkynyl” means a linear or branched alkenyl group having 2 to 6 carbon atoms, which is a linear or branched alkynyl group containing one triple bond. And straight-chain 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 examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. C _3-10 cycloalkyl is included in the range of the above C _1-30 alkyl.

In the present specification, “C _3-10 cycloalkyloxy” includes, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

In the present specification, “C _3-10 cycloalkylene” means a divalent group in which saturated carbocyclic rings having 3 to 10 carbon atoms are connected at two positions.

  As used herein, “5- to 10-membered heterocyclyl” is a saturated or partially unsaturated fat containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and having 5 to 10 ring atoms. Means a heterocyclic group. Specific examples include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl and the like.

  In the present specification, “5- to 10-membered heterocyclyloxy” includes, for example, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, morpholinyloxy, tetrahydro Such as thiopyranyloxy.

  In the present specification, the “5- to 10-membered heterocyclylene” means a divalent group in which 5- to 10-membered heterocycles are linked at two positions.

“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 this specification, “(C _6-10 aryl) carbonyl” includes, for example, benzoyl and the like.

In the present specification, “C _6-10 arylene” means a divalent group in which C _6-10 aromatic carbocycles are linked at two positions. For example, in the case of a phenylene group, 1,2-substituted ( Ortho-substituted), 1,3-substituted (meta-substituted), 1,4-substituted (para-substituted) groups are included.

In the present specification, “C _7-14 aralkyl” means an arylalkyl group having 7 to 14 carbon atoms including an aryl group, such as benzyl, 1-phenethyl, 2-phenethyl, 1-naphthylmethyl, 2- Naphthylmethyl and the like are included. Carbon number of an alkyl group part is 1-4, for example.

“C _7-14 aralkyloxy” in the present specification includes, for example, benzyloxy, 1-phenethyloxy, 2-phenethyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy and the like.

In this specification, “(C _7-14 aralkyloxy) carbonyl” includes, for example, benzyloxycarbonyl, 1-phenethyloxycarbonyl, 2-phenethyloxycarbonyl, 1-naphthylmethyloxycarbonyl, 2-naphthylmethyloxycarbonyl, and the like. Is included.

  As used herein, “5 to 10-membered heteroaryl” refers to a monocyclic aromatic heterocyclic group having 5 to 10 ring atoms, including one or more heteroatoms selected from an oxygen atom, a nitrogen atom and a 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, oxazolyl Ruoxy, oxadiazolyloxy, thiazolyloxy, thiadiazolyloxy and the like.

  As used herein, “5- to 10-membered heteroarylene” means a divalent group in which 5- to 10-membered aromatic heterocycles are linked at two positions. For example, in the case of a 6-membered heteroarylene group, A group linked on adjacent ring atoms, a group in which another ring is present at two ring atoms at one ring, and a ring atom at three rings in one ring Groups with another linking site are included. Specific examples of the heterocyclic ring constituting the group include pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, furan, thiophene, oxazole, oxadiazole, thiazole, thiadiazole 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 Q ¹ , Q ² and Q ³ are carbon atoms, it means CH or CR ¹ .

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

  The present invention relating to the compound represented by the above formula (I) includes various stereoisomers such as tautomers, geometric isomers and optical isomers, and mixtures thereof.

  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 pharmaceutical product. 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. Specific examples of the salt include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and other mineral acids; 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, “polycyclic lysophosphatidylserine derivative” refers to a compound having a structure in which the fatty chain structure of lysophosphatidylserine is replaced with an alternative structure of a fatty acid having a plurality of three or more ring structures.

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

  Furthermore, the compound of the present invention includes hydrates, various solvates and crystal polymorphs.

The atoms (for example, hydrogen atom, carbon atom, oxygen atom, nitrogen atom, sulfur atom and phosphorus atom) contained in the compound of the present invention are isotope atoms other than the most naturally occurring isotopes. The isotope atom may be a radioactive conductor atom. That is, according to one aspect of the present invention, there is provided a compound of formula (I) as defined herein, or a salt thereof, labeled with an isotope atom. 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 a derivative thereof.

In one embodiment of the invention, the compound of the formula (I) is administered as a prodrug and is converted into the active compound in vivo. For example, R ⁴ and R ⁸ in formula (I) may be a group forming a carboxylic acid ester or a phosphoric acid ester. Specific examples thereof include 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 alkyl) carbonyloxy C _1-6 alkyl (eg, pivaloyloxymethyl), (C _1-6 alkoxy) carbonyloxy C _1-6 alkyl (eg, Isopropoxycarbonyloxymethyl), optionally substituted phenyl (eg C _1-3 alkoxyphenyl), optionally substituted benzyl (eg C _1-6 alkoxy, hydroxy, (C _1-6 alkyl)) carbonyloxy, nitro, and benzyl optionally substituted by 1 to 3 groups selected from halogen atoms), phthalidyl (e.g., 1 to 4 selected from C _1-6 alkoxy Good -isobenzofuranone 3-yl) optionally substituted by di-oxo Lennon yl methyl (e.g., optionally substituted by a group Jiokisorenon ring 5-position is selected from C _1-6 alkoxy or phenyl Jiokisorenon - 4-ylmethyl), or furylmethyl (for example, 2-furylmethyl in which the 5-position of the furan ring may be substituted with nitro).

Synthesis of a compound or salt thereof The lysophosphatidylserine receptor is composed 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. Therefore, the compounds of the present invention and salts thereof can be synthesized by systematically converting each modular structure according to the following general synthesis method. For example, a compound having the linking site (deoxytype) of formula (Id) can be synthesized by the steps shown in the following scheme.

[Wherein R ³ is as defined herein; the —O-acyl side chain corresponds to a carboxylic acid structure of formula (IV) as defined herein; 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, and PG ³ is tert-butoxycarbonyl ( Boc)].

  The compound contained in the formula (Id) can be obtained, for example, by condensing and oxidizing one of the hydroxy groups of the linking site (deoxytype) and the phosphoramidite in step a and then condensing the acyl side chain site in step b. Then, it can prepare by performing deprotection of phosphoric acid, carboxylic acid, and an amine at the process c.

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

  The acylation step of the alcohol of step b may be prepared using acid chloride, in this case, in a suitable solvent, in the presence of a suitable base (eg 4-dimethylaminopyridine, etc.) or absence of a base. Can be done below. The acylation is performed 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 to appropriate deprotection conditions, and for example, trifluoroacetic acid (TFA) can be used. Furthermore, the compound contained in the target formula (Id) can be obtained by performing substituent conversion.

  These steps are not particularly limited, but can be performed, for example, at a reaction temperature of 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 the formula (Id) is condensed with one of the hydroxy groups of the linking site (deoxytype) and the acyl side chain in step a ′, and then condensed and oxidized with the phosphoramidite in step b ′. Then, it can be prepared by 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 an amide as a linking group instead of an ester can be synthesized.

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

The amino acid moiety used in the synthesis of formula (I) can be prepared, for example, by protecting the carboxylic acid and amine of the amino acid alcohol in step a with the appropriate substituents PG ² and PG ³ .

  The protection reaction of the carboxylic acid and amine in step a can be performed by subjecting 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 formula (I) can be prepared, for example, by reacting the alcohol (amino acid moiety) synthesized in Scheme 2 with bis (diisopropylamino) -tert-butylphosphine. 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, l, m, and A ³ are as previously defined herein; PG ⁶ represents a protecting group, eg, PG ⁶ represents TBS or C _1-6 alkyl (methyl, Ethyl, tert-butyl); L means a leaving group, for example, L is a halogen atom such as Br, I, etc.].

The side chain moiety having a benzene ring used in the synthesis of formula (I), for example, protects the carboxylic acid of the phenol having a carboxylic acid group in step a, alkylates the phenol in step b, and by a coupling reaction in step c. It can be prepared by introducing the substituent A ³ and deprotecting the carboxylic acid in step d.

The step of protecting the carboxylic acid in step a can be performed by subjecting it to appropriate protection conditions. The phenol coupling reaction in step b can be performed under appropriate conditions using a reagent such as diethyl azodicarboxylate (DEAD). The coupling reaction of step c can be carried out under appropriate conditions using an appropriate reactant. For example, when A ³ is a benzene derivative, a halogenated benzene and an organoboron compound (eg, Ph-B (OH ) ₂ , Ph—B (OR) (OR ′), wherein R and R ′ are independently selected from C _1-6 alkyl, or together with a boron atom and an oxygen atom form a ring And the substituents on Ph are as defined above)), and when A ³ is an acetylene derivative, it is carried out by cross-coupling of halogenated benzene and terminal alkylene. Can do. The deprotection step of step d can be performed by subjecting to appropriate deprotection conditions.

[Wherein n, l and A ³ 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); L means a leaving group, for example, L is a halogen atom such as Br, I, etc.].

The side chain moiety having a benzene ring used in the synthesis of formula (I) can be obtained, for example, by reducing the aldehyde substituted for the benzene ring in step a to alcohol, coupling it with phenol in step b, and coupling reaction in step c. It can be prepared by introducing the substituent A ³ and deprotecting the carboxylic acid in step d.

The step of reducing the aldehyde in step a can be performed, 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 performed under suitable conditions using, for example, DEAD as a reactant. The coupling reaction of step c can be carried out under appropriate conditions using an appropriate reactant. For example, when A ³ is a benzene derivative, a halogenated benzene and an organoboron compound (eg, Ph-B (OH ) ₂ , Ph—B (OR) (OR ′), wherein R and R ′ are independently selected from C _1-6 alkyl, or together with a boron atom and an oxygen atom form a ring And the substituents on Ph are as defined above)), and when A ³ is an acetylene derivative, it is carried out by cross-coupling of halogenated benzene and terminal alkylene. Can do. The deprotection step of step d can be performed by subjecting to appropriate deprotection conditions.

Pharmaceutical Composition The pharmaceutical composition of the present invention can be used in various dosage forms such as tablets, capsules, powders, granules, pills, solutions, emulsions, suspensions, solutions, spirits for oral administration. , Syrup, extract, and elixir. Examples of parenterals include injections such as subcutaneous injections, intravenous injections, intramuscular injections, and intraperitoneal injections; Or a patch, ointment or lotion; a sublingual or buccal patch for buccal administration; and an aerosol for nasal administration, but is not limited thereto. These preparations can be produced by known methods usually used in the preparation process. The compound of formula (I) is preferably administered as a parenteral agent.

  The pharmaceutical composition may contain various commonly used components, such as one or more pharmaceutically acceptable excipients, disintegrants, diluents, lubricants, flavoring agents, and coloring agents. , Sweeteners, flavoring agents, suspending agents, wetting agents, emulsifying agents, dispersing agents, adjuvants, preservatives, buffering agents, binders, stabilizers, coating agents and the like. The pharmaceutical composition of the present invention may be in a sustained or sustained release dosage form.

  The dosage of the therapeutic agent, prophylactic agent, or pharmaceutical composition of the present invention can be appropriately selected depending on the administration route, the patient's body shape, age, physical condition, degree of disease, elapsed time after onset, etc. The pharmaceutical composition may comprise a therapeutically effective amount and / or a prophylactically effective amount of a compound of formula (I) as described above. In the present invention, the compound of the above formula (I) can generally be used at a dose of 1 to 10,000 mg / day / adult. The pharmaceutical composition may be administered in a single dose or multiple doses, such as immunosuppressants (cyclosporine, tacrolimus, sirolimus, methotrexate, azathioprine, etc.), steroidal anti-inflammatory drugs (hydrocortisone, prednisolone, dexamethasone, etc.) ), Nonsteroidal anti-inflammatory drugs (such as loxoprofen sodium, indomethacin, diclofenac sodium) or antibody drugs (such as infliximab, adalimumab, tocilizumab, sertolizumab pegol, etanercept) it can.

  The therapeutic agent or prophylactic agent of the present invention may contain a conventionally known coloring agent, preservative, flavoring, flavoring agent, coating agent, antioxidant, vitamin, amino acid, peptide, protein, and mineral content (iron, zinc, if necessary). , Magnesium, iodine, etc.). The therapeutic agent 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 (including chewables), powders (powder), pills, or liquid preparations for internal use (including liquids, suspensions, syrups) May be. In addition, the therapeutic agent or prophylactic agent of the present invention can be used as it is as a pharmaceutical composition, functional food, health food, supplement or the like.

  As additives for formulation, for example, excipients, lubricants, binders, disintegrants, fluidizers, dispersants, wetting agents, preservatives, thickeners, pH adjusters, colorants, Examples include flavoring agents, surfactants, and solubilizing agents. Moreover, when making it into the form of a liquid agent, thickeners, such as pectin, xanthan gum, and guar gum, can be mix | blended. Moreover, it can also be set as a coating tablet using a coating agent, or it can also be set as a paste-form glue. Furthermore, even when preparing in other forms, conventional methods may be followed.

  Based on the chemical structure of the compound represented by formula (I), the pharmaceutical composition that is one embodiment of the present invention has, for example, any one or more lysophosphatidylserine receptors selected from GPR34, P2Y10, and GPR174. Acting lysophosphatidylserine receptor function regulating activity, lysophosphatidylserine receptor agonist activity, mast cell degranulation inhibitory effect, histamine release inhibitory effect, leukotriene production inhibitory effect, prostaglandin production inhibitory effect, IL-13 production inhibitory effect , Have tryptase secretion inhibitory action, antigen-antibody reaction inhibitory action and the like. In addition, 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, such as malignant rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Graves' disease, antiphospholipid antibody syndrome, Examples include Sjogren's syndrome, primary biliary cirrhosis, polymyositis, and autoimmune hepatitis.

Lysophosphatidylserine receptor function regulator According to one aspect of the present invention, there is provided a function regulator of one or more lysophosphatidylserine receptors selected from GPR34, P2Y10 and GPR174, comprising the above-mentioned compound or a salt thereof. Is done. In addition, the lysophosphatidylserine receptor function regulator may selectively regulate any two functions selected from GPR34, P2Y10, and GPR174, or selectively regulate the function of P2Y10. It may be.

  The “lysophosphatidylserine receptor function regulator” as used in the present invention acts on lysophosphatidylserine receptors such as GPR34, P2Y10 and GPR174, and promotes or suppresses the expression of the target receptor, An agent used to enhance or suppress the in vivo function specific to the receptor.

Here, the lysophosphatidylserine receptor is a modular type comprising a hydrophilic part (amino acid part and phosphodiester part), a hydrophobic part (acyl side chain part), and a linking part that connects the hydrophilic part and the hydrophobic part. Since it is a molecule, systematically transforming each modular structure according to the general synthesis method of the above compound, and examining whether each module structure is necessary for the expression of biological activity, the expression for the biological activity of lysophosphatidylserine It becomes possible to elucidate a necessary structure and a structure requirement for receptor-selective agonist creation. That is, for example, the lysophosphatidylserine receptor function regulator referred to in the present invention is a compound having agonist activity for one or more receptors, agonist activity selective for two receptors (dual agonist activity), or 1 By containing a compound having selective agonist activity in one receptor, it can be used as a chemical tool for elucidating an unknown physiological function of a lysophosphatidylserine receptor. Moreover, the lysophosphatidylserine receptor function regulator of this invention can also be used as an active ingredient of an above-described 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. Furthermore, in the pulmonary infection experiment of pathogenic bacteria (Cryptococcus neoformans), it has also been found that GPR34 knockout mice have a larger number of pathogenic bacteria than wild-type mice, and the pathogenic bacteria removal function is abnormal. That is, it has been suggested that GPR34 is involved in a wide range of immune responses via mononuclear cells, and lysophosphatidylserine receptor function regulators that selectively regulate GPR34 function are related to mononuclear cells. It can be used to elucidate physiological functions.

  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 promoted in GPR34 knockout mice. 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 suppression of cytokine production in vivo.

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

It is also useful as a medicament such as a prophylactic / therapeutic agent for diseases related to the function of P2Y10.
<GPR174 function regulator>
GPR174, like P2Y10, is highly expressed in lymphoid organs such as the thymus and spleen, and its expression is greatly increased particularly in activated lymphocytes. Therefore, GPR174 also has some important functions 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 a single nucleotide polymorphism of GPR174 is associated with Graves' disease or hyperthyroidism characterized by autoantibody target antigens that are 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 physiological functions related to suppression of IL-2 production of activated lymphocytes.

  It is also useful as a medicament for preventing or treating diseases related to the function of GPR174, such as diseases related to the immune system, particularly Graves' disease or hyperthyroidism.

Method for evaluating compound or salt thereof The agonist activity of a test compound against a lysophosphatidylserine receptor can be evaluated using GPR34, P2Y10 or GPR174. That is, the method for evaluating or screening the above-mentioned compound or its salt as a test compound is not particularly limited as long as GPR34, P2Y10 or GPR174 is used. For example, a gene encoding GPR34, P2Y10 or GPR174 is expressed. Cells, transgenic non-human mammals that overexpress genes encoding GPR34, P2Y10, or GPR174, transgenic non-human mammals that express genes encoding human GPR34, human P2Y10, or human GPR174, etc. be able to. Here, the cells used for evaluation or screening are not particularly limited, and examples thereof include well-known cultured cells that are commonly used, such as HEK293 cells. Examples of non-human mammals include mice, rats, rabbits, dogs, cats, monkeys and the like. Screening may also use animal tissues and cells. In that case, administration of the test compound can be performed by allowing the test compound to act on the subject, for example, by including the test compound in a solution or medium in which the tissue or cells are retained.

  Evaluation or screening of a compound or a salt thereof can be performed using a cultured cell that expresses a gene encoding GPR34, P2Y10, or GPR174, and the use of the cultured cell is preferable in terms of screening efficiency. Further, since GPR34, P2Y10 or GPR174 is a G protein-coupled receptor, the assay can be performed using calcium response, cAMP production, reporter gene and the like as indicators. The assay can also be performed by expressing a gene encoding a human epidermal growth factor receptor (EGFR) ligand further labeled in the cultured cells and quantifying the amount of the labeled compound to be cleaved. Here, specific examples of the labeled EGFR ligand include a fusion protein of an EGFR ligand and alkaline phosphatase (AP). An example of the EGFR ligand to be labeled is 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.

  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. For example, GPR34, P2Y10 or GPR174 derived from mammals such as humans, mice and rats is used. Is done. As specific examples, polypeptides having GPR34, P2Y10 or GPR174 activity as disclosed in Patent Documents 2 and 5 can be used.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

Reagents and data measurement reagents are available from Sigma-Aldrich Chemical Co. Those purchased from Tokyo Chemical Industry, Wako Pure Chemicals, and Kanto Chemical were used without further purification. ¹ H- and ¹³ C-NMR were measured using a BRUKER AVANCE 400 spectrometer (400 MHz), and chemical shift was deuterated chloroform (7.26 ppm ( ¹ H-NMR), 77.00 ppm ( ¹³ C-NMR)). In ppm. 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 BRUKER microTOF-05 spectrometer (ESI-TOF) or SHIMADZU AXIMA-TOF (MALDI-TOF) positive and negative ion modes. 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]
O-((3-((3- (2-((3-((4 ′-(tert-butyl)-[1,1′-biphenyl] -4-yl) oxy) benzyl) oxy) phenyl) propanoyl) Synthesis of) oxy) propoxy) (hydroxy) phosphoryl) -L-serine

Synthesis of intermediate 1-1

To a solution of copper acetate (690.9 mg, 3.804 mmol) in anhydrous methylene chloride (30 mL), pyridine (2400 μL, 29.79 mmol), 4Å molecular sieve, p-iodophenol (664.8 mg, 3.022 mmol), 3-formylphenyl Boronic acid (680.9 g, 4.541 mmol) was added and stirred at ambient temperature for 48 hours under ambient atmosphere. Polyvinylpyridine (891.3 mg) was further added to the resulting reaction solution, and the mixture was stirred for 10 minutes. The mixture was filtered over Celite® and the filtrate was evaporated to give a green solid. The obtained residue was purified by open column chromatography (n-hexane: diethyl ether = 10: 1) to obtain the title compound (808.7 mg, 2.495 mmol, 82%, colorless oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 9.967 (1H, s), 7.664 (2H, dt, J = 8.88 Hz, 2.62 Hz), 7.630 (1H, dt, J = 7.56 Hz, 1.26 Hz), 7.512 (1H, t, J = 7.84 Hz), 7.459 (1H, dd, J = 2.44 Hz, 0.72 Hz), 7.281 (1H, ddd, J = 8.13 Hz, 2.58 Hz, 1.04 Hz), 6.803 (2H, dt , J = 8.88 Hz, 2.60 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 191.38, 157.71, 156.34, 138.98, 138.14, 130.59, 125.25, 124.75, 121.43, 118.24, 87.14.
Elemental analysis C ₁₃ H ₁₉ IO ₂ : calculated C, 48.17; H, 2.80. Found C, 48.46; H, 2.98.

Synthesis of intermediate 1-2

To a methanol (7.5 mL) solution of intermediate 1-1 (478.9 mg, 1.478 mmol), NaBH ₄ (111.9 mg, 2.958 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 methylene chloride (10 mL), saturated NaHCO ₃ (5 mL), water (10 mL), and the aqueous layer was extracted 3 times with methylene chloride (15 mL). The organic layer was collected and washed with brine, dried over sodium sulfate and filtered, and the solvent was evaporated to give a yellow oil. The residue was purified by open column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain the title compound (430.2 mg, 1.319 mmol, 89%, colorless oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.615 (2H, dt, J = 8.92 Hz, 2.60 Hz), 7.330 (1H, t, J = 7.86 Hz), 7.120 (1H, dd, J = 7.64 Hz) , 0.32 Hz), 7.015 (1H, s), 6.923 (1H, dd, J = 8.10 Hz, 1.02 Hz), 6.773 (2H, dt, J = 8.96 Hz, 2.60 Hz), 4.679 (2H, d, J = 4.32 Hz), 1.702 (1H, t, J = 5.20 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 157.25, 156.93, 143.12, 138.69, 130.01, 122.02, 120.99, 118.14, 117.29, 86.06, 64.83.

Synthesis of Intermediate 1-3

3- (2-hydroxyphenyl) propanoic acid methyl ester (311.8 mg, 1.730 mmol), intermediate 1-2 (688.8 mg, 2.112 mmol), triphenylphosphine (531.9 mg, 2.028 mmol) in anhydrous toluene (30 mL) To the solution, DEAD (2M toluene solution, 1.9 mL) was added dropwise at room temperature. The mixture which changed from yellow to orange when heated to 70 to 80 ° C. was stirred for 4 hours under an argon atmosphere, and the solvent of the reaction mixture was distilled off to obtain an orange oil. The residue was purified by open column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain the title compound (751.1 mg, 1.538 mmol, 73%, pink oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.611 (2H, dt, J = 8.84 Hz, 2.58 Hz), 7.349 (1H, t, J = 7.88 Hz), 7.190-7.142 (3H, m), 7.060 (1H, s), 6.941 (1H, dd, J = 8.02 Hz, 1.14 Hz), 6.915-6.840 (2H, m), 6.775 (2H, dt, J = 8.88 Hz, 2.58 Hz), 5.060 (2H, s ), 3.636 (3H, s), 2.972 (2H, t, J = 7.74 Hz), 2.608 (2H, t, J = 7.74 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.63, 157.08, 156.92, 156.25, 139.46, 138.68, 130.11, 130.03, 129.11, 127.55, 122.08, 121.04, 120.89, 118.16, 117.35, 111.52, 86.15, 69.17, 51.48 , 33.97, 26.11.
HRMS (ESI-TOF, [M + Na] ⁺ ): C ₂₃ H ₂₁ INaO ₄ ⁺ : calculated value 511.0377. Found value 511.0398.

Synthesis of Intermediate 1-4

Intermediate 1-3 (776.0 mg, 1.589 mmol), p-tert-butylphenylboronic acid (426.0 mg, 2.393 mmol), sodium carbonate (766.4 mg, 7.231 mmol), triphenylphosphine (28.6 mg, 0.109 mmol), Palladium (II) acetate (14.0 mg, 0.0624 mmol) was dissolved in a mixed solution of ethanol (3.5 mL), water (7.0 mL), and toluene (7.0 mL), and the mixture was freeze-degassed twice and under an argon atmosphere. , And stirred at 80 ° C. for 23.3 hours. Water (10 mL) was added and the aqueous layer was extracted 3 times with ethyl acetate (20 mL). The organic layer was collected, washed with brine, dried over sodium sulfate, filtered, and evaporated to a colorless oil and black droplets. The residue was purified by open column chromatography (n-hexane: ethyl acetate = 20: 1 to 10: 1 to 4: 1) to obtain the title compound (497.8 mg, 1.006 mmol, 63%, white solid).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.547 (2H, dt, J = 8.68 Hz, 2.44 Hz), 7.508 (2H, dt, J = 8.52 Hz, 2.04 Hz), 7.454 (2H, dt, J = 8.56 Hz, 1.98 Hz), 7.354 (1H, t, J = 7.86 Hz), 7.182-7.142 (3H, m), 7.119 (1H, brs), 7.068 (2H, dt, J = 8.68 Hz, 2.44 Hz) , 6.997 (1H, dd, J = 8.08 Hz, 0.94 Hz), 6.909-6.855 (2H, m), 5.072 (2H, s), 3.608 (3H, s), 2.978 (2H, t, J = 7.72 Hz) , 2.610 (2H, t, J = 7.72 Hz), 1.360 (9H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.68, 157.60, 156.37, 156.26, 150.07, 139.34, 137.59, 136.39, 130.13, 129.93, 129.19, 128.29, 127.57, 126.53, 125.71, 121.65, 120.86, 119.23, 118.05 , 117.23, 111.60, 69.33, 51.43, 34.50, 34.02, 31.35, 26.17.
HRMS (ESI-TOF, [M + Na] ⁺ ): C ₃₃ H ₃₄ NaO ₄ ⁺ : calculated value 517.2349. Found value 517.2323.
Elemental analysis C ₃₃ H ₃₄ O ₄ : Calculated C, 80.13; H, 6.93.Observed C, 79.95; H, 7.07.
Mp: 110.1-113.2 ° C. (recrystallized from CH ₂ Cl ₂ / MeOH, colorless cubic solid).

Synthesis of Intermediate 1-5

To a mixed solution of Intermediate 1-4 (461.5 mg, 0.9330 mmol) in methanol (2.0 mL) and THF (2.0 mL) was added 2M aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 3.3 hours. . 2M aqueous hydrochloric acid was added to acidify the reaction mixture to pH2. The aqueous layer was extracted three times with ethyl acetate (20 mL), and the organic layer was collected, washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated to give a white powder. The residue was purified by open column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (416.4 mg, 0.8664 mmol, 93%, white solid).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.545 (2H, dt, J = 8.80 Hz, 2.50 Hz), 7.507 (2H, dt, J = 8.72 Hz, 2.12 Hz), 7.450 (2H, dt, J = 8.68 Hz, 2.08 Hz), 7.354 (1H, t, J = 7.88 Hz), 7.197-7.152 (3H, m), 7.110 (1H, t, J = 1.76 Hz), 7.065 (2H, dt, J = 8.76 Hz, 2.52 Hz), 7.014-6.987 (1H, m), 6.914-6.864 (2H, m), 5.075 (2H, s), 2.981 (2H, t, J = 7.68 Hz), 2.653 (2H, t, J = 7.68 Hz), 1.358 (9H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 157.59, 156.35, 156.22, 150.01, 139.23, 137.57, 136.37, 130.12, 129.96, 128.83, 128.27, 127.66, 126.51, 125.69, 121.63, 120.86, 119.27, 118.05, 117.19 , 111.58, 69.32, 34.47, 33.86, 31.33, 25.85.
HRMS (ESI-TOF, [MH ] -): Calculated ^{_{C 32 H 31 O 4 -:}} . 479.2228 Found 479.2235.
Elemental analysis C ₃₂ H ₃₂ O ₄ : Calculated C, 79.97; H, 6.71.Observed C, 79.71; H, 6.68.
Mp: 140.1-141.2 ° C. (recrystallized from CH ₂ Cl ₂ / MeOH, colorless cubic solid).

Synthesis of Intermediate 1-6

(2S) -3-[(diisopropylamino) -tert-butoxyphosphinooxy] -2- (tert-butoxycarbonylamino) propionic acid tert-butyl ester (1.2815 g, 2.761) synthesized according to the method described in WO2012 / 157746 mmol) was dissolved in dichloromethane (10 mL) and toluene (0.5 mL) to remove the water, and then the solvent was removed in vacuo. To the obtained residue was added 1- (tert-butyldimethylsilyloxy) propanol (648.4 mg, 3.406 mmol), 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. A white powder precipitated in a few minutes. The reaction mixture was stirred at room temperature for 4 hours under an argon atmosphere. tert-Butyl hydroperoxide (TBHP in decane (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 hours. The reaction mixture was diluted with water (12 mL), and the aqueous layer was separated. The organic layer was collected, washed with brine, dried over sodium sulfate, and the solvent was distilled off.The residue was subjected to 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 value 592.3041. Found value 592.3022.

Synthesis of Intermediate 1-7

HF / pyridine (1.18 mL) dissolved in pyridine (2.9 mL) was added dropwise at 0 ° C. to a solution of intermediate 1-6 (1.1397 g, 2.000 mmol) in THF (12 mL), 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 resulting solution, and the aqueous layer was separated and extracted with ethyl acetate (15 mL × 3). The organic layer was collected and dried over sodium sulfate, and the solvent was distilled off. 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 478.2176. Found 478.2177.
Elemental analysis: C ₁₉ H ₃₈ NO ₉ P: Calculated value C, 50.10; H, 8.41; N, 3.08.Measured value 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 1-8

Intermediate 1-5 (134.8 mg, 0.280 mmol) and Intermediate 1-7 (95.0 mg, 0.209 mmol) were dissolved in anhydrous methylene chloride (1.5 mL), DMAP (8.0 mg, 0.065 mmol) was added and iced. Cooled to 0 ° C. with bath. EDCI.HCl (88.7 mg, 0.463 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 14.6 hours under an argon atmosphere. EDCI.HCl (36.2 mg) and methanol (1.0 mL) were added and the reaction mixture was stirred for 3 hours. Water (10 mL) was added and the aqueous layer was extracted three times with methylene chloride (10 mL). The collected organic layer was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated. A colorless oil was obtained. The residue was purified by column chromatography (n-hexane: ethyl acetate = 2: 1 to 1: 1) to obtain the title compound (154.7 mg, 0.169 mmol, 81%, colorless oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.547 (2H, dt, J = 8.72 Hz, 2.46 Hz), 7.508 (2H, dt, J = 8.52 Hz, 1.96 Hz), 7.454 (2H, dt, J = 8.52 Hz, 1.96 Hz), 7.355 (1H, t, J = 7.88 Hz), 7.188-7.145 (3H, m), 7.110 (1H, s), 7.064 (2H, dt, J = 8.68 Hz, 2.48 Hz) , 6.989 (1H, dd, J = 7.98 Hz, 0.98 Hz), 6.906-6.855 (2H, m), 5.493 (1H, d, J = 7.60 Hz), 5.081 (2H, s), 4.363-4.298 (2H, m), 4.221-4.176 (1H, m), 4.149-4.107 (2H, m), 4.028-3.942 (2H, m), 2.980 (2H, t, J = 7.62 Hz), 2.645-2.603 (2H, m) , 1.958-1.873 (2H, m), 1.471-1.431 (27H, m), 1.360 (9H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.03, 168.31, 157.53, 156.34, 156.21, 155.20, 150.03, 139.33, 137.54, 136.36, 130.09, 129.92, 129.04, 128.25, 127.56, 126.49, 125.68, 121.60, 120.81 , 119.19, 117.96, 117.22, 111.61, 83.58, 82.62, 82.59, 79.88, 69.32, 67.36, 64.04, 63.98, 60.39, 54.45, 34.46, 34.02, 31.32, 29.75, 29.71, 29.52, 29.47, 28.26, 27.91, 26.09
HRMS (ESI-TOF, [M + Na] ⁺ ): C ₅₁ H ₆₈ NNaO ₁₂ P ⁺ : calculated 940.4371. Found 940.4376.

Synthesis of compound 1

Intermediate 1-8 (133.6 mg, 0.146 mmol) was dissolved in TFA (1.0 mL) at 0 ° C. and the reaction mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 1.5 hours. The reaction mixture was diluted with methylene chloride (6 mL) and the solvent was distilled off. The residue was purified by column chromatography (chloroform: methanol: acetic acid = 8: 1: 1 to 7: 1: 2), and the resulting colorless oil was dissolved in a mixed solvent of methylene chloride and TFA, and the mixture was dissolved at 40 ° C. Drying in vacuo overnight gave the TFA salt of the title compound (72.7 mg, 0.103 mmol, 71%, white powder).
¹ H NMR (400 MHz, CDCl ₃ / TFA-d): δ = 7.561 (2H, d, J = 8.68 Hz), 7.524-7.461 (4H, m), 7.355 (1H, t, J = 7.88 Hz), 7.211-7.158 (2H, m), 7.116-7.047 (4H, m), 7.005 (1H, dd, J = 8.10 Hz, 1.00 Hz), 6.918-6.883 (2H, m), 5.095 (2H, s), 4.600 (2H, brs), 4.476 (1H, brs), 4.178 (2H, t, J = 5.96 Hz), 4.018 (2H, brs), 2.970 (2H, t, J = 7.40 Hz), 2.720 (2H, t, J = 7.42 Hz), 1.932 (2H, t, J = 5.18 Hz), 1.363 (9H, s).
HRMS (ESI-TOF, [MH ] -): C 38 H 43 NO 10 P -:. Calculated 704.2630 Found 704.2649.
Elemental analysis _{C 38 H 44 NO 10 P ·} 1.9CF 3 CO 2 H:. Calculated C, 54.43; H, 5.02; N, 1.52 Found C, 54.41; H, 5.38; N, 1.63.

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

Synthesis of intermediate 2-1

Synthesis was performed in the same manner as in Intermediate 1-4 of Example 1 except that m-tert-butylphenylboronic acid was used instead of p-tert-butylphenylboronic acid, and column chromatography (n-hexane : Ethyl acetate = 20: 1) to obtain the title compound (619.9 mg, 1.253 mmol, 96%, colorless oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.581-7.538 (3H, m), 7.374-7.337 (4H, m), 7.184-7.145 (3H, m), 7.123 (1H, s), 7.086 (2H , dt, J = 8.72 Hz, 2.46 Hz), 7.001 (1H, dd, J = 7.98 Hz, 0.92 Hz), 6.910-6.857 (2H, m), 5.073 (2H, s), 3.609 (3H, s), 2.982 (2H, t, J = 7.72 Hz), 2.616 (2H, t, J = 7.74 Hz), 1.377 (9H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.66, 157.61, 156.36, 156.31, 151.61, 140.27, 139.33, 137.18, 130.12, 129.93, 129.16, 128.59, 128.47, 127.57, 124.16, 124.11, 124.07, 121.64, 120.84 , 119.26, 117.98, 117.18, 111.57, 69.31, 51.42, 34.79, 34.00, 31.39, 26.17.
HRMS (ESI-TOF, [M + Na] ⁺ ): C ₃₃ H ₃₄ NaO ₄ ⁺ : calculated 517.2349. Found 517.2364.

Synthesis of intermediate 2-2

The synthesis was performed in the same manner as the synthesis method of Intermediate 1-5 of Example 1 except that Intermediate 2-1 was used instead of Intermediate 1-4, and column chromatography (n-hexane: ethyl acetate) was performed. = 4: 1 to 0: 1) to obtain the title compound (486.2 mg, 1.012 mmol, 83%, white solid).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.580-7.532 (3H, m), 7.372-7.329 (4H, m), 7.190-7.147 (3H, m), 7.108-7.063 (3H, m), 6.996 (1H, dd, J = 7.86 Hz, 0.92 Hz), 6.906-6.855 (2H, m), 5.067 (2H, s), 2.974 (2H, t, J = 7.64 Hz), 2.649 (2H, t, J = 7.68 Hz), 1.370 (9H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 178.89, 157.64, 156.36, 156.30, 151.61, 140.28, 139.26, 137.20, 130.14, 129.98, 128.84, 128.59, 128.47, 127.68, 124.17, 124.11, 124.07, 121.63, 120.88 , 119.33, 118.01, 117.14, 111.59, 69.34, 34.78, 33.82, 31.39, 25.87.
Mp: 97.0-100.8 ° C. (recrystallized from CH ₂ Cl ₂ / MeOH, colorless plate solid).

Synthesis of intermediate 2-3

Synthesis was performed in the same manner as in the synthesis of intermediate 1-8 in Example 1, except that intermediate 2-2 was used instead of intermediate 1-5, and column chromatography (n-hexane: ethyl acetate) was performed. = 2: 1 to 1: 1) to obtain the title compound (140.7 mg, 0.1533 mmol, 80%, colorless oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.583-7.540 (3H, m), 7.375-7.340 (4H, m), 7.193-7.144 (3H, m), 7.115 (1H, s), 7.085 (2H , dt, J = 8.72 Hz, 2.46 Hz), 6.993 (1H, dd, J = 8.10 Hz, 0.88 Hz), 6.909-6.858 (2H, m), 5.501 (1H, d, J = 7.68 Hz), 5.084 ( 2H, s), 4.367-4.302 (2H, m), 4.225-4.179 (1H, m), 4.152-4.121 (2H, m), 4.032-3.972 (2H, m), 2.986 (2H, t, J = 7.62 Hz), 2.651-2.610 (2H, m), 1.960-1.886 (2H, m), 1.474-1.433 (27H, m), 1.378 (9H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.03, 168.31, 157.56, 156.33, 156.27, 155.20, 151.58, 140.23, 139.33, 137.16, 130.09, 129.92, 129.03, 128.56, 128.44, 127.56, 124.13, 124.09, 124.03 , 121.59, 120.81, 119.24, 117.90, 117.16, 111.60, 83.67, 83.60, 82.63, 82.60, 79.88, 69.31, 67.37, 64.04, 63.98, 60.38, 60.32, 54.45, 54.36, 34.75, 34.01, 31.36, 29.75, 29.73 , 29.52, 29.46, 28.26, 27.90, 26.09.
HRMS (ESI-TOF, [M + Na] ⁺ ): C ₅₁ H ₆₈ NNaO ₁₂ P ⁺ : calculated 940.4371. Found 940.4352.

Synthesis of compound 2

The synthesis was performed in the same manner as the synthesis method of Compound 1 of Example 1 except that Intermediate 2-3 was used instead of Intermediate 1-8, and column chromatography (chloroform: methanol: acetic acid = 8: 1). : 1 to 7: 1: 2), the obtained white solid was dissolved in a mixed solvent of methylene chloride and TFA and dried in vacuo at 40 ° C. overnight, and the TFA salt of the title compound (64.0 mg, 0.0907 mmol) 66%, white powder).
¹ H NMR (400 MHz, CDCl ₃ / TFA-d): (= 7.586-7.549 (3H, m), 7.392-7.325 (4H, m), 7.197-7.151 (2H, m), 7.106-7.058 (4H, m), 6.996 (1H, d, J = 7.96 Hz), 6.898-6.878 (2H, m), 5.083 (2H, s), 4.555 (2H, brs), 4.445 (1H, brs), 4.165 (2H, brs ), 3.986 (2H, brs), 2.963 (2H, brs), 2.711 (2H, brs), 1.915 (2H, brs), 1.373 (9H, s).
HRMS (ESI-TOF, [MH ] -): C 38 H 43 NO 10 P -:. Calculated 704.2630 Found 704.2613.
Elemental analysis C ₃₈ H ₄₄ NO ₁₀ P · 3CF ₃ CO ₂ H: Calculated C, 50.44; H, 4.52; N, 1.34. Found C, 50.40; H, 4.77; N, 1.51.

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

Synthesis of intermediate 3-1

The synthesis was performed in the same manner as the synthesis method of intermediate 1-1 of Example 1 except that p-bromophenol was used instead of p-iodophenol, and column chromatography (n-hexane: diethyl ether = 10 : 1) to give the title compound (644.7 mg, 2.326 mmol, 38%, colorless oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 9.964 (1H, s), 7.624 (1H, dt, J = 7.56 Hz, 1.22 Hz), 7.515 (1H, t, J = 7.88 Hz), 7.487-7.447 (3H, m), 7.277 (1H, ddd, J = 8.11 Hz, 2.56 Hz, 1.04 Hz), 6.919 (2H, dt, J = 8.92 Hz, 2.74 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 191.38, 157.85, 155.43, 138.12, 133.00, 130.57, 125.20, 124.63, 121.06, 118.07, 116.73.

Synthesis of intermediate 3-2

The synthesis was performed in the same manner as the synthesis method of Intermediate 1-2 in Example 1 except that Intermediate 3-1 was used instead of Intermediate 1-1, and column chromatography (n-hexane: acetic acid) was performed. Purification by ethyl = 3: 1) gave the title compound (582.7 mg, 2.088 mmol, 93%, colorless oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.428 (2H, dt, J = 8.96 Hz, 2.74 Hz), 7.326 (1H, t, J = 7.86 Hz), 7.112 (1H, dd, J = 7.58 Hz , 0.32 Hz), 7.008 (1H, s), 6.929-6.865 (3H, m), 4.671 (2H, s), 1.753 (1H, brs).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 157.07, 156.33, 143.09, 132.69, 129.99, 121.94, 120.58, 118.01, 117.17, 115.77, 64.81.

Synthesis of Intermediate 3-3

The synthesis was performed in the same manner as the synthesis method of Intermediate 1-3 of Example 1 except that Intermediate 3-2 was used instead of Intermediate 1-2, and column chromatography (n-hexane: acetic acid) was performed. Purification by ethyl = 10: 1) gave the title compound (640.0 mg, 1.450 mmol, 72%, pink oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.433 (2H, dt, J = 8.92 Hz, 2.72 Hz), 7.353 (1H, t, J = 7.88 Hz), 7.187-7.147 (3H, m), 7.060 (1H, s), 6.943 (1H, dd, J = 8.44 Hz, 1.04 Hz), 6.919-6.845 (4H, m), 5.066 (2H, s), 3.640 (3H, s), 2.973 (2H, t, J = 7.88 Hz), 2.610 (2H, t, J = 7.76 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.56, 157.11, 156.27, 156.21, 139.47, 132.72, 130.13, 130.04, 129.13, 127.57, 122.03, 120.90, 120.67, 118.07, 117.25, 115.86, 111.53, 69.19, 51.49 , 33.98, 26.13.
HRMS (ESI-TOF, [M + Na] ⁺ ): Calcd for C ₂₃ H ₂₁ BrNaO ₄ ⁺ : 463.0515, 465.0495. Found: 463.0498, 465.0483.

Synthesis of Intermediate 3-4

Synthesis of Intermediate 1-4 of Example 1 except that Intermediate 3-3 is used instead of Intermediate 1-3 and o-methylphenylboronic acid is used instead of p-tert-butylphenylboronic acid The title compound (362.4 mg, 0.8008 mmol, 78%, colorless oil) was obtained by synthesis using the same method as that described above and purification by column chromatography (n-hexane: ethyl acetate = 10: 1).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.365 (1H, t, J = 7.86 Hz), 7.298-7.220 (6H, m), 7.190-7.145 (4H, m), 7.050 (2H, dt, J = 8.64 Hz, 2.42 Hz), 7.015 (1H, dd, J = 8.10 Hz, 0.94 Hz), 6.910-6.863 (2H, m), 5.082 (2H, s), 3.615 (3H, s), 2.986 (2H, t, J = 7.72 Hz), 2.623 (2H, t, J = 7.74 Hz), 2.287 (3H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.66, 157.47, 156.37, 155.95, 141.21, 139.35, 137.07, 135.38, 130.53, 130.33, 130.12, 129.94, 129.81, 129.17, 127.57, 127.20, 125.77, 121.74, 120.86 , 118.43, 118.17, 117.39, 111.59, 69.34, 51.43, 34.02, 26.18, 20.49.

Synthesis of Intermediate 3-5

The synthesis was performed in the same manner as the synthesis method of Intermediate 1-5 of Example 1 except that Intermediate 3-4 was used instead of Intermediate 1-4, and column chromatography (n-hexane: acetic acid) was performed. Purification by ethyl = 2: 1) gave the title compound (290.7 mg, 0.6629 mmol, 93%, white solid).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.358 (1H, t, J = 7.86 Hz), 7.285-7.223 (6H, m), 7.188-7.153 (3H, m), 7.126 (1H, s), 7.063-6.999 (3H, m), 6.906-6.863 (2H, m), 5.076 (2H, s), 2.977 (2H, t, J = 7.68 Hz), 2.655 (2H, t, J = 7.68 Hz), 2.280 (3H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 178.91, 157.50, 156.37, 155.92, 141.22, 139.27, 137.09, 135.39, 130.53, 130.32, 130.14, 129.98, 129.82, 128.83, 127.68, 127.19, 125.77, 121.73, 120.88 , 118.49, 118.19, 117.35, 111.60, 69.36, 33.83, 25.88, 20.50.
HRMS (ESI-TOF, [MH ] -): Calcd for C 29 H 25 O 4 -:. Calculated 437.1758 Found 437.1730.

Synthesis of Intermediate 3-6

The synthesis was performed in the same manner as the synthesis method of Intermediate 1-8 of Example 1 except that Intermediate 3-5 was used instead of Intermediate 1-5, and column chromatography (n-hexane: acetic acid was used). Purification by ethyl = 2: 1 to 1: 2) afforded the title compound (105.5 mg, 0.1204 mmol, 64%, colorless oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.370 (1H, t, J = 7.88 Hz), 7.295-7.228 (6H, m), 7.200-7.136 (4H, m), 7.050 (2H, dt, J = 8.68 Hz, 2.44 Hz), 7.012 (1H, dd, J = 7.88 Hz, 0.88 Hz), 6.910-6.866 (2H, m), 5.493 (1H, d, J = 7.76 Hz), 5.094 (2H, s) , 4.366-4.301 (2H, m), 4.233-4.178 (1H, m), 4.156-4.113 (2H, m), 4.033-3.973 (2H, m), 2.988 (2H, t, J = 7.64 Hz), 2.656 -2.614 (2H, m), 2.290 (3H, s), 1.965-1.890 (2H, m), 1.475-1.433 (27H, m).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.03, 168.31, 157.42, 156.34, 155.90, 155.20, 141.16, 139.34, 137.05, 135.34, 130.50, 130.30, 130.10, 129.94, 129.78, 129.03, 127.57, 127.18, 125.75 , 121.67, 120.82, 118.41, 118.09, 117.35, 111.60, 83.65, 83.57, 832.63, 82.60, 79.88, 69.33, 67.37, 64.03, 63.97, 60.40, 54.44, 54.36, 34.01, 29.75, 29.71, 29.53, 29.46, 28.26 , 26.09, 20.47.
HRMS (ESI-TOF, [M + Na] ⁺ ): C ₄₈ H ₆₂ NNaO ₁₂ P ⁺ : calculated 898.3902. Found 898.3897.

Synthesis of compound 3

The synthesis was performed in the same manner as the synthesis method of Compound 1 of Example 1 except that Intermediate 3-6 was used instead of Intermediate 1-8, and column chromatography (chloroform: methanol: acetic acid = 8: 1). : 1 to 7: 1: 2), the resulting white solid was dissolved in a mixed solvent of methylene chloride and TFA, dried in vacuo at 40 ° C. overnight, and the TFA salt of the title compound (47.3 mg, 0.0713 mmol) 61%, white powder).
¹ H NMR (400 MHz, CDCl ₃ / TFA-d): δ = 7.370 (1H, t, J = 7.86 Hz), 7.309-7.173 (8H, m), 7.143 (1H, s), 7.098 (1H, d , J = 6.96 Hz), 7.056-7.016 (3H, m), 6.927-6.886 (2H, m), 5.109 (2H, s), 4.607 (2H, brs), 4.495 (1H, brs), 4.193 (2H, brs), 4.027 (2H, brs), 2.982 (2H, t, J = 7.20 Hz), 2.737 (2H, t, J = 7.20 Hz), 2.286 (3H, s), 1.945 (2H, brs).
HRMS (ESI-TOF, [MH ] -): Calcd for C 35 H 37 NO 10 P -:. 662.2161 Found: 662.2153.
Elemental analysis _{C 35 H 38 NO 10 P ·} 1.9CF 3 CO 2 H:. Calculated C, 52.94; H, 4.57; N, 1.59 Found C, 52.94; H, 4.80; N, 1.67.

[Example 4]
O-((3-((3- (2-((3-([1,1 ′: 4 ′, 1 ″ -terphenyl] -4-yloxy) benzyl) oxy) phenyl) propanoyl) oxy) propoxy) Synthesis of (hydroxy) phosphoryl) -L-serine

Synthesis of Intermediate 4-1

Synthesis was performed in the same manner as in Intermediate 3-4 of Example 3 except that 4-biphenylboronic acid was used instead of o-methylphenylboronic acid, and column chromatography (n-hexane: ethyl acetate = 10 : 1-7: 1) to give the title compound (281.3 mg, 0.5466 mmol, 73%, yellow solid).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.682-7.586 (8H, m), 7.471-7.433 (2H, m), 7.384-7.331 (2H, m), 7.190-7.081 (6H, m), 7.010 (1H, dd, J = 8.10 Hz, 0.88 Hz), 6.911-6.855 (2H, m), 5.075 (2H, s), 3.612 (3H, s), 2.982 (2H, t, J = 7.72 Hz), 2.615 (2H, t, J = 7.72 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.67, 157.52, 156.59, 156.39, 156.36, 140.65, 139.90, 139.38, 135.96, 130.13, 129.97, 129.18, 128.80, 128.35, 127.58, 127.50, 127.32, 127.22, 126.99 , 121.75, 120.87, 119.32, 118.10, 117.28, 111.58, 69.31, 51.44, 34.01, 26.16.
HRMS (ESI-TOF, [M + Na] ⁺ ): C ₃₅ H ₃₀ NaO ₄ ⁺ : calculated value 537.2036. Found value 537.2043.
Mp: 101.0-102.5 ° C. (recrystallized from n-hexane / CH ₂ Cl ₂ , colorless acicular solid).

Synthesis of intermediate 4-2

The synthesis was performed in the same manner as in the synthesis of Intermediate 3-5 of Example 3 except that Intermediate 4-1 was used instead of Intermediate 3-4, and n-hexane: ethyl acetate = 4: 1. The title compound (161.3 mg, 0.3222 mmol, 71%, white solid) was obtained by washing with a solvent and filtering.
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.673-7.579 (8H, m), 7.466-7.428 (2H, m), 7.377-7.328 (2H, m), 7.195-7.155 (3H, m), 7.119 -7.076 (3H, m), 7.008 (1H, dd, J = 8.10 Hz, 0.92 Hz), 6.908-6.859 (2H, m), 5.069 (2H, s), 2.974 (2H, t, J = 7.68 Hz) , 2.647 (2H, t, J = 7.70 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 178.19, 157.55, 156.58, 156.36, 140.66, 139.89, 139.39, 139.29, 135.96, 130.15, 130.01, 128.84, 128.80, 128.35, 127.70, 127.50, 127.31, 127.22, 127.00 , 121.76, 120.90, 119.37, 118.16, 117.27, 111.60, 69.34, 31.71, 25.90.
HRMS (ESI-TOF, [MH ] -): Calcd for C 34 H 27 O 4 -:. 499.1915 Found: 499.1926.
Elemental analysis C ₃₄ H ₂₈ O ₄ : Calculated C, 81.58; H, 5.64.Observed C, 81.19; H, 5.88.
Mp: 141.2-142.0 ° C. (recrystallized from n-hexane / CH ₂ Cl ₂ , colorless needle-like solid).

Synthesis of Intermediate 4-3

Synthesis was performed in the same manner as in the synthesis of intermediate 3-6 of Example 3 except that intermediate 4-2 was used instead of intermediate 3-5, and column chromatography (n-hexane: ethyl acetate) was performed. = 2: 1 to 0: 1) to obtain the title compound (166.4 mg, 0.1774 mmol, 90%, white solid).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.686-7.591 (8H, m), 7.474-7.436 (2H, m), 7.389-7.333 (2H, m), 7.202-7.146 (3H, m), 7.128 -7.082 (3H, m), 7.006 (1H, dd, J = 8.10 Hz, 0.88 Hz), 6.912-6.858 (2H, m), 5.492 (1H, d, J = 7.68 Hz), 5.088 (2H, s) , 4.364-4.298 (2H, m), 4.220-4.175 (1H, m), 4.154-4.112 (2H, m), 4.034-3.971 (2H, m), 2.987 (2H, t, J = 7.64 Hz), 2.652 -2.610 (2H, m), 1.962-1.887 (2H, m), 1.471-1.431 (27H, m).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.05, 168.33, 157.47, 156.57, 156.35, 155.22, 140.62, 139.90, 139.39, 139.35, 135.95, 130.11, 129.97, 129.06, 128.79, 128.34, 127.59, 127.48, 127.31 , 127.20, 126.97, 121.71, 120.85, 119.30, 118.04, 117.29, 111.62, 83.65, 83.58, 82.64, 82.61, 79.90, 69.32, 67.38, 64.05, 63.99, 60.42, 54.39, 34.04, 29.77, 29.73, 29.55, 28.48 , 27.92, 26.10.
HRMS (ESI-TOF, [M + Na] ⁺ ): C ₅₃ H ₆₄ NNaO ₁₂ P ⁺ : calculated value 960.4058. Found value 960.4086.

Synthesis of compound 4

The synthesis was performed in the same manner as the synthesis method of Compound 3 of Example 3 except that Intermediate 4-3 was used instead of Intermediate 3-6, and column chromatography (chloroform: methanol: acetic acid = 8: 1). : 1-7: 1: 2-6: 1: 3-5: 2: 2), the obtained white powder was dissolved in a mixed solvent of methylene chloride and TFA and dried in vacuo at 40 ° C. overnight. The TFA salt of the title compound (50.0 mg, 0.0689 mmol, 50%, white powder) was obtained.
¹ H NMR (400 MHz, CDCl ₃ / TFA-d): δ = 7.695-7.609 (8H, m), 7.477-7.439 (2H, m), 7.386-7.348 (2H, m), 7.213-7.175 (2H, m), 7.129-7.082 (4H, m), 7.023 (1H, d, J = 7.84 Hz), 6.923-6.904 (2H, m), 5.102 (2H, s), 4.630 (2H, brs), 4.517 (1H , brs), 4.189 (2H, brs), 4.056 (2H, brs), 2.982 (2H, brs), 2.734 (2H, brs), 1.952 (2H, brs).
HRMS (ESI-TOF, [MH ] -): C 40 H 39 NO 10 P -:. Calculated 724.2317 Found 724.2341.
Elemental analysis C ₄₀ H ₄₀ NO ₁₀ P · 1.6CF ₃ CO ₂ H: Calculated C, 57.13; H, 4.62; N, 1.54. Found C, 57.15; H, 4.83; N, 1.66.

[Example 5]
Synthesis of intermediate 5-3 (compound 5 precursor)

Synthesis of intermediate 5-1

Palladium (II) chloride (4.0 mg, 0.023 mmol) and triphenylphosphine (10.8 mg, 0.0412 mmol) were diluted in anhydrous acetonitrile (1.0 mL) and stirred at room temperature for 70 minutes under an argon atmosphere. To a solution of intermediate 1-3 (409.7 mg, 0.8390 mmol) used in Example 1 in anhydrous acetonitrile (5.0 mL), ethynylbenzene (276 μL, 2.51 mmol), triethylamine (1.200 mL, 8.609 mmol), copper iodide (I) (13.2 mg, 0.0693 mmol) was added and the mixture was freeze degassed twice and stirred at room temperature for 49.5 hours under an argon atmosphere. Water (20 mL) was added and extracted three times with methylene chloride (20 mL). The organic layer was collected, washed with brine, dried over sodium sulfate, filtered, and evaporated to a black oil. The residue was purified by open column chromatography (n-hexane: ethyl acetate = 1: 0 to 10: 1) to obtain the title compound (249.1 mg, 0.5385 mmol, 64%, dark orange oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.539-7.486 (4H, m), 7.395-7.322 (4H, m), 7.218-7.156 (3H, m), 7.115 (1H, s), 7.003-6.968 (3H, m), 6.923-6.861 (2H, m), 5.083 (2H, s), 3.641 (3H, s), 2.991 (2H, t, J = 7.74 Hz), 2.628 (2H, t, J = 7.74 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.67, 157.27, 156.86, 156.32, 139.50, 133.24, 131.51, 130.13, 130.05, 129.19, 128.33, 128.14, 127.58, 123.34, 122.19, 120.91, 118.62, 118.49, 118.10 , 117.70, 111.59, 88.89, 88.83, 69.26, 51.48, 34.02, 26.16.
HRMS (ESI-TOF, [M + Na] ⁺ ): C ₃₁ H ₂₆ NaO ₄ ⁺ : calculated 485.1723. Found 485.1744.

Synthesis of intermediate 5-2

The synthesis was performed in the same manner as the synthesis method of Intermediate 1-5 of Example 1 except that Intermediate 5-1 was used instead of Intermediate 1-4, and column chromatography (n-hexane: ethyl acetate) was performed. = 2: 1) to give the title compound (203.2 mg, 0.4530 mmol, 90%, yellow solid).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.544-7.490 (4H, m), 7.396-7.320 (4H, m), 7.222-7.169 (3H, m), 7.110 (1H, s), 7.008-6.974 (3H, m), 6.934-6.869 (2H, m), 5.081 (2H, s), 2.998 (2H, t, J = 7.68 Hz), 2.676 (2H, t, J = 7.70 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 179.16, 157.22, 156.87, 156.30, 139.40, 133.22, 131.50, 130.11, 130.06, 128.82, 128.29, 128.10, 127.66, 123.32, 122.15, 120.92, 118.66, 118.47, 118.08 , 117.64, 111.57, 88.90, 88.82, 69.24, 33.86, 25.83.
HRMS (ESI-TOF, [MH] ⁻ ): C ₃₀ H ₂₃ O ₄ ⁻ : measured value 447.1602. Measured value 447.1604.

Synthesis of Intermediate 5-3

Synthesis was performed in the same manner as in the synthesis of intermediate 1-8 of Example 1 except that intermediate 5-2 was used instead of intermediate 1-5, and column chromatography (n-hexane: ethyl acetate) was performed. = 2: 1 to 4: 5) to give the title compound (164.6 mg, 0.1858 mmol, 94%, colorless sticky oil).
¹ H NMR (400 MHz, CDCl ₃ ): (= 7.530-7.478 (4H, m), 7.389-7.314 (4H, m), 7.217-7.145 (3H, m), 7.098 (1H, s), 6.987-6.965 (3H, m), 6.914-6.850 (2H, m), 5.493 (1H, d, J = 7.80 Hz), 5.083 (2H, s), 4.365-4.300 (2H, m), 4.222-4.177 (1H, m ), 4.162-4.120 (2H, m), 4.034-3.963 (2H, m), 2.984 (2H, t, J = 7.64 Hz), 2.652-2.610 (2H, m), 1.969-1.895 (2H, m), 1.474-1.433 (27H, m).
¹³ C NMR (100 MHz, CDCl ₃ ): (= 172.98, 168.27, 157.18, 156.76, 156.25, 155.16, 139.45, 133.16, 131.43, 130.05, 130.00, 129.00, 128.26, 128.08, 127.53, 123.24, 122.09, 120.83, 118.54 , 118.37, 118.03, 117.63, 111.56, 88.80, 88.78, 83.60, 83.53, 82.58, 82.56, 79.84, 69.20, 67.33, 63.99, 63.94, 60.37, 54.42, 54.33, 33.97, 29.71, 29.67, 29.50, 29.43, 28.23 , 26.02.
HRMS (ESI-TOF, [M + Na] ⁺ ): C ₄₉ H ₆₀ NNaO ₁₂ P ⁺ : calculated value 908.3745. Found value 908.3716.

[Example 6]
Synthesis of intermediate 6-3 (compound 6 precursor)

Synthesis of intermediate 6-1

Synthesis was performed in the same manner as in Intermediate 5-1 of Example 5 except that 4-tert-butylphenylacetylene was used instead of ethynylbenzene, and column chromatography (n-hexane: ethyl acetate = 1: 0). To 10: 1) to give the title compound (287.7 mg, 0.5547 mmol, 62%, brown oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.504-7.438 (4H, m), 7.383-7.344 (3H, m), 7.204-7.147 (3H, m), 7.102 (1H, s), 6.990-6.955 (3H, m), 6.917-6.853 (2H, m), 5.073 (2H, s), 3.634 (3H, s), 2.983 (2H, t, J = 7.72 Hz), 2.621 (2H, t, J = 7.74 Hz), 1.324 (9H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.67, 157.06, 156.94, 156.32, 151.43, 139.47, 133.18, 131.23, 130.13, 130.03, 129.18, 127.57, 125.33, 122.11, 120.90, 120.27, 118.65, 118.42, 118.38 , 117.63, 111.57, 88.98, 88.21, 69.26, 51.48, 34.77, 34.01, 31.17, 26.16.
HRMS (ESI-TOF, [M + Na] ⁺ ): C ₃₅ H ₃₄ NaO ₄ ⁺ : calculated 541.2349. Found 541.2371.

Synthesis of intermediate 6-2

The synthesis was performed in the same manner as the synthesis method of Intermediate 5-2 of Example 5 except that Intermediate 6-1 was used instead of Intermediate 5-1, and column chromatography (n-hexane: ethyl acetate) was performed. = 1: 1) to give the title compound (237.8 mg, 0.4712 mmol, 91%, white solid).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.478 (2H, dt, J = 8.80 Hz, 2.30 Hz), 7.447 (2H, d, J = 8.52 Hz), 7.373-7.334 (3H, m), 7.198 -7.149 (3H, m), 7.085 (1H, s), 6.983-6.955 (3H, m), 6.911-6.850 (2H, m), 5.064 (2H, s), 2.979 (2H, t, J = 7.68 Hz ), 2.657 (2H, t, J = 7.70 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 178.69, 157.04, 156.95, 156.31, 151.39, 139.38, 133.18, 131.23, 130.12, 130.06, 128.83, 127.67, 125.31, 122.09, 120.91, 120.27, 118.70, 118.41, 118.37 , 117.59, 111.57, 88.97, 88.22, 69.26, 34.75, 33.79, 31.16, 25.86.
HRMS (ESI-TOF, [MH] ⁻ ): C ₃₄ H ₃₁ O ₄ ⁻ : calculated value 503.2228. Found value 503.2249.

Synthesis of Intermediate 6-3

The synthesis was performed in the same manner as the synthesis method of Intermediate 5-3 of Example 5 except that Intermediate 6-2 was used instead of Intermediate 5-2, and column chromatography (n-hexane: ethyl acetate) was performed. = 2: 1 to 1: 1) to obtain the title compound (153.9 mg, 0.1634 mmol, 81%, yellow sticky oil).
¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.485 (2H, dt, J = 8.80 Hz, 2.36 Hz), 7.451 (2H, dt, J = 8.52 Hz, 2.00 Hz), 7.384-7.345 (3H, m ), 7.212-7.144 (3H, m), 7.092 (1H, s), 6.980-6.958 (3H, m), 6.912-6.851 (2H, m), 5.493 (1H, d, J = 7.84 Hz), 5.080 ( 2H, s), 4.365-4.300 (2H, m), 4.245-4.176 (1H, m), 4.162-4.119 (2H, m), 4.060-3.964 (2H, m), 2.984 (2H, t, J = 7.64 Hz), 2.652-2.611 (2H, m), 1.970-1.895 (2H, m), 1.473-1.432 (27H, m), 1.323 (9H, s).
¹³ C NMR (100 MHz, CDCl ₃ ): δ = 173.05, 168.33, 157.04, 156.89, 156.31, 155.22, 151.42, 139.49, 133.17, 131.22, 130.11, 130.04, 129.06, 127.58, 125.31, 122.08, 120.88, 120.25, 118.63 , 118.37, 118.36, 117.63, 111.61, 88.98, 88.17, 83.59, 82.64, 82.62, 79.90, 69.27, 67.39, 64.05, 63.99, 60.42, 54.46, 54.38, 34.75, 34.03, 31.15, 29.77, 29.73, 29.56, 28.49 , 27.92, 26.09.
HRMS (ESI-TOF, [M + Na] ⁺ ): C ₅₈ H ₆₈ NNaO ₁₂ P ⁺ : calculated value 964.4371. Found value 964.4363.

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 at 4 mL each in a 60 mm dish. 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-tagged 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. 151, 209-220 (2000). Twenty-four hours after transfection, the cells were detached using trypsin / EDTA, resuspended in a culture solution to 2.0 × 10 ⁴ cells / well, and seeded in 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 further allowed to stand for 1 hour in the presence of 5% CO ₂ . The 96-well plate was centrifuged (190 × g, 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), heated at 37 ° C. for 1 hour, and then measured again. For each well, the AP activity was calculated by applying a value obtained by subtracting the background from the second absorbance to the following equation.

  Further, a graph was created using the value obtained by subtracting the AP activity (%) of the unstimulated group on the vertical axis. Table 3 below shows the results of calculating the agonist activity of each compound by comparing the EC50 value calculated for each test compound of Examples 1 to 4 with the EC50 value of Reference Compound 1 below. The activity was calculated by plotting the compound concentration and AP activity (%). The activity of Reference Compound 1 (LPS18: 1) was 3+ (++), and the activity of Reference Compound 1 was 5 times higher than that of Reference Compound 1 3.5+. 10 times the activity 4+, 50 times the activity 4.5+, 100 times the activity 5+, 1/5 of the activity 2.5+, 1/10 of the activity 2+, 1/50 of the activity The activity of 1.5+, 1/100 is represented by 1+, the activity of 1/500 is represented by 0.5+, and the activity less than that is represented by −. The EC50 value of each compound is also shown in parenthesis.

Test results of TGFα cleavage assay As shown in Table 3, compounds 1-4 were found to be dual agonists with strong activity against GPR34 and P2Y10.

Claims (13)

Formula (I):
[Where:
R ¹ , R ² and R ³ are independently selected from C _1-6 alkyl, C _1-6 alkoxy, and a halogen atom;
p, q and r are independently 0-4,
l and m are independently 0-3;
n is 0-5;
Z ¹ and Z ² , when m is 0 or 1, either 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 independently selected from the group consisting of oxygen atoms and direct bonds;
Z ³ and Z ⁴ are groups in which when l is 0 or 1, one is a direct bond and the other is an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO ₂ —, and difluoromethylene. Or both are direct bonds and when l is 2 or 3, Z ³ and Z ⁴ are independently an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO _2. Selected from the group consisting of-, 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 alkyl) carbonyl, (C _6-10 aryl) carbonyl, (C _1- Selected from the group consisting of ₆ alkoxy) carbonyl, C _1-6 alkoxy C _1-6 alkyl, and (C _7-14 aralkyloxy) carbonyl;
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 ¹ -Y is
A group selected from the group consisting of:
Wherein R ¹⁰ and R ¹¹ are independently a hydrogen atom, a halogen atom, C _1-6 alkyl, hydroxy, or C _1-6 alkoxy optionally substituted by one or more R ¹² , R ¹² is 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;
A ² is an oxygen atom or —NR ¹³ —, wherein 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;
A ³ is,
A group selected from the group consisting of:
Wherein B ¹ and B ² are independently selected from C _3-10 cycloalkylene, 5-10 membered heterocyclylene, C _6-10 arylene, and 5-10 membered heteroarylene,
R ¹⁴ and R ¹⁵ are 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 Selected from 10-membered heteroaryloxy, cyano, amino, nitro, trifluoromethyl, halogen atoms, and hydroxy;
R ¹⁶ is C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 Selected from membered heteroaryl, C _6-10 aryloxy, and 5-10 membered heteroaryloxy;
t is 1-5,
u is 1 to 5]
Or a salt thereof. A ³ is
And
Here, R ¹⁴ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aryl. The compound according to claim 1, or a salt thereof, selected from oxy, 5- to 10-membered heteroaryloxy, cyano, trifluoromethyl, a halogen atom, and hydroxy. A ³ is
And
Here, R ¹⁵ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aryl. The compound according to claim 1, or a salt thereof, selected from oxy, 5- to 10-membered heteroaryloxy, cyano, trifluoromethyl, a halogen atom, and hydroxy. A ³ is
And
Wherein R ¹⁶ is selected from C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, or a salt thereof.   The compound of any one of Claims 1-4 whose p, q, and r are 0, or its salt. Z ³ (CH ₂ ) ₁ Z ⁴ is selected from the group consisting of an oxygen atom, —NH—, —CH ₂ —, —OCH ₂ —, —CH ₂ O—, and a direct bond. The compound of any one of these, or its salt. The compound of any one of Claims 1-6 whose R < ⁵ > is a hydrogen atom or methyl, or its salt. R ⁴ is a hydrogen atom;
R ⁶ and R ⁷ are hydrogen atoms;
R ⁸ is a hydrogen atom;
The compound of any one of Claims 1-7, or its salt. X-A ¹ -Y is
One group selected from the group consisting of:
X and Y are direct bonds;
The compound of any one of Claims 1-8, or its salt. Formula (IV):
[Where:
R ¹ , R ² and R ³ are independently selected from C _1-6 alkyl, C _1-6 alkoxy, and a halogen atom;
p, q and r are independently 0-4,
l and m are independently 0-3;
n is 0-5;
Z ¹ and Z ² , when m is 0 or 1, either one is an oxygen atom and the other is a direct bond, or both are direct bonds, and Z ¹ and Z ² are independently oxygen atoms And selected from the group consisting of direct bonds;
Z ³ and Z ⁴ are groups in which when l is 0 or 1, one is a direct bond and the other is an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO ₂ —, and difluoromethylene. Or both are direct bonds and when l is 2 or 3, Z ³ and Z ⁴ are independently an oxygen atom, a sulfur atom, —NR ⁹ —, —CO—, —SO _2. Selected from the group consisting of-, 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;
A ³ is,
A group selected from the group consisting of:
Wherein B ¹ and B ² are independently selected from C _3-10 cycloalkylene, 5-10 membered heterocyclylene, C _6-10 arylene, and 5-10 membered heteroarylene,
R ¹⁴ and R ¹⁵ are 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 Selected from 10-membered heteroaryloxy, cyano, amino, nitro, trifluoromethyl, halogen atoms, and hydroxy;
R ¹⁶ is C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-10 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl, 5-10 Selected from membered heteroaryl, C _6-10 aryloxy, and 5-10 membered heteroaryloxy;
t is 1-5,
u is 1 to 5]
Or a salt thereof.   A pharmaceutical composition for treating an autoimmune disease comprising the compound according to any one of claims 1 to 9 or a salt thereof.   A lysophosphatidylserine receptor comprising the compound or a salt thereof according to any one of claims 1 to 9, and acting 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 lysophosphatidylserine receptor agonist activity.