JP5225076B2 - Pharmaceutical use of carboxylic acid derivatives containing thiazole ring - Google Patents

Description

  The present invention relates to a pharmaceutical comprising a carboxylic acid derivative containing a thiazole ring as an active ingredient.

  Diabetes is a disease in which the number of patients has been increasing rapidly in recent years, and is known to be a risk factor with a high incidence of macrovascular disorders (coronary artery disease). Most diabetics have type 2 diabetes, which may be caused by insulin secretion deficiency or insulin action deficiency associated with insulin resistance, and may be accompanied by abnormal lipid metabolism (hyperlipidemia) in addition to hyperglycemia. Many. Hyperlipidemia associated with diabetes is frequently observed in an increase in triglycerides (hereinafter sometimes referred to as “TG”), and in this connection, HDL cholesterol (hereinafter referred to as “HDL-C”). There is also a lot of decline. Both high TG and low HDL-C are considered as risk factors for coronary artery disease. Correcting these factors is extremely important for controlling the onset of coronary artery disease in diabetic patients as well as controlling blood glucose.

  Peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor that was cloned in 1990 as a receptor that responds to peroxisome proliferators, and other nuclear receptors, retinoid X receptor (RXR) and heterodimers And activate various target genes as transcription factors. There are three types of PPARs (PPARα, β (δ), γ), fibrates that are hyperlipidemic agents for PPARα, and insulin resistance improvement for PPARγ. It has become clear that thiazolidine derivatives, which are drugs, each act as a ligand.

  Fibrate drugs are widely used as antihyperlipidemic drugs, and clofibrate, clofibrate aluminum, simfibrate, clinofibrate, etc. have been used so far, but are now said to be the second generation. Bezafibrate (Bezator SR (registered trademark), Bezalip (registered trademark)) and fenofibrate (Repankle, Tricore (registered trademark)) are widely used.

  Fibrate drugs activate PPARα to activate genes involved in fatty acid metabolism (acyl CoA synthase, lipoprotein lipase, fatty acid transport protein, etc.) and apolipoproteins involved in TG and cholesterol metabolism (AI, AII, AV). , CIII) regulates gene expression, lowers TG and LDL cholesterol (hereinafter sometimes referred to as “LDL-C”), and increases HDL-C, and thus is highly effective as a therapeutic agent for hyperlipidemia. It is known to show.

However, conventional fibrate drugs have weak PPARα agonist activity (EC ₅₀ ) on the order of μmol / L (30 μmol / L or more), and the drug dosage is as high as 134-1500 mg / day. Various side effects such as gastrointestinal discomfort, gastrointestinal symptoms such as nausea, skin symptoms such as rash, liver dysfunction, and pancreatitis have been reported (above, Ripanpur (registered trademark) package insert) and have PPARα agonistic activity. There remains room for further improvement as a drug.
From the above, by creating a compound capable of specifically activating PPARα more than conventional fibrate drugs, pharmacological actions based on PPARα activation (TG lowering action, LDL-C lowering action, HDL-C increasing action) And is expected to be used as a compound that is superior in terms of anti-arteriosclerosis action and the like.
Among them, compounds that strongly activate PPARα may be useful drugs for the treatment of hyperlipidemia associated with diabetes by showing superior TG-lowering action and HDL-C-increasing action than conventional drugs. Be expected.
In view of this background, various carboxylic acid derivatives have recently been reported for PPARα agonists. For example, Patent Document 1, Non-Patent Document 1 and Non-Patent Document 2 include (phenylthio) acetic acid derivatives, Patent Document 2 and Non-Patent Document 3 include 3-phenylpropionic acid derivatives, and Patent Document 3 and Non-Patent Document 4. Is a phenoxyacetic acid derivative, Patent Document 4 is a phenoxyacetic acid derivative, Patent Document 5 and Non-Patent Document 5 are 2,2-dichloroalkanecarboxylic acid derivatives, and Patent Document 6 is 1,3-dioxane-2. -Carboxylic acid derivatives are reported in Patent Document 7 as phenoxyacetic acid derivatives, but there is no description suggesting (1,3-thiazol-2-yl) -thioacetic acid derivatives like the compounds of the present invention. .
International pamphlet WO00 / 23407 International publication pamphlet WO00 / 75103 International publication pamphlet WO02 / 38553 International publication pamphlet WO02 / 28821 International pamphlet WO 96/15784 International pamphlet WO01 / 90087 International publication pamphlet WO02 / 096894 J. et al. Med. Chem. , 42, 3785 (1999) Bioorg. Med. Chem. Lett. , 11, 1225 (2001) Bioorg. Med. Chem. Lett. , 12, 333 (2002) J. et al. Med. Chem. , 46, 5121 (2003) Am. J. et al. Physiol. , 283 (3, Pt. 2), H949 (2002)

An object of the present invention is to provide a novel pharmaceutical use of a carboxylic acid derivative containing a thiazole ring, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

  The inventors of the present invention have conducted research focusing on the role of PPARα in relation to lipid metabolism for the purpose of creating a drug useful as a prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes. The compound represented by I) has an excellent plasma TG lowering action, a free fatty acid lowering action on male Zucker fatty rats, which are high TG model animals having insulin resistance, and an increase in serum HDL cholesterol in rats treated with high cholesterol diet The present invention has been completed by finding that it exhibits an action.

That is, the gist of the present invention is as follows.
(1) The following formula (I)

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom or an alkyl group, or R ¹ and R ² are bonded to each other to form a cycloalkyl group;
R ³ represents a hydrogen atom or an alkyl group;
R ⁴ represents a hydrogen atom, an alkyl group or an aryl group;
n represents an integer of 1 to 5;
Y represents an oxygen atom, a sulfur atom, —NR ⁵ —, —CONR ⁵ —, —NR ⁵ CO— or —NHCONR ⁵ — (wherein R ⁵ represents a hydrogen atom, an alkyl group, a cycloalkylalkyl group, an aryl group, an aryl group, An alkyl group, an arylalkenyl group, an aryloxyalkyl group, a heteroaryl group or a heteroarylalkyl group));
Z represents a cycloalkyl group, an aryl group, an arylalkyl group, an arylalkenyl group, an aryloxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
Of the above groups, each of the alkyl group, cycloalkyl group, cycloalkylalkyl group, aryl group, arylalkyl group, arylalkenyl group, aryloxyalkyl group, heteroaryl group or heteroarylalkyl group has a substituent. You may do it. And / or the prevention of hyperlipidemia associated with diabetes containing a carboxylic acid derivative containing a thiazole ring represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. Or a therapeutic agent.
(2) The following formula (I ')

[Wherein, R ¹ , R ² , R ³ , R ⁴ , n, Y, Z are as defined above]. Hyperlipidemia associated with diabetes according to the above (1), which contains, as an active ingredient, a carboxylic acid derivative containing a thiazole ring represented by formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. Preventive and / or therapeutic agent for symptom.
(3) In formula (I) or formula (I ′), n is an integer of 1 to 3, and Y is an oxygen atom, a sulfur atom, —NR ⁶ —, —CONR ⁶ —, —NR ⁶ CO— or — NHCONR ⁶ — (wherein R ⁶ represents a hydrogen atom, an alkyl group, a cycloalkylalkyl group, an arylalkyl group, an arylalkenyl group, an aryloxyalkyl group or a heteroarylalkyl group. Among these groups, an alkyl group , An arylalkyl group, an arylalkenyl group, an aryloxyalkyl group, or a heteroarylalkyl group each may have a substituent, and Z is a cycloalkyl group that may have a substituent. Including a thiazole ring which may be an aryl group which may have a group, an arylalkyl group which may have a substituent or a heteroaryl group which may have a substituent The prevention of hyperlipidemia associated with diabetes according to the above (1) or (2) comprising a rubonic acid derivative or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient, and / Or therapeutic agent.
(4) In formula (I) or formula (I ′), Y represents an oxygen atom, sulfur atom, or —NR ⁷ — [wherein R ⁷ represents a hydrogen atom, an alkyl group, or —CH ₂ —W (wherein W Represents an aryl group or a heteroaryl group. Of the above groups, the alkyl group, aryl group or heteroaryl group may have a substituent. Z is the following formula (II)

[Wherein, R ⁸ , R ⁹ and R ¹⁰ are the same or different and are each a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a halogen atom, a haloalkyl group, a haloalkyloxy group, a cyano group, a nitro group, —NR ¹³ R ¹⁴ , —NR ¹⁵ COR ¹⁶ , —CONR ¹⁷ R ¹⁸ (wherein R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ may be the same or different and are each independently hydrogen; Represents an atom, an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group, or R ¹³ and R ¹⁴ , R ¹⁵ and R ¹⁶ are bonded to each other to form a carbon atom and a hetero atom; -OR ¹⁹ , -COR ²⁰ or -C≡CR ²¹ (wherein R ¹⁹ , R ²⁰ and R ²¹ are each independently a hydrogen atom, A kill group, a cycloalkyl group, an aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group).
R ¹¹ represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a halogen atom, a haloalkyl group, a cyano group or a nitro group;
R ¹² represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group;
E ¹ represents an oxygen atom, a sulfur atom or —NR ²² — (wherein R ²² represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group or a heteroarylalkyl group). Indicates.
Of the above groups, each of the alkyl group, cycloalkyl group, cycloalkylalkyl group, aryl group, arylalkyl group, heteroaryl group, heteroarylalkyl group or heterocycle may have a substituent. The carboxylic acid derivative containing a thiazole ring represented by the substituent selected from the above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient (1) to (3) A prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to any one of the above.
(5) In Formula (I) or Formula (I ′), Y is an oxygen atom, a sulfur atom, or —NR ²³ — {wherein R ²³ is a hydrogen atom, an alkyl group that may have a substituent, or Formula (III) below

[Wherein, R ²⁴ and R ²⁵ are the same or different and are each a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an arylcarbonyl group, a heteroaryl group, a halogen atom, a haloalkyl group, a haloalkyloxy group, —NR ²⁶ R ²⁷ , —NR ²⁸ COR ²⁹ , —CONR ³⁰ R ³¹ (wherein R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ may be the same or different and each independently represents a hydrogen atom) Represents an alkyl group, an aryl group or a heteroaryl group, or R ²⁶ and R ²⁷ , R ³⁰ and R ³¹ are bonded to each other to form a heterocycle optionally having carbon and heteroatoms.) or -OR ³² (wherein, R ³² represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a heteroaryl group or heteroarylalkyl group ) Shows the. Of the above groups, each of the alkyl group, cycloalkyl group, aryl group, arylalkyl group, heteroaryl group, heteroarylalkyl group and heterocycle may have a substituent. ] Is a substituent selected from the group consisting of the following formula (IV)

[Wherein, R ⁸ , R ⁹ and R ¹⁰ are as defined above. The carboxylic acid derivative containing a thiazole ring represented by the substituent selected from the above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient (1) to (4) A prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to any one of the above.
(6)
(34) 2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (38) 2-[(4- {2-[(4′-Chlorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (68) 2- [ (4- {2-[(3′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (76) 2-[(4- {2-[(4′-fluorobiphenyl-4-yl) thio] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (79) 2-[(4- {2- [(3,4'-difluorobiphenyl-4-yl) oxy] ethyl} -1,3- Azol-2-yl) thio] -2-methylpropionic acid (100) 2-{[4- (2-{[5- (4-fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3 -Thiazol-2-yl] thio-2-methylpropionic acid (102) 2-methyl-2-({4- [2-({5- [4- (trifluoromethyl) phenyl] pyridin-2-yl} Oxy) ethyl] -1,3-thiazol-2-yl} thio) propionic acid (103) 2-methyl-2-({4- [2-({5- [3- (trifluoromethyl) phenyl] pyridine) -2-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) propionic acid (104) 2-methyl-2-({4- [2-({5- [4- (trifluoro) Methoxy) phenyl] pyridin-2-yl} oxy ) Ethyl] -1,3-thiazol-2-yl} thio) propionic acid (106) 2-{[4- (2-{[5- (4-chlorophenyl) pyridin-2-yl] oxy} ethyl)- 1,3-thiazol-2-yl] thio} -2-methylpropionic acid (107) 2-{[4- (2-{[5- (3-chlorophenyl) pyridin-2-yl] oxy} ethyl)- 1,3-thiazol-2-yl] thio} -2-methylpropionic acid (108) 2-{[4- (2-{[5- (3,4-dichlorophenyl) pyridin-2-yl] oxy} ethyl ) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (109) 2-{[4- (2-{[5- (3-chloro-4-fluorophenyl) pyridine-2-] Yl] oxy} ethyl) -1,3-thiazole 2-yl] thio} -2-methylpropionic acid (152) 2-methyl-2-{[4-({[4 ′-(trifluoromethyl) biphenyl-4-yl] methoxy} methyl) -1,3 -Thiazol-2-yl] thio} propionic acid (162) 2-methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl ] -1,3-thiazol-2-yl} thio) propionic acid (220) 2-{[4- (2-{[6- (4-chloro-2-fluorophenyl) pyridazin-3-yl] amino} Ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (224) 2-({4- [2-({6- [2-fluoro-4- (trifluoromethyl) phenyl] ] Pyridazin-3-yl} amino) Ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid (226) 2-{[4- (2-{[5- (4-chlorophenyl) pyrazin-2-yl] amino} Ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (227) 2-[(4- {2-[[5- (4-chlorophenyl) pyrazin-2-yl] (methyl) ) Amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (229) 2-methyl-2-({4- [2- (methyl {5- [4- (tri Fluoromethyl) phenyl] pyrazin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) propionic acid (231) 2-methyl-2-({4- [2- (methyl {5 -[4- (trifluoromethoxy) phenyl] Pyrazin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) propionic acid (232) 2-({4- [2-({5- [2-fluoro-4- (tri) Fluoromethyl) phenyl] pyrazin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid (243) 2-methyl-2-({4- [2- ({5- [4- (trifluoromethyl) phenyl] pyridin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) propionic acid (260) 2-{[4- (2 -{[6- (4-Chlorophenyl) pyridin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (261) 2-methyl-2-({ 4- [2-({6- [4- (Triflu Olomethyl) phenyl] pyridin-3-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) propionic acid (265) 2-[(4- {2-[(5-ethylpyrimidine-2- Yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (267) 2-[(4- {2- [heptyl (5-propylpyrimidine-2-]) Yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (319) 2-[(4- {2- [3- (2,4-difluorophenyl) -1] -Heptylureido] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (320) 2-({4- [2- (3-cyclohexyl-1-peptylureido) ethyl] -1 , 3-thiazole -2-yl} thio) -2-methylpropionic acid (326) 2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) Methyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (329) 2-[(4- {2-[(5-ethylpyrimidin-2-yl) (hexyl) ) Amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (346) 2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(2E ) -3-Phenylprop-2-en-1-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (379) 2-[(4- {2- [(3-Butoxypropyl) (5-ethylpyrimidine-2 Yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (430) 2-methyl-2-[(4- {2-[[(1-phenyl-1H- Pyrazol-4-yl) methyl] (5-propylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid (442) 2-[(4- {2- [ Heptyl (5-morpholin-4-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (449) 2-[(4- {2- [(3-Ethyl-1H-pyrazol-5-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (450) 2-[(4- { 2- [Heptyl (3-propyl- A carboxylic acid derivative containing a thiazole ring selected from H-pyrazol-5-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid, or a pharmaceutically acceptable salt thereof, or The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to any one of (1) to (5) above, which contains a hydrate or solvate thereof as an active ingredient.
(7) In formula (I), Y is an oxygen atom, and Z is a carboxylic acid derivative containing a thiazole ring represented by an aryl group or a heteroaryl group, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to (1), which contains a solvate as an active ingredient.
(8) In formula (I), Y is an oxygen atom, and Z is a carboxylic acid derivative containing a thiazole ring represented by an aryl group, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to (1) or (7), which is contained as an active ingredient.
(9)
(34) 2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (38) 2-[(4- {2-[(4′-Chlorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (68) 2- [ (4- {2-[(3′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (76) 2-[(4- {2-[(4′-fluorobiphenyl-4-yl) thio] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (79) 2-[(4- {2- [(3,4'-difluorobiphenyl-4-yl) oxy] ethyl} -1,3- Azol-2-yl) thio] -2-methylpropionic acid (100) 2-{[4- (2-{[5- (4-fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3 -Thiazol-2-yl] thio-2-methylpropionic acid (102) 2-methyl-2-({4- [2-({5- [4- (trifluoromethyl) phenyl] pyridin-2-yl} Oxy) ethyl] -1,3-thiazol-2-yl} thio) propionic acid (103) 2-methyl-2-({4- [2-({5- [3- (trifluoromethyl) phenyl] pyridine) -2-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) propionic acid (104) 2-methyl-2-({4- [2-({5- [4- (trifluoro) Methoxy) phenyl] pyridin-2-yl} oxy ) Ethyl] -1,3-thiazol-2-yl} thio) propionic acid (106) 2-{[4- (2-{[5- (4-chlorophenyl) pyridin-2-yl] oxy} ethyl)- 1,3-thiazol-2-yl] thio} -2-methylpropionic acid (107) 2-{[4- (2-{[5- (3-chlorophenyl) pyridin-2-yl] oxy} ethyl)- 1,3-thiazol-2-yl] thio} -2-methylpropionic acid (108) 2-{[4- (2-{[5- (3,4-dichlorophenyl) pyridin-2-yl] oxy} ethyl ) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (109) 2-{[4- (2-{[5- (3-chloro-4-fluorophenyl) pyridine-2-] Yl] oxy} ethyl) -1,3-thiazole 2-yl] thio} -2-methylpropionic acid (152) 2-methyl-2-{[4-({[4 ′-(trifluoromethyl) biphenyl-4-yl] methoxy} methyl) -1,3 -Thiazol-2-yl] thio} propionic acid (162) 2-methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl ] -1,3-thiazol-2-yl} thio) propionic acid (220) 2-{[4- (2-{[6- (4-chloro-2-fluorophenyl) pyridazin-3-yl] amino} Ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (224) 2-({4- [2-({6- [2-fluoro-4- (trifluoromethyl) phenyl] ] Pyridazin-3-yl} amino) A carboxylic acid derivative containing a thiazole ring selected from ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to any one of (1), (7) and (8), which is contained as an active ingredient.
(10) In formula (I), Y is —NR ^5a — (wherein R ^5a represents an alkyl group having 4 to 10 carbon atoms), and Z includes a thiazole ring represented by a heteroaryl group. The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to (1) above, which contains a carboxylic acid derivative or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient.
(11) In formula (I), Y is —NR ^5b — (wherein R ^5b represents an alkyl group having 6 to 9 carbon atoms), and Z includes a thiazole ring represented by a heteroaryl group. The prevention of hyperlipidemia associated with diabetes according to (1) or (10) above, which contains a carboxylic acid derivative or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient, and / Or therapeutic agent.
(12)
(265) 2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid ( 267) 2-[(4- {2- [Heptyl (5-propylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (329) 2 -[(4- {2-[(5-ethylpyrimidin-2-yl) (hexyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (442) 2- [(4- {2- [Heptyl (5-morpholin-4-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (449) 2 -[(4- {2-[(3-D Ru-1H-pyrazol-5-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (450) 2-[(4- {2- [heptyl] (3-propyl-1H-pyrazol-5-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid-containing carboxylic acid derivative containing a thiazole ring or a drug thereof Prevention of hyperlipidemia associated with diabetes according to any one of (1), (10) and (11) above, which contains an acceptable salt or a hydrate or solvate thereof as an active ingredient And / or therapeutic agents.
(13) In formula (I), Y is —NR ^5c — (wherein R ^5c represents an arylalkyl group or a heteroarylalkyl group), and Z includes a thiazole ring represented by a heteroaryl group. The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to (1) above, which contains a carboxylic acid derivative or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient.
(14) In formula (I), Y is —NR ^5d — (wherein R ^5d represents a heteroarylalkyl group), and Z is a carboxylic acid derivative containing a thiazole ring represented by a heteroaryl group or The prophylactic and / or therapeutic agent for hyperlipidemia associated with diabetes according to (1) or (13) above, which contains a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient .
(15)
(326) 2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole- 2-yl] thio} -2-methylpropionic acid (430) 2-methyl-2-[(4- {2-[[(1-phenyl-1H-pyrazol-4-yl) methyl] (5-propylpyrimidine -2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid, a carboxylic acid derivative containing a thiazole ring, or a pharmaceutically acceptable salt thereof, or a hydrate or solvent thereof The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to any one of (1), (13) and (14), comprising a Japanese product as an active ingredient.
(16)
(34) 2-[(4- {2-[(4′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid A prophylactic and / or therapeutic agent for hyperlipidemia associated with diabetes, comprising a thiazole ring-containing carboxylic acid derivative or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient.
(17)
(442) 2-[(4- {2- [Heptyl (5-morpholin-4-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropion Prevention and / or treatment of hyperlipidemia associated with diabetes containing a carboxylic acid derivative containing a thiazole ring represented by an acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient medicine.
(18)
(326) 2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole- Combining with diabetes containing a carboxylic acid derivative containing a thiazole ring represented by 2-yl] thio} -2-methylpropionic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient For preventing and / or treating hyperlipidemia.
(19)
Prevention and / or prevention of diabetic hyperlipidemia containing a carboxylic acid derivative containing a thiazole ring represented by the general formula (I) or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient Or a therapeutic agent.
(20)
A prophylactic and / or therapeutic agent for diabetes comprising a carboxylic acid derivative containing a thiazole ring represented by formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

  According to the present invention, a compound useful as a prophylactic and / or therapeutic agent for hyperlipidemia associated with diabetes can be provided.

  According to the present invention, a compound useful as a preventive and / or therapeutic agent for diabetic hyperlipidemia can be provided.

  Moreover, according to this invention, the compound useful as a prophylactic and / or therapeutic agent of hyperlipidemia for administering to the patient who shows hyperlipidemia complicated with diabetes can be provided.

  Hereinafter, the present invention will be described in detail.

  Specific examples of each group in the general formula (I) are as follows.

The alkyl group represented by R ¹ and R ² means a linear or branched alkyl having 1 to 15 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert -Butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. Preferably, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl is used, and methyl or ethyl is more preferable.

The cycloalkyl group represented by R ¹ and R ² has 3 to 7 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Preferred is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and more preferred is cyclopropyl or cyclobutyl.

The alkyl group represented by R ³ has the same meaning as the alkyl group in R ¹ , and preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl, and more Preferably, methyl or ethyl is used.

The alkyl group represented by R ⁴ has the same meaning as the alkyl group in R ¹ , and preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, more preferably methyl Is mentioned.

The aryl group represented by R ⁴ means an aryl group having 6 to 14 carbon atoms, for example, phenyl, naphthyl, or ortho-fused bicyclic group having 8 to 10 ring atoms and at least one ring atom. The ring is an aromatic ring (for example, indenyl etc.).

The alkyl group represented by R ⁵ is synonymous with the alkyl group in R ¹ , preferably an alkyl group having 5 to 9 carbon atoms, more preferably an alkyl group having 6 to 8 carbon atoms.

As the cycloalkylalkyl group represented by R ⁵ , the cycloalkyl part is the same as the cycloalkyl group in R ¹ , and the alkyl part means a linear or branched chain having 1 to 8 carbon atoms. Examples include propylmethyl, 2-cyclobutylethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl and the like.

The aryl group represented by R ⁵ has the same meaning as the aryl group in R ⁴ .

As the arylalkyl group represented by R ⁵ , the aryl moiety is the same as the aryl group in R ⁴ , and the alkyl moiety may have 1 to 8 carbon atoms and may be linear or branched. For example, benzyl, benzhydryl, 1- Examples include phenylethyl, 2-phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, naphthylmethyl, naphthylethyl, and the like. Preferably, the above R ²³ a is used.

The arylalkenyl group represented by R ^5, means that the aryl group for R ⁴ is bonded to the alkenyl group having 2 to 6 carbon atoms, such as 1-phenylethenyl, 2-phenylethenyl, 1-phenyl - 1-propenyl, 2-phenyl-1-propenyl, 3-phenyl-1-propenyl, 1-phenyl-2-propenyl, 2-phenyl-2-propenyl, 3-phenyl-2-propenyl, 1-phenyl-1- Butenyl, 2-phenyl-1-butenyl, 3-phenyl-2-butenyl, 4-phenyl-2-butenyl, 3-phenyl-2-propenyl, 2-phenyl-1-pentenyl, 2-phenyl-3-pentenyl, 2-phenyl-1-hexenyl and the like can be mentioned. Preferably, the above R ²³ d is used.

The aryloxy group represented by R ^5, the aryl group is equivalent to the aryl group in R ⁴ is also bound via an alkyl group and an oxygen atom in linear or branched with 1 to 8 carbon atoms For example, (phenyloxy) methyl group, (1-naphthyloxy) methyl group, (2-naphthyloxy) methyl group, 1- (phenyloxy) ethyl group, 2- (phenyloxy) ethyl group, 1- (1-naphthyloxy) ethyl group, 2- (1-naphthyloxy) ethyl group, 1- (phenyloxy) propyl group, 2- (phenyloxy) propyl group, 3- (phenyloxy) propyl group, 4 -(Phenyloxy) butyl group, 5- (phenyloxy) pentyl group, 6- (phenyloxy) hexyl group and the like can be mentioned.

The heteroaryl group represented by R ⁵ has a 5- to 6-membered ring group having carbon and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), or 8 to 10 ring atoms derived therefrom. Examples include ortho-fused bicyclic heteroaryls, especially benz derivatives, or those derived by fusing propenylene, trimethylene or tetramethylene groups thereto, and stable N-oxides thereof. For example, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1, 2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl Benzisothiazolyl, benzimidazolyl, oxazolopyridyl, imidazopyridazinyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, benzothienyl, chromenyl, isoindolyl, indolyl, Ndoriniru, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, 2,1,3 benzoxadiazolyl, benzoxazinyl and the like.

The heteroaryl group represented by R ^5, heteroaryl unit is equivalent to heteroaryl groups in R ^5, alkyl portion may be a branched be linear with 1-3 carbon atoms, for example 2- Pyrrolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 2- (2-pyridyl) ethyl, 2- (3-pyridyl) ethyl, 2- (4-pyridyl) ethyl, 3 -(2-Pyrrolyl) propyl, 4-imidazolylmethyl and the like can be mentioned. Preferably, the R ²³ b and R ²³ c are mentioned.

When R ⁵ represents an arylalkyl group, an arylalkenyl group or a heteroarylalkyl group, it is particularly preferably a substituent selected from the above general formula (III).

The cycloalkyl group represented by Z has the same meaning as the cycloalkyl group in R ¹ , and preferably cyclohexyl.

The aryl group represented by Z has the same meaning as the aryl group for R ⁵ , but phenyl or naphthyl is preferable.

The arylalkyl group represented by Z has the same meaning as the arylalkyl group for R ⁵ , but benzyl or naphthylmethyl is preferable.

The arylalkenyl group represented by Z has the same meaning as the arylalkenyl group for R ⁵ .

The aryloxyalkyl group represented by Z has the same meaning as the aryloxyalkyl group for R ⁵ .

The heteroaryl group represented by Z has the same meaning as the heteroaryl group for R ⁵ .

The heteroarylalkyl group represented by Z has the same meaning as the heteroarylalkyl group for R ⁵ .

  When Z represents an aryl group or a heteroaryl group, a substituent selected from the above general formula (II) is particularly preferable.

Examples of the halogen atom represented by R ⁸ , R ⁹ and R ¹⁰ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom, a chlorine atom and a bromine atom.

Examples of the haloalkyl group represented by R ⁸ , R ⁹ and R ¹⁰ include an alkyl group equivalent to the alkyl group in R ¹ substituted with the halogen atom. For example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl 2,2,2-trifluoroethyl, pentafluoroethyl and the like.

Examples of the haloalkyloxy group represented by R ⁸ , R ⁹ and R ¹⁰ include an alkyloxy group substituted with the halogen atom, such as trifluoromethyloxy, 2,2,2-trifluoroethyloxy, difluoromethyloxy. Etc.

The heterocycle represented by R ¹³ and R ¹⁴ or R ¹⁵ and R ¹⁶ has 2 carbon atoms containing 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. 10 non-aromatic heterocyclic groups such as azetidinyl, pyrrolidinyl, piperidino, piperazino, morpholino, 1,2,5,6-tetrahydropyridyl, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, 3-azaspiro [5,5] undecyl, 1,3,8-triazaspiro [4,5] decyl and the like.

As the arylcarbonyl group represented by R ²⁴ and R ²⁵ , the aryl moiety is the same as the aryl group in R ⁴ , and examples thereof include benzoyl and 1-naphthoyl.

  Among the above substituents, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, an arylalkenyl group, an aryloxyalkyl group, a heteroaryl group, a heteroarylalkyl group, and a heterocycle are It may have 1 to 3 substituents at each substitutable position. Examples of such a substituent include an alkyl group, an alkyloxy group, a halogen atom, a haloalkyl group, a haloalkoxy group, an aryl group, and a heteroaryl group. The substituents mentioned here are as defined above.

  Pharmaceutically acceptable salts of the compounds of general formula (I) include all salts, but salts with inorganic acids such as hydrochloric acid or hydrobromic acid, salts with organic acids, salts with alkali metals And salts with organic bases or salts with amino acids.

  In the present invention, the compound of the general formula (I) or a salt thereof is a solvate (for example, hydrate), a prodrug that is metabolized in vivo and converted to the carboxylic acid or salt of the general formula (I) Or all active metabolites of the above general formula (I).

  The compound (I) of the present invention can be synthesized, for example, by the following method, but the production method is not limited thereto.

  Among the compounds represented by the general formula (I), the compounds represented by the general formulas (I-2) and (I-4) in which the bonding mode of the Y moiety is an oxygen atom can be produced, for example, by the following method (production method). 1, 2). Even when the bonding mode of the Y moiety is a nitrogen atom, it can be produced by the same method (production methods 1 and 2).

[Production method 1]
By reacting an alcohol represented by the general formula (II-1) (the synthesis method will be described later) and a compound having a leaving group represented by the general formula (III-1) in the presence of a base, the general formula The ether compound represented by (I-1) can be obtained (Step 1). Alternatively, the compound represented by the general formula (II-2) having a leaving group on the alkyl chain (the synthesis method will be described later) is reacted with the alcohol derivative represented by the general formula (III-2) in the presence of a base. By making it, the ether compound represented by general formula (I-1) can be obtained (process 2). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-2) (step 3). In addition, compound (III-1) and compound (III-2) which are raw material compounds are normally easily synthesize | combined by a well-known method.

[Wherein R ¹ , R ² , R ⁴ and n are as defined above, R ³⁸ represents an alkyl group, Z ¹ represents an aryl group, heteroaryl group, arylalkyl group, heteroarylalkyl group or cycloalkyl group] X ¹ represents —SO ₂ R ³⁹ (wherein R ³⁹ represents an alkyl group or an aryl group) or a halogen atom, and X ² represents —OSO ₂ R ⁴⁰ (wherein R ⁴⁰ represents an alkyl group). A group, a haloalkyl group or an aryl group) or a halogen atom. ]
Steps 1 and 2 are usually performed in the presence of a base in a solvent that does not adversely influence the reaction. Examples of the base include alkali metal carbonates such as potassium carbonate, sodium carbonate and cesium carbonate, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tertiary butoxide, potassium hydroxide, sodium hydroxide and lithium hydroxide. Metal hydrides such as alkali metal hydroxides such as potassium hydride and sodium hydride, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline, 4-dimethylaminopyridine, 1 , 8-diazabicyclo [5.4.0] undec-7-ene and the like. The amount of the base to be used is preferably 1 to 5 molar equivalents relative to compound (II-1) or compound (II-2). The reaction temperature is usually −50 to 200 ° C., preferably −10 to 100 ° C. Solvents that do not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N, N-dimethyl Examples include amides such as formamide and N-methyl-2-pyrrolidone, and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.

Step 3 is usually performed in a water-containing solvent in the presence of an acid or a base. Examples of the acid include formic acid, hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, trifluoroacetic acid and the like. Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, and alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide. It is done. The amount of the acid or base used is usually an excess amount relative to compound (I-1). Preferably, the amount of acid used is 2 to 100 equivalents relative to compound (I-1), and the amount of base used is 1.2 to 5 equivalents relative to compound (I-1). Examples of the water-containing solvent include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, a mixed solvent of one or more solvents selected from dimethyl sulfoxide and acetone, and the like. When ^R38 is a tert-butyl group, in addition to the reaction in the water-containing solvent, acid decomposition can be performed. As the acid, for example, formic acid, hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid, paratoluenesulfonic acid and the like are used. At this time, the solvent may be mixed in an appropriate ratio. As the solvent, for example, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and the like are used. The amount of acid used is usually an excess amount relative to compound (I-1). Preferably, the usage-amount of an acid is 2-100 equivalent with respect to compound (I-1). The reaction temperature is generally −20 to 150 ° C., preferably −10 to 100 ° C.

[Production method 2]
Reaction of alcohol represented by general formula (II-1) (synthesis method will be described later) and aryl alcohol or heteroaryl alcohol represented by general formula (III-3) in the presence of phosphines and azodicarboxylic acid derivatives By making it, the ether compound represented by general formula (I-3) can be obtained (process 4). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-4) (step 5). In addition, the compound (III-3) which is a raw material compound is usually easily synthesized by a known method.

[Wherein, R ¹ , R ² , R ⁴ and n are as defined above, R ⁴¹ represents an alkyl group or a resin, and Z ² represents an aryl group or a heteroaryl group. ]
Step 4 is usually performed in the presence of phosphines and an azodicarboxylic acid derivative in a solvent that does not adversely influence the reaction. Examples of phosphines include triphenylphosphine and tributylphosphine, and examples of azodicarboxylic acid derivatives include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and azodicarbonyldipiperazine. The amount of phosphines and azodicarboxylic acid derivative used is preferably 1 to 5 molar equivalents relative to compound (II-1). The reaction temperature is usually −50 to 150 ° C., preferably −10 to 100 ° C. Solvents that do not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N, N-dimethyl Amides such as formamide and sulfoxides such as dimethyl sulfoxide are used. These solvents may be mixed and used at an appropriate ratio.

Step 5 can be carried out in the same manner as in Step 3 when R ⁴¹ is an alkyl group. When R ⁴¹ is a resin, it can be carried out in the same manner as in Step 3, but it can usually be carried out by using an excess amount of water-containing or non-water-containing trifluoroacetic acid, and does not adversely affect the reaction. You may mix and use a solvent in a suitable ratio. As the solvent that does not affect the reaction, ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, and hydrocarbons such as hexane, benzene and toluene are used. The reaction temperature is generally -20 to 150 ° C, preferably -10 ° C to 60 ° C.

  Among the compounds represented by the general formula (I), the compounds represented by the general formulas (I-6) and (I-8) in which the bonding mode of the Y moiety is an amide structure can be produced, for example, by the following method (production method) 3, 4).

[Production Method 3]
A primary amine represented by general formula (II-3) (the synthesis method will be described later) and a carboxylic acid represented by general formula (III-4) in the presence of a condensing agent, or general formula (III-5) The amide compound represented by general formula (I-5) can be obtained by reacting the carboxylic acid chloride represented by general formula (I-5) in the presence of a base (step 6). Subsequently, this compound can be converted to the carboxylic acid form (I-6) by deesterification (step 7). In addition, the compound (III-4) and the compound (III-5) which are raw material compounds are usually easily synthesized by a known method.

[Wherein, R ¹ , R ² , R ⁴ , R ³⁸ , n, and Z ¹ are as defined above]. ]
When the carboxylic acid compound (III-4) is used, Step 6 is usually performed in the presence of a condensing agent that activates the carboxylic acid in a solvent that does not adversely influence the reaction. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) or its hydrochloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxy Quinoline (EEDQ), carbonyldiimidazole (CDI), diethyl phosphoryl cyanide, benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide (DPPA), isobutyl chloroformate, diethylacetyl chloride, And trimethylacetyl chloride. These condensing agents are used alone, or N-hydroxysuccinimide (HONSu), hydroxybenzotriazole (HOBT), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBT), Alternatively, an additive such as 4-dimethylaminopyridine (DMAP) is used in combination. The amount of the condensing agent and additive to be used is preferably 1 to 5 molar equivalents relative to compound (II-3). The reaction temperature is usually −30 to 80 ° C., preferably −10 to 50 ° C. Solvents that do not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N, N-dimethyl Examples include amides such as formamide and N-methyl-2-pyrrolidone, and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio. When the carboxylic acid chloride compound (III-5) is used, it is usually carried out in the presence of a base in a solvent that does not adversely influence the reaction. Examples of the base include alkali metal carbonates such as potassium carbonate, sodium carbonate and cesium carbonate, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tertiary butoxide, potassium hydroxide, sodium hydroxide and lithium hydroxide. Metal hydrides such as alkali metal hydroxides such as potassium hydride and sodium hydride, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline, 4-dimethylaminopyridine, 1 , 8-diazabicyclo [5.4.0] undec-7-ene and the like. The amount of the base used is preferably 1 to 5 molar equivalents relative to compound (II-3). The reaction temperature is usually −50 to 100 ° C., preferably −10 to 50 ° C. Solvents that do not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N, N-dimethyl Examples include amides such as formamide and N-methyl-2-pyrrolidone, and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.

  Step 7 can be performed according to a method similar to that of step 3.

[Production Method 4]
Carrying out the reaction of the carboxylic acid represented by the general formula (II-4) (the synthesis method will be described later) and the amine represented by the general formula (III-6) in the presence of a condensing agent in the same manner as in Production Method 3. Thus, an amide compound represented by the general formula (I-7) can be obtained (step 8). Subsequently, this compound can be converted to the carboxylic acid form (I-8) by deesterification (step 9). In addition, the compound (III-6) which is a raw material compound is usually easily synthesized by a known method.

[Wherein, R ¹ , R ² , R ⁴ , R ³⁸ , Z ¹ are as defined above, and m represents an integer of 0-4. ]
Step 8 can be performed according to a method similar to that of step 6.

  Step 9 can be performed according to a method similar to that of step 3.

  Among the compounds represented by general formula (I), the compound represented by general formula (I-10) in which the bonding mode of the Y moiety is —NH— can be produced, for example, by the following method (Production Methods 5 and 6).

[Production Method 5]
By reacting a primary amine represented by general formula (II-3) (the synthesis method will be described later) with a compound having a leaving group represented by general formula (III-1) in the presence of a base. A secondary amine compound represented by the general formula (I-9) can be obtained (step 10). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-10) (step 11). In addition, compound (III-1) which is a raw material compound is normally easily synthesized by a known method.

[Wherein, R ¹ , R ² , R ⁴ , R ³⁸ , n, Z ¹ , X ¹ are as defined above]. ]
Step 10 can be performed according to a method similar to that of step 1.

  Step 11 can be performed according to a method similar to that of step 3.

[Production Method 6]
A secondary amine compound represented by general formula (I-9) is obtained by reacting the amide compound represented by general formula (I-7) synthesized by production method 4 in the presence of a reducing agent. (Step 12). Subsequently, this compound can be converted to the carboxylic acid form (I-10) by deesterification (step 13).

[Wherein, R ¹ , R ² , R ³ , R ⁴¹ , Z ¹ , n, m are as defined above]. N and m indicate a relationship of n = m + 1. ]
Step 12 is usually performed in the presence of a reducing agent in a solvent that does not adversely influence the reaction. As the reducing agent, for example, borane-tetrahydrofuran complex, borane-methyl sulfide complex, diborane, tetrabutylammonium borohydride, sodium borohydride in the presence of Lewis acid, and the like are used. The amount of the reducing agent to be used is preferably 1 to 5 molar equivalents relative to compound (I-7). The reaction temperature is usually −50 to 150 ° C., preferably −10 to 100 ° C. Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, and hydrocarbons such as hexane, benzene and toluene. These solvents may be mixed and used at an appropriate ratio.

  Step 13 can be performed according to a method similar to that of step 5.

Among the compounds of general formula (I), the bonding mode of the Y moiety is —NR ⁴² — (wherein R ⁴² represents an alkyl group, an arylalkyl group, an arylalkenyl group, an aryloxyalkyl group, a heteroarylalkyl group, The compounds of general formula (I-12), which may each have a substituent, can be produced, for example, by the following method (production methods 7 to 9).

[Production Method 7]
Reaction of a secondary amine represented by general formula (I-9) synthesized by production method 5 or 6 with a compound having a leaving group represented by general formula (III-7) in the presence of a base By making it, the tertiary amine compound represented by general formula (I-11) can be obtained (process 14). Alternatively, the tertiary amine compound represented by the general formula (I-11) is obtained by reacting the ketone compound represented by the general formula (III-8) and then reacting in the presence of a reducing agent. Can be obtained (step 15). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-12) (step 16). In addition, the compound (III-7) and the compound (III-8) which are raw material compounds are usually easily synthesized by a known method.

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁴¹ , R ⁴² , n, Z ¹ , X ² are as defined above, and R ⁴³ and R ⁴⁴ may be the same or different, Independently, it represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group. ]
Step 14 can be performed according to a method similar to that of step 1.

  Step 15 is usually performed in the presence of a reducing agent in a solvent that does not adversely influence the reaction. Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. Reaction temperature can be normally implemented at 0-100 degreeC. Examples of solvents that do not affect the reaction include ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, alcohols such as methanol and ethanol, and nitriles such as acetonitrile. These solvents may be mixed and used at an appropriate ratio. Moreover, you may use an acidic catalyst, for example, an acetic acid, p-toluenesulfonic acid, a boron trifluoride, diethyl ether complex etc. as needed.

  Step 16 can be performed according to a method similar to that of step 5.

[Production Method 8]
Carboxylic acid represented by general formula (II-4) (synthesis method will be described later) and amine derivative represented by general formula (III-9) are reacted in the presence of a condensing agent in the same manner as in Production Method 3. Thus, an amide compound represented by the general formula (I-13) can be obtained (step 17). Next, by reacting this amide compound in the presence of a reducing agent, a secondary amine compound represented by the general formula (I-15) can be obtained (step 19). Alternatively, using the primary amine represented by the general formula (II-3) (the synthesis method will be described later) and the carboxylic acid derivative represented by the general formula (III-10), the same as in Step 17 and Step 19 The secondary amine compound represented by the general formula (I-15) can also be obtained by performing a condensation reaction or a reduction reaction (steps 18 and 19). Subsequently, a tertiary amine compound represented by the general formula (I-11) is obtained by reacting a compound having a leaving group represented by the general formula (III-1) in the presence of a base. (Step 20). Finally, this compound can be converted to the carboxylic acid form (I-12) by deesterification (step 21). In addition, the compounds (III-1), (III-9), and (III-10) that are raw material compounds are usually easily synthesized by a known method.

[Wherein R ¹ , R ² , R ⁴ , R ⁴¹ , R ⁴² , Z ¹ , X ¹ , n, m are as defined above, R ⁴⁵ is an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, An aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group is shown. N and m indicate a relationship of n = m + 1. ]
Step 17 can be performed according to a method similar to that of step 6.

  Step 18 can be performed according to a method similar to that of step 6.

  Step 19 can be performed according to a method similar to that of step 12.

  Step 20 can be performed according to a method similar to that of step 1.

  Step 21 can be performed according to a method similar to that of step 5.

[Production Method 9]
A sulfonamide compound represented by the general formula (III-11) can be obtained by reacting a compound having an amino group represented by the general formula (III-6) in the presence of a base (step 22). ). Furthermore, this compound and the alcohol represented by the general formula (II-1) (the synthesis method will be described later) are reacted in the presence of a phosphine and an azodicarboxylic acid derivative, thereby being represented by the general formula (I-16). Can be obtained (step 23). Further, a secondary amine compound represented by the general formula (I-9) is obtained by reacting the present compound with a compound having a thiol group represented by the general formula (III-12) in the presence of a base. (Step 24). Furthermore, by using this compound and general formula (III-7) or general formula (III-8) in the same manner as in production method 7, the carboxylic acid form (I-12) can be obtained (step) 25-step 27). The starting compounds (III-6), (III-7), (III-8), and (III-12) are usually easily synthesized by known methods.

[Wherein, R ¹ , R ² , R ⁴ , R ³⁸ , R ⁴² , R ⁴³ , R ⁴⁴ , Z ¹ , X ² , n are as defined above, and R ⁴⁶ represents an alkyl group or an aryl group. . ]
Step 22 to Step 24 are non-patent documents [Tetrahedron Lett. 36, 6373 (1995) and Tetrahedron Lett. , 33, 5831 (1997)] and the like, and a secondary amine compound represented by the general formula (I-9) by 2-nitrobenzenesulfonylation, Mitsunobu reaction and de-2-nitrobenzenesulfonylation Can be obtained.

  Step 22 can be generally carried out in the same manner as in Step 3, using 2-nitrobenzenesulfonyl chloride.

  Step 23 can be performed according to a method similar to that of step 4.

  Step 24 can be usually carried out in the same manner as in Step 1 using benzenethiol.

  Step 25 can be performed according to a method similar to that of step 1.

  Step 26 can be performed according to a method similar to that of step 15.

  Step 27 can be performed according to a method similar to that of step 3.

Among the compounds represented by the general formula (I), the compound represented by the general formula (I-18) in which the binding mode of the Y moiety is —CONR ⁴² — (wherein R ⁴² is as defined above) For example, the secondary amine compound represented by the general formula (I-15) to be synthesized can be produced by the following method (Production Method 10).

[Manufacturing method 10]
Similarly to the secondary amine represented by the general formula (I-15) synthesized by the production method 8 and the production method 3, the carboxylic acid compound represented by the general formula (III-4) is added in the presence of a condensing agent. Alternatively, the amide compound represented by the general formula (I-17) can be obtained by reacting the carboxylic acid chloride represented by the general formula (III-5) in the presence of a base (step 28). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-18) (step 29). In addition, the compound (III-4) and the compound (III-5) which are raw material compounds are usually easily synthesized by a known method.

[Wherein, R ¹ , R ² , R ⁴ , R ³⁸ , R ⁴² , n, Z ¹ are as defined above]. ]
Step 28 can be performed according to a method similar to that of step 6.

  Step 29 can be performed according to a method similar to that of step 3.

Among the compounds represented by general formula (I), the compound represented by general formula (I-20) in which the bonding mode of the Y moiety is —NHCONR ⁴² — (wherein R ⁴² is as defined above) is For example, it can be produced from the secondary amine compound represented by the general formula (I-15) to be synthesized by the following method (Production Method 11).

[Production Method 11]
It is represented by the general formula (I-19) by reacting the secondary amine represented by the general formula (I-15) synthesized by the production method 8 with the isocyanate represented by the general formula (III-13). Can be obtained (step 30). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-20) (step 31). In addition, the compound (III-13) which is a raw material compound is usually easily synthesized by a known method.

[Wherein, R ¹ , R ² , R ⁴ , R ³⁸ , R ⁴² , n, Z ¹ are as defined above]. ]
Step 30 is usually performed in a solvent that does not adversely affect the reaction. The amount of isocyanate (III-13) to be used is preferably 1 to 5 molar equivalents relative to compound (I-15). The reaction temperature is usually −30 to 100 ° C., preferably −10 to 50 ° C. Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, and hydrocarbons such as hexane, benzene and toluene. These solvents may be mixed and used at an appropriate ratio.

  Step 31 can be performed according to a method similar to that of step 3.

  Of the compounds of the general formula (I), Z is an aryl group, heteroaryl group, arylalkyl group or heteroarylalkyl group, and the aryl group or heteroaryl group has an aryl group or heteroaryl group on the ring of the aryl group or heteroaryl group The compounds of formula (I-23), general formula (I-26), and general formula (I-30) can be produced by, for example, the following methods in addition to the methods shown in production methods 1 to 12. (Manufacturing method 12-14).

[Production method 12]
Z in the general formula (I) is an aryl group, heteroaryl group, arylalkyl group or heteroarylalkyl group, and a leaving group such as a halogen atom or trifluoromethanesulfonyloxy group on the ring of the aryl group or heteroaryl group In the presence of a metal catalyst, a boron compound represented by the general formula (I-21) and a boron compound represented by the general formula (III-14) or a tin compound represented by the general formula (III-15) The compound which introduce | transduced the aryl group or heteroaryl group represented by general formula (I-22) can be obtained by making it react by (process 32). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-23) (step 33). In addition, the compounds (III-14) and (III-15) which are raw material compounds are usually easily synthesized by a known method.
Step 32 is usually performed in the presence of a metal catalyst in a solvent that does not adversely influence the reaction. At this time, a base may be added. Examples of the metal catalyst include zero-valent palladium, divalent palladium, and zero-valent nickel. Here, examples of the zero-valent palladium catalyst include tetrakis (triphenylphosphine) palladium and tris (dibenzylideneacetone) dipalladium, and examples of the divalent palladium catalyst include palladium acetate and dichlorobis (triphenylphosphine) palladium. Examples of the zero-valent nickel catalyst include 1,1′-bis (diphenylphosphino) ferrocene nickel. Monodentate ligands such as triphenylphosphine and tris (o-tolyl) phosphine, and bidentate ligands such as diphenylphosphinopropane and diphenylphosphinobutane may be added. Examples of the base include alkali metal hydrogen carbonates such as sodium hydrogen carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal phosphates such as tripotassium phosphate. However, in the case of reaction with R ⁴⁷ -Sn (R ⁴⁹ ) ₃ (III-15), it is not necessary to use a base. The amount of the metal catalyst to be used is, for example, 0.01 to 1 molar equivalent, preferably 0.05 to 0.5 molar equivalent, relative to compound (I-21). The amount of the base to be used is, for example, 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (I-21). The reaction temperature is usually 0 ° C. to the reflux temperature of the solvent. Solvents that do not adversely affect the reaction include ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, methanol, Alcohols such as ethanol, water and the like are used. These solvents may be mixed and used at an appropriate ratio. In the case of the reaction with R ⁴⁷ —Sn (R ⁴⁹ ) ₃ (III-15), it is preferably carried out in a non-aqueous solvent. The amount of R ⁴⁷ -B (OR ⁴⁸ ) ₃ (III-14) or R ⁴⁷ -Sn (R ⁴⁹ ) ₃ (III-15) used is, for example, 1 to 5 molar equivalents relative to compound (I-21). Preferably it is 1-3 molar equivalent.

  Step 33 can be performed according to a method similar to that of step 3.

[Manufacturing method 13]
An alcohol represented by the general formula (I-1) (the synthesis method will be described later) and an aryl alcohol or heteroaryl alcohol having a borate group on Z represented by the general formula (III-16) are converted into phosphines and azo By making it react using a dicarboxylic acid derivative, the ether compound represented by general formula (I-24) can be obtained (process 34). Subsequently, by reacting the compound having a leaving group represented by the general formula (III-17) in the presence of a metal catalyst, an aryl group or a heteroaryl group represented by the general formula (I-25) The introduced compound can be obtained (step 35). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-26) (step 36).
The starting compounds (III-16) and (III-17) are usually easily synthesized by a known method.

[Wherein R ¹ , R ² , R ⁴ , R ³⁸ , n are as defined above, Z ⁴ represents an aryl group or a heteroaryl group, X ⁴ represents a halogen atom or a trifluoromethanesulfonyloxy group, R ⁵⁰ represents an aryl group or a heteroaryl group. ]
Step 34 can be performed according to a method similar to that of step 4.

  Step 35 can be performed according to a method similar to that of step 32.

  Step 36 can be performed according to a method similar to that of step 3.

[Production Method 14]
A compound having a halogen atom on Z ^{1 of the} compound represented by the general formula (I-16) synthesized by the production method 9 [represented by the general formula (I-27)] and the general formula (III-14) By reacting the boric acid compound represented by general formula (I-28), a compound into which the aryl group or heteroaryl group represented by general formula (I-28) has been introduced can be obtained (step 37). . Furthermore, the secondary amine compound represented by the general formula (I-29) is obtained by reacting the compound having a thiol group represented by the general formula (III-12) in the presence of a base. (Step 38). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-30) (step 39). The starting compounds (III-12) and (III-14) are usually easily synthesized by a known method.

[Wherein R ¹ , R ² , R ⁴ , R ³⁸ , R ⁴⁶ , R ⁴⁷ , R ⁴⁸ , n are as defined above, Z ⁵ represents an aryl group or a heteroaryl group, and X ⁵ represents a halogen atom. Or a trifluoromethanesulfonyloxy group; ]
Step 37 can be performed according to a method similar to that of step 32.

  Step 38 can be performed according to a method similar to that of step 24.

  Step 39 can be performed according to a method similar to that of step 3.

  Among the compounds of the general formula (I), Z is an aryl group, heteroaryl group, arylalkyl group or heteroarylalkyl group, and the general formula (I- The compound of 32) can be produced, for example, by the following method in addition to the methods shown in Production methods 1 to 12 (Production method 15).

[Production Method 15]
By reacting a compound having a leaving group represented by the general formula (I-21) with an amine compound represented by the general formula (III-18) in the presence of a metal catalyst and a base, the general formula (I The compound which introduce | transduced the amino group represented by -31) can be obtained (process 40). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-32) (step 41). In addition, compound (III-18) which is a raw material compound is usually easily synthesized by a known method.

[Wherein, R ¹ , R ² , R ⁴ , R ³⁸ , n, Y, Z ³ , X ³ are as defined above, and R ⁵¹ and R ⁵² may be the same or different, and each independently. Represents a hydrogen atom, an alkyl group, a cycloalkyl group, or R ⁵¹ and R ⁵² combine with each other to form a heterocycle which may have carbon and heteroatoms. ]
Step 40 is a non-patent document [J. Org. Chem. , 65, 1158 (2000)] and the like, by performing an amination reaction, an amine compound represented by the general formula (I-31) can be obtained. Usually, it is carried out in the presence of a metal catalyst, a metal ligand and a base in a solvent that does not adversely influence the reaction. Examples of the metal catalyst include tris (dibenzylideneacetone) dipalladium, palladium acetate and the like. Examples of the metal ligand include 2- (di-tert-butylphosphino) biphenyl. Examples of the base include cesium carbonate, tripotassium phosphate, sodium tertiary butoxide and the like. The amount of the metal catalyst to be used is, for example, 0.01 to 1 molar equivalent, preferably 0.05 to 0.5 molar equivalent, relative to compound (I-21). The amount of the base to be used is, for example, 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (I-21). The reaction temperature is usually 0 ° C. to the reflux temperature of the solvent. Examples of the solvent that does not adversely influence the reaction include ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol and ethanol, and the like. These solvents may be mixed and used at an appropriate ratio. The amount of R ⁵¹ (R ⁵² ) NH (III-18) to be used is, for example, 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (I-21).

  Step 41 can be performed according to a method similar to that of step 3.

  Of the compounds represented by the general formula (I), Z is an aryl group, heteroaryl group, arylalkyl group or heteroarylalkyl group, and the general formula (I-) having an alkynyl group on the ring of the aryl group or heteroaryl group The compound 34) can be produced, for example, by the following method in addition to the methods shown in Production methods 1 to 12 (Production method 16).

[Production Method 16]
By reacting a compound having a leaving group represented by the general formula (I-21) and a compound represented by the general formula (III-19) in the presence of a metal catalyst and a base, the general formula (I- A compound into which an alkynyl group represented by 33) is introduced can be obtained (step 42). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-34) (step 43). In addition, compound (III-19) which is a raw material compound is usually easily synthesized by a known method.

[Wherein, R ¹ , R ² , R ⁴ , R ³⁸ , n, Y, Z ³ , X ³ are as defined above, and R ⁵³ represents an aryl group or a heteroaryl group. ]
Step 42 is carried out by performing an alkynylation reaction with reference to a method described in non-patent literature [Comprehensive Organic Synthesis, Pergamon Press, New York, 3,521 (1991)], etc. The compound which introduce | transduced the alkynyl group represented by these can be obtained. Usually, it is carried out in the presence of a metal catalyst and a base in a solvent that does not adversely influence the reaction. Examples of the metal catalyst include dichlorobis (triphenylphosphine) palladium. Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine and the like. As an additive, it is preferred to add a catalytic amount of copper (I) iodide. The amount of the metal catalyst to be used is, for example, 0.01 to 1 molar equivalent, preferably 0.05 to 0.5 molar equivalent, relative to compound (I-21). The amount of the base to be used is, for example, 1 to 50 molar equivalents, preferably 10 to 20 molar equivalents, relative to compound (I-21). The reaction temperature is usually 0 ° C. to the reflux temperature of the solvent. As a solvent that does not adversely influence the reaction, ethers such as tetrahydrofuran and dioxane, amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidone and the like are used. These solvents may be mixed and used at an appropriate ratio. The amount of alkynyl compound (III-19) to be used is, for example, 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (I-21).

  Step 43 can be performed according to a method similar to that of step 3.

  Among the compounds represented by the general formula (I), the compounds represented by the general formulas (I-38) and (I-41) in which Z is a thiazole group or a pyrazole group and Y is a nitrogen atom are produced by the production methods 5-11. In addition to the method described in (1), for example, it can also be produced by the following method (Manufacturing methods 17 and 18).

[Production Method 17]
A primary amine compound represented by general formula (II-3) or a secondary amine compound represented by general formula (I-15) synthesized by compound production method 8 [in general formula (I-35) And the β-ketocarboxylic acid represented by the diketene, the general formula (III-20), and the β-ketoester represented by the general formula (III-21) to react with the general formula (I-36). (Beta) -ketoamide compound represented by these can be obtained (step 44). Further, by reacting this compound with a compound having a hydrazino group represented by the general formula (III-22) to obtain a hydrazone compound, an appropriate dehydrating agent is used, or an appropriate sulfurizing agent is used. In the reaction system, a compound in which Z represented by the general formula (I-37) is a pyrazole ring can be obtained by performing a desulfurization reaction in the presence of a base via a thioamide compound (step). 45). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-38) (step 46). In addition, the compounds (III-20), (III-21), and (III-22) that are raw material compounds are usually easily synthesized by a known method.

[Wherein R ¹ , R ² , R ⁴ , R ³⁸ , n are as defined above, A is a hydrogen atom or R ⁴² (wherein R ⁴² is as defined above), R ⁵⁴ Represents an alkyl group or an aryl group, R ⁵⁵ represents an alkyl group, and R ⁵⁶ represents an alkyl group or an aryl group. ]
Step 44 is performed in a solvent that does not adversely influence the reaction when diketene is used as a reaction reagent. The reaction temperature can usually be carried out at 0 ° C. to room temperature. As the solvent that does not adversely influence the reaction, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide, and the like are used. These solvents may be mixed and used at an appropriate ratio. Further, when β-ketocarboxylic acid is used as a reaction reagent, it can be carried out in the same manner as in Step 6. Moreover, when using (beta) -ketoester as a reaction reagent, it is performed in the solvent which does not exert a bad influence on reaction. The reaction temperature is usually 0 ° C. to the reflux temperature of the solvent. As the solvent that does not adversely influence the reaction, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene are used. These solvents may be mixed and used at an appropriate ratio.

  The hydrazone formation step in Step 45 is usually performed in a solvent that does not adversely influence the reaction. At this time, an acid or base catalyst may coexist. Examples of the acid catalyst include acetic acid, hydrochloric acid, p-toluenesulfonic acid and the like, and examples of the base catalyst include sodium methoxide and piperidine. The reaction temperature is usually 0 ° C. to the reflux temperature of the solvent. Examples of the solvent that does not adversely influence the reaction include ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol and ethanol, and the like. These solvents may be mixed and used at an appropriate ratio. The subsequent cyclization step is usually performed in the presence of a suitable dehydrating agent in a solvent that does not adversely influence the reaction. As the dehydrating agent, for example, phosphorus oxychloride is used. The amount of the dehydrating agent to be used is preferably 1 to 2 equivalents relative to compound (I-36). The reaction temperature is usually 0 ° C. to the reflux temperature of the solvent. As the solvent that does not adversely influence the reaction, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene are used. These solvents may be mixed and used at an appropriate ratio. When a sulfurizing agent is used, it is usually carried out in the presence of a base in a solvent that does not adversely influence the reaction. As the sulfiding agent, for example, diphosphorus pentasulfide, Lawson's reagent, or the like is used. The amount of the sulfurizing agent to be used is preferably 1-2 equivalents relative to compound (I-36). Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tertiary butoxide, water such as potassium hydroxide, sodium hydroxide and lithium hydroxide. Metal hydrides such as alkali metal oxides, potassium hydride, sodium hydride, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4. Amines such as 0] undec-7-ene are used. The amount of the base to be used is preferably 1 to 5 molar equivalents relative to compound (I-36). Usually, it can be carried out from 0 ° C. to the reflux temperature of the solvent. As the solvent that does not adversely influence the reaction, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene are used. These solvents may be mixed and used at an appropriate ratio.

  Step 46 can be performed according to a method similar to that of step 3.

[Production Method 18]
The secondary amine compound represented by the general formula (I-15) synthesized by the production method 8 is converted into a thiourea compound represented by the general formula (I-39) (step 47), and then the general formula (III The thiazole compound represented by the general formula (I-40) can be obtained by reacting with the α-haloketone represented by −23) (step 48). Furthermore, this compound can be deesterified and converted into the carboxylic acid form (I-41) (step 49). In addition, compound (III-23) which is a raw material compound is usually easily synthesized by a known method.

[Wherein R ¹ , R ² , R ⁴ , R ⁴¹ , R ⁴² , n are as defined above, R ⁵⁷ represents an alkyl group, a haloalkyl group, an aryl group, a heteroaryl group, and X ⁶ represents a halogen atom. Fmoc represents 9H-fluoren-9-ylmethyloxycarbonyl group. ]
In step 47, 9H-fluoren-9-ylmethyloxycarbonyl isothiocyanate (Fmoc-NCS) is reacted to obtain a 9H-fluoren-9-ylmethyloxycarbonylureido derivative, which is then treated with a base to give a general formula. A thiourea compound represented by (I-39) can be obtained. The reaction with Fmoc-NCS is usually performed in a solvent that does not affect the reaction. The amount of Fmoc-NCS to be used is preferably 1 to 5 molar equivalents relative to compound (I-15). The reaction temperature is usually −30 to 100 ° C., preferably −10 to 50 ° C. Solvents that do not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, N, N-dimethylformamide, N-methyl-2-pyrrolidone and the like. Amides, hydrocarbons such as hexane, benzene, and toluene are used. These solvents may be mixed and used at an appropriate ratio. The subsequent base treatment step is usually performed in a solvent that does not affect the reaction. Examples of the base include amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, morpholine, piperidine, and 1,8-diazabicyclo [5.4.0] undec-7-ene. The amount of the base used is preferably 1 to 5 molar equivalents relative to the 9H-fluoren-9-ylmethyloxycarbonylureido derivative obtained above. The reaction temperature is usually −30 to 100 ° C., preferably −10 to 50 ° C. Solvents that do not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N, N-dimethyl Examples include amides such as formamide and N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide, alcohols such as methanol and ethanol, and the like. These solvents may be mixed and used at an appropriate ratio.

  Step 48 is usually performed in a solvent that does not adversely affect the reaction. The amount of α-haloketone (III-23) to be used is preferably 1 to 5 molar equivalents relative to compound (I-39). The reaction temperature can usually be −30 to 200 ° C., preferably 0 to 150 ° C. As the solvent that does not adversely influence the reaction, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol, ethanol and isopropanol are used. These solvents may be mixed and used at an appropriate ratio.

  Step 49 can be performed according to a method similar to that of step 5.

  Next, the typical manufacturing method of a raw material compound is shown.

  The compounds represented by the general formulas (II-1), (II-2), (II-3), and (II-4) used in the above production method include, for example, the following general formula (VI -1) or the general formula (VI-1) (obtained in the raw material compound production method 1) as a starting material, it can be produced by the methods shown in the raw material compound production methods 2 to 5.

[Production Method 1 of Raw Material Compound]
By reacting the dithiocarbamate (IV) with an α-haloketone compound having an ester group in the structure represented by the general formula (V-1) or (V-2), the general formula (VI-1) or ( A thiazole compound represented by VI-2) can be obtained (step 50). In addition, the compound (IV), (V-1) or (V-2) which is a raw material compound is usually easily synthesized by a known method.

[Wherein, R ⁴ and m are as defined above, R ⁵⁸ represents an alkyl group, and X ⁷ represents a halogen atom. ]
In step 50, the reaction is usually performed under heating in a solvent that does not adversely influence the reaction. The amount of dithiocarbamate (IV) used is preferably 1 to 5 molar equivalents relative to α-haloketone (V-1) or (V-2). The reaction temperature can usually be −30 to 200 ° C., preferably 0 to 150 ° C. As the solvent that does not adversely influence the reaction, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol, ethanol and isopropanol are used. These solvents may be mixed and used at an appropriate ratio.

[Production Method 2 of Raw Material Compound]
The carboxylic acid compound represented by the general formula (II-4) is obtained from the thiazole compound represented by the general formula (VI-3) synthesized by the production method 1 of the raw material compound by, for example, the following two methods. Can be manufactured. First, after obtaining the diester compound represented by the general formula (II-5) by reacting the α-haloester compound represented by the general formula (VII) in the presence of a base (Step 51). ) And monodeesterification of this compound to convert it to a monocarboxylic acid compound (II-4) (step 52). Second, after deesterifying the thiazole compound represented by the general formula (VI-3) to obtain a carboxylic acid form (VI-4) (step 53), α- represented by the general formula (VII) By reacting the haloester compound in the presence of a base, it can be converted to the carboxylic acid compound (II-4) (step 54). The α-haloester compound (VII), which is a raw material compound, is usually easily synthesized by a known method.

[Wherein, R ¹ , R ² , R ⁴ , R ³⁸ , R ⁵⁸ , X ² , m are as defined above]. ]
Step 51 is usually performed in the presence of a base in a solvent that does not adversely influence the reaction. Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tertiary butoxide, water such as potassium hydroxide, sodium hydroxide and lithium hydroxide. Metal hydrides such as alkali metal oxides, potassium hydride, sodium hydride, triethylamine, N, N-diisopropylethylamine, piperidine, pyrrolidine, N-methylmorpholine, pyridine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene are used. The amount of the base used is preferably 1 to 5 molar equivalents relative to compound (VI-3). The amount of α-haloester (VII) to be used is preferably 1 to 3 molar equivalents relative to compound (VI-3). The reaction temperature is usually −50 to 200 ° C., preferably −10 to 100 ° C. Solvents that do not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N, N-dimethyl Amides such as formamide and N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide, alcohols such as methanol and ethanol, water and the like are used. These solvents may be mixed and used at an appropriate ratio.

  Step 52 is usually performed in a water-containing solvent in the presence of a base. Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, and alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide. It is done. The amount of the base to be used is generally an excess amount, preferably 1 to 5 equivalents, relative to compound (II-5). Examples of the water-containing solvent include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, a mixed solvent of one or more solvents selected from dimethyl sulfoxide and acetone, and the like. The reaction temperature is generally −20 to 150 ° C., preferably −10 to 100 ° C.

  Step 53 can be performed according to a method similar to that of step 52.

  Step 54 can be performed according to a method similar to that of step 51.

[Production Method 3 of Raw Material Compound]
The alcohol compound represented by the general formula (II-1) is obtained by reacting the carboxylic acid compound represented by the general formula (II-4) synthesized by the above-described raw material compound production method 2 in the presence of a reducing agent. (Step 55).

[Wherein, R ¹ , R ² , R ⁴ , R ³⁸ , n, m are as defined above]. N and m indicate a relationship of n = m + 1. ]
Step 55 can be performed according to a method similar to that of step 12.

[Production Method 4 of Raw Material Compound]
The compound having a leaving group represented by the general formula (II-2) sulfonylates or halogenates the alcohol compound represented by the general formula (II-1) synthesized by the above raw material compound production method 3. (Step 56).

[Wherein, R ¹ , R ² , R ⁴ , R ³⁸ , X ² , n are as defined above] ]
In step 56, a sulfonic acid ester is obtained by allowing methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride and the like to react in a solvent that does not adversely influence the reaction, usually in the presence of a base. Examples of the base include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tertiary butoxide, water such as potassium hydroxide, sodium hydroxide and lithium hydroxide. Metal hydrides such as alkali metal oxides, potassium hydride, sodium hydride, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline, 4-dimethylaminopyridine, 1,8- Amines such as diazabicyclo [5.4.0] undec-7-ene are used. The amount of sulfonyl chloride used is preferably 1 to 5 molar equivalents relative to compound (II-1), and the amount of base used is preferably 1 to 5 molar equivalents relative to compound (II-1). The reaction temperature is generally −50 to 200 ° C., preferably −30 to 80 ° C. Solvents that do not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N, N-dimethyl Amides such as formamide and N-methyl-2-pyrrolidone are used. These solvents may be mixed and used at an appropriate ratio. The sulfonic acid ester thus obtained can be converted into a halogen compound using various halogenating agents. For chlorination, for example, lithium chloride, pyridine hydrochloride and the like are used, and for bromination, for example, hydrobromic acid, sodium bromide, calcium bromide and the like are reacted in a solvent that does not adversely influence the reaction. A halogen compound is obtained. Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, and sulfoxides such as dimethyl sulfoxide.

[Production Method 5 of Raw Material Compound]
The primary amine compound represented by the general formula (II-3) can be produced from the alcohol compound represented by the general formula (II-1) synthesized by the above raw material compound production method 3. Numerous methods for converting alcohol compounds to primary amine compounds are known, for example, non-patent literature [Comprehensive Organic Transformation, VCH Publishers, Inc. 1989] can be referred to. For example, after converting a hydroxyl group of an alcohol compound into a compound having a leaving group by sulfonylation or halogenation, for example, potassium phthalimide, hexamethyltetramine, sodium azide, sodium diformylimide, di-tert-butyliminodicarboxylic acid A compound into which a nitrogen atom is introduced can be obtained by reacting an acid or the like. Subsequently, these compounds can be converted into primary amine compounds by appropriate hydrolysis or reduction. Below, an example of the manufacturing method of the primary amine compound represented by general formula (II-3) which passes through general formula (II-2) synthesize | combined with the manufacturing method 4 is shown. By reacting the compound having the leaving group represented by the general formula (II-2) synthesized by the production method 4 with potassium phthalimide, a compound (II-6) into which a nitrogen atom has been introduced can be obtained ( Step 57). Subsequently, these compounds can be converted to primary amine compounds (II-3) by performing a deprotection reaction (step 58).

[Wherein, R ¹ , R ² , R ⁴ , R ³⁸ , X ² , n are as defined above] ]
Step 57 is usually performed using potassium phthalimide in a solvent that does not adversely affect the reaction. The amount of potassium phthalimide used is preferably 1 to 5 molar equivalents relative to compound (II-6). Reaction temperature can be normally implemented at 0-120 degreeC. Examples of the solvent that does not adversely influence the reaction include amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, and sulfoxides such as dimethyl sulfoxide.
Step 58 is usually performed in a solvent that does not adversely influence the reaction using a hydrazine compound such as hydrazine monohydrate, methyl hydrazine, or phenyl hydrazine. The amount of the hydrazine compound to be used is preferably 1 to 5 molar equivalents relative to compound (II-6). Reaction temperature can be normally implemented at 0-120 degreeC. Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol and ethanol.

  Among the primary amine compounds represented by the general formula (II-3), the primary amine compound represented by the general formula (II-8) is shown below in addition to the above-described production method 5 of the raw material compound. It can also be produced by a method.

[Production Method 6 of Raw Material Compound]
By reacting a ketone compound having a leaving group in the structure represented by the general formula (V-3) with potassium phthalimide, a compound in which a nitrogen atom represented by the general formula (VI-5) is introduced is obtained. (Step 59). Subsequently, an α-bromoketone compound represented by the general formula (VI-6) can be obtained by performing a bromination reaction of these compounds (step 60). Furthermore, the thiazole compound represented by the general formula (VI-7) can be obtained by reacting these compounds with the dithiocarbamate represented by (IV) (Step 61). Furthermore, after reacting these compounds with an α-haloester compound represented by the general formula (VII) in the presence of a base, an ester compound represented by the general formula (II-7) was obtained ( It can be converted to the primary amine compound (II-8) by performing a deprotection reaction in step 62) (step 63). In addition, the compound (IV), (V-3) or (VII) which is a raw material compound is usually easily synthesized by a known method.

[Wherein, R ¹ , R ² , R ³⁸ , n, and X ² are as defined above. ]
Step 59 can be performed according to a method similar to that of step 57.
Step 60 is usually performed using a suitable brominating agent in a solvent that does not adversely affect the reaction. Examples of brominating agents include bromine, pyridinium bromide perbromide, benzyltrimethylammonium tribromide, and phenyltrimethylammonium tribromide. The amount of the brominating agent to be used is preferably 1 to 5 molar equivalents relative to compound (IV-5). Reaction temperature can be normally implemented at 0-120 degreeC. As a solvent that does not adversely influence the reaction, ethers such as tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, acetic acid and the like are used.

  Step 61 can be performed according to a method similar to that of step 50.

  Step 62 can be performed according to a method similar to that of step 51.

  Step 63 can be performed according to a method similar to that of step 58.

The carboxylic acid derivative containing the thiazole ring of the general formula (I) of the present invention thus produced is appropriately subjected to known separation and purification means such as concentration, extraction, chromatography, reprecipitation, recrystallization and the like. By applying, it can be collected as having an arbitrary purity.
In addition, the compound of the general formula (I) obtained in this way is optionally an inorganic acid such as hydrochloric acid or hydrobromic acid, an organic acid such as trifluoroacetic acid, acetic acid, methanesulfonic acid or benzenesulfonic acid, sodium or potassium. These salts can be obtained by treating with alkali metals such as calcium, organic bases such as dicyclohexylamine, and amino acids such as lysine and arginine.

  “Hyperlipidemia combined with diabetes” as an application target of the medicament of the present invention refers to a case in which a diabetic patient has hyperlipidemia, and is sometimes referred to as diabetic hyperlipidemia.

  The pathological condition in which a diabetic patient is accompanied by hyperlipidemia is a pathological condition in which TG value, LDL-C value, HDL-C value, etc. do not show normal values even if blood glucose level is improved by treatment of diabetes. Okay, the medicament of the present invention can be applied to these pathological conditions for therapeutic purposes. In addition, even if the patient is diabetic or has a risk of recurrence and the TG value, LDL-C value, HDL-C value, etc. are within the normal value range, the medicament of the present invention is applied for the purpose of treatment or prevention. It is possible.

  Patients with hyperlipidemia associated with diabetes are those whose TG value, LDL-C value, HDL-C value, etc. do not show normal values even if blood glucose levels are improved by treatment of diabetes. Okay, the medicament of the present invention can be administered to these patients.

  The WHO classification that classifies hyperlipidemia by lipoprotein phenotype is known. Phenotypes with elevated triglycerides include type I hyperlipidemia, type IIb hyperlipidemia, type III hyperlipidemia, type IV hyperlipidemia, type V hyperlipidemia, among which serum Those who are strongly suspected of having diabetes with high TG and / or low HDL or who cannot rule out the possibility of diabetes are preferred targets for application of the medicament of the present invention. However, the medicament of the present invention can also be applied to patients who belong to other classifications and are diagnosed with hyperlipidemia associated with diabetes. In addition, even if the patient is a diabetic patient or a patient who has a risk of recurrence, the TG value, LDL-C value, HDL-C value, etc. are within the normal value range. It is possible to apply in.

  Furthermore, the compound of the present invention can also be used as a preventive and / or therapeutic agent for diabetes.

  Here, diabetes refers to a case where the fasting blood glucose level is 126 mg / dL or more, or the 75 g glucose tolerance test 2 hour value is 200 mg / dL. Diabetes mellitus also occurs when the blood glucose level is 200 mg / dL or higher.

  The compound (I) of the present invention can be administered to the same subject simultaneously with other antihyperlipidemic agents and the like, and can be administered to the same subject with a time lag. Examples of antihyperlipidemic agents include statins that are cholesterol synthetase inhibitors, squalene synthetases inhibitors, and fibrate compounds that have a triglyceride-lowering action. When the compound of the present invention is used in combination with a multidrug, the compounding ratio can be appropriately selected depending on the administration subject, age and weight of the administration subject, symptoms, administration time, dosage form, administration method, combination and the like.

  The dose of the compound (I) or a pharmacologically acceptable salt thereof varies depending on the administration route, target disease, patient symptom, body weight or age, and the compound to be used, and may be appropriately set depending on the purpose of administration. it can. Usually, when orally administered to an adult, 0.1 to 1000 mg / human / day, preferably 0.5 to 100 mg / human / day, is preferably administered in one to several times a day.

  When the compound (I) and the salt thereof of the present invention are used as the above-mentioned medicament, they are mixed with themselves or appropriate pharmacologically acceptable carriers, excipients, diluents, etc., powders, granules, tablets, It can be administered orally or parenterally in the form of capsules, injections and the like. In the above preparation, an effective amount of compound (I) or a pharmacologically acceptable salt thereof is blended.

  EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

^For chemical shift of ¹ H-NMR, tetramethylsilane (TMS) was used as an internal standard, and relative delta (δ) values were expressed in parts per million (ppm). The coupling constant is expressed in hertz (Hz), and the obvious multiplicity is s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), dd (doublet) Of doublets), td (triplet of doublets), and brs (broad singlet). Column chromatography was performed using silica gel manufactured by Fuji Silysia Chemical.
[Example 1]
(2-Mercapto-1,3-thiazol-4-yl) acetic acid ethyl ester

102 g of ammonium salt of dithiocarbamic acid was dissolved in 700 mL of ethanol, and a 200 mL ethanol solution of 152 g of 4-chloro-3-oxobutanoic acid ethyl ester was added dropwise over 30 minutes under ice cooling. The temperature was gradually raised and the mixture was heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, 1 L of water was added, and the precipitated solid was collected by filtration. This solid was dissolved in 4 L of ethyl acetate and washed with 2 L of water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained solid was suspended and washed with 500 mL of diethyl ether and filtered to give 165 g of the title compound as a slightly yellow solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.31 (3H, t, J = 7.2 Hz), 3.59 (2H, s), 4.23 (2H, q, J = 7.2 Hz) 6.46 (1H, s).
[Example 2]
2-{[4- (2-Ethoxy-2-oxoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  88.6 g of (2-mercapto-1,3-thiazol-4-yl) acetic acid ethyl ester synthesized in Example 1 and 105.3 g of tert-butyl 2-bromo-2-methylpropionate were mixed with N, N-dimethyl ester. It melt | dissolved in formamide 700mL, potassium carbonate 66.3g was added, and it stirred at room temperature for 8 hours. 1 L of water was added to the reaction solution, followed by extraction with 1 L of ethyl acetate, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 150 g of the title compound as a light brown oil. This compound was used in the next step without further purification.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.27 (3H, t, J = 7.2 Hz), 1.44 (9H, s), 1.57 (6H, s), 3.83 (2H , S), 4.18 (2H, q, J = 7.2 Hz) 7.27 (1H, s).
[Example 3]
{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid

  150 g of 2-{[4- (2-ethoxy-2-oxoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 2 was added to 700 mL of methanol. After dissolution, 448 mL of 1N aqueous sodium hydroxide solution was added at room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, 1 L of 10% aqueous citric acid solution was added, and the mixture was extracted with 1 L of ethyl acetate. The organic layer was washed 3 times with 500 mL of water and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 123 g of the title compound as a slightly yellow solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.59 (6H, s), 3.86 (2H, s) 7.22 (1H, s).
[Example 4]
2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  127 g of {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid synthesized in Example 3 was cooled with 1M- The mixture was added to 800 mL of borane / tetrahydrofuran complex, and then stirred at room temperature for 8 hours. After cooling the reaction solution with ice, 400 mL of methanol was added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. Subsequently, 300 mL of saturated aqueous ammonium chloride was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, poured into water, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give 110 g of the title compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.59 (6H, s), 2.98 (2H, t, J = 5.7 Hz), 3.04-3 .10 (1H, m), 3.92-3.97 (2H, m), 7.02 (1H, s).
[Example 5]
2-Methyl-2-[(4- {2-[(methylsulfonyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester

  98 g of 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and 50 mL of triethylamine were added to 800 mL of dichloromethane. After dissolution, 38.8 g of methanesulfonyl chloride was added dropwise under ice cooling, and the mixture was stirred at 0 ° C. for 2 hours. Water was added to the reaction solution, and the organic layer was separated. After washing with saturated brine, the solution was dried over anhydrous sodium sulfate, and the solvent was distilled off. The title compound, an unpurified brown oil obtained quantitatively, was used in the next step as it was.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.58 (6H, s), 2.95 (3H, s), 3.20 (2H, t, J = 6) .5 Hz), 4.56 (2H, t, J = 6.5 Hz), 7.14 (1 H, s).
[Example 6]
2-Methyl-2-{[4- (2-phthalimidoethyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester

  123 g of 2-methyl-2-[(4- {2-[(methylsulfonyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester synthesized in Example 5 was used. The product was dissolved in 800 mL of N, N-dimethylformamide, 59.7 g of potassium phthalimide was added, and the mixture was stirred at 85 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to give 136 g of the title compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.55 (6H, s), 3.17 (2H, t, J = 7.3 Hz), 4.56 (2H , T, J = 7.3 Hz), 7.07 (1H, s), 7.69-7.72 (2H, m), 7.81-7.84 (2H, m).
[Example 7]
2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  136 g of 2-methyl-2-{[4- (2-phthalimidoethyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester synthesized in Example 6 was dissolved in 800 mL of ethanol, 47.2 g of hydrazine monohydrate was added and refluxed for 4 hours. A white precipitate was removed from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloroethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (77.6 g) as a brown oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.58 (6H, s), 2.89 (2H, t, J = 6.6 Hz), 3.06 (2H , T, J = 6.6 Hz), 7.03 (1H, s).
[Example 8]
2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazole-4-carboxylic acid ethyl ester

  The title compound was obtained in the same manner as in Example 1 and Example 2, using 3-bromo-2-oxopropionic acid as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.39 (3H, t, J = 7.5 Hz), 1.42 (9H, s), 1.61 (6H, s), 4.40 (2H , Q, J = 7.5 Hz), 8.21 (1H, s).
[Example 9]
2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazole-4-carboxylic acid

  Starting from 2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazole-4-carboxylic acid ethyl ester synthesized in Example 8, Example 2 The title compound was obtained in the same manner as in.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.64 (6H, s), 8.26 (1H, s).
[Example 10]
2-{[4- (hydroxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  Similar to Example 3 starting from 2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazole-4-carboxylic acid synthesized in Example 9 To give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.58 (6H, s), 4.75 (2H, s), 7.26 (1H, s).
[Example 11]
2-Methyl-2-[(4-{[(methylsulfonyl) oxy] methyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester

  As in Example 4, starting from 2-{[4- (hydroxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 10 To give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.60 (6H, s), 3.04 (3H, s), 5.30 (2H, s), 7. 46 (1H, s).
[Example 12]
2-Methyl-2-{[4- (phthalimidomethyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester

  Starting from 2-methyl-2-[(4-{[(methylsulfonyl) oxy] methyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester synthesized in Example 11 The title compound was obtained in the same manner as in Example 5.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.38 (9H, s), 1.56 (6H, s), 4.99 (2H, s), 7.18 (1H, s), 7. 71-7.75 (2H, m), 7.85-7.89 (2H, m).
[Example 13]
2-{[4- (Aminomethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  As in Example 6, starting from 2-methyl-2-{[4- (phthalimidomethyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester synthesized in Example 12 To give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.59 (6H, s), 3.95 (2H, s), 7.13 (1H, s).
[Example 14]
2-{[4- (2-Ethoxy-2-oxoethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  The title compound was obtained in the same manner as in Example 1 and Example 2, using 4-bromo-3-oxopentanoic acid ethyl ester as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.23 (3H, t, J = 7.3 Hz), 1.44 (9H, s), 1.53 (6H, s), 2.38 (3H , S), 3.72 (2H, s), 4.13 (2H, q, J = 7.3 Hz).
[Example 15]
{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -5-methyl-1,3-thiazol-4-yl} acetic acid

  2-{[4- (2-Ethoxy-2-oxoethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 14 The title compound was obtained in the same manner as in Example 2 using the starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.56 (6H, s), 2.38 (3H, s), 3.75 (2H, s).
[Example 16]
2-{[4- (2-hydroxyethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  Starting from {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -5-methyl-1,3-thiazol-4-yl} acetic acid synthesized in Example 15 The title compound was obtained in the same manner as in Example 3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.55 (6H, s), 2.35 (3H, s), 2.84 (2H, t, J = 5) .6 Hz), 3.41-3.47 (1H, m), 3.90-3.97 (2H, m).
[Example 17]
2-Methyl-2-[(5-methyl-4- {2-[(methylsulfonyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester

  Starting from 2-{[4- (2-hydroxyethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 16 The title compound was obtained in the same manner as in Example 4.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.45 (9H, s), 1.55 (6H, s), 2.39 (3H, s), 2.93 (3H, s), 3. 09 (2H, t, J = 6.6 Hz), 4.53 (2H, t, J = 6.6 Hz).
[Example 18]
2-methyl-2-{[5-methyl-4- (phthalimidoethyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester

  2-methyl-2-[(5-methyl-4- {2-[(methylsulfonyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid synthesized in Example 17 tert- The title compound was obtained in the same manner as in Example 5 using butyl ester as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.45 (9H, s), 1.50 (6H, s), 2.34 (3H, s), 3.05 (2H, t, J = 7 .5 Hz), 4.00 (2H, t, J = 7.5 Hz), 7.68-7.72 (2H, m), 7.79-7.84 (2H, m).
[Example 19]
2-{[4- (2-Aminoethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  Using 2-methyl-2-{[5-methyl-4- (phthalimidoethyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester synthesized in Example 18 as a starting material The title compound was obtained in the same manner as in Example 6.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.45 (9H, s), 1.55 (6H, s), 2.37 (3H, s), 2.79 (2H, t, J = 6) .6 Hz), 3.04 (2H, t, J = 6.6 Hz).
[Example 20]
{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -4-methyl-1,3-thiazol-5-yl} acetic acid

  15 g of commercially available (2-mercapto-4-methyl-1,3-thiazol-5-yl) acetic acid is dissolved in 360 mL of methanol and 174 mL of 1N aqueous sodium hydroxide solution, and 2-bromo-2-methylpropionic acid tert-butyl ester is dissolved. 19.4g was added and it stirred at 60 degreeC for 6 hours. After concentrating the reaction solution, the residue was dissolved in water and acidified with 10% aqueous citric acid solution. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 25 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.56 (6H, s), 2.37 (3H, s), 3.77 (2H, s).
[Example 21]
2-{[5- (2-hydroxyethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  Starting from {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -4-methyl-1,3-thiazol-5-yl} acetic acid synthesized in Example 20 The title compound was obtained in the same manner as in Example 3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.56 (6H, s), 2.37 (3H, s), 2.97 (2H, t, J = 6) .3 Hz), 3.79-3.84 (2H, m).
[Example 22]
2-Methyl-2-[(4-methyl-5- {2-[(methylsulfonyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester

  Starting from 2-{[5- (2-hydroxyethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 21 The title compound was obtained in the same manner as in Example 4.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.45 (9H, s), 1.56 (6H, s), 2.38 (3H, s), 2.98 (3H, s), 3. 18 (2H, t, J = 6.6 Hz), 4.34 (2H, t, J = 6.6 Hz).
[Example 23]
2-methyl-2-{[4-methyl-5- (phthalimidoethyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester

  2-methyl-2-[(4-methyl-5- {2-[(methylsulfonyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid synthesized in Example 22 tert- The title compound was obtained in the same manner as in Example 5 using butyl ester as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.52 (6H, s), 2.35 (3H, s), 3.12 (2H, t, J = 7 .5 Hz), 3.89 (2H, t, J = 7.5 Hz), 7.71-7.75 (2H, m), 7.82-7.85 (2H, m).
[Example 24]
2-{[5- (2-Aminoethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  2-Methyl-2-{[4-methyl-5- (phthalimidoethyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester synthesized in Example 23 was used as a starting material. The title compound was obtained in the same manner as in Example 6.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.56 (6H, s), 2.36 (3H, s), 2.82-2.87 (2H, m ), 2.91-2.97 (2H, m).
[Example 25]
2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester

  The title compound was obtained in the same manner as in Example 1 and Example 2, using 2-chloro-3-oxobutanoic acid ethyl ester as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.35 (3H, t, J = 7.2 Hz), 1.44 (9H, s), 1.64 (6H, s), 2.68 (3H , S), 4.31 (2H, q, J = 7.2 Hz).
[Example 26]
2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -4-methyl-1,3-thiazole-5-carboxylic acid

  2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester synthesized in Example 25 was used as a starting material. The title compound was obtained in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.67 (6H, s), 2.68 (3H, s).
[Example 27]
2-{[5- (hydroxymethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -4-methyl-1,3-thiazole-5-carboxylic acid synthesized in Example 26 was used as a starting material. The title compound was obtained in the same manner as in Example 3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.45 (9H, s), 1.57 (6H, s), 2.39 (3H, s), 4.77 (2H, s).
[Example 28]
2-{[4- (Chloromethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  2-{[5- (hydroxymethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 27 was used as a starting material. The same operation as in Example 4 was performed to obtain the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.59 (6H, s), 2.41 (3H, s), 4.70 (2H, s).
[Example 29]
2-methyl-2-{[4-methyl-5- (phthalimidomethyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester

  Starting from 2-{[4- (chloromethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 28 The title compound was obtained in the same manner as in Example 5.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.37 (9H, s), 1.56 (6H, s), 2.56 (3H, s), 4.92 (2H, s), 7. 71-7.76 (2H, m), 7.82-7.87 (2H, m).
[Example 30]
2-{[5- (aminomethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  2-Methyl-2-{[4-methyl-5- (phthalimidomethyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester synthesized in Example 29 was used as a starting material. The title compound was obtained in the same manner as in Example 6.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.45 (9H, s), 1.56 (6H, s), 2.35 (3H, s), 3.96 (2H, s).
[Example 31]
2-mercapto-4- (3-phthalimidopropyl) -1,3-thiazole

  2- (5-Bromo-4-oxopentyl) -iso synthesized using 1-chloro-4-oxopentane and potassium phthalimide as starting materials and referring to non-patent literature [Pharmacazie, 47, 86 (1992)]. 17.8 g of indoline-1,3-dione and 6.96 g of ammonium dithiocarbamate were suspended in 250 mL of ethanol and refluxed for 6 hours. The precipitated crystals were collected by filtration and washed with ethanol to obtain 10.1 g of the title compound as white crystals.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 1.80-2.00 (2H, m), 3.25-3.50 (2H, m), 3.60 (2H, t, J = 6.8 Hz), 6.60 (1 H, s), 7.76-7.90 (4 H, m), 13.10 (1 H, s).
[Example 32]
2-methyl-2-{[4- (3-phthalimidopropyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester

  22.6 g of 2-mercapto-4- (3-phthalimidopropyl) -1,3-thiazole obtained in Example 31 was dissolved in 200 mL of N, N-dimethylformamide, and 11.3 g of potassium carbonate and 2-bromo-2 -17.4 g of methylpropionic acid tert-butyl ester was added and stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added and stirred, and the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 7: 3) to give 32.0 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 1.42 (9H, s), 1.52 (6H, s), 2.03 to 2.20 (2H, m), 2.82 (2H, t , J = 7.8 Hz), 3.76 (2H, t, J = 7.8 Hz), 7.06 (1H, s), 7.67-7.91 (4H, m), 13.10 (1H , S).
[Example 33]
2-{[4- (3-Aminopropyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  2-methyl-2-{[4- (3-phthalimidopropyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester 31.1 g obtained in Example 32 was dissolved in 400 mL of ethanol. Then, 10 mL of hydrazine monohydrate was added and refluxed for 2 hours. The precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure. Water and dichloromethane were added to the residue, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 20.1 g of the title compound. The obtained compound was used for the next reaction without purification.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 1.43 (9H, s), 1.57 (6H, s), 1.78-1.93 (2H, m), 2.74 (2H, t , J = 7.6 Hz), 2.81 (2H, t, J = 7.6 Hz), 6.97 (1H, s).
[Example 34]
2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (Example 34-1) )
2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 451 mg and 4′-fluorobiphenyl- 280 mg of 4-ol was dissolved in 10 ml of tetrahydrofuran, 430 mg of triphenylphosphine and 0.88 ml of diisopropyl azodicarboxylate (40% toluene solution) were added under ice cooling, and then the mixture was stirred at room temperature for 17 hours. After the reaction solution was concentrated under reduced pressure, about 10 ml of hexane was added, the precipitated crystals were removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to give 390 mg of the title compound as a colorless oil.

¹ H-NMR (DMSO, 300 MHz) δ: 1.33 (9H, s), 1.51 (6H, s), 3.18 (2H, t, J = 6.6 Hz), 4.33 (2H, t, J = 6.6 Hz), 7.01 (2H, d, J = 9 Hz), 7.25 (2H, t, J = 9 Hz), 7.56 (2H, d, J = 9 Hz), 7. 57 (1H, s), 7.61-7.66 (2H, m).
MS: 474 (M ⁺⁺ 1).
(Example 34-2)
2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(4′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2- obtained in Example 34-1 351 mg of methylpropionic acid tert-butyl ester was dissolved in 2 ml of dichloromethane, 1 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give 293 mg of the title compound as a white solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.19 (2H, t, J = 6.6 Hz), 4.33 (2H, t, J = 6. 6 Hz), 7.03 (2H, d, J = 9.0 Hz), 7.25 (2H, t, J = 9.0 Hz), 7.57 (2H, d, J = 9.0 Hz), 7. 58 (1H, s), 7.64 (2H, dd, J = 5.7 Hz, 9.0 Hz), 12.94 (1H, brs).
MS: 418 (M ⁺⁺ 1).
[Example 35]
2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) oxy] ethyl} -5-methyl-1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 16 and 4′- The title compound was obtained in the same manner as in Example 34, using fluorobiphenyl-4-ol as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 2.49 (3H, s), 3.22 (2H, t, J = 6.0 Hz), 4.29 (2H , T, J = 6.0 Hz), 6.91 (2H, d, J = 7.0 Hz), 7.06-7.12 (2H, m), 7.42-7.49 (4H, m) .
MS: 432 (M ⁺⁺ 1).
[Example 36]
2-[(5- {2-[(4′-Fluorobiphenyl-4-yl) oxy] ethyl} -4-methyl-1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[5- (2-hydroxyethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 21 and 4′- The title compound was obtained in the same manner as in Example 34, using fluorobiphenyl-4-ol as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 2.43 (3H, s), 3.21 (2H, t, J = 6.0 Hz), 4.18 (2H , T, J = 6.0 Hz), 6.96 (2H, d, J = 6.9 Hz), 7.07-7.13 (2H, m), 7.26-7.51 (4H, m) .
MS: 432 (M ⁺⁺ 1).
[Example 37]
2-[(4-{[(4′-Fluorobiphenyl-4-yl) oxy] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (hydroxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4'-fluorobiphenyl-4-ol synthesized in Example 10 Was used as a starting material, and the title compound was obtained in the same manner as in Example 34.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 5.25 (2H, s) 7.00-7.13 (5H, m), 7.46-7.51 ( 4H, m).
MS: 404 (M ⁺⁺ 1).
[Example 38]
2-[(4- {2-[(4′-Chlorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4'-chlorobiphenyl-4 synthesized in Example 4 -The title compound was obtained in the same manner as in Example 34 using ol as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.19 (2H, t, J = 6.6 Hz), 4.34 (2H, t, J = 6. 6 Hz), 7.03 (2H, d, J = 8.7 Hz), 7.47 (2H, t, J = 8.4 Hz), 7.58 (1H, s), 7.60 (2H, d, J = 8.4 Hz), 7.64 (2H, dd, J = 5.7 Hz, 8.7 Hz), 12.92 (1H, brs).
MS: 434 (M ⁺⁺ 1).
[Example 39]
2-[(4- {2-[(4′-methoxybiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4'-methoxybiphenyl-4 synthesized in Example 4 -The title compound was obtained in the same manner as in Example 34 using ol as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.18 (2H, t, J = 6.6 Hz), 3.27 (3H, s), 4.32. (2H, t, J = 6.6 Hz), 6.97 (4H, m), 7.52 (4H, m), 7.58 (1H, s), 12.92 (1H, s).
MS: 430 (M ⁺⁺ 1).
[Example 40]
2-[(4- {2-[(4′-cyanobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4′-hydroxybiphenyl-4 synthesized in Example 4 The title compound was obtained in the same manner as in Example 34 using carbonitrile as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.19 (2H, t, J = 6.6 Hz), 4.36 (2H, t, J = 6. 6 Hz), 7.04 (2 H, d, J = 8.4 Hz), 7.58 (1 H, s), 7.71 (2 H, t, J = 8.4 Hz), 7.83 (2 H, d, J = 8.7 Hz), 7.88 (2H, d, J = 8.7 Hz), 12.90 (1H, s).
MS: 425 (M ⁺⁺ 1).
[Example 41]
2-[(4- {2- [4- (4-Chlorobenzoyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and 4-chloro-4′- The title compound was obtained in the same manner as in Example 34 using hydroxybenzophenone as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.21 (2H, t, J = 6.6 Hz), 4.41 (2H, t, J = 6. 6 Hz), 7.10 (2H, d, J = 8.7 Hz), 7.58 (1H, s), 7.62 (2H, t, J = 8.7 Hz), 7.69-7.75 ( 4H, m), 12.98 (1H, brs).
MS: 462 (M ⁺⁺ 1).
[Example 42]
2-({4- [2- (4-Benzoylphenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid

  2-{[4- (2-Hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and (4-hydroxyphenyl) ( The title compound was obtained in the same manner as in Example 34 using phenyl) methanone as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.21 (2H, t, J = 6.6 Hz), 4.41 (2H, t, J = 6. 6 Hz), 7.04 (2H, d, J = 8.7 Hz), 7.50-7.58 (3H, m), 7.60-7.75 (5H, m), 12.91 (1H, brs).
MS: 428 (M ⁺⁺ 1).
[Example 43]
2-Methyl-2-[(4- {2- [4- (trifluoromethyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4- (trifluoromethyl) synthesized in Example 4 The title compound was obtained in the same manner as in Example 34 using phenol as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.26 (2H, t, J = 6.1 Hz), 4.27 (2H, t, J = 6.1 Hz) 6.87 (2H, d, J = 9.1 Hz), 7.12 (2H, d, J = 9.1 Hz), 7.26 (1H, s).
MS: 392 (M ⁺⁺ 1).
[Example 44]
2-Methyl-2-[(4- {2- [4- (trifluoromethoxy) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4- (trifluoromethoxy) synthesized in Example 4 The title compound was obtained in the same manner as in Example 34 using phenol as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 3.31 (2H, t, J = 6.1 Hz), 4.34 (2H, t, J = 6.1 Hz) 6.97 (2H, d, J = 8.6 Hz), 7.16 (1H, s), 7.55 (2H, d, J = 8.6 Hz).
MS: 408 (M ⁺⁺ 1).
[Example 45]
2-Methyl-2-({4- [2- (4-phenoxyphenoxy) ethyl] -1,3-thiazol-2-yl} thio) propionic acid

  Starting materials were 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-phenoxyphenol synthesized in Example 4 In the same manner as in Example 34, the title compound was obtained.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.16 (2H, t, J = 6.6 Hz), 4.27 (2H, t, J = 6. 6 Hz), 6.91 (2H, d, J = 9.0 Hz), 6.97 (4H, s), 7.06 (1H, t, J = 9.0 Hz), 7.34 (2H, d, J = 9.0 Hz), 7.56 (1H, s), 12.90 (1H, s).
MS: 416 (M ⁺⁺ 1).
[Example 46]
2-Methyl-2-({4- [2- (4- (4-trifluoromethylphenoxy) phenoxy)] ethyl} -1,3-thiazol-2-yl) thio) propionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4- (4-trifluoro synthesized in Example 4 The title compound was obtained in the same manner as in Example 34 using (methylphenoxy) phenol as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.18 (2H, t, J = 6.6 Hz), 4.32 (2H, t, J = 6. 6Hz), 7.05 (6H, m), 6.97 (4H, s), 7.57 (1H, s), 7.69 (2H, d, J = 8.8 Hz), 12.90 (1H) , S).
MS: 484 (M ⁺⁺ 1).
[Example 47]
2-[(4- {2- [4- (4-Fluorophenoxy) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4- (4-fluorophenoxy) synthesized in Example 4 ) The title compound was obtained in the same manner as in Example 34 using phenol as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.25 (2H, t, J = 6.2 Hz), 4.27 (2H, t, J = 6.2 Hz) 6.83-7.01 (8H, m), 7.11 (1H, s).
MS: 434 (M ⁺⁺ 1).
[Example 48]
2-Methyl-2-({4- [2- (4-phenoxy-2-propylphenoxy) ethyl] -1,3-thiazol-2-yl} thio) propionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and non-patent literature [Bioorg. Med. Chem. Lett. 13, 2795 (2003)] and the like, and the title compound was obtained in the same manner as in Example 34 using 4-phenoxy-2-propylphenol synthesized as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.86 (3H, t, J = 7.2 Hz), 1.41-1.49 (2H, m), 1.61 (6H, s), 2 .44 (2H, t, J = 7.5 Hz), 3.28 (2H, t, J = 6.3 Hz), 4.29 (2H, t, J = 6.3 Hz), 6.80-6. 83 (3H, m), 6.92 (2H, d, J = 7.5 Hz), 7.03 (1H, d, J = 7.5 Hz), 7.10 (1H, s), 7.26- 7.31 (2H, m).
MS: 458 (M ⁺⁺ 1).
[Example 49]
2-[(4- {2- [4- (4-Fluorophenoxy) -2-propylphenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and non-patent literature [Bioorg. Med. Chem. Lett. 13, 2795 (2003)] and the like, and the title compound was obtained in the same manner as in Example 34 using 4- (4-fluorophenoxy) -2-propylphenol synthesized as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.85 (3H, t, J = 7.3 Hz), 1.40-1.48 (2H, m), 1.61 (6H, s), 2 .43 (2H, t, J = 7.4 Hz), 3.27 (2H, t, J = 6.1 Hz), 4.28 (2H, t, J = 6.1 Hz), 6.77-7. 01 (7H, m), 7.11 (1H, s).
MS: 476 (M ⁺⁺ 1).
[Example 50]
2-{[4- (2- {4-[(4-chlorobenzyl) oxy] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (Example 50-1) )
Benzoic acid 4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxyethyl) thio] -1,3-thiazol-4-yl} ethoxy) phenyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and benzoic acid 4- 4.24 g of hydroxyphenyl ester was dissolved in 60 mL of tetrahydrofuran, and 5.19 g of triphenylphosphine and 3.45 g of diethyl diazodicarboxylate were added under ice cooling, followed by stirring at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 7.7 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.58 (6H, s), 3.25 (2H, t, J = 6.6 Hz), 4.31 (2H , T, J = 6.6 Hz), 6.93 (2H, d, J = 9.0 Hz), 7.09-7.13 (3H, m), 7.50 (2H, t, J = 7. 6 Hz), 7.63 (1 H, t, J = 7.5 Hz), 8.19 (2 H, d, J = 7.2 Hz).
(Example 50-2)
2-({4- [2- (4-Hydroxyphenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester

  Benzoic acid 4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxyethyl) thio] -1,3-thiazol-4-yl} obtained in Example 50-1 Ethoxy) phenyl ester (7.7 g) was dissolved in methanol (20 mL) and tetrahydrofuran (20 mL), 1 mol / L aqueous sodium hydroxide solution (18.5 ml) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1 to 2: 1) to give 6.3 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.57 (6H, s), 3.21 (2H, t, J = 6.6 Hz), 4.22 (2H , T, J = 6.6 Hz), 6.75 (4H, s), 7.13 (1H, s).
(Example 50-3)
2-{[4- (2- {4-[(4-Chlorobenzyl) oxy] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  600 mg of 2-({4- [2- (4-hydroxyphenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester obtained in Example 50-2 312 mg of 4-chlorobenzyl bromide was dissolved in 10 mL of acetone, and 210 mg of potassium carbonate was added and refluxed for 6 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give the title compound (420 mg) as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.57 (6H, s), 3.21 (2H, t, J = 6.6 Hz), 4.25 (2H , T, J = 6.6 Hz), 4.97 (2H, s), 6.80-6.88 (4H, m), 7.11 (1H, s), 7.34 (4H, s).
(Example 50-4)
2-{[4- (2- {4-[(4-chlorobenzyl) oxy] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-{[4- (2- {4-[(4-chlorobenzyl) oxy] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2- obtained in Example 50-3 Methylpropionic acid tert-butyl ester (420 mg) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give the title compound (260 mg) as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.23 (2H, t, J = 6.0 Hz), 4.24 (2H, t, J = 6.0 Hz) , 4.97 (2H, s), 6.97-6.88 (4H, m), 7.10 (1H, s), 7.34 (4H, s).
MS: 464 (M ⁺⁺ 1).
[Example 51]
2-[(4- {2- [4- (Benzyloxy) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-({4- [2- (4-hydroxyphenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 50-2 and The title compound was obtained in the same manner as in Example 50-3 and Example 50-4 using benzyl bromide as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.22 (2H, t, J = 6.0 Hz), 4.24 (2H, t, J = 6.0 Hz) , 5.01 (2H, s), 6.81 (2H, d, J = 9.0 Hz), 6.88 (2H, d, J = 9.0 Hz), 7.09 (1H, s), 7 .30-7.43 (5H, m).
MS: 430 (M ⁺⁺ 1).
[Example 52]
2-{[4- (2- {4-[(4-Fluorobenzyl) oxy] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-({4- [2- (4-hydroxyphenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 50-2 and The title compound was obtained in the same manner as in Example 50-3 and Example 50-4, using 4-fluorobenzyl bromide as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 3.28 (2H, t, J = 6.0 Hz), 4.24 (2H, t, J = 6.0 Hz) , 4.97 (2H, s), 6.81 (2H, d, J = 9.0 Hz), 6.87 (2H, d, J = 9.0 Hz), 7.02-7.08 (3H, m), 7.35-7.40 (2H, m).
MS: 448 (M ⁺⁺ 1).
[Example 53]
2-Methyl-2-({4- [2- (4-{[4- (trifluoromethyl) benzyl] oxy} phenoxy) ethyl] -1,3-thiazol-2-yl} thio) propionic acid

  2-({4- [2- (4-hydroxyphenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 50-2 and The title compound was obtained in the same manner as in Example 50-3 and Example 50-4, using 4- (trifluoromethyl) benzyl bromide as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.23 (2H, t, J = 6.0 Hz), 4.24 (2H, t, J = 6.0 Hz) , 5.07 (2H, s), 6.81 (2H, d, J = 9.0 Hz), 6.88 (2H, d, J = 9.0 Hz), 7.09 (1H, s), 7 .53 (2H, d, J = 8.1 Hz), 7.63 (2H, d, J = 8.1 Hz).
MS: 498 (M ⁺⁺ 1).
[Example 54]
2-[(4- {2- [4- (Benzoylamino) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (Example 54-1)
2-[(4- {2- [4- (Benzoylamino) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester 1.0 g and N- (4) synthesized in Example 4 -Hydroxyphenyl) benzamide (703 mg) was dissolved in tetrahydrofuran (10 mL). Under ice-cooling, triphenylphosphine (866 mg) and diazodicarboxylate (575 mg) were added, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 1.1 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.58 (6H, s), 3.25 (2H, t, J = 6.0 Hz), 4.30 (2H , T, J = 6.0 Hz), 6.91 (2H, d, J = 9.0 Hz), 7.13 (1H, s), 7.45-7.55 (5H, m), 7.74. (1H, s), 7.86 (2H, d, J = 7.0 Hz).
(Example 54-2)
2-[(4- {2- [4- (Benzoylamino) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2- [4- (Benzoylamino) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert- obtained in Example 54-1 550 mg of butyl ester was dissolved in 6 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 350 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.26 (2H, t, J = 6.0 Hz), 4.30 (2H, t, J = 6.0 Hz) 6.89 (2H, d, J = 9.0 Hz), 7.11 (1H, s), 7.45-7.55 (5H, m), 7.80-7.87 (3H, m) .
MS: 443 (M ⁺⁺ 1).
[Example 55]
2-{[4- (2- {4- [Benzoyl (methyl) amino] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (Example 55-1)
2-{[4- (2- {4- [Benzoyl (methyl) amino] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  2-[(4- {2- [4- (Benzoylamino) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 54-1 tert- 500 mg of butyl ester and 170 mg of methyl iodide were dissolved in 6 mL of N, N-dimethylformamide, 135 mg of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to give 290 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.40 (9H, s), 1.56 (6H, s), 3.18 (2H, t, J = 6.0 Hz), 3.44 (3H , S), 4.21 (2H, t, J = 6.0 Hz), 6.71 (2H, d, J = 8.6 Hz), 6.93 (2H, d, J = 8.6 Hz), 7 .08 (1H, s), 7.12-7.21 (3H, m), 7.28 (2H, d, J = 8.1 Hz).
(Example 55-2)
2-{[4- (2- {4- [Benzoyl (methyl) amino] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-{[4- (2- {4- [Benzoyl (methyl) amino] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropion obtained in Example 55-1 290 mg of acid tert-butyl ester was dissolved in 6 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 170 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.59 (6H, s), 3.22 (2H, t, J = 6.1 Hz), 3.45 (3H, s), 4.21 (2H , T, J = 6.1 Hz), 6.72 (2H, d, J = 8.7 Hz), 6.94 (2H, d, J = 8.7 Hz), 7.07 (1H, s), 7 .14-7.29 (5H, m).
MS: 457 (M ⁺⁺ 1).
[Example 56]
2-{[4- (2- {4-[(4-Fluorobenzoyl) amino] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-fluoro-N- (synthesized in Example 4 The title compound was obtained in the same manner as in Example 54, using 4-hydroxyphenyl) benzamide as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.25 (2H, t, J = 6.1 Hz), 4.29 (2H, t, J = 6.1 Hz) , 6.87 (2H, d, J = 9.0 Hz), 7.10-7.17 (3H, m), 7.49 (2H, d, J = 8.9 Hz), 7.80 (1H, s), 7.85-7.89 (2H, m).
MS: 461 (M ⁺⁺ 1).
[Example 57]
2-{[4- (2- {4-[(4-chlorobenzoyl) amino] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-chloro-N- (synthesized in Example 4 The title compound was obtained in the same manner as in Example 54, using 4-hydroxyphenyl) benzamide as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.27 (2H, t, J = 6.0 Hz), 4.30 (2H, t, J = 6.1 Hz) 6.90 (2H, d, J = 9.0 Hz), 7.11 (1H, s), 7.44-7.51 (4H, m), 7.74 (1H, s), 7.80 (2H, d, J = 8.1 Hz).
MS: 477 (M ⁺⁺ 1).
[Example 58]
2-{[4- (2- {4-[(4-Fluorobenzoyl) (methyl) amino] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-{[4- (2- {4-[(4-Fluorobenzoyl) amino] phenoxy} ethyl) -1,3-thiazol-2-yl] thio}-, an intermediate synthesized in Example 56 The title compound was obtained in the same manner as in Example 55, using 2-methylpropionic acid tert-butyl ester as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.24 (2H, t, J = 6.2 Hz), 3.44 (3H, s), 4.23 (2H , T, J = 6.2 Hz), 6.75 (2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.08 (1H, s), 7 .14 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz).
MS: 475 (M ⁺⁺ 1).
[Example 59]
2-{[4- (2- {4-[(4-Chlorobenzoyl) (methyl) amino] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  The intermediate synthesized in Example 57 is 2-{[4- (2- {4-[(4-chlorobenzoyl) amino] phenoxy} ethyl) -1,3-thiazol-2-yl] thio}- The title compound was obtained in the same manner as in Example 55, using 2-methylpropionic acid tert-butyl ester as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.60 (6H, s), 3.23 (2H, t, J = 6.1 Hz), 3.44 (3H, s), 4.23 (2H , T, J = 6.1 Hz), 6.75 (2H, d, J = 8.9 Hz), 6.85 (2H, d, J = 8.7 Hz), 6.93 (2H, d, J = 8.9 Hz), 7.08 (1 H, s), 7.28-7.31 (2 H, m).
MS: 491 (M ⁺⁺ 1).
[Example 60]
2-[(4- {2- [4- (anilinocarbonyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (Example 60-1)
4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy) benzoic acid methyl ester

  7.0 g of 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and 4-hydroxybenzoic acid 3.5 g of acid methyl ester was dissolved in 100 mL of tetrahydrofuran, and 6.06 g of triphenylphosphine and 4.0 g of diethyl diazodicarboxylate were added under ice cooling, followed by stirring at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to give 7.0 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.41 (9H, s), 1.57 (6H, s), 3.26 (2H, t, J = 6.6 Hz), 3.88 (3H , S), 4.36 (2H, t, J = 6.6 Hz), 6.90 (2H, d, J = 8.1 Hz), 7.12 (1H, s), 7.97 (2H, d) , J = 8.1 Hz).
(Example 60-2)
4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy) benzoic acid

  4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy obtained in Example 60-1 Benzoic acid methyl ester (7.0 g) was dissolved in methanol (50 mL) and tetrahydrofuran (30 mL), 1 mol / L aqueous sodium hydroxide solution (24 ml) was added, and the mixture was stirred at 60 ° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.8 g) as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.41 (9H, s), 1.58 (6H, s), 3.27 (2H, t, J = 6.6 Hz), 4.38 (2H , T, J = 6.6 Hz), 6.93 (2H, d, J = 8.1 Hz), 7.14 (1H, s), 8.03 (2H, d, J = 8.1 Hz).
(Example 60-3)
2-[(4- {2- [4- (anilinocarbonyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy obtained in Example 60-2 Benzoic acid 500 mg and aniline 132 mg were dissolved in 6 mL of dichloromethane, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) hydrochloride 339 mg, 4-dimethylaminopyridine (DMAP) 217 mg were sequentially added, Stir at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 480 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.58 (6H, s), 3.27 (2H, t, J = 6.6 Hz), 4.37 (2H , T, J = 6.6 Hz), 6.96 (2H, d, J = 8.9 Hz), 7.12-7.16 (2H, m), 7.36 (2H, t, J = 8. 1 Hz), 7.62 (2H, d, J = 8.1 Hz), 7.74 (1H, s), 7.82 (2H, d, J = 8.9 Hz).
(Example 60-4)
2-[(4- {2- [4- (anilinocarbonyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2- [4- (anilinocarbonyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid obtained in Example 60-3 tert -480 mg of butyl ester was dissolved in 6 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 400 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.28 (2H, t, J = 6.2 Hz), 4.35 (2H, t, J = 6.2 Hz) 6.94 (2H, d, J = 8.8 Hz), 7.10-7.16 (2H, m), 7.36 (2H, t, J = 7.8 Hz), 7.63 (2H, d, J = 7.8 Hz), 7.81 (2H, d, J = 8.8 Hz), 7.87 (1H, s).
MS: 443 (M ⁺⁺ 1).
[Example 61]
2-Methyl-2-({4- [2- (4-{[methyl (phenyl) amino] carbonyl} phenoxy) ethyl] -1,3-thiazol-2-yl} thio) propionic acid

  4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy synthesized in Example 60-2) The title compound was obtained in the same manner as in Example 60-3 and Example 60-4 using benzoic acid and N-methylaniline as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.59 (6H, s), 3.20 (2H, t, J = 6.0 Hz), 3.48 (3H, s), 4.22 (2H , T, J = 6.0 Hz), 6.64 (2H, d, J = 8.7 Hz), 7.01-7.26 (8H, m).
MS: 457 (M ⁺⁺ 1).
[Example 62]
2-({4- [2- (4-{[(4-Fluorophenyl) amino] carbonyl} phenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid

  4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy synthesized in Example 60-2) The title compound was obtained in the same manner as in Example 60-3 and Example 60-4 using benzoic acid and (4-fluorophenyl) aniline as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.28 (2H, t, J = 6.3 Hz), 4.35 (2H, t, J = 6.3 Hz) 6.94 (2H, d, J = 8.7 Hz), 7.05 (2H, t, J = 8.7 Hz), 7.11 (1H, s), 7.56-7.61 (2H, m), 7.80 (2H, d, J = 8.7 Hz), 7.88 (1H, s).
MS: 461 (M ⁺⁺ 1).
[Example 63]
2-{[4- (2- {4-[(Benzylamino) carbonyl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy synthesized in Example 60-2) The title compound was obtained in the same manner as in Example 60-3 and Example 60-4 using benzoic acid and benzylamine as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.60 (6H, s), 3.26 (2H, t, J = 6.1 Hz), 4.32 (2H, t, J = 6.1 Hz) , 4.63 (2H, d, J = 5.5 Hz), 6.37-6.39 (1H, m), 6.90 (2H, d, J = 8.9 Hz), 7.09 (1H, s), 7.27-7.37 (5H, m), 7.73 (2H, d, J = 8.9 Hz).
MS: 457 (M ⁺⁺ 1).
[Example 64]
2-({4- [2- (4-{[(4-Fluorobenzyl) amino] carbonyl} phenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid

  4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy synthesized in Example 60-2) The title compound was obtained in the same manner as in Example 60-3 and Example 60-4 using benzoic acid and (4-fluorobenzyl) amine as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.60 (6H, s), 3.26 (2H, t, J = 6.1 Hz), 4.32 (2H, t, J = 6.1 Hz) , 4.58 (2H, d, J = 5.8 Hz), 6.45-6.48 (1 H, m), 6.89 (2H, d, J = 8.9 Hz), 7.01 (2H, t, J = 8.8 Hz), 7.10 (1H, s), 7.28-7.33 (2H, m), 7.72 (2H, d, J = 8.9 Hz).
MS: 475 (M ⁺⁺ 1).
[Example 65]
2-Methyl-2-[(4- {2- [4-({[4- (trifluoromethyl) benzyl] amino} carbonyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propion acid

  4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy synthesized in Example 60-2) The title compound was obtained in the same manner as in Example 60-3 and Example 60-4 using benzoic acid and [4- (trifluoromethyl) benzyl] amine as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.28 (2H, t, J = 6.0 Hz), 4.34 (2H, t, J = 6.1 Hz) , 4.69 (2H, d, J = 6.0 Hz), 6.39-6.42 (1H, m), 6.92 (2H, d, J = 8.7 Hz), 7.09 (1H, s), 7.46 (2H, d, J = 8.1 Hz), 7.60 (2H, d, J = 8.1 Hz), 7.74 (2H, d, J = 8.7 Hz).
MS: 525 (M ⁺⁺ 1).
[Example 66]
2-Methyl-2-[(4- {2- [4- (morpholin-4-ylcarbonyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy synthesized in Example 60-2) The title compound was obtained in the same manner as in Example 60-3 and Example 60-4 using benzoic acid and morpholine as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.27 (2H, t, J = 6.0 Hz), 3.50-3.78 (8H, m), 4 .33 (2H, t, J = 6.0 Hz), 6.90 (2H, d, J = 8.7 Hz), 7.09 (1H, s), 7.36 (2H, d, J = 8. 7 Hz).
MS: 437 (M ⁺⁺ 1).
[Example 67]
2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid (Example 67-1)
2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 3.077 g and 4-bromophenol 1.75 g was dissolved in 50 ml of tetrahydrofuran, and 3.20 g of triphenylphosphine and 6.54 ml of diisopropyl diazodicarboxylate (40% toluene solution) were added under ice cooling, followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 5: 1) to give the title compound (3.45 g) as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.57 (6H, s), 3.22 (2H, t, J = 6.6 Hz), 4.27 (2H , T, J = 6.6 Hz), 6.77 (2H, d, J = 8.7 Hz), 7.10 (1H, s), 7.35 (2H, d, J = 8.7 Hz).
MS: 458 (M ⁺⁺ 1).
(Example 67-2)
2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid

  The 2-({4- [2- (4-bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester obtained in Example 67-1 was used. The title compound was obtained by the same procedures as in Example 34-2 as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.15 (2H, t, J = 6.6 Hz), 4.28 (2H, t, J = 6. 6 Hz), 6.91 (2H, d, J = 8.7 Hz), 7.43 (2H, d, J = 87 Hz), 7.56 (1 H, s), 12.93 (1 H, s).
MS: 404 (M ⁺⁺ 1).
[Example 68]
2-[(4- {2-[(3′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (Example 68-1) )
2-[(4- {2-[(3′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid synthesized in Example 67-1 under nitrogen atmosphere -447 mg of butyl ester and 273 mg of 3-fluorophenylboric acid were dissolved in 10 ml of tetrahydrofuran and 10 ml of 1 mol / l sodium hydrogen carbonate, and 231 mg of tetrakis (triphenylphosphine) palladium was added and refluxed for 6.5 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1) to give 296 mg of the title compound as a pale yellow oil.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.33 (9H, s), 1.51 (6H, s,), 3.18 (2H, t, J = 6.6 Hz), 7. 02 (2H, d, J = 8.7 Hz), 7.13 (1H, m), 7.43-7.48 (3H, m), 7.58 (1H, s), 7.64 (2H, d, J = 8.7 Hz).
MS: 474 (M ⁺⁺ 1).

(Example 68-2)
2-[(4- {2-[(3′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(3′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2- obtained in Example 68-1 Methylpropionic acid tert-butyl ester was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 151 mg of the title compound as a white solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.19 (2H, t, J = 6.6 Hz), 4.34 (2H, t, J = 6. 6 Hz), 7.04 (2H, d, J = 8.7 Hz), 7.12 (1 H, m), 7.43-7.48 (2 H, m), 7.58 (1 H, s), 7 .64 (2H, d, J = 8.7 Hz), 12.93 (1H, brs).
MS: 418 (M ⁺⁺ 1).
[Example 69]
2-Methyl-2-{[4- (2-{[4 ′-(trifluoromethyl) biphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} propionic acid

  2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 67-1 and The title compound was obtained in the same manner as in Example 68, using 4- (trifluoromethyl) phenylboric acid as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.20 (2H, t, J = 6.6 Hz), 4.36 (2H, t, J = 6. 6 Hz), 7.07 (2H, d, J = 9.0 Hz), 7.59 (1H, s), 7.69 (2H, t, J = 9.0 Hz), 7.77 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 12.94 (1H, brs).
MS: 468 (M ⁺⁺ 1).
[Example 70]
2-Methyl-2-{[4- (2-{[3 ′-(trifluoromethyl) biphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} propionic acid

  2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 67-1 and The title compound was obtained in the same manner as in Example 68, using 3- (trifluoromethyl) phenylboric acid as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.20 (2H, t, J = 6.6 Hz), 4.35 (2H, t, J = 6. 6 Hz), 7.06 (2H, d, J = 8.4 Hz), 7.58 (1H, s), 7.65-7.70 (4H, m), 7.90-7.95 (2H, m), 12.95 (1H, brs).
MS: 468 (M ⁺⁺ 1).
[Example 71]
2-Methyl-2-{[4- (2-{[4 '-(trifluoromethoxy) biphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} propionic acid

  2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 67-1 and The title compound was obtained in the same manner as in Example 68, using 4- (trifluoromethoxy) phenylboric acid as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.19 (2H, t, J = 6.6 Hz), 4.34 (2H, t, J = 6. 6 Hz), 7.05 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.58 (1H, s), 7.62 (2H, d, J = 8.7 Hz), 7.73 (2H, d, J = 8.7 Hz), 12.95 (1H, brs).
MS: 484 (M ⁺⁺ 1).
[Example 72]
2-Methyl-2-{[4- (2-{[3 ′-(trifluoromethoxy) biphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} propionic acid

  2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 67-1 and The title compound was obtained in the same manner as in Example 68, using 3- (trifluoromethoxy) phenylboric acid as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.19 (2H, t, J = 6.6 Hz), 4.35 (2H, t, J = 6. 6 Hz), 7.05 (2H, d, J = 8.7 Hz), 7.30 (1 H, d, J = 8.4 Hz), 7.53-7.58 (3H, m), 7.63- 7.69 (3H, m), 12.95 (1H, brs).
MS: 484 (M ⁺⁺ 1).
[Example 73]
2-{[4- (2-{[4 '-(acetylamino) biphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 67-1 and The title compound was obtained in the same manner as in Example 68, using [4- (acetylamino) phenyl] boric acid as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 2.05 (3H, s), 3.18 (2H, t, J = 6.6 Hz), 4.32. (2H, t, J = 6.6 Hz), 7.00 (2H, d, J = 8.7 Hz), 7.52-7.58 (5H, m), 7.63 (2H, d, J = 8.7 Hz), 9.98 (1H, s), 12.93 (1H, s).
MS: 457 (M ⁺⁺ 1).
[Example 74]
2-{[4- (2-{[4 ′-(Dimethylamino) biphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 67-1 and The title compound was obtained in the same manner as in Example 68, using [4- (dimethylamino) phenyl] boric acid as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.52 (6H, s), 2.91 (6H, s), 3.17 (2H, t, J = 6.6 Hz), 4.30 (2H, t, J = 6.6 Hz), 6.77 (2H, d, J = 8.7 Hz), 6.96 (2H, d, J = 8.7 Hz), 7.42-7.57 ( 4H, m), 7.63 (1H, s), 12.92 (1H, s).
MS: 443 (M ⁺⁺ 1).
[Example 75]
2-Methyl-2-[(4- {2- [4- (5-methyl-2-thienyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 67-1 and The title compound was obtained in the same manner as in Example 68, using 5-methyl-2-thiopheneboronic acid as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 2.44 (3H, s), 3.17 (2H, t, J = 6.6 Hz), 4.30 (2H, t, J = 6.6 Hz), 6.77 (1H, d, J = 3.9 Hz), 6.96 (2H, d, J = 8.4 Hz), 7.15 (1H, d, J = 3.6 Hz), 7.48 (2H, d, J = 8.4 Hz), 7.57 (1H, s), 12.92 (1H, s).
MS: 420 (M ⁺⁺ 1).
[Example 76]
2-[(4- {2-[(4'-Fluorobiphenyl-4-yl) thio] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  Starting from 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-bromobenzenethiol synthesized in Example 4 The title compound was obtained by performing the same operation as in Example 67-1 as the starting material, and then performing the same operation as in Example 68 using 4-fluorophenylboric acid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.52 (6H, s), 3.02 (2H, t, J = 7.2 Hz), 3.33 (2H, t, J = 7. 2 Hz), 7.29 (2H, t, J = 9.0 Hz), 7.43 (2H, d, J = 8.4 Hz), 7.53 (1H, s), 7.61 (2H, d, J = 8.4 Hz), 7.70 (2H, m), 12.91 (1H, s).
MS: 434 (M ⁺⁺ 1).
[Example 77]
2-[(4- {2-[(4′-Fluorobiphenyl-3-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  Starting from 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 3-bromophenol synthesized in Example 4 As in Example 67-1, the same operation as in Example 68 was carried out using 4-fluorophenylboric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.19 (2H, t, J = 6.6 Hz), 4.37 (2H, t, J = 6. 6 Hz), 6.94 (1 H, dd, J = 2.1, 7.8 Hz), 7.18 (1 H, s), 7.20 (1 H, d, J = 7.8 Hz), 7.27 ( 2H, t, J = 8.7 Hz), 7.36 (1H, t, J = 7.8 Hz), 7.59 (1H, s), 7.71 (2H, m), 12.92 (1H, s).
MS: 418 (M ⁺⁺ 1).
[Example 78]
2-[(4- {2-[(4′-chloro-3-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-bromo-2-fluoro synthesized in Example 4 The title compound was obtained by the same procedures as in Example 67-1 using phenol as a starting material, and then the same procedures as in Example 68 using 4-chlorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 3.36 (2H, t, J = 6.0 Hz), 4.39 (2H, t, J = 6.0 Hz) 7.03 (1H, d, J = 8.4 Hz), 7.22-7.45 (7H, m).
MS: 452 (M ⁺⁺ 1).
[Example 79]
2-[(4- {2-[(3,4'-Difluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-bromo-2-fluoro synthesized in Example 4 The title compound was obtained by performing the same operation as in Example 67-1 using phenol as a starting material, and then performing the same operation as in Example 68 using 4-fluorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 3.33 (2H, t, J = 6.0 Hz), 4.40 (2H, t, J = 6.0 Hz) 7.02-7.14 (3H, m) 7.21-7.26 (3H, m), 7.44-7.49 (2H, m).
MS: 436 (M ⁺⁺ 1).
[Example 80]
2-[(4- {2-[(4′-Chloro-3-methoxybiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-bromo-2-methoxy synthesized in Example 4 The title compound was obtained by the same procedures as in Example 67-1 using phenol as a starting material, and then the same procedures as in Example 68 using 4-chlorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 3.35 (2H, t, J = 6.2 Hz), 3.90 (3H, t), 4.37 (2H , T, J = 6.2 Hz), 6.95 (1H, d, J = 8.3 Hz), 7.05-7.11 (2H, m), 7.33-7.40 (3H, m) 7.47 (2H, d, J = 8.7 Hz).
MS: 464 (M ⁺⁺ 1).
[Example 81]
2-[(4- {2-[(4′-Fluoro-3-methoxybiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-bromo-2-methoxy synthesized in Example 4 The title compound was obtained by performing the same operation as in Example 67-1 using phenol as a starting material, and then performing the same operation as in Example 68 using 4-fluorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 3.35 (2H, t, J = 6.0 Hz), 3.90 (3H, s), 4.38 (2H , T, J = 6.0 Hz), 6.93-7.13 (5H, m), 7.32 (1H, s), 7.46-7.51 (2H, m).
MS: 448 (M ⁺⁺ 1).
[Example 82]
2-[(4- {2-[(4′-chloro-3-methylbiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-iodo-2-methyl synthesized in Example 4 The title compound was obtained by the same procedures as in Example 67-1 using phenol as a starting material, and then the same procedures as in Example 68 using 4-chlorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 2.18 (3H, s), 3.31 (2H, t, J = 6.0 Hz), 4.34 (2H , T, J = 6.0 Hz), 6.88 (1H, d, J = 7.8 Hz), 7.13 (1H, s), 7.31-7.38 (4H, m), 7.45. (2H, d, J = 8.7 Hz).
MS: 448 (M ⁺⁺ 1).
[Example 83]
2-[(4- {2-[(4′-Fluoro-3-methylbiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-iodo-2-methyl synthesized in Example 4 The title compound was obtained by performing the same operation as in Example 67-1 using phenol as a starting material, and then performing the same operation as in Example 68 using 4-fluorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 2.18 (3H, s), 3.32 (2H, t, J = 6.0 Hz), 4.34 (2H , T, J = 6.0 Hz), 6.88 (1H, d, J = 8.1 Hz), 7.08 (2H, t, J = 8.7 Hz), 7.16 (1H, s), 7 .29-7.33 (2H, m), 7.44-7.50 (2H, m).
MS: 432 (M ⁺⁺ 1).
[Example 84]
2-[(4- {2-[(3-Cyano-4'-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo-2-hydroxy synthesized in Example 4 The title compound was obtained by the same procedures as in Example 67-1 using benzonitrile as a starting material, and then the same procedures as in Example 68 using 4-fluorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.36 (2H, t, J = 6.0 Hz), 4.43 (2H, t, J = 6.0 Hz) 7.03-7.06 (1H, m), 7.10-7.16 (2H, m), 7.30 (1H, s), 7.42-7.47 (2H, m), 7 .67-7.70 (2H, m).
MS: 423 (M ⁺⁺ 1).
[Example 85]
2-[(4- {2-[(4′-chloro-3-cyanobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo-2-hydroxy synthesized in Example 4 The title compound was obtained by conducting the same operation as in Example 67-1 using benzonitrile as a starting material, and then performing the same operation as in Example 68 using 4-chlorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.36 (2H, t, J = 6.0 Hz), 4.43 (2H, t, J = 6.0 Hz) 7.03-7.07 (1H, m), 7.30 (1H, s), 7.42 (4H, s), 7.68-7.72 (2H, m).
MS: 459 (M ⁺⁺ 1).
[Example 86]
2-{[4- (2-{[5- (4-Chlorophenyl) -3-methylpyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropion acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo-3-methyl synthesized in Example 4 The title compound was obtained by the same procedures as in Example 67-1 using pyridin-2-ol as a starting material, and then the same procedure as in Example 68 using 4-chlorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 2.18 (3H, s), 3.31 (2H, t, J = 6.0 Hz), 4.70 (2H , T, J = 6.0 Hz), 7.08 (1H, s), 7.37-7.45 (4H, m), 7.56 (1H, s), 8.15 (1H, s).
MS: 449 (M ⁺⁺ 1).
[Example 87]
2-{[4- (2-{[5- (4-Fluorophenyl) -3-methylpyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo-3-methyl synthesized in Example 4 The title compound was obtained by performing the same operation as in Example 67-1 using pyridin-2-ol as a starting material, and then performing the same operation as in Example 68 using 4-fluorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 2.18 (3H, s), 3.31 (2H, t, J = 6.6 Hz), 4.70 (2H , T, J = 6.6 Hz), 7.08-7.15 (3H, m), 7.43-7.48 (2H, m), 7.55 (1H, s), 8.13 (1H , S).
MS: 433 (M ⁺⁺ 1).
[Example 88]
2-{[4- (2-{[6- (4-Fluorophenyl) pyridin-3-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid hydrochloride

  Reference is made to 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and patent document [WO9825920] The same operation as in Example 67-1 was performed using 2-chloro-5-hydroxypyridine synthesized as a starting material, and then the same operation as in Example 68 was performed using 4-fluorophenylboric acid. . The title compound was obtained by dissolving the obtained compound in diethyl ether and allowing 4 mol / L hydrochloric acid-ethyl acetate to act.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.22 (2H, t, J = 6.6 Hz), 4.45 (2H, t, J = 6. 6Hz), 7.28-7.34 (2H, m), 7.58-7.62 (2H, m), 7.96 (1H, d, J = 8.7 Hz), 8.03-8. 08 (2H, m), 8.39 (1 H, d, J = 3.0 Hz).
MS: 419 (M ⁺⁺ 1).
[Example 89]
2-{[4- (2-{[6- (4-Chlorophenyl) pyridin-3-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid hydrochloride

  Reference is made to 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and patent document [WO9825920] The same operation as in Example 67-1 was performed using 2-chloro-5-hydroxypyridine synthesized as a starting material, and then the same operation as in Example 68 was performed using 4-chlorophenylboric acid. The title compound was obtained by dissolving the obtained compound in diethyl ether and allowing 4 mol / L hydrochloric acid-ethyl acetate to act.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.22 (2H, t, J = 6.4 Hz), 4.45 (2H, t, J = 6. 4Hz), 7.53 (2H, d, J = 8.6 Hz) 7.58-7.62 (2H, m), 7.98 (1H, d, J = 8.9 Hz), 8.03 (2H , D, J = 8.7 Hz), 8.39 (1H, d, J = 2.9 Hz).
MS: 435 (M ⁺⁺ 1).
[Example 90]
2-[(4-{[(4′-Chlorobiphenyl-3-yl) oxy] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  Performed using 2-{[4- (hydroxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 3-bromophenol synthesized in Example 10 as starting materials The title compound was obtained by the same procedures as in Example 67-1 and then the same procedure as in Example 68 using 4-chlorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 5.26 (2H, s), 6.95-7.52 (9H, m).
MS: 420 (M ⁺⁺ 1).
[Example 91]
2-[(4-{[(4′-Fluorobiphenyl-3-yl) oxy] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  Performed using 2-{[4- (hydroxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 3-bromophenol synthesized in Example 10 as starting materials The title compound was obtained by the same procedures as in Example 67-1 and then the same procedure as in Example 68 using 4-fluorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 5.26 (2H, s) 6.90-6.97 (1H, m), 7.08-7.19 ( 4H, m), 7.33-7.39 (2H, m), 7.50-7.55 (2H, m).
MS: 404 (M ⁺⁺ 1).
[Example 92]
2-{[4- (2-{[4′-Fluoro-3- (methoxycarbonyl) biphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropion Acid (Example 92-1)
2- (2- {2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy) -5-iodobenzoic acid methyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and 5-iodosalicylic acid 7.3 g of methyl ester was dissolved in 130 mL of tetrahydrofuran, and 9.0 g of triphenylphosphine and 14.9 g of diethyl diazodicarboxylate were added under ice cooling, and then stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 5: 1) to give the title compound (14.3 g) as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.41 (9H, s), 1.56 (6H, s), 3.28 (2H, t, J = 6.6 Hz), 3.85 (3H , S), 4.32 (2H, t, J = 6.6 Hz), 6.75 (1H, d, J = 8.7 Hz), 7.29 (1H, s), 7.70 (1H, dd) , J = 2.4, 8.7 Hz) 8.05 (1H, d, J = 2.4 Hz)
(Example 92-2)
4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy) -4'-fluoro-biphenyl-3 -Carboxylic acid methyl ester

  2- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazole-4-synthesized in Example 92-1 under nitrogen atmosphere. Yl} ethoxy) -5-iodobenzoic acid methyl ester (5.0 g) and 4-fluorophenylboric acid (1.5 g) are dissolved in dioxane (40 mL) and 2 mol / L aqueous sodium carbonate solution (20 mL), and tetrakis (triphenylphosphine) palladium (0.51 g) is dissolved. And refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 2.7 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.56 (6H, s), 3.32 (2H, t, J = 6.3 Hz), 3.89 (3H , S), 4.39 (2H, t, J = 6.3 Hz), 7.03-7.14 (3H, m), 7.33 (1H, s), 7.48-7.53 (2H , M), 7.60-7.63 (1H, m), 7.96 (1H, d, J = 2.6 Hz)
(Example 92-3)
2-{[4- (2-{[4′-Fluoro-3- (methoxycarbonyl) biphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropion acid

  4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy obtained in Example 92-2 250 mg of -4′-fluoro-biphenyl-3-carboxylic acid methyl ester was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 175 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.34 (2H, t, J = 6.0 Hz), 3.87 (3H, s), 4.40 (2H , T, J = 6.0 Hz), 7.03-7.14 (3H, m), 7.38 (1H, s), 7.48-7.52 (2H, m), 7.63 (1H) , Dd, J = 2.4, 8.4 Hz), 7.95 (1H, d, J = 2.4 Hz)
MS: 476 (M ⁺⁺ 1).
[Example 93]
2-{[4- (2-{[4′-Fluoro-3- (morpholin-4-ylcarbonyl) biphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio}- 2-Methylpropionic acid (Example 93-1)
4′-Fluoro-4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy) biphenyl-3- carboxylic acid

  4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethoxy) synthesized in Example 92-2 1.6 g of -4′-fluoro-biphenyl-3-carboxylic acid methyl ester was dissolved in 15 mL of methanol and 20 mL of tetrahydrofuran, 15 mL of 1 mol / L aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 1.3 g of the title compound as an oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.41 (9H, s), 1.56 (6H, s), 3.34 (2H, t, J = 6.1 Hz), 4.63 (2H , T, J = 6.1 Hz), 7.09-7.18 (4H, m), 7.51-7.55 (2H, m), 7.45 (1H, dd, J = 2.4). 8.6 Hz), 8.33 (1H, d, J = 2.5 Hz).
(Example 93-2)
2-{[4- (2-{[4′-Fluoro-3- (morpholin-4-ylcarbonyl) biphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio}- 2-Methylpropionic acid tert-butyl ester

  4′-Fluoro-4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazole-4- obtained in Example 93-1. Yl} ethoxy) biphenyl-3-carboxylic acid (170 mg) and morpholine (43 mg) were dissolved in dichloromethane (2 mL), and N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) hydrochloride 94 mg, 1-hydroxybenztriazole ( HOBt) monohydrate (75 mg) was sequentially added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 180 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.58 (6H, s), 3.13-3.27 (4H, m), 3.49-3.53 (2H, m), 3.68-3.90 (4H, m), 4.10-4.40 (2H, m), 7.00 (1H, d, J = 8.7 Hz), 7.07 -7.14 (3H, m), 7.43 (1H, d, J = 2.4Hz), 7.46-7.52 (3H, m).
(Example 93-3)
2-{[4- (2-{[4′-Fluoro-3- (morpholin-4-ylcarbonyl) biphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio}- 2-Methylpropionic acid

  2-{[4- (2-{[4′-Fluoro-3- (morpholin-4-ylcarbonyl) biphenyl-4-yl] oxy} ethyl) -1,3- obtained in Example 93-2 180 mg of thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 120 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 to 1.66 (6H, m), 3.14 to 3.28 (4H, m), 3.51 to 3.55 (2H, m) 3.67-3.83 (4H, m), 4.37-4.45 (2H, m), 7.00 (1H, d, J = 8.7 Hz), 7.07-7.13 ( 3H, m), 7.40 (1H, d, J = 2.1 Hz), 7.46-7.54 (3H, m).
MS: 531 (M ⁺⁺ 1).
[Example 94]
2-({4- [2-({3-[(Dimethylamino) carbonyl] -4'-fluorobiphenyl-4-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) -2 -Methylpropionic acid

  4′-Fluoro-4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazole-4- obtained in Example 93-1. Yl} ethoxy) biphenyl-3-carboxylic acid and dimethylamine hydrochloride were used as starting materials to give the title compound in the same manner as in Example 93-2 and Example 93-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 2.77 (3H, s), 3.07 (3H, s), 3.24 (2H, t, J = 5) .8 Hz), 4.38 (2H, brs), 6.98 (1 H, d, J = 8.9 Hz), 7.06-7.12 (3 H, m), 7.39 (1 H, d, J = 2.3 Hz), 7.45-7.51 (3H, m).
MS: 489 (M ⁺⁺ 1).
[Example 95]
2-({4- [2-({4′-fluoro-3-[(methylamino) carbonyl] biphenyl-4-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) -2 -Methylpropionic acid

  4′-Fluoro-4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazole-4- obtained in Example 93-1. Yl} ethoxy) biphenyl-3-carboxylic acid and methylamine hydrochloride were used as starting materials to give the title compound in the same manner as in Example 93-2 and Example 93-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.59 (6H, s), 2.91-2.92 (3H, m), 3.34 (2H, t, J = 6.0 Hz), 4 .54 (2H, t, J = 6.0 Hz), 7.02-7.13 (4H, m), 7.51-7.61 (4H, m) 8.35 (1H, d, J = 2) .4 Hz).
MS: 475 (M ⁺⁺ 1).
[Example 96]
2-{[4- (2-{[3- (aminocarbonyl) -4′-fluorobiphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropion acid

  4′-Fluoro-4- (2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazole-4- obtained in Example 93-1. Yl} ethoxy) biphenyl-3-carboxylic acid and ammonium acetate as starting materials, and the title compound was obtained in the same manner as in Example 93-2 and Example 93-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 3.31 (2H, t, J = 6.3 Hz), 4.49 (2H, t, J = 6.3 Hz) 6.89 (1H, brs), 6.99 (1H, d, J = 8.4 Hz), 7.06 (2H, t, J = 8.4 Hz) 7.11 (1H, s), 7. 43-7.48 (2H, m), 7.53 (1H, dd, J = 2.7, 8.7 Hz), 7.85 (1H, brs), 8.29 (1H, d, J = 2) .4 Hz).
MS: 461 (M ⁺⁺ 1).
[Example 97]
2-[(4- {2-[(4′-Fluoro-3-nitrobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Example 97-1)
2-({4- [2- (4-Bromo-3-nitrophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and 4-bromo- 3.6 g of 2-nitrophenol was dissolved in 82 mL of tetrahydrofuran, and 5.6 g of triphenylphosphine and 9.3 g of diethyl diazodicarboxylate were added under ice cooling, and then stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1-3: 1) to give 8.0 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.41 (9H, s), 1.56 (6H, s), 3.28 (2H, t, J = 6.3 Hz), 4.40 (2H , T, J = 6.3 Hz), 6.99 (1H, d, J = 9.0 Hz), 7.22 (1H, s), 7.61 (1H, dd, J = 2.5, 9.). 0 Hz), 8.00 (1H, d, J = 2.5 Hz).
(Example 97-2)
2-[(4- {2-[(4′-Fluoro-3-nitrobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert- Butyl ester

  2-({4- [2- (4-Bromo-3-nitrophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2- synthesized in Example 97-1 under a nitrogen atmosphere Dissolve 4.0 g of methylpropionic acid tert-butyl ester and 1.33 g of 4-fluorophenylboric acid in 40 mL of dioxane and 20 mL of 2 mol / L sodium carbonate aqueous solution, add 0.46 g of tetrakis (triphenylphosphine) palladium and reflux for 4 hours. did. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1 to 2: 1) to give 4.3 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.41 (9H, s), 1.58 (6H, s), 3.32 (2H, t, J = 6.3 Hz), 4.46 (2H , T, J = 6.3 Hz), 7.11-7.17 (3H, m), 7.27 (1H, s), 7.48-7.52 (2H, m), 7.68 (1H) , Dd, J = 2.4, 8.7 Hz), 8.00 (1H, d, J = 2.4 Hz).
(Example 97-3)
2-[(4- {2-[(4′-Fluoro-3-nitrobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(4′-Fluoro-3-nitrobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] obtained in Example 97-2 2-methylpropionic acid tert-butyl ester (300 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 167 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.60 (6H, s), 3.34 (2H, t, J = 6.0 Hz), 4.46 (2H, t, J = 6.0 Hz) , 7.11-7.17 (3H, m), 7.27 (1H, s), 7.47-7.52 (2H, m), 7.70 (1H, dd, J = 2.4). 9.0 Hz), 7.9 (1H, d, J = 2.4 Hz).
MS: 463 (M ⁺⁺ 1).
[Example 98]
2-[(4- {2-[(3-Amino-4′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (implemented) Example 98-1)
2-[(4- {2-[(3-Amino-4′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert- Butyl ester

  2-[(4- {2-[(4′-Fluoro-3-nitrobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] obtained in Example 97-2 2-methylpropionic acid tert-butyl ester (2.0 g) was dissolved in methanol (20 mL), a catalytic amount of iron (III) chloride (62 mg), activated carbon (1.0 g), and hydrazine monohydrate (580 mg) were sequentially added and heated to reflux for 3 hours. . After filtration through celite, methanol was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.5 g).

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.58 (6H, s), 3.29 (2H, t, J = 6.3 Hz), 3.84 (2H , Brs), 4.38 (2H, t, J = 6.3 Hz), 6.86-6.89 (3H, m), 7.04-7.14 (3H, m), 7.44-7. .48 (2H, m).
(Example 98-2)
2-[(4- {2-[(3-Amino-4′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(3-Amino-4′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] obtained in Example 98-1. 2-methylpropionic acid tert-butyl ester (230 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 1: 1) to give 148 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.31 (2H, t, J = 6.0 Hz), 4.36 (2H, t, J = 6.0 Hz) 6.82-6.92 (3H, m), 7.04-7.11 (3H, m), 7.42-7.47 (2H, m).
MS: 433 (M ⁺⁺ 1).
Example 99
2-{[4- (2-{[3- (acetylamino) -4′-fluorobiphenyl-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropion acid

  2-[(4- {2-[(3-Amino-4′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] obtained in Example 98-1. 2-methylpropionic acid tert-butyl ester (300 mg) was dissolved in dichloromethane (3 mL), and triethylalumine (0.13 mL) and acetyl chloride (72 mg) were added under ice cooling. After 1 hour, water was added to the reaction mixture, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to obtain 260 mg of an N-acetylated compound as a white solid. Thereafter, the title compound was obtained in the same manner as in Example 98-2.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 2.22 (3H, s), 3.32 (2H, t, J = 5.7 Hz), 4.42 (2H , T, J = 5.7 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.05-7.11 (3H, m), 7.18-7.21 (1H, m) 7.49-7.54 (2H, m), 7.83 (1H, brs), 8.54 (1H, brs).
MS: 475 (M ⁺⁺ 1).
[Example 100]
2-{[4- (2-{[5- (4-Fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio-2-methylpropionic acid (Examples) 100-1)
2-[(4- {2-[(5-Bromopyridin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 2.12 g and 5-bromopyridine 1.22 g of 2-ol was dissolved in 20 ml of tetrahydrofuran, and 2.02 g of triphenylphosphine and 4.14 ml of diisopropyl diazodicarboxylate (40% toluene solution) were added under ice-cooling, and then stirred at room temperature for 12 hours. . After the reaction solution was concentrated under reduced pressure, about 10 ml of hexane was added, the precipitated crystals were removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 1.84 g of the title compound as a pale yellow oil.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.32 (9H, s), 1.50 (6H, s), 3.15 (2H, t, J = 6.6 Hz), 4.54 (2H, t, J = 6.6 Hz), 6.77 (1H, d, J = 8.8 Hz), 7.54 (1H, s), 7.88 (1H, dd, J = 2.5 Hz, 8.8 Hz), 8.27 (1H, d, J = 2.5 Hz).
(Example 100-2)
2-{[4- (2-{[5- (4-Fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert- Butyl ester

  2-[(4- {2-[(5-Bromopyridin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] synthesized in Example 100-1 under a nitrogen atmosphere 486 mg of 2-methylpropionic acid tert-butyl ester and 297 mg of 4-fluorophenylboric acid were dissolved in 10 ml of tetrahydrofuran and 10 ml of 1 mol / l sodium hydrogen carbonate, and 245 mg of tetrakis (triphenylphosphine) palladium was added and refluxed for 4.5 hours. . The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 5: 1) to give 304 mg of the title compound as a pale yellow oil.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.36 (9H, s), 1.51 (6H, s), 3.19 (2H, t, J = 6.6 Hz), 4.61 (2H, t, J = 6.6 Hz), 6.85 (1H, d, J = 8.7 Hz), 7.29 (2H, t, J = 9.0 Hz), 7.56 (1H, s) 7.70 (2H, dd, J = 5.4 Hz, 9 Hz), 7.98 (1H, dd, J = 2.7 Hz, 8.7 Hz), 8.45 (1H, d, J = 2.7 Hz) ).
(Example 100-3)
2-{[4- (2-{[5- (4-Fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-{[4- (2-{[5- (4-Fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio obtained in Example 100-2 } -2-Methylpropionic acid tert-butyl ester was dissolved in 2 ml of dichloromethane, 1 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1 to 2: 1) to give 201 mg of the title compound as a white solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.19 (2H, t, J = 6.6 Hz), 4.61 (2H, t, J = 6. 6 Hz), 6.86 (1 H, d, J = 8.7 Hz), 7.29 (2 H, t, J = 9.0 Hz), 7.56 (1 H, s), 7.70 (2 H, m) 7.98 (1H, dd, J = 2.7 Hz, 8.7 Hz), 8.46 (1H, d, J = 2.7 Hz), 12.91 (1H, s).
MS: 419 (M ⁺⁺ 1).
[Example 101]
2-{[4- (2-{[5- (3-Fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyridin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 100-1 The title compound was obtained in the same manner as in Example 100-2 and Example 100-3, using propionic acid tert-butyl ester and 3-fluorophenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.20 (2H, t, J = 6.6 Hz), 4.62 (2H, t, J = 6. 6Hz), 6.88 (1H, d, J = 8.7 Hz), 7.18 (1H, m), 7.51 (2H, m), 7.56 (1H, s), 8.05 (1H) , Dd, J = 2.7 Hz, 6.3 Hz), 8.53 (1H, d, J = 2.7 Hz), 12.91 (1H, s).
MS: 419 (M ⁺⁺ 1).
[Example 102]
2-methyl-2-({4- [2-({5- [4- (trifluoromethyl) phenyl] pyridin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid hydrochloride

  2-[(4- {2-[(5-Bromopyridin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 100-1 Using propionic acid tert-butyl ester and 4- (trifluoromethyl) phenylboric acid as starting materials, a compound obtained by the same procedure as in Example 100-2 and Example 100-3 was treated with 4 mol / L hydrochloric acid-ethyl acetate. To give the title compound.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.21 (2H, t, J = 6.6 Hz), 4.64 (2H, t, J = 6. 6 Hz), 6.92 (1 H, d, J = 8.7 Hz), 7.58 (1 H, s), 7.81 (2 H, t, J = 8.4 Hz), 7.91 (2 H, d, J = 8.4 Hz), 8.10 (1H, dd, J = 2.7 Hz, 8.7 Hz), 8.57 (1H, d, J = 2.7 Hz).
MS: 469 (M ⁺⁺ 1).
[Example 103]
2-methyl-2-({4- [2-({5- [3- (trifluoromethyl) phenyl] pyridin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-[(4- {2-[(5-Bromopyridin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 100-1 The title compound was obtained in the same manner as in Example 100-2 and Example 100-3, using propionic acid tert-butyl ester and 3- (trifluoromethyl) phenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.21 (2H, t, J = 6.6 Hz), 4.63 (2H, t, J = 6. 6 Hz), 6.90 (2H, d, J = 8.7 Hz), 7.57 (1H, s), 7.61-7.74 (2H, m), 7.98-8.00 (2H, m), 8.11 (1H, dd, J = 2.4 Hz, 8.4 Hz), 8.57 (1H, d, J = 2.4 Hz), 12.93 (1H, brs).
MS: 469 (M ⁺⁺ 1).
[Example 104]
2-methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyridin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-[(4- {2-[(5-Bromopyridin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 100-1 The title compound was obtained in the same manner as in Example 100-2 and Example 100-3 using propionic acid tert-butyl ester and 4- (trifluoromethoxy) phenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.18 (2H, t, J = 6.6 Hz), 4.62 (2H, t, J = 6. 6 Hz), 6.89 (1 H, d, J = 8.4 Hz), 7.46 (2 H, d, J = 8.4 Hz), 7.57 (1 H, s), 7.79 (2 H, d, J = 8.7 Hz), 8.03 (1H, dd, J = 2.7 Hz, 8.4 Hz), 8.50 (1H, d, J = 2.7 Hz), 12.95 (1H, brs).
MS: 485 (M ⁺⁺ 1).
[Example 105]
2-methyl-2-({4- [2-({5- [3- (trifluoromethoxy) phenyl] pyridin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-[(4- {2-[(5-Bromopyridin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 100-1 The title compound was obtained in the same manner as in Example 100-2 and Example 100-3 using propionic acid tert-butyl ester and 3- (trifluoromethoxy) phenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.20 (2H, t, J = 6.6 Hz), 4.62 (2H, t, J = 6. 6 Hz), 6.89 (2H, d, J = 8.4 Hz), 7.36 (1 H, s), 7.56-7.62 (2 H, m), 7.67 (1 H, s), 7 .72 (1H, d, J = 8.1 Hz), 8.07 (1H, dd, J = 2.1 Hz, 9.0 Hz), 8.54 (1H, d, J = 2.7 Hz), 12. 93 (1H, brs).
MS: 485 (M ⁺⁺ 1).
[Example 106]
2-{[4- (2-{[5- (4-Chlorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyridin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 100-1 The title compound was obtained in the same manner as in Example 100-2 and Example 100-3, starting from propionic acid tert-butyl ester and 4-chlorophenylboric acid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.19 (2H, t, J = 6.6 Hz), 4.61 (2H, t, J = 6. 6 Hz), 6.88 (1 H, d, J = 8.7 Hz), 7.52 (2 H, d, J = 8.7 Hz), 7.57 (1 H, s), 7.70 (2 H, d, J = 8.7 Hz), 8.05 (1H, dd, J = 2.7 Hz, 8.7 Hz), 8.50 (1H, d, J = 2.7 Hz), 12.95 (1H, s).
MS: 435 (M ⁺⁺ 1).
[Example 107]
2-{[4- (2-{[5- (3-Chlorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyridin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 100-1 The title compound was obtained in the same manner as in Example 100-2 and Example 100-3 using propionic acid tert-butyl ester and 3-chlorophenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.20 (2H, t, J = 6.6 Hz), 4.62 (2H, t, J = 6. 6 Hz), 6.88 (1 H, d, J = 8.4 Hz), 7.43-7.52 (2 H, m), 7.57 (1 H, s), 7.64 (1 H, d, J = 7.5 Hz), 7.75 (1 H, s), 8.05 (1 H, dd, J = 2.7 Hz, 8.4 Hz), 8.52 (1 H, d, J = 2.7 Hz), 12. 95 (1H, s).
MS: 435 (M ⁺⁺ 1).
[Example 108]
2-{[4- (2-{[5- (3,4-Dichlorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyridin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 100-1 The title compound was obtained in the same manner as in Example 100-2 and Example 100-3, starting from propionic acid tert-butyl ester and 3,4-dichlorophenylboric acid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.19 (2H, t, J = 6.6 Hz), 4.62 (2H, t, J = 6. 6 Hz), 6.88 (2H, d, J = 8.7 Hz), 7.56 (1H, s), 7.67 (2H, d, J = 8.4 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.97 (1H, s), 8.07 (1H, dd, J = 2.7 Hz, 8.7 Hz), 8.55 (1H, d, J = 2.7 Hz), 12.95 (1H, s).
MS: 469 (M ⁺⁺ 1).
[Example 109]
2-{[4- (2-{[5- (3-Chloro-4-fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid

  2-[(4- {2-[(5-Bromopyridin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 100-1 The title compound was obtained in the same manner as in Example 100-2 and Example 100-3 using propionic acid tert-butyl ester and 3-chloro-4-fluorophenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.20 (2H, t, J = 6.6 Hz), 4.62 (2H, t, J = 6. 6 Hz), 6.87 (2H, d, J = 8.4 Hz), 7.51 (1 H, t, J = 9.0 Hz), 7.66 (1 H, s), 7.69 (1 H, m) 7.91 (1H, dd, J = 2.4 Hz, 7.2 Hz), 8.07 (1H, dd, J = 2.7 Hz, 8.7 Hz), 8.51 (1H, d, J = 2) .4 Hz), 12.93 (1 H, s).
MS: 453 (M ⁺⁺ 1).
[Example 110]
2-methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid (Example 110-1)
2-[(4- {2-[(5-Bromopyrimidin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4. 7.84 g and 5-bromo- 2-chloropyrimidine (5.0 g) was dissolved in N, N-dimethylformamide (70 mL), potassium tert-butoxide (3.47 g) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to give 6.0 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.57 (6H, s), 3.28 (2H, t, J = 6.6 Hz), 4.67 (2H , T, J = 6.6 Hz), 7.14 (1H, s), 8.51 (2H, s).
(Example 110-2)
2-methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid tert-butyl ester

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] synthesized in Example 110-1 under a nitrogen atmosphere 2-methylpropionic acid tert-butyl ester (600 mg) and 4-trifluoromethoxyphenylboric acid (400 mg) were dissolved in dioxane (6 mL) and 2 mol / L aqueous sodium carbonate solution (3 mL), tetrakis (triphenylphosphine) palladium (75 mg) was added, and the mixture was refluxed for 4 hours. . The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to give 600 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.58 (6H, s), 3.32 (2H, t, J = 6.7 Hz), 4.75 (2H , T, J = 6.7 Hz), 7.18 (1H, s), 7.33 (2H, d, J = 8.7 Hz), 7.54 (2H, d, J = 8.7 Hz), 8 .68 (2H, s).
(Example 110-3)
2-methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-Methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} oxy) ethyl] -1,3 obtained in Example 110-2 -Thiazol-2-yl} thio) propionic acid tert-butyl ester (600 mg) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 350 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.32 (2H, t, J = 6.2 Hz), 4.75 (2H, t, J = 6.2 Hz) , 7.13 (1H, s), 7.35 (2H, d, J = 8.7 Hz), 7.53 (2H, d, J = 8.7 Hz), 8.69 (2H, s).
MS: 486 (M ⁺⁺ 1).
[Example 111]
2-{[4- (2-{[5- (4-Chlorophenyl) pyrimidin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 110-1 The title compound was obtained in the same manner as in Example 110-2 and Example 110-3, starting from propionic acid tert-butyl ester and 4-chlorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.32 (2H, t, J = 6.1 Hz), 4.74 (2H, t, J = 6.1 Hz) , 7.13 (1H, s), 7.45 (4H, s), 8.68 (2H, s).
MS: 436 (M ⁺⁺ 1).
[Example 112]
2-{[4- (2-{[5- (3-Chlorophenyl) pyrimidin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 110-1 The title compound was obtained in the same manner as in Example 110-2 and Example 110-3, starting from propionic acid tert-butyl ester and 3-chlorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.66 (6H, s), 3.32 (2H, t, J = 6.0 Hz), 4.74 (2H, t, J = 6.0 Hz) , 7.13 (1H, s), 7.38 (3H, s), 7.50 (1H, s), 8.69 (2H, s).
MS: 436 (M ⁺⁺ 1).
[Example 113]
2-methyl-2-({4- [2-({5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 110-1 The title compound was obtained in the same manner as in Example 110-2 and Example 110-3, starting from propionic acid tert-butyl ester and 4- (trifluoromethyl) phenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.33 (2H, t, J = 6.0 Hz), 4.76 (2H, t, J = 6.0 Hz) 7.14 (1H, s), 7.63 (2H, d, J = 8.4 Hz), 7.75 (2H, d, J = 8.4 Hz), 8.74 (2H, s).
MS: 470 (M ⁺⁺ 1).
[Example 114]
2-methyl-2-({4- [2-({5- [3- (trifluoromethyl) phenyl] pyrimidin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 110-1 The title compound was obtained in the same manner as in Example 110-2 and Example 110-3, starting from propionic acid tert-butyl ester and 3- (trifluoromethyl) phenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.66 (6H, s), 3.33 (2H, t, J = 6.0 Hz), 4.76 (2H, t, J = 6.0 Hz) 7.14 (1H, s), 7.59-7.75 (4H, m), 8.73 (2H, s).
MS: 470 (M ⁺⁺ 1).
[Example 115]
2-{[4- (2-{[5- (3-Chloro-4-fluorophenyl) pyrimidin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 110-1 The title compound was obtained in the same manner as in Example 110-2 and Example 110-3, starting from propionic acid tert-butyl ester and 3-chloro-4-fluorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.32 (2H, t, J = 6.3 Hz), 4.74 (2H, t, J = 6.2 Hz) , 7.13 (1H, s), 7.23-7.39 (2H, m), 7.53-7.56 (1H, m), 8.66 (2H, s).
MS: 454 (M ⁺⁺ 1).
[Example 116]
2-{[4- (2-{[5- (3,4-Dichlorophenyl) pyrimidin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 110-1 The title compound was obtained in the same manner as in Example 110-2 and Example 110-3, starting from propionic acid tert-butyl ester and 3,4-dichlorophenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.32 (2H, t, J = 6.0 Hz), 4.75 (2H, t, J = 6.0 Hz) , 7.13 (1H, s), 7.34 (1H, dd, J = 2.1, 8.4 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.60 (1H, d, J = 2.1 Hz), 8.68 (2H, s).
MS: 470 (M ⁺⁺ 1).
[Example 117]
2-Methyl-2-({4- [2-({5- [4- (2,2,2-trifluoroethoxy) phenyl] pyrimidin-2-yl} oxy) ethyl] -1,3-thiazole- 2-yl} thio) propionic acid (Reference Example 1)
4,4,5,5-tetramethyl-2- [4- (2,2,2-trifluoroethoxy) phenyl] -1,3,2-dioxaborolane

Trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester 5.0 g and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol 5.0 g , N-dimethylformamide was dissolved in 50 ml, potassium carbonate 1.86 g was added, and the mixture was stirred at 50 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 2.6 g of the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.34 (12H, s), 4.37 (2H, q, J = 8.1 Hz), 6.93 (2H, d, J = 8.7 Hz) , 7.78 (2H, d, J = 8.7 Hz).

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 110-1 Propionic acid tert-butyl ester and 4,4,5,5-tetramethyl-2- [4- (2,2,2-trifluoroethoxy) phenyl] -1,3,2- synthesized in Reference Example 1 The title compound was obtained in the same manner as in Example 110-2 and Example 110-3 using dioxaborolane as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.31 (2H, t, J = 6.0 Hz), 4.40 (2H, q, J = 8.4 Hz) 4.73 (2H, t, J = 6.0 Hz), 7.06 (2H, d, J = 8.7 Hz), 7.13 (1H, s), 7.47 (2H, d, J = 8.7 Hz), 8.66 (2H, s).
MS: 500 (M ⁺⁺ 1).
[Example 118]
2-Methyl-2-({4- [2-({5- [3- (2,2,2-trifluoroethoxy) phenyl] pyrimidin-2-yl} oxy) ethyl] -1,3-thiazole- 2-yl} thio) propionic acid (Reference Example 2)
4,4,5,5-tetramethyl-2- [3- (2,2,2-trifluoroethoxy) phenyl] -1,3,2-dioxaborolane

Reference Example 1 using trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester and 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol as starting materials The title compound was obtained in the same manner as in.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.37 (12H, s), 4.38 (2H, q, J = 8.1 Hz), 7.04-7.08 (1H, m), 7 .30-7.36 (2H, m), 7.48-7.51 (1H, m).

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 110-1 Propionic acid tert-butyl ester and 4,4,5,5-tetramethyl-2- [3- (2,2,2-trifluoroethoxy) phenyl] -1,3,2- synthesized in Reference Example 2 The title compound was obtained in the same manner as in Example 110-2 and Example 110-3 using dioxaborolane as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.32 (2H, t, J = 6.0 Hz), 4.42 (2H, q, J = 8.4 Hz) 4.74 (2H, t, J = 6.0 Hz), 6.96-7.20 (4H, m), 7.44 (1 H, t, J = 8.1 Hz), 8.69 (2H, s).
MS: 500 (M ⁺⁺ 1).
[Example 119]
2-methyl-2-{[4- (2-{[5- (4-propylphenyl) pyrimidin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 110-1 The title compound was obtained in the same manner as in Example 110-2 and Example 110-3, starting from propionic acid tert-butyl ester and 4-propylphenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.96 (3H, t, J = 7.3 Hz), 1.60-1.71 (8H, m), 2.63 (2H, t, J = 7.3 Hz), 3.31 (2H, t, J = 6.1 Hz), 4.72 (2H, t, J = 6.1 Hz), 7.13 (1H, s), 7.28 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 8.68 (2H, s).
MS: 444 (M ⁺⁺ 1).
[Example 120]
2-methyl-2-{[4- (2-{[5- (4-isopropylphenyl) pyrimidin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 110-1 The title compound was obtained in the same manner as in Example 110-2 and Example 110-3, starting from propionic acid tert-butyl ester and 4-isopropylphenylboric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.28 (6H, d, J = 6.9 Hz), 1.65 (6H, s), 2.91-3.01 (1H, m), 3 .31 (2H, t, J = 6.1 Hz), 4.72 (2H, t, J = 6.1 Hz), 7.13 (1H, s), 7.34 (2H, d, J = 8. 2 Hz), 7.43 (2H, d, J = 8.2 Hz), 8.68 (2H, s).
MS: 444 (M ⁺⁺ 1).
[Example 121]
2-{[4- (2-{[3-Cyano-5- (4-fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and patent document [WO0224694] The same procedure as in Example 110-1 was carried out using 5-bromo-2-chloronicotinonitrile synthesized by reference as a starting material, and then Examples 110-2 and 110- using 4-fluorophenylboric acid. The title compound was obtained in the same manner as in 3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 3.35 (2H, t, J = 6.3 Hz), 4.79 (2H, t, J = 6.3 Hz) , 7.14-7.20 (3H, m), 7.42-7.48 (2H, m), 8.00 (1H, d, J = 2.7 Hz), 8.49 (1H, d, J = 2.4 Hz).
MS: 444 (M ⁺⁺ 1).
[Example 122]
2-{[4- (2-{[5- (4-Chlorophenyl) -3-cyanopyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropion acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and patent document [WO0224694] The same procedure as in Example 110-1 was performed using 5-bromo-2-chloronicotinonitrile synthesized as a starting material as a starting material, and then Examples 110-2 and 110-3 were used using 4-chlorophenylboric acid. The title compound was obtained by carrying out the same operation as.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 3.35 (2H, t, J = 6.3 Hz), 4.79 (2H, t, J = 6.3 Hz) , 7.20 (1H, s), 7.40-7.48 (4H, m), 8.01 (1H, d, J = 2.4 Hz), 8.51 (1H, d, J = 2. 7 Hz).
MS: 460 (M ⁺⁺ 1).
[Example 123]
2-{[4- (2-{[6- (4-Fluorophenyl) pyridazin-3-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (implemented) Example 123-1)
2-[(4- {2-[(6-chloropyridazin-3-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  The 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 (2.0 g) and 3,6- 1.2 g of dichloropyridazine was dissolved in 30 mL of N, N-dimethylformamide, 0.9 g of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 1.7 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.58 (6H, s), 3.30 (2H, t, J = 6.6 Hz), 4.83 (2H , T, J = 6.6 Hz), 6.92 (1H, d, J = 9.0 Hz), 7.09 (1H, s), 7.36 (1H, d, J = 9.6 Hz).
(Example 123-2)
2-{[4- (2-{[6- (4-Fluorophenyl) pyridazin-3-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert- Butyl ester

  2-[(4- {2-[(6-Chloropyridazin-3-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] synthesized in Example 123-1 under nitrogen atmosphere 2-methylpropionic acid tert-butyl ester 500 mg and 4-fluorophenylboric acid 292 mg were dissolved in dioxane 6 mL and 2 mol / L sodium carbonate aqueous solution 3 mL, tetrakis (triphenylphosphine) palladium 80 mg was added, and the mixture was refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to give 400 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.58 (6H, s), 3.35 (2H, t, J = 6.6 Hz), 4.91 (2H , T, J = 6.6 Hz), 7.02 (1H, d, J = 9.3 Hz), 7.12-7.18 (3H, m), 7.74 (1H, d, J = 9. 3 Hz), 7.97-8.02 (2H, m).
(Example 123-3)
2-{[4- (2-{[6- (4-Fluorophenyl) pyridazin-3-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-{[4- (2-{[6- (4-Fluorophenyl) pyridazin-3-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio obtained in Example 123-2 } -2-Methylpropionic acid tert-butyl ester (400 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 290 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.36 (2H, t, J = 6.1 Hz), 4.89 (2H, t, J = 6.1 Hz) 7.08-7.22 (4H, m), 7.77 (1H, d, J = 9.0 Hz), 7.96-8.01 (2H, m).
MS: 420 (M ⁺⁺ 1).
[Example 124]
2-{[4- (2-{[6- (4-Chlorophenyl) pyridazin-3-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl obtained in Example 123-1 The title compound was obtained in the same manner as in Example 123-2 and Example 123-3 using propionic acid tert-butyl ester and 4-chlorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.36 (2H, t, J = 6.0 Hz), 4.89 (2H, t, J = 6.0 Hz) , 7.08 (1H, s), 7.14 (1H, d, J = 9.3 Hz), 7.46-7.50 (2H, m), 7.78 (1H, d, J = 9. 3 Hz), 7.92-7.96 (2H, m).
MS: 436 (M ⁺⁺ 1).
[Example 125]
2-methyl-2-({4- [2-({6- [4- (trifluoromethyl) phenyl] pyridazin-3-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl obtained in Example 123-1 The title compound was obtained in the same manner as in Example 123-2 and Example 123-3, using propionic acid tert-butyl ester and 4- (trifluoromethyl) phenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.37 (2H, t, J = 6.3 Hz), 4.91 (2H, t, J = 6.3 Hz) , 7.09 (1H, s), 7.19 (1H, d, J = 9.3 Hz), 7.76 (2H, d, J = 8.1 Hz), 7.84 (1H, d, J = 9.0 Hz), 8.12 (2H, d, J = 8.4 Hz).
MS: 470 (M ⁺⁺ 1).
[Example 126]
2-methyl-2-({4- [2-({6- [4- (trifluoromethoxy) phenyl] pyridazin-3-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl obtained in Example 123-1 The title compound was obtained in the same manner as in Example 123-2 and Example 123-2 using propionic acid tert-butyl ester and 4- (trifluoromethoxy) phenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.37 (2H, t, J = 6.2 Hz), 4.90 (2H, t, J = 6.2 Hz) , 7.08 (1H, s), 7.16 (1H, d, J = 9.5 Hz), 7.35 (2H, brd, J = 8.4 Hz), 7.79 (1H, d, J = 9.1 Hz), 8.02-8.05 (2H, m).
MS: 486 (M ⁺⁺ 1).
[Example 127]
2-methyl-2-{[4- (2- {4- [5- (trifluoromethyl) pyridin-2-yl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} propionic acid ( Example 127-1)
2-Methyl-2-[(4- {2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethyl} -1,3-thiazole -2-yl) thio] propionic acid tert-butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4. 6.89 g and 4- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (5.0 g) is dissolved in 100 mL of tetrahydrofuran, and 5.95 g of triphenylphosphine and diethyl diazodicarboxylate are added under ice cooling. 95 g was added and then stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 9.1 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.33 (12H, s), 1.41 (9H, s), 1.57 (6H, s), 3.25 (2H, t, J = 6) .6 Hz), 4.32 (2H, t, J = 6.6 Hz), 6.88 (2H, d, J = 8.4 Hz), 7.12 (1H, s), 7.73 (2H, d) , J = 8.4 Hz).
(Example 127-2)
2-methyl-2-{[4- (2- {4- [5- (trifluoromethyl) pyridin-2-yl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} propionic acid tert -Butyl ester

  2-methyl-2-[(4- {2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) synthesized in Example 127-1 under nitrogen atmosphere -Yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester 700 mg and 2-bromo-5- (trifluoromethyl) pyridine 313 mg in dioxane 6 mL and 2 mol / L sodium carbonate It melt | dissolved in 3 mL of aqueous solution, 80 mg of tetrakis (triphenylphosphine) palladium was added, and it recirculate | refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to give 650 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.58 (6H, s), 3.28 (2H, t, J = 6.6 Hz), 4.38 (2H , T, J = 6.6 Hz), 7.00 (2H, d, J = 8.7 Hz), 7.15 (1H, s), 7.78 (1H, d, J = 8.7 Hz), 7 .91-7.95 (1H, m), 7.9 (2H, d, J = 8.7 Hz), 8.89 (1H, s).
(Example 127-3)
2-Methyl-2-{[4- (2- {4- [5- (trifluoromethyl) pyridin-2-yl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} propionic acid

  2-Methyl-2-{[4- (2- {4- [5- (trifluoromethyl) pyridin-2-yl] phenoxy} ethyl) -1,3-thiazole- obtained in Example 127-2 2-yl] thio} propionic acid tert-butyl ester (650 mg) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 340 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.30 (2H, t, J = 6.2 Hz), 4.37 (2H, t, J = 6.2 Hz) , 7.00 (2H, d, J = 8.9 Hz), 7.12 (1H, s), 7.77 (1H, d, J = 8.3 Hz), 7.93-7.98 (3H, m), 8.91 (1H, s).
MS: 469 (M ⁺⁺ 1).
[Example 128]
2-Methyl-2-{[4- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} propionic acid

  2-Methyl-2-[(4- {2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy synthesized in Example 127-1 ] Ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester and 2-chloro-6- (trifluoromethyl) pyridine as starting materials, Example 127-2 and Example 127- The title compound was obtained in the same manner as in 3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.30 (2H, t, J = 6.0 Hz), 4.36 (2H, t, J = 6.0 Hz) , 6.99 (2H, d, J = 9.0 Hz), 7.13 (1H, s), 7.54 (1H, dd, J = 1.2, 6.6 Hz), 7.82-7. 88 (2H, m), 8.01 (2H, d, J = 9.0 Hz).
MS: 469 (M ⁺⁺ 1).
[Example 129]
2-[(4- {2- [4- (5-Fluoropyridin-2-yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-Methyl-2-[(4- {2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy synthesized in Example 127-1 ] Ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester and 2-bromo-5-fluoropyridine as starting materials, similar to Example 127-2 and Example 127-3 The title compound was obtained by manipulation.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.29 (2H, t, J = 6.0 Hz), 4.36 (2H, t, J = 6.0 Hz) 6.97 (2H, d, J = 9.0 Hz), 7.11 (1H, s), 7.44-7.48 (1H, m), 7.62-7.67 (1H, m) 7.85 (2H, d, J = 9.0 Hz), 8.50 (1H, d, J = 2.7 Hz).
MS: 419 (M ⁺⁺ 1).
[Example 130]
2-[(4- {2- [4- (5-chloropyridin-2-yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-Methyl-2-[(4- {2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy synthesized in Example 127-1 ] Ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester and 2,5-dichloropyridine as starting materials, and the same operations as in Example 127-2 and Example 127-3 The title compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.28 (2H, t, J = 6.1 Hz), 4.35 (2H, t, J = 6.1 Hz) 6.97 (2H, d, J = 8.8 Hz), 7.11 (1H, s), 7.61 (1H, d, J = 8.3 Hz), 7.73 (1H, dd, J = 2.3, 8.3 Hz), 7.85 (2H, d, J = 8.8 Hz), 8.63 (1H, d, J = 2.3 Hz).
MS: 435 (M ⁺⁺ 1).
[Example 131]
2-[(4- {2- [4- (5-Ethylpyrimidin-2-yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-Methyl-2-[(4- {2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy synthesized in Example 127-1 ] Ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester and 2-chloro-5-ethylpyrimidine as starting materials, similar to Example 127-2 and Example 127-3 The title compound was obtained by manipulation.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.31 (3H, t, J = 7.7 Hz), 1.62 (6H, s), 2.68 (2H, q, J = 7.7 Hz) 3.29 (2H, t, J = 6.1 Hz), 4.37 (2H, t, J = 6.1 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.12 ( 1H, s), 8.31 (2H, d, J = 8.8 Hz), 8.66 (2H, s).
MS: 430 (M ⁺⁺ 1).
[Example 132]
2-[(4- {2- [4- (5-propylpyrimidin-2-yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

    2-Methyl-2-[(4- {2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy synthesized in Example 127-1 ] Ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester and 2-chloro-5-propylpyrimidine as starting materials, similar to Example 127-2 and Example 127-3 The title compound was obtained by manipulation.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.98 (3H, t, J = 7.2 Hz), 1.61 (6H, s), 1.62-1.72 (2H, m), 2 .59 (2H, t, J = 7.4 Hz), 3.29 (2H, t, J = 6.0 Hz), 4.37 (2H, t, J = 6.0 Hz), 6.97 (2H, d, J = 8.9 Hz), 7.11 (1H, s), 8.32 (2H, d, J = 8.9 Hz), 8.58 (2H, s).
MS: 444 (M ⁺⁺ 1).
[Example 133]
2-methyl-2-{[4- (2- {4- [4- (trifluoromethyl) pyrimidin-2-yl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} propionic acid

  2-Methyl-2-[(4- {2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy synthesized in Example 127-1 ] Ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester and 2-chloro-4- (trifluoromethyl) pyrimidine as starting materials, Example 127-2 and Example 127- The title compound was obtained in the same manner as in 3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.31 (2H, t, J = 6.0 Hz), 4.38 (2H, t, J = 6.0 Hz) , 6.99 (2H, d, J = 9.0 Hz), 7.13 (1H, s), 7.42 (1H, d, J = 4.8 Hz), 8.43 (2H, d, J = 9.0 Hz), 8.97 (1H, d, J = 4.8 Hz).
MS: 470 (M ⁺⁺ 1).
[Example 134]
2-[(4- {2- [4- (1,3-Benzoxazol-2-yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-Methyl-2-[(4- {2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy synthesized in Example 127-1 ] Ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester and 2-chloro-1,3-benzoxazole as starting materials, Example 127-2 and Example 127-3 The title compound was obtained by the same operation.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.30 (2H, t, J = 6.2 Hz), 4.37 (2H, t, J = 6.2 Hz) 7.01 (2H, d, J = 8.7 Hz), 7.12 (1H, s), 7.31-7.34 (2H, m), 7.53-7.57 (1H, m) , 7.72-7.76 (1H, m) 8.17 (2H, d, J = 8.7 Hz).
MS: 441 (M ⁺⁺ 1).
[Example 135]
2-[(4- {2- [4- (1,3-Benzothiazol-2-yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-Methyl-2-[(4- {2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy synthesized in Example 127-1 ] Ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester and 2-bromo-benzothiazole as starting materials, and the same procedure as in Example 127-2 and Example 127-3 The title compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.28 (2H, t, J = 6.2 Hz), 4.34 (2H, t, J = 6.2 Hz) 6.97 (2H, d, J = 8.7 Hz), 7.11 (1H, s), 7.32-7.38 (1H, m), 7.44-7.50 (1H, m) 7.86 (1H, d, J = 8.0 Hz), 7.97-8.05 (3H, m).
MS: 457 (M ⁺⁺ 1).
[Example 136]
2-{[4- (2- {2,6-dimethyl-4- [5- (trifluoromethyl) pyridin-2-yl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio}- 2-Methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2,6-dimethyl-4 synthesized in Example 4 The title compound was obtained in the same manner as in Example 127, using-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.67 (6H, s), 2.29 (6H, s), 3.32 (2H, t, J = 6.3 Hz), 4.16 (2H , T, J = 6.3 Hz), 7.20 (1H, s), 7.66 (2H, s), 7.80 (1H, d, J = 8.3 Hz), 7.96-8.00. (1H, m), 8.93 (1H, s).
MS: 497 (M ⁺⁺ 1).
[Example 137]
2-{[4- (2- {2-methoxy-4- [5- (trifluoromethyl) pyridin-2-yl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2- Methyl propionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and 2-methoxy-4- ( The title compound was obtained in the same manner as in Example 127 using 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 3.37 (2H, t, J = 6.3 Hz), 3.97 (3H, s), 4.44 (2H , T, J = 6.3 Hz), 7.00 (1H, d, J = 8.4 Hz), 7.23 (1H, s), 7.53 (1H, dd, J = 2.0, 8. 4 Hz), 7.71 (1 H, d, J = 2.0 Hz), 7.82 (1 H, d, J = 8.3 Hz), 7.97 (1 H, dd, J = 2.0, 8.3 Hz) ), 8.93 (1H, s).
MS: 499 (M ⁺⁺ 1).
[Example 138]
2-[(4- {2- [4- (5-Ethylpyrimidin-2-yl) -2,6-dimethylphenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropion acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2,6-dimethyl-4 synthesized in Example 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol was used as a starting material and the same operation as in Example 127-1 was carried out, followed by 2-chloro-5- The title compound was obtained by the same procedures as in Example 127-2 and Example 127-3 using ethylpyrimidine.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.30 (3H, t, J = 7.6 Hz), 1.65 (6H, s), 2.26 (6H, s), 2.67 (2H , Q, J = 7.6 Hz), 3.28 (2H, t, J = 6.2 Hz), 4.13 (2H, t, J = 6.2 Hz), 7.17 (1H, s), 8 .01 (2H, s), 8.63 (2H, s).
MS: 458 (M ⁺⁺ 1).
[Example 139]
2-[(4- {2- [4- (5-Ethylpyrimidin-2-yl) -2-methoxyphenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and 2-methoxy-4- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol was used as a starting material and the same operation as in Example 127-1 was carried out, followed by 2-chloro-5-ethylpyrimidine. Was used for the same operation as in Example 127-2 and Example 127-3 to give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.30 (3H, t, J = 7.6 Hz), 1.62 (6H, s), 2.66 (2H, q, J = 7.6 Hz) , 3.34 (2H, t, J = 6.3 Hz), 3.96 (3H, s), 4.41 (2H, t, J = 6.3 Hz), 7.20 (1H, s), 7 .95-8.00 (2H, m), 8.61 (2H, s).
MS: 460 (M ⁺⁺ 1).
[Example 140]
2-Methyl-2-{[4- (2- {2-methyl-4- [5- (trifluoromethyl) pyridin-2-yl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio } Propionic acid (Example 140-1)
2-({4- [2- (4-Iodo-2-methylphenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 3.89 g and 4-iodo- 3.0 g of 2-methylphenol was dissolved in 30 mL of tetrahydrofuran, and 3.36 g of triphenylphosphine and 2.23 g of diethyl diazodicarboxylate were added under ice cooling, and then stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 6: 1) to give 4.4 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.41 (9H, s), 1.56 (6H, s), 2.09 (3H, s), 3.24 (2H, t, J = 6) .6 Hz), 4.25 (2H, t, J = 6.6 Hz), 6.58 (1H, d, J = 9.3 Hz), 7.10 (1H, s), 7.39-7.42. (2H, m).
(Example 140-2)
2-methyl-2-[(4- {2- [2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethyl} -1 , 3-Thiazol-2-yl) thio] propionic acid tert-butyl ester

  Non-patent literature [J. Org. Chem. 65, 164 (2000)], etc., and 2-({4- [2- (4-iodo-2-methylphenoxy) ethyl] -1, synthesized in Example 140-1 under a nitrogen atmosphere. 3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester 2.40 g, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane 887 mg and triethylamine 1.53 g in dioxane It melt | dissolved in 20 mL, [1,1'-bis (diphenylphosphino) ferrocene] dichloro palladium (II) 110 mg was added, and it stirred at 80 degreeC for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 7: 1-4: 1) to give 800 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.35 (12H, s), 1.42 (9H, s), 1.59 (6H, s), 2.17 (3H, s), 3. 29 (2H, t, J = 6.5 Hz), 4.34 (2H, t, J = 6.5 Hz), 6.84 (1H, d, J = 8.1 Hz), 7.14 (1H, s ), 7.59 (1H, s), 7.63 (1H, d, J = 8.1 Hz).
(Example 140-3)
2-Methyl-2-{[4- (2- {2-methyl-4- [5- (trifluoromethyl) pyridin-2-yl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio } Propionic acid

  2-methyl-2-[(4- {2- [2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) synthesized in Example 140-2 Example 127-2 and Example using -yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester and 2-bromo-5- (trifluoromethyl) pyridine The title compound was obtained by the same procedures as in 127-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.60 (6H, s), 2.20 (3H, s), 3.32 (2H, t, J = 6.0 Hz), 4.38 (2H , T, J = 6.0 Hz), 6.93 (1H, d, J = 8.1 Hz), 7.12 (1H, s), 7.75-7.82 (3H, m), 7.94 (1H, d, J = 8.3 Hz), 8.89 (1H, s).
MS: 483 (M ⁺⁺ 1).
[Example 141]
2-[(4- {2- [4- (5-Ethylpyrimidin-2-yl) -2-methylphenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-methyl-2-[(4- {2- [2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) synthesized in Example 140-2 -Yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester and 2-chloro-5-ethylpyrimidine with Example 127-2 and Example 127-3 The title compound was obtained by carrying out the same operation.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.32 (3H, t, J = 7.6 Hz), 1.60 (6H, s), 2.63 (3H, s), 2.66 (2H , Q, J = 7.6 Hz), 3.31 (2H, t, J = 6.1 Hz), 4.38 (2H, t, J = 6.1 Hz), 6.67 (1H, d, J = 8.6 Hz), 7.11 (1H, s), 8.14-8.19 (2H, m), 8.63 (2H, s).
MS: 444 (M ⁺⁺ 1).
[Example 142]
2-{[4- (2- {2-Fluoro-4- [5- (trifluoromethyl) pyridin-2-yl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2- Methylpropionic acid (Example 142-1)

2-({4- [2- (4-Bromo-2-fluorophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 4 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester 3.0 g and 4-bromo-2-fluorophenol 91 g was dissolved in 20 mL of tetrahydrofuran, 2.62 g of triphenylphosphine and 1.74 g of diethyl diazodicarboxylate were added under ice cooling, and then the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 6: 1) to give 3.2 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.41 (9H, s), 1.57 (6H, s), 3.26 (2H, t, J = 6.6 Hz), 4.33 (2H , T, J = 6.6 Hz), 6.85 (1H, t, J = 8.5 Hz), 7.14-7.24 (3H, m).
(Example 142-2)
2-[(4- {2- [2-Fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethyl} -1,3-thiazole -2-yl) thio] -2-methylpropionic acid tert-butyl ester

  Non-patent literature [J. Org. Chem. 65, 164 (2000)] and the like, 2-({4- [2- (4-bromo-2-fluorophenoxy) ethyl] -1, synthesized in Example 142-1 under a nitrogen atmosphere, 3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester 1.65 g, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane 665 mg and triethylamine 1.05 g in dioxane It melt | dissolved in 20 mL, 73 mg of dichlorobis (triphenylphosphine) palladium was added, and it stirred at 100 degreeC for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 6: 1 to 4: 1) to give 440 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.35 (12H, s), 1.42 (9H, s), 1.59 (6H, s), 3.30 (2H, t, J = 6) .7Hz), 4.39 (2H, t, J = 6.7 Hz), 6.97 (1H, t, J = 8.1 Hz), 7.20 (1H, s), 7.47-7.53. (2H, m).
(Example 142-3)
2-{[4- (2- {2-Fluoro-4- [5- (trifluoromethyl) pyridin-2-yl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2- Methyl propionic acid

  2-[(4- {2- [2-Fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy synthesized in Example 142-2 ] Ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester and 2-bromo-5- (trifluoromethyl) pyridine using Example 127-2 and Example The title compound was obtained by the same procedures as in 127-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.33 (2H, t, J = 6.1 Hz), 4.44 (2H, t, J = 6.1 Hz) , 7.07 (1H, t, J = 8.5 Hz), 7.18 (1H, s), 7.74-7.84 (3H, m), 7.93-7.97 (1H, m) , 8.89 (1H, s).
MS: 487 (M ⁺⁺ 1).
[Example 143]
2-[(4- {2- [4- (5-Ethylpyrimidin-2-yl) -2-fluorophenoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2- [2-Fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy synthesized in Example 142-2 ] Ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester and 2-chloro-5-ethylpyrimidine with Example 127-2 and Example 127-3 The title compound was obtained by carrying out the same operation.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.30 (3H, t, J = 7.5 Hz), 1.62 (6H, s), 2.67 (2H, q, J = 7.5 Hz) 3.33 (2H, t, J = 6.1 Hz), 4.43 (2H, t, J = 6.1 Hz), 7.04 (1H, t, J = 8.6 Hz), 7.18 ( 1H, s), 8.08-8.10 (1H, m), 8.13 (1H, s), 8.63 (2H, s).
MS: 448 (M ⁺⁺ 1).
[Example 144]
2-Methyl-2-[(4- {2- [4- (phenylethynyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid (Example 144-1)
2-({4- [2- (4-Iodophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and 4-iodophenol 5.08 g was dissolved in 100 mL of tetrahydrofuran, and 6.06 g of triphenylphosphine and 4.02 g of diethyl diazodicarboxylate were added under ice cooling, followed by stirring at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1) to give 7.5 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.41 (9H, s), 1.57 (6H, s), 3.22 (2H, t, J = 6.6 Hz), 4.26 (2H , T, J = 6.6 Hz), 6.67 (2H, d, J = 8.7 Hz), 7.10 (1H, s), 7.53 (2H, d, J = 8.7 Hz).
(Example 144-2)
2-({4- [2- (4-Iodophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid methyl ester

  2-({4- [2- (4-Iodophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester 6 obtained in Example 144-1 0.0 g was dissolved in dichloromethane (25 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at room temperature for 12 hr. After concentrating the reaction solution under reduced pressure, the residue was dissolved in 60 mL of methanol, and 5.63 g of thionyl chloride was added under ice-cooling and refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 6: 1-4: 1) to give 5.2 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.60 (6H, s), 3.22 (2H, t, J = 6.6 Hz), 3.69 (3H, s), 4.27 (2H , T, J = 6.6 Hz), 6.68 (2H, d, J = 9.0 Hz), 7.10 (1H, s), 7.54 (2H, d, J = 9.0 Hz).
(Example 144-3)
2-Methyl-2-[(4- {2- [4- (phenylethynyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid methyl ester

  Methyl 2-({4- [2- (4-iodophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid synthesized in Example 144-2 under nitrogen atmosphere 600 mg of ester and 145 mg of ethynylbenzene were dissolved in 2 mL of N, N-dimethylformamide and 6 mL of triethylamine, 10 mg of dichlorobis (triphenylphosphine) palladium and 5 mg of copper (I) iodide were added, and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 400 mg of the title compound as a yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.25 (2H, t, J = 6.6 Hz), 3.69 (3H, s), 4.32 (2H , T, J = 6.6 Hz), 6.87 (2H, d, J = 8.8 Hz), 7.13 (1H, s), 7.31-7.34 (3H, m), 7.43 -7.52 (4H, m).
(Example 144-4)
2-Methyl-2-[(4- {2- [4- (phenylethynyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-methyl-2-[(4- {2- [4- (phenylethynyl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid methyl ester obtained in Example 144-3 400 mg was dissolved in 4 mL of methanol and 4 mL of tetrahydrofuran, 2 mL of 1 mol / L sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 290 mg of the title compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.27 (2H, t, J = 6.3 Hz), 4.31 (2H, t, J = 6.3 Hz) 6.86 (2H, d, J = 9.0 Hz), 7.10 (1H, s), 7.31-7.34 (3H, m), 7.43-7.52 (4H, m) .
MS: 424 (M ⁺⁺ 1).
[Example 145]
2-{[4- (2- {4-[(4-Fluorophenyl) ethynyl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-({4- [2- (4-Iodophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid methyl ester synthesized in Example 144-2 and 1- The title compound was obtained in the same manner as in Example 144-3 and Example 144-4 using ethynyl-4-fluorobenzene as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.27 (2H, t, J = 6.1 Hz), 4.31 (2H, t, J = 6.1 Hz) 6.86 (2H, d, J = 8.9 Hz), 6.99-7.05 (2H, m), 7.10 (1H, s), 7.41-7.50 (4H, m) .
MS: 442 (M ⁺⁺ 1).
[Example 146]
2-Methyl-2-({4- [2- (4-{[4- (trifluoromethyl) phenyl] ethynyl} phenoxy) ethyl] -1,3-thiazol-2-yl} thio) propionic acid

  2-({4- [2- (4-Iodophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid methyl ester synthesized in Example 144-2 and 1- The title compound was obtained in the same manner as in Example 144-3 and Example 144-4 using ethynyl-4- (trifluoromethyl) benzene as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.28 (2H, t, J = 6.0 Hz), 4.32 (2H, t, J = 6.0 Hz) 6.88 (2H, d, J = 8.7 Hz), 7.10 (1H, s), 7.46 (2H, d, J = 8.7 Hz), 7.59 (4H, s).
MS: 492 (M ⁺⁺ 1).
[Example 147]
2-Methyl-2-({4- [2- (4-{[3- (trifluoromethyl) phenyl] ethynyl} phenoxy) ethyl] -1,3-thiazol-2-yl} thio) propionic acid

  2-({4- [2- (4-Iodophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid methyl ester synthesized in Example 144-2 and 1- The title compound was obtained in the same manner as in Example 144-3 and Example 144-4 using ethynyl-3- (trifluoromethyl) benzene as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.28 (2H, t, J = 6.0 Hz), 4.32 (2H, t, J = 6.0 Hz) , 6.88 (2H, d, J = 8.7 Hz), 7.10 (1H, s), 7.42-7.48 (3H, m), 7.55 (1H, d, J = 8. 7 Hz), 7.66 (1 H, d, J = 7.8 Hz), 7.76 (1 H, s).
MS: 492 (M ⁺⁺ 1).
[Example 148]
2-Methyl-2-[(4- {2- [4- (4-phenylpiperazin-1-yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid (Example 148-) 1)
2-methyl-2-[(4- {2- [4- (4-phenylpiperazin-1-yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester

  2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid synthesized in Example 67-1 under nitrogen atmosphere -800 mg of butyl ester and 425 mg of 1-phenylpiperazine were dissolved in 5 mL of toluene, 185 mg of sodium tert-butoxide, 80.1 mg of tris (dibenzylideneacetone) dipalladium, 52.2 mg of 2- (di-tert-butylphosphino) biphenyl Was added and refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to give 490 mg of the title compound as a yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.58 (6H, s), 3.20-3.25 (6H, m), 3.32-3.36 (4H, m), 4.26 (2H, t, J = 6.6 Hz), 6.84-7.00 (7H, m), 7.13 (1H, s), 7.26-7.32. (2H, m).
(Example 148-2)
2-Methyl-2-[(4- {2- [4- (4-phenylpiperazin-1-yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-Methyl-2-[(4- {2- [4- (4-phenylpiperazin-1-yl) phenoxy] ethyl} -1,3-thiazol-2-yl) obtained in Example 148-1) Thio] propionic acid tert-butyl ester (490 mg) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 330 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.25 (2H, t, J = 6.0 Hz), 3.42-3.60 (8H, m), 4 .30 (2H, t, J = 6.0 Hz), 6.94 (2H, d, J = 9.0 Hz), 7.02-7.09 (4H, m), 7.32-7.38 ( 4H, m).
MS: 484 (M ⁺⁺ 1).
[Example 149]
2-{[4- (2- {4- [4- (4-Fluorophenyl) piperazin-1-yl] phenoxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 67-1 and The title compound was obtained in the same manner as in Example 148 using 1- (4-fluorophenyl) piperazine as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.26 (2H, t, J = 6.0 Hz), 3.45-3.56 (8H, m), 4 .30 (2H, t, J = 6.0 Hz), 6.94 (2H, d, J = 9.0 Hz), 7.01-7.04 (4H, m), 7.09 (1H, s) , 7.33 (2H, d, J = 9.0 Hz).
MS: 502 (M ⁺⁺ 1).
[Example 150]
2-methyl-2-({4- [2- (4- {4- [4- (trifluoromethyl) phenyl] piperazin-1-yl} phenoxy) ethyl] -1,3-thiazol-2-yl} Thio) propionic acid

  2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 67-1 and The title compound was obtained in the same manner as in Example 148, using 1- [4- (trifluoromethyl) phenyl] piperazine as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 3.22-3.27 (6H, m), 3.43-3.52 (4H, m), 4.26 (2H, t, J = 6.1 Hz), 6.86 (2H, d, J = 8.8 Hz), 6.95-6.99 (4H, m), 7.09 (1H, s), 7 .52 (2H, d, J = 8.8 Hz).
MS: 552 (M ⁺⁺ 1).
[Example 151]
2-Methyl-2-[(4- {2- [4- (4-phenylpiperidin-1-yl) phenoxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-({4- [2- (4-Bromophenoxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 67-1 and The title compound was obtained in the same manner as in Example 148 using 1-phenylpiperidine as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 2.04-2.12 (2H, m), 2.45-2.57 (2H, m), 2.77 -2.85 (1H, m), 3.24-3.34 (4H, m), 3.76-3.81 (2H, m), 4.31 (2H, t, J = 6.0 Hz) 6.97 (2H, d, J = 9.0 Hz), 7.09 (1 H, s), 7.23-7.38 (5 H, m), 7.53 (2H, d, J = 9. 0 Hz).
MS: 483 (M ⁺⁺ 1).
[Example 152]
2-Methyl-2-{[4-({[4 ′-(trifluoromethyl) biphenyl-4-yl] methoxy} methyl) -1,3-thiazol-2-yl] thio} propionic acid (Example 152) -1)
2-[(4-{[(4-Bromobenzyl) oxy] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (hydroxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 10 and 4-bromobenzyl bromide 4 .75 g was dissolved in 50 mL of N, N-dimethylformamide, 2.33 g of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 7: 1) to give 4.5 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.45 (9H, s), 1.62 (6H, s), 4.61 (2H, s), 4.69 (2H, s), 7. 27 (2H, d, J = 8.3 Hz), 7.34 (1H, s), 7.50 (2H, d, J = 8.3 Hz).
(Example 152-2)
2-Methyl-2-{[4-({[4 ′-(trifluoromethyl) biphenyl-4-yl] methoxy} methyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester

  2-[(4-{[(4-Bromobenzyl) oxy] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 152-1 under nitrogen atmosphere 1.0 g of tert-butyl ester and 621 mg of 4- (trifluoromethyl) phenyl boric acid were dissolved in 10 mL of dioxane and 5 mL of 2 mol / L aqueous sodium hydrogen carbonate solution, and 162 mg of tetrakis (triphenylphosphine) palladium was added and refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 900 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.59 (6H, s), 4.69 (2H, s), 4.72 (2H, s), 7. 34 (1H, s), 7.47 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.69 (4H, s).
(Example 152-3)
2-Methyl-2-{[4-({[4 ′-(trifluoromethyl) biphenyl-4-yl] methoxy} methyl) -1,3-thiazol-2-yl] thio} propionic acid

  2-Methyl-2-{[4-({[4 ′-(trifluoromethyl) biphenyl-4-yl] methoxy} methyl) -1,3-thiazol-2-yl obtained in Example 152-2 ] 900 mg of thio} propionic acid tert-butyl ester was dissolved in 10 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 420 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.67 (6H, s), 4.72 (2H, s), 4.72 (2H, s), 7.34 (1H, s), 7. 49 (2H, d, J = 8.1 Hz), 7.62 (2H, d, J = 8.1 Hz), 7.71 (4H, s).
MS: 468 (M ⁺⁺ 1).
[Example 153]
2-[(4-{[(4′-Fluorobiphenyl-4-yl) methoxy] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4-{[(4-Bromobenzyl) oxy] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester synthesized in Example 152-1 The title compound was obtained in the same manner as in Example 152-2 and Example 152-3 using 4-fluorophenylboric acid as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 4.68 (4H, s), 7.09-7.15 (2H, m), 7.30 (1H, s) ), 7.43 (2H, d, J = 8.1 Hz), 7.51-7.56 (4H, m).
MS: 418 (M ⁺⁺ 1).
[Example 154]
2-[(4-{[(4′-Chlorobiphenyl-4-yl) methoxy] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4-{[(4-Bromobenzyl) oxy] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester synthesized in Example 152-1 The title compound was obtained in the same manner as in Example 152-2 and Example 152-3 using 4-chlorophenylboric acid as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.68 (6H, s), 4.72 (4H, s), 7.33 (1H, s), 7.42-7.60 (8H, m ).
MS: 434 (M ⁺⁺ 1).
[Example 155]
2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) methoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (Example 155-1) )
2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid ethyl ester

  8.4 g of 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester obtained in Example 4 was dissolved in 50 mL of dichloromethane. Then, 50 mL of trifluoroacetic acid was added and stirred at room temperature for 12 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in 100 mL of ethanol, 8 mL of thionyl chloride was added under ice-cooling, and the mixture was refluxed for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution under ice-cooling, and the solvent was concentrated under reduced pressure. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give 6.7 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.25 (3H, t, J = 7.1 Hz), 1.62 (6H, s), 2.97 (2H, t, J = 5.6 Hz) , 3.95 (2H, t, J = 5.6 Hz), 4.18 (2H, q, J = 7.1 Hz), 7.02 (1H, s).
(Example 155-2)
2-[(4- {2-[(4-Bromobenzyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid ethyl ester

  1.6 g of 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid ethyl ester synthesized in Example 155-1 and 4-bromobenzyl 1.7 g of bromide was dissolved in 30 mL of N, N-dimethylformamide, 0.72 g of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1-3: 1) to give 1.3 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.23 (3H, t, J = 7.2 Hz), 1.60 (6H, s), 3.07 (2H, t, J = 6.6 Hz) 3.80 (2H, t, J = 6.6 Hz), 4.14 (2H, q, J = 7.2 Hz), 4.46 (2H, s), 7.07 (1H, s), 7 .13-7.19 (2H, m), 7.42-7.47 (2H, m).
(Example 155-3)
2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) methoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid ethyl ester

  2-[(4- {2-[(4-Bromobenzyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 155-2 under nitrogen atmosphere 0.9 g of propionic acid ethyl ester and 425 mg of 4-fluorophenylboric acid were dissolved in 10 mL of dioxane and 5 mL of a 2 mol / L aqueous sodium carbonate solution, 117 mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 400 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.23 (3H, t, J = 7.5 Hz), 1.61 (6H, s), 3.10 (2H, t, J = 6.3 Hz) 3.84 (2H, t, J = 6.3 Hz), 4.30 (2H, q, J = 7.5 Hz), 4.56 (2H, s), 7.09-7.15 (3H, m), 7.34-7, 37 (2H, m), 7.49-7.55 (4H, m).
(Example 155-4)
2-[(4- {2-[(4'-Fluorobiphenyl-4-yl) methoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) methoxy] ethyl} -1,3-thiazol-2-yl) thio] -2- synthesized in Example 155-3 400 mg of methyl propionic acid ethyl ester was dissolved in 4 mL of methanol and 4 mL of tetrahydrofuran, 2 mL of 1 mol / L aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1 to 1: 1) to give 245 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.10 (2H, t, J = 6.3 Hz), 3.84 (2H, t, J = 6.3 Hz) , 4.56 (2H, s), 7.05 (1H, s), 7.09-7.15 (2H, m), 7.34 (2H, d, J = 8.1 Hz), 7.49. -7.55 (4H, m).
MS: 432 (M ⁺⁺ 1).
[Example 156]
2-[(4- {2-[(4′-Chlorobiphenyl-4-yl) methoxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(4-Bromobenzyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid ethyl ester synthesized in Example 155-2 The title compound was obtained in the same manner as in Examples 155-3 and 155-4 using 4-chlorophenylboric acid as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.10 (2H, t, J = 6.2 Hz), 3.85 (2H, t, J = 6.2 Hz) , 4.56 (2H, s), 7.05 (1H, s), 7.34-7.42 (4H, m), 7.48-7.53 (4H, m).
MS: 448 (M ⁺⁺ 1).
[Example 157]
2-Methyl-2-{[4- (2-{[4 ′-(trifluoromethyl) biphenyl-4-yl] methoxy} ethyl) -1,3-thiazol-2-yl] thio} propionic acid

  2-[(4- {2-[(4-Bromobenzyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid ethyl ester synthesized in Example 155-2 The title compound was obtained in the same manner as in Example 155-3 and Example 155-4 using 4- (trifluoromethyl) phenylboric acid as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.11 (2H, t, J = 6.3 Hz), 3.86 (2H, t, J = 6.3 Hz) , 4.58 (2H, s), 7.05 (1H, s), 7.38 (2H, d, J = 8.1 Hz), 7.56 (2H, d, J = 8.1 Hz), 7 .68 (4H, brs).
MS: 482 (M ⁺⁺ 1).
[Example 158]
2-Methyl-2-({4- [2-({1- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl} oxy) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid (Example 158-1)
2-Methyl-2-({4- [2-({1- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl} oxy) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid tert-butyl ester

  2-methyl-2-[(4- {2-[(methylsulfonyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester synthesized in Example 5 0 g and 600 mg of 1- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-ol were dissolved in 10 mL of N, N-dimethylformamide, 363 mg of potassium carbonate was added, and the mixture was stirred at 85 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 4: 1) to give 400 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.58 (6H, s), 3.23 (2H, t, J = 6.6 Hz), 4.30 (2H , T, J = 6.6 Hz), 7.12 (1H, s), 7.47-7.58 (3H, m), 7.66 (1H, s), 7.82 (1H, d, J = 8.2 Hz), 7.92 (1H, s).
(Example 158-2)
2-Methyl-2-({4- [2-({1- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl} oxy) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid

  2-Methyl-2-({4- [2-({1- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl} oxy) ethyl]-obtained in Example 158-1 400 mg of 1,3-thiazol-2-yl} thio) propionic acid tert-butyl ester was dissolved in 6 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 290 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 3.26 (2H, t, J = 6.0 Hz), 4.29 (2H, t, J = 6.0 Hz) , 7.11 (1H, s), 7.48-7.58 (3H, m), 7.65 (1H, s), 7.80 (1H, d, J = 7.8 Hz), 7.92 (1H, s).
MS: 458.
[Example 159]
2-Methyl-2-[(4- {2-[(1-phenyl-1H-pyrazol-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

2-methyl-2-[(4- {2-[(methylsulfonyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester synthesized in Example 5 and non- The title compound was obtained in the same manner as in Example 158 using 1-phenyl-1H-pyrazol-4-ol synthesized with reference to Patent Literature [Organic Preparations and Procedures International, 34 , 98 (2002)] as a starting material. It was.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.24 (2H, t, J = 6.1 Hz), 4.28 (2H, t, J = 6.1 Hz) , 7.11 (1H, s), 7.22-7.27 (1H, m), 7.40-7.45 (3H, m), 7.59-7.62 (3H, m).
MS: 390 (M ⁺⁺ 1).
[Example 160]
2-{[4- (2-{[1- (4-Fluorophenyl) -1H-pyrazol-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropion acid

2-methyl-2-[(4- {2-[(methylsulfonyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester synthesized in Example 5 and non- Operation similar to Example 158 using 1- (4-fluorophenyl) -1H-pyrazol-4-ol synthesized as a starting material synthesized with reference to the patent document [Organic Preparations and Procedures International, 34 , 98 (2002)]. Gave the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.24 (2H, t, J = 6.1 Hz), 4.27 (2H, t, J = 6.1 Hz) 7.08-7.15 (3H, m), 7.43 (1H, s), 7.54-7.59 (3H, m).
MS: 408 (M ⁺⁺ 1).
[Example 161]
2-{[4- (2-{[1- (4-Chlorophenyl) -1H-pyrazol-4-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

2-methyl-2-[(4- {2-[(methylsulfonyl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester synthesized in Example 5 and non- According to the same procedure as in Example 158, starting from 1- (4-chlorophenyl) -1H-pyrazol-4-ol synthesized with reference to the patent document [Organic Preparations and Procedures International, 34 , 98 (2002)]. The title compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 3.24 (2H, t, J = 6.2 Hz), 4.27 (2H, t, J = 6.2 Hz) , 7.10 (1H, s), 7.39 (2H, t, J = 8.8 Hz), 7.44 (1H, s), 7.55-7.57 (3H, m).
MS: 424 (M ⁺⁺ 1).
[Example 162]
2-methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid (Example 162-1)

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 15.6 g and 5-bromo- 10 g of 2-chloropyrimidine was dissolved in 170 mL of N-methylpyrrolidone, 18.0 mL of diisopropylethylamine was added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 5: 1) to give 20 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.59 (6H, s), 3.04 (2H, t, J = 6.5 Hz), 3.76 (2H , T, J = 6.5 Hz), 5.61 (1H, brs), 7.01 (1H, s), 8.26 (2H, s).
MS: 461 (M ⁺⁺ 1).
(Example 162-2)
2-methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid tert-butyl ester

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] synthesized in Example 162-1 under nitrogen atmosphere 2-methylpropionic acid tert-butyl ester (1.0 g) and 4-trifluoromethoxyphenylboric acid (0.54 g) were dissolved in dioxane (10 mL) and 2 mol / L sodium carbonate (5 mL), and tetrakis (triphenylphosphine) palladium (0.13 g) was dissolved. The mixture was refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 1: 1) to give 1.0 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.60 (6H, s), 3.10 (2H, t, J = 6.3 Hz), 3.83-3 .89 (2H, m), 5.61 (1H, brs), 7.04 (1H, s), 7.28-7.30 (2H, m), 7.46-7.50 (2H, m ), 8.49 (2H, s).
MS: 541 (M ⁺⁺ 1).
(Example 162-3)
2-methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-Methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3 obtained in Example 162-2 -Thiazol-2-yl} thio) propionic acid tert-butyl ester (370 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 1: 1) to give 297 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.04 (2H, t, J = 5.7 Hz), 3.71-3.77 (2H, m), 7 .06 (1H, s), 7.28-7.33 (3H, m), 7.45-7.51 (2H, m), 8.49 (2H, brs).
MS: 485 (M ⁺⁺ 1).
[Example 163]
2-Methyl-2-({4- [2- (methyl {5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio ) Propionic acid (Example 163-1)
2-Methyl-2-({4- [2- (methyl {5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio ) Propionic acid tert-butyl ester

  2-Methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3 synthesized in Example 162-2 -Thiazol-2-yl} thio) propionic acid tert-butyl ester (620 mg) and methyl iodide (325 mg) were dissolved in N, N-dimethylformamide (6.0 mL), potassium tertiary butoxide (154 mg) was added, and the mixture was stirred at room temperature for 8 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to give 215 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.45 (9H, s), 1.58 (6H, s), 3.09-3.17 (5H, m), 4.03 (2H, t , J = 6.9 Hz), 7.03 (1H, s), 7.27-7.30 (2H, m), 7.47-7.50 (2H, m), 8.52 (2H, s) ).
MS: 555 (M ⁺⁺ 1).
(Example 163-2)
2-Methyl-2-({4- [2- (methyl {5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio ) Propionic acid

  2-methyl-2-({4- [2- (methyl {5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1, obtained in Example 163-1 3-Thiazol-2-yl} thio) propionic acid tert-butyl ester (210 mg) was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 1: 1) to give 150 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.66 (6H, s), 3.12-3.17 (5H, m), 4.03 (2H, t, J = 7.2 Hz), 6 .99 (1H, s), 7.27-7.30 (2H, m), 7.45-7.51 (2H, m), 8.51 (2H, s).
MS: 499 (M ⁺⁺ 1).
[Example 164]
2-methyl-2-({4- [2-({5- [3- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid (Example 164-1)
2-methyl-2-({4- [2-({5- [3- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid tert-butyl ester

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] synthesized in Example 162-1 under nitrogen atmosphere 920 mg of 2-methylpropionic acid tert-butyl ester and 380 mg of 3- (trifluoromethyl) phenylboric acid were dissolved in 10 mL of dioxane and 5 mL of 2 mol / L sodium carbonate, 115 mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed for 4 hours. . The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1 to 2: 1) to give 890 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.59 (6H, s), 3.10 (2H, t, J = 6.6 Hz), 3.83-3 .90 (2H, m), 5.67 (1H, brs), 7.05 (1H, s), 7.53-7.71 (4H, m), 8.52 (2H, s).
(Example 164-2)
2-methyl-2-({4- [2-({5- [3- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid hydrochloride

  2-Methyl-2-({4- [2-({5- [3- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3 obtained in Example 164-1 -Thiazol-2-yl} thio) propionic acid tert-butyl ester (190 mg) was dissolved in 4 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1). The obtained compound was dissolved in 4 mL of diethyl ether, 0.5 mL of 4 mol / L hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give 151 mg of the title compound as a white solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.52 (6H, s), 3.02 (2H, t, J = 7.2 Hz), 3.67-3.75 (2H, m) 7.51 (1H, s), 7.67-7.69 (2H, m), 7.96-7.98 (2H, m), 8.75 (2H, s).
MS: 469 (M ⁺⁺ 1).
[Example 165]
2-methyl-2-({4- [2-({5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2 and Example 162-3, using propionic acid tert-butyl ester and 4-trifluoromethylphenylboronic acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.68 (6H, s), 3.05 (2H, t, J = 5.4 Hz), 3.81 (2H, m), 6.91 (1H , S), 7.58 (2H, d, J = 8.4 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.74 (1H, s), 8.63 (2H, s) ).
MS: 469 (M ⁺⁺ 1).
[Example 166]
2-{[4- (2-{[5- (4-Chlorophenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2 and Example 162-3, using propionic acid tert-butyl ester and 4-chlorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.04 (2H, t, J = 5.7 Hz), 3.71-3.77 (2H, m), 7 .05 (1H, s), 7.28-7.43 (5H, m), 8.49 (2H, brs).
MS: 435 (M ⁺⁺ 1).
[Example 167]
2-[(4- {2-[[5- (4-Chlorophenyl) pyrimidin-2-yl] (isopropyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 Starting from propionic acid tert-butyl ester and 4-chlorophenylboric acid as starting materials, the same operation as in Example 162-2 was performed, and then the same operation as in Example 163 was performed using isopropyl iodide. Got.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.23 (6H, d, J = 6.6 Hz), 1.67 (6H, s), 3.13-3.18 (2H, m), 3 .74-3.79 (2H, m), 5.04-5.08 (1H, m), 7.02 (1H, s), 7.41 (4H, s), 8.54 (2H, s) ).
MS: 477 (M ⁺⁺ 1).
[Example 168]
2-({4- [2- (ethyl {5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) -2- Methyl propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 Propionic acid tert-butyl ester and 4- (trifluoromethyl) phenyl boric acid were used as starting materials, and the same operation as in Example 162-2 was performed, followed by the same operation as in Example 163 using ethyl iodide. The title compound was obtained.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.10 (3H, t, J = 7.1 Hz), 1.52 (6H, s), 3.05-3.07 (2H, m) 3.56-3.58 (2H, m), 3.90-3.92 (2H, m), 7.49 (1H, s), 7.77-7.79 (2H, m), 7 .86-7.89 (2H, m), 8.79 (2H, s).
MS: 497 (M ⁺⁺ 1).
[Example 169]
2-({4- [2- (ethyl {5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) -2- Methyl propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 Propionic acid tert-butyl ester and 4- (trifluoromethoxy) phenyl boric acid were used as starting materials, and the same operation as in Example 162-2 was performed, followed by the same operation as in Example 1634 using ethyl iodide. The title compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19 (3H, t, J = 6.9 Hz), 1.66 (6H, s), 3.15 (2H, t, J = 6.9 Hz) , 3.62 (2H, q, J = 6.9 Hz), 3.95 (2H, t, J = 6.9 Hz), 7.00 (1H, s), 7.27-7.30 (2H, m), 7.47-7.50 (2H, m), 8.51 (2H, s).
MS: 513 (M ⁺⁺ 1).
[Example 170]
2-({4- [2- (isopropyl {5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) -2- Methyl propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 Using propionic acid tert-butyl ester and 4- (trifluoromethoxy) phenylboric acid as starting materials, the same operation as in Example 162-2 is performed, and then the same operation as in Example 163 is performed using isopropyl iodide. This gave the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.24 (6H, d, J = 6.9 Hz), 1.68 (6H, s), 3.16 (2H, t, J = 7.8 Hz) , 3.78 (2H, t, J = 7.8 Hz), 5.04-5.09 (1H, m), 7.02 (1H, s), 7.28-7.30 (2H, m) 7.48-7.51 (2H, m), 8.55 (2H, s).
MS: 527 (M ⁺⁺ 1).
[Example 171]
2-Methyl-2-({4- [2-({5- [4- (2,2,2-trifluoroethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazole- 2-yl} thio) propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 Starting from propionic acid tert-butyl ester and 4- (2,2,2-trifluoroethoxy) phenylboric acid as starting materials, the title compound was obtained by the same procedure as in Example 162-2 and Example 162-3. It was.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.04 (2H, t, J = 5.7 Hz), 3.71-3.76 (2H, m), 4 .39 (2H, q, J = 8.1 Hz), 7.01-7.05 (3H, m), 7.38-7.41 (2H, m), 8.46 (2H, brs).
MS: 499 (M ⁺⁺ 1).
[Example 172]
2-Methyl-2-({4- [2-({5- [3- (2,2,2-trifluoroethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazole- 2-yl} thio) propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound is obtained by performing the same procedures as in Example 162-2 and Example 162-3 using propionic acid tert-butyl ester and 3- (2,2,2-trifluoroethoxy) phenylboric acid as starting materials. It was.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.04 (2H, t, J = 5.7 Hz), 3.71-3.77 (2H, m), 4 .40 (2H, q, J = 8.1 Hz), 6.90-6.94 (1H, m), 7.03-7.05 (2H, m), 7.13 (1H, d, J = 7.2 Hz), 7.29-7.42 (2H, m), 8.51 (2H, brs).
MS: 499 (M ⁺⁺ 1).
[Example 173]
2-Methyl-2-{[4- (2-{[5- (4-propylphenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2 and Example 162-3, using propionic acid tert-butyl ester and 4-propylphenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.97 (3H, t, J = 7.5 Hz), 1.61-1.71 (8H, m), 2.62 (2H, t, J = 7.7 Hz), 3.04 (2H, t, J = 5.7 Hz), 3.71-3.77 (2H, m), 7.05 (1H, s), 7.24-7.27 ( 2H, m), 7.35-7.38 (2H, m), 8.50 (2H, brs).
MS: 443 (M ⁺⁺ 1).
[Example 174]
2-Methyl-2-{[4- (2-{[5- (4-propoxyphenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2 and Example 162-3 using propionic acid tert-butyl ester and 4-propoxyphenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.05 (3H, t, J = 7.5 Hz), 1.69 (6H, s), 1.80-1.87 (2H, m), 3 .04 (2H, t, J = 5.7 Hz), 3.70-3.76 (2H, m), 3.95 (2H, t, J = 6.6 Hz), 6.96-6.98 ( 2H, m), 7.04 (1H, s), 7.20-7.25 (1H, m), 7.34-7.37 (2H, m), 8.46 (2H, brs).
MS: 459 (M ⁺⁺ 1).
[Example 175]
2-{[4- (2-{[5- (4-Isopropylphenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2 and Example 162-3 using propionic acid tert-butyl ester and 4-isopropylphenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.28 (6H, d, J = 6.6 Hz), 1.69 (6H, s), 2.88-3.00 (1H, m), 3 .04 (2H, t, J = 5.7 Hz), 3.71-3.77 (2H, m), 7.05 (1H, s), 7.28-7.32 (2H, m), 7 .36-7.40 (2H, m), 8.50 (2H, brs).
MS: 443 (M ⁺⁺ 1).
[Example 176]
2-{[4- (2-{[5- (4-Isopropoxyphenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2 and Example 162-3, using propionic acid tert-butyl ester and 4-isopropoxyphenyl boric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.36 (6H, d, J = 6.0 Hz), 1.69 (6H, s), 3.04 (2H, t, J = 5.7 Hz) 3.70-3.76 (2H, m), 4.54-4.62 (1H, m), 6.95 (2H, d, J = 8.7 Hz), 7.04 (1H, s) , 7.21 (1H, brs), 7.35 (2H, d, J = 8.7 Hz), 8.46 (2H, brs).
MS: 459 (M ⁺⁺ 1).
[Example 177]
2-{[4- (2-{[5- (4-Chloro-2-fluorophenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid (Reference Example 3)
4-chloro-2-fluorophenylboric acid

n-Butyllithium (1.6 mol / Ln-hexane, 18.8 mL) was added dropwise to a solution of 11 mL of n-hexane and 30 mL of tetrahydrofuran at −78 ° C. in a nitrogen atmosphere. Subsequently, a solution of 5.24 g of 1-bromo-4-chloro-2-fluorobenzene in 15 mL of n-hexane and 15 mL of tetrahydrofuran was added dropwise. After stirring at −78 ° C. for 1 hour, 4.0 mL of boric acid trimethyl ester and 15 mL of tetrahydrofuran were added dropwise, and the temperature was raised to room temperature. After 2 hours, 120 mL of a 3 mol / L hydrochloric acid aqueous solution was added, and the mixture was extracted with 100 mL of diethyl ether. The aqueous layer was extracted again with 100 mL of diethyl ether, the combined organic layers were dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. N-Hexane was added to the residue, and the precipitated solid was collected by filtration to obtain 2.0 g of the title compound as a white solid.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 7.08-7.12 (1H, m), 7.20-7.23 (1H, m), 7.78 (1H, t, J = 7. 6 Hz).

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2 and Example 162-3 using propionic acid tert-butyl ester and 4-chloro-2-fluorophenylboric acid synthesized in Reference Example 3 as starting materials. .

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.68 (6H, s), 3.04 (2H, t, J = 5.7 Hz), 3.71-3.77 (2H, m), 7 .05 (1H, s), 7.18-7.34 (3H, m), 8.41-8.46 (2H, m).
MS: 453 (M ⁺⁺ 1).
[Example 178]
2-{[4- (2-{[5- (2,4-dichlorophenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2 and Example 162-3, using propionic acid tert-butyl ester and 2,4-dichlorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.05 (2H, t, J = 5.4 Hz), 3.72 to 3.78 (2H, m), 7 .06 (1H, s), 7.21 (1H, d, J = 8.1 Hz), 7.31-7.37 (2H, m), 7.51 (1H, d, J = 2.1 Hz) , 8.21-8.43 (2H, m).
MS: 469 (M ⁺⁺ 1).
[Example 179]
2-[(4- {2-[[5- (2,4-Dichlorophenyl) pyrimidin-2-yl] (methyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2 and Example 163 using propionic acid tert-butyl ester and 4-2,4-dichlorophenylphenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.15 (2H, t, J = 6.9 Hz), 3.18 (3H, s), 4.04 (2H , T, J = 6.9 Hz), 7.00 (1H, s), 7.24 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 1.8, 8. 4 Hz), 7.50 (1 H, d, J = 1.8 Hz), 8.39 (2 H, s).
MS: 483 (M ⁺⁺ 1).
[Example 180]
2-({4- [2-({5- [2-Chloro-4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) -2-Methylpropionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 Using [2-chloro-4- (trifluoromethyl) phenyl] boric acid synthesized in the same manner as in Reference Example 3 using propionic acid tert-butyl ester and 3-chloro-4-iodobenzotrifluoride as starting materials The title compound was obtained in the same manner as in Example 162-2 and Example 162-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.05 (2H, t, J = 5.7 Hz), 3.73-3.79 (2H, m), 7 .07 (1H, s), 7.39-7.43 (2H, m), 7.58-7.61 (1H, m), 7.76 (1H, brs), 8.32-8.50 (2H, m).
MS: 503 (M ⁺⁺ 1).
[Example 181]
2-({4- [2-({5- [2-Fluoro-4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) -2-Methylpropionic acid

2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 Propionic acid tert-butyl ester and 4-bromo-3-fluorobenzotrifluoride are used as starting materials and synthesized in the same manner as in Reference Example 3 [2-fluoro-4- (trifluoromethyl) phenyl] boric acid as starting material In the same manner as in Example 162-2 and Example 162-3, the title compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.68 (6H, s), 3.04 (2H, t, J = 5.7 Hz), 3.72 to 3.78 (2H, m), 7 .06 (1H, s), 7.41-7.50 (4H, m), 8.43 (1H, brs), 8.59 (1H, brs).
MS: 487 (M ⁺⁺ 1).
[Example 182]
2-[(4- {2-[{5- [2-Fluoro-4- (trifluoromethyl) phenyl] pyrimidin-2-yl} (methyl) amino] ethyl} -1,3-thiazol-2-yl ) Thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2 and Example 163 using propionic acid tert-butyl ester and [2-fluoro-4- (trifluoromethyl) phenyl] boric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 3.09-3.13 (5H, m), 4.01 (2H, t, J = 6.9 Hz), 7 .01 (1H, s), 7.38-7.49 (3H, m), 8.53 (2H, s).
MS: 501 (M ⁺⁺ 1).
[Example 183]
2-Methyl-2-[(4- {3-[(5-phenylpyrimidin-2-yl) amino] propyl} -1,3-thiazol-2-yl) thio] -propionic acid
(Example 183-1)
2-[(4- {3-[(5-Bromopyrimidin-2-yl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (3-Aminopropyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 33 and 5-bromo- 2-Chloropyrimidine (3.24 g) was dissolved in N-methylpyrrolidone (60 mL), diisopropylethylamine (5.8 mL) was added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 5: 1) to give 5.65 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.57 (6H, s), 1.97-2.07 (2H, m), 2.84 (2H, t , J = 7.2 Hz), 3.39-3.46 (2H, m), 5.34 (1H, brs), 6.99 (1H, s), 8.26 (2H, s).
(Example 183-2)
2-Methyl-2-[(4- {3-[(5-phenylpyrimidin-2-yl) amino] propyl} -1,3-thiazol-2-yl) thio] -propionic acid

  2-[(4- {3-[(5-Bromopyrimidin-2-yl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 183-1 The title compound was obtained in the same manner as in Example 162-2 and Example 162-3, using propionic acid tert-butyl ester and phenylphenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.70 (6H, s), 2.05-2.14 (2H, m), 2.93 (2H, t, J = 6.0 Hz), 3 .52-3.58 (2H, m), 6.48 (1H, brs), 6.93 (1H, s), 7.34-7.45 (5H, m) 8.51 (2H, s) .
MS: 415 (M ⁺⁺ 1).
[Example 184]
2-{[4- (3-{[5- (4-Fluorophenyl) pyrimidin-2-yl] amino} propyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {3-[(5-Bromopyrimidin-2-yl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 183-1 The title compound was obtained in the same manner as in Example 162-2 and Example 162-3 using propionic acid tert-butyl ester and 4-fluorophenylphenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 2.05-2.13 (2H, m), 2.91-2.95 (2H, m), 3.49 -3.57 (2H, m), 6.48 (1H, brs), 6.93 (1H, s), 7.10-7.17 (2H, m), 7.38-7.42 (2H , M), 8.46 (2H, s).
MS: 433 (M ⁺⁺ 1).
[Example 185]
2-{[4- (3-{[5- (4-Methylphenyl) pyrimidin-2-yl] amino} propyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {3-[(5-Bromopyrimidin-2-yl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 183-1 The title compound was obtained in the same manner as in Example 162-2 and Example 162-3, using propionic acid tert-butyl ester and 4-methylphenylphenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.70 (6H, s), 2.05-2.13 (2H, m), 2.39 (3H, s), 2.93 (2H, t , J = 6.3 Hz), 3.51-3.57 (2H, m), 6.45-6.47 (1H, m), 6.93 (1H, s), 7.23-7.26. (2H, m), 7.33-7.36 (2H, m), 8.48 (2H, s).
MS: 429 (M ⁺⁺ 1).
[Example 186]
2-methyl-2-({4- [3-({5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) propyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-[(4- {3-[(5-Bromopyrimidin-2-yl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 183-1 The title compound was obtained in the same manner as in Example 162-2 and Example 162-3, using propionic acid tert-butyl ester and 4- (trifluoromethyl) phenylphenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 2.05-2.14 (2H, m), 2.93 (2H, t, J = 6.3 Hz), 3 .53-3.59 (2H, m), 6.54-6.56 (1H, m), 6.94 (1H, s), 7.57 (2H, d, J = 8.4 Hz), 7 .70 (2H, d, J = 8.4 Hz), 8.53 (2H, s).
MS: 483 (M ⁺⁺ 1).
[Example 187]
2-Methyl-2-{[4- (2-{[5- (4-methylphenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} propionic acid hydrochloride

2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 164, using propionic acid tert-butyl ester and 4-methylphenylboronic acid as starting materials.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 2.33 (3H, s), 3.02 (2H, t, J = 7.2 Hz), 3.68 (2H, t, J = 7.2 Hz), 7.27 (2H, d, J = 7.8 Hz), 7.54 (2H, d, J = 7.8 Hz), 7.53 (1H, s) , 8.70 (2H, s).
MS: 415 (M ⁺⁺ 1).
[Example 188]
2-{[4- (2-{[5- (4-Fluorophenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid hydrochloride

2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 164, using propionic acid tert-butyl ester and 4-fluorophenylboronic acid as starting materials.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.02 (2H, t, J = 7.2 Hz), 3.69 (2H, t, J = 7. 2Hz), 7.30 (2H, t, J = 9.0 Hz), 7.53 (1H, s), 7.71 (2H, m), 8.70 (2H, s).
MS: 419 (M ⁺⁺ 1).
[Example 189]
2-{[4- (2-{[5- (4-methoxyphenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid hydrochloride

2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 164, using propionic acid tert-butyl ester and 4-methoxyphenylboronic acid as starting materials.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.02 (2H, t, J = 7.2 Hz), 3.68 (2H, t, J = 7. 2 Hz), 3.79 (3 H, s), 7.03 (2 H, d, J = 8.7 Hz), 7.53 (1 H, s), 7.59 (2 H, d, J = 8.7 Hz) , 8.69 (2H, s).
MS: 431 (M ⁺⁺ 1).
[Example 190]
2-Methyl-2-({4- [2- (methyl {5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio ) Propionic acid hydrochloride

2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2, Example 163-1 and Example 164-2, starting from propionic acid tert-butyl ester and 4-trifluoromethylphenylboronic acid.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.04 (2H, t, J = 7.2 Hz), 3.09 (3H, s), 3.98 (2H, t, J = 7.2 Hz), 7.50 (1H, s), 7.78 (2H, d, J = 8.1 Hz), 7.88 (2H, d, J = 8.1 Hz) , 8.79 (2H, s).
MS: 483 (M ⁺⁺ 1).
[Example 191]
2-Methyl-2-{[4- (2-{[5- (2-naphthyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} propionic acid hydrochloride

2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 164, using propionic acid tert-butyl ester and 2-naphthylboronic acid as starting materials.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.52 (6H, s), 3.03 (2H, t, J = 7.2 Hz), 7.53 (1H, s), 7.55 (2H, m), 7.83 (1H, d, J = 8.3 Hz), 7.94 (2H, m), 8.00 (1H, d, J = 8.5 Hz), 8.20 (1H , S), 8.83 (2H, s).
MS: 451 (M ⁺⁺ 1).
[Example 192]
2-{[4- (2-{[5- (4-tert-Butylphenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid Hydrochloride

2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 164, using propionic acid tert-butyl ester and 4-tert-butylphenylboronic acid as starting materials.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.31 (9H, s), 1.51 (6H, s), 3.03 (2H, t, J = 7.2 Hz), 3.71 (2H, t, J = 7.2 Hz), 7.48 (2H, d, J = 8.4 Hz), 7.54 (1H, s), 7.58 (2H, d, J = 8.4 Hz) , 8.75 (2H, s).
MS: 457 (M ⁺⁺ 1).
[Example 193]
2-[(4- {2-[[5- (4-Chlorophenyl) pyrimidin-2-yl] (methyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2, Example 163-1 and Example 164-2, using propionic acid tert-butyl ester and 4-chlorophenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.03-3.07 (5H, m), 3.94-3.99 (2H, m), 7 .48-7.51 (3H, m), 7.67 (2H, d, J = 8.4 Hz), 8.70 (2H, s).
MS: 449 (M ⁺⁺ 1).
[Example 194]
2-methyl-2-({4- [2-({5- [3- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid hydrochloride

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 164, using propionic acid tert-butyl ester and 3- (trifluoromethoxy) phenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.01 (2H, t, J = 7.2 Hz), 3.68 (2H, t, J = 7. 2Hz), 7.32-7.34 (1H, m), 7.52 (1H, s), 7.55-7.61 (1H, m), 7.68-7.72 (2H, m) , 8.75 (2H, s).
MS: 485 (M ⁺⁺ 1).
[Example 195]
2-Methyl-2-({4- [2- (methyl {5- [3- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio ) Propionic acid hydrochloride

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 162-2, Example 163-1 and Example 164-2, using propionic acid tert-butyl ester and 3- (trifluoromethoxy) phenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.04 (2H, t, J = 7.0 Hz), 3.09 (3H, s), 3.98 (2H, t, J = 7.0 Hz), 7.31-7.34 (1H, m), 7.50 (1H, s), 7.55-7.60 (1H, m), 7.66 -7.71 (2H, m), 8.76 (2H, s).
MS: 499 (M ⁺⁺ 1).
[Example 196]
2-[(4- {2-[[5- (4-Chlorophenyl) pyrimidin-2-yl] (ethyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The same operation as in Example 1-2 was performed using propionic acid tert-butyl ester and 4-chlorophenylboric acid, and then the same operation as in Example 163-1 and Example 164-2 was performed using ethyl iodide. This gave the title compound.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.10 (3H, t, J = 6.9 Hz), 1.52 (6H, s), 3.04 (2H, t, J = 6. 9 Hz), 3.56 (2H, q, J = 6.9 Hz), 3.91 (2H, t, J = 6.9 Hz), 7.48-7.51 (3H, m), 7.65- 7.70 (2H, m), 8.71 (2H, s).
MS: 463 (M ⁺⁺ 1).
[Example 197]
2-{[4- (2-{[5- (3-Chloro-4-fluorophenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid hydrochloride

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 164, using propionic acid tert-butyl ester and 3-chloro-4-fluorophenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.00 (2H, t, J = 7.2 Hz), 3.64-3.80 (2H, m) 7.46-7.52 (2H, m), 7.64-7.66 (1H, m), 7.89-7.91 (1H, m), 8.69 (2H, s).
MS: 453 (M ⁺⁺ 1).
[Example 198]
2-{[4- (2-{[5- (3,4-Dichlorophenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid hydrochloric acid salt

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 164, using propionic acid tert-butyl ester and 3,4-dichlorophenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.00 (2H, t, J = 7.2 Hz), 3.67-3.80 (2H, m) 7.51 (1H, s), 7.64-7.71 (2H, m), 7.96 (1H, s), 8.72 (2H, s).
MS: 469 (M ⁺⁺ 1).
[Example 199]
2-Methyl-2-[(4- {2-[(5-phenylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid trifluoroacetate

2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 Starting from propionic acid tert-butyl ester and phenylboronic acid, the compound obtained by the same procedure as in Example 162-2 was subjected to dichloromethane and trifluoroacetic acid, and stirred at room temperature for 12 hours. The solid obtained by concentrating the reaction solution under reduced pressure was pulverized and washed with hexane-ethyl acetate to give the title compound as a white solid.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.01 (2H, t, J = 7.0 Hz), 3.66 (2H, t, J = 7. 0 Hz), 7.34 (1 H, t, J = 7.6 Hz), 7.45 (2 H, t, J = 7.6 Hz), 7.52 (1 H, s), 7.63 (2 H, d, J = 8.0 Hz), 8.68 (2H, s).
MS: 401 (M ⁺⁺ 1).
[Example 200]
2-methyl-2-{[4- (2-{[5- (2-thienyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} propionic acid trifluoroacetic acid salt

2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 Starting from propionic acid tert-butyl ester and 2-thiopheneboronic acid, the compound obtained by the same procedure as in Example 162-2 was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The solid obtained by concentrating the reaction solution under reduced pressure was pulverized and washed with hexane-ethyl acetate to give the title compound as a white solid.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 2.99 (2H, t, J = 7.5 Hz), 3.62 (2H, m), 7.12 (1H, m), 7.39 (1H, d, J = 2.7 Hz), 7.49 (1H, d, J = 4.5 Hz), 7.50 (1H, s), 7.52 (1H , S), 8.59 (2H, s).
MS: 407 (M ⁺⁺ 1).
[Example 201]
2-methyl-2-({4- [3-({5- [3- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) propyl] -1,3-thiazol-2-yl} thio) Propionic acid hydrochloride

  2-[(4- {3-[(5-Bromopyrimidin-2-yl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 183-1 The title compound was obtained in the same manner as in Example 164, using propionic acid tert-butyl ester and 3- (trifluoromethyl) phenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 1.89-1.99 (2H, m), 2.79 (2H, t, J = 7.2 Hz) 3.42 (2H, t, J = 7.2 Hz), 7.49 (1H, s), 7.66-7.70 (2H, m), 7.97-8.01 (3H, m) , 8.82 (2H, s).
MS: 483 (M ⁺⁺ 1).
[Example 202]
2-Methyl-2-({4- [3- (methyl {5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) propyl] -1,3-thiazol-2-yl} thio ) Propionic acid hydrochloride

  2-[(4- {3-[(5-Bromopyrimidin-2-yl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 183-1 The title compound was obtained in the same manner as in Example 162-2, Example 163-1 and Example 164-2 using propionic acid tert-butyl ester and 4- (trifluoromethyl) phenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 1.91-2.03 (2H, m), 2.75 (2H, t, J = 7.5 Hz) 3.17 (3H, s), 3.71 (2H, t, J = 7.5 Hz), 7.48 (1H, s), 7.78 (2H, d, J = 8.4 Hz), 7 .88 (2H, d, J = 8.4 Hz), 8.79 (2H, s).
MS: 497 (M ⁺⁺ 1).
[Example 203]
2-Methyl-2-({4-[({5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) methyl] -1,3-thiazol-2-yl} thio) propionic acid Hydrochloride

  2-{[4- (aminomethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo-2-chloropyrimidine synthesized in Example 13 The same operation as in Example 162-1 is performed as a starting material, and then the same operation as in Example 162-2 and Example 164-2 is performed using [4- (trifluoromethyl) phenyl] boric acid. Gave the title compound.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 4.68 (2H, s), 7.50 (1H, s), 7.79 (2H, d, J = 8.1 Hz), 7.89 (2H, d, J = 8.1 Hz), 8.79 (2H, s).
MS: 455 (M ⁺⁺ 1).
[Example 204]
2-Methyl-2-({4-[(methyl {5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) methyl] -1,3-thiazol-2-yl} thio) propion Acid hydrochloride

  2-{[4- (aminomethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo-2-chloropyrimidine synthesized in Example 13 The same operation as in Example 162-1 was carried out as a starting material, and then, using [4- (trifluoromethyl) phenyl] boric acid, Example 162-2, Example 163-1 and Example 164-2 The title compound was obtained by carrying out the same operation.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.24 (3H, s), 4.99 (2H, s), 7.51 (1H, s), 7.79 (2H, d, J = 8.1 Hz), 7.89 (2H, d, J = 8.1 Hz), 8.82 (2H, s).
MS: 469 (M ⁺⁺ 1).
[Example 205]
2-Methyl-2-({4-[({5- [3- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) methyl] -1,3-thiazol-2-yl} thio) propionic acid Hydrochloride

  2-{[4- (aminomethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo-2-chloropyrimidine synthesized in Example 13 The same operation as in Example 162-1 is performed as a starting material, and then the same operation as in Example 162-2 and Example 164-2 is performed using [3- (trifluoromethyl) phenyl] boric acid. Gave the title compound.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 4.71 (2H, s), 7.54 (1H, s), 7.62-7.71 (2H M), 7.96-8.02 (2H, m), 8.86 (2H, s).
MS: 455 (M ⁺⁺ 1).
[Example 206]
2-Methyl-2-({5-methyl-4- [2-({5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazole-2- Il} thio) propionic acid hydrochloride

  2-{[4- (2-Aminoethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo synthesized in Example 19 2-Chloropyrimidine was used as a starting material, and the same operation as in Example 162-1 was carried out. Subsequently, using [4- (trifluoromethyl) phenyl] boric acid, Example 162-2 and Example 164-2 The title compound was obtained by carrying out the same operation.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.48 (6H, s), 2.35 (3H, s), 2.89-2.97 (2H, m), 3.62-3 .69 (2H, m), 7.80 (2H, d, J = 8.4 Hz), 7.90 (2H, d, J = 8.4 Hz), 8.83 (2H, s).
MS: 483 (M ⁺⁺ 1).
[Example 207]
2-Methyl-2-({5-methyl-4- [2- (methyl {5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazole-2 -Il} thio) propionic acid hydrochloride

  2-{[4- (2-Aminoethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo synthesized in Example 19 2-Chloropyrimidine was used as a starting material, and the same operation as in Example 162-1 was performed. Subsequently, Example 162-2, Example 163-1 and [16- (trifluoromethyl) phenyl] boric acid were used. The title compound was obtained by the same procedures as in Example 164-2.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.48 (6H, s), 2.28 (3H, s), 2.97 (2H, t, J = 6.8 Hz), 3.07 (3H, s), 3.92 (2H, d, J = 6.8 Hz), 7.79 (2H, d, J = 8.2 Hz), 7.89 (2H, d, J = 8.2 Hz) , 8.80 (2H, s).
MS: 497 (M ⁺⁺ 1).
[Example 208]
2-Methyl-2-({5-methyl-4- [2-({5- [3- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazole-2- Il} thio) propionic acid hydrochloride

  2-{[4- (2-Aminoethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo synthesized in Example 19 2-Chloropyrimidine was used as a starting material, and the same operation as in Example 162-1 was carried out. Subsequently, using [3- (trifluoromethyl) phenyl] boric acid, Example 162-2 and Example 164-2 The title compound was obtained by carrying out the same operation.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.48 (6H, s), 2.36 (3H, s), 2.90-2.97 (2H, m), 3.63-3 .71 (2H, m), 7.67-7.71 (2H, m), 7.98-8.03 (2H, m), 8.86 (2H, s).
MS: 483 (M ⁺⁺ 1).
[Example 209]
2-Methyl-2-({4-methyl-5- [2-({5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazole-2- Il} thio) propionic acid hydrochloride

  2-{[5- (2-Aminoethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo synthesized in Example 24 2-Chloropyrimidine was used as a starting material, and the same operation as in Example 162-1 was carried out. Subsequently, using [4- (trifluoromethyl) phenyl] boric acid, Example 162-2 and Example 164-2 The title compound was obtained by carrying out the same operation.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.46 (6H, s), 2.29 (3H, s), 3.04 (2H, t, J = 6.8 Hz), 3.52 -3.57 (2H, m), 7.78 (2H, d, J = 8.1 Hz), 7.88 (2H, d, J = 8.1 Hz), 8.76 (2H, s).
MS: 483 (M ⁺⁺ 1).
[Example 210]
2-Methyl-2-({4-methyl-5- [2- (methyl {5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazole-2 -Il} thio) propionic acid hydrochloride

  2-{[5- (2-Aminoethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo synthesized in Example 24 2-Chloropyrimidine was used as a starting material, and the same operation as in Example 162-1 was performed. Subsequently, Example 162-2, Example 163-1 and [16- (trifluoromethyl) phenyl] boric acid were used. The title compound was obtained by the same procedures as in Example 164-2.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.43 (6H, s), 2.28 (3H, s), 3.06-3.12 (5H, m), 3.83-3 .89 (2H, m), 7.78 (2H, d, J = 8.4 Hz), 7.89 (2H, d, J = 8.4 Hz), 8.79 (2H, s).
MS: 497 (M ⁺⁺ 1).
[Example 211]
2-Methyl-2-({4-methyl-5- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazole-2- Il} thio) propionic acid hydrochloride

  2-{[5- (2-Aminoethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo synthesized in Example 24 2-Chloropyrimidine was used as a starting material, and the same operation as in Example 162-1 was carried out. Subsequently, using [4- (trifluoromethoxy) phenyl] boric acid, Example 162-2 and Example 164-2 The title compound was obtained by carrying out the same operation.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.46 (6H, s), 2.29 (3H, s), 3.04 (2H, t, J = 6.9 Hz), 3.52 -3.58 (2H, m), 7.44 (2H, d, J = 8.3 Hz), 7.78 (2H, d, J = 8.3 Hz), 8.73 (2H, s).
MS: 499 (M ⁺⁺ 1).
[Example 212]
2-Methyl-2-({4-methyl-5- [2- (methyl {5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazole-2 -Il} thio) propionic acid hydrochloride

  2-{[5- (2-Aminoethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo synthesized in Example 24 2-Chloropyrimidine as a starting material, the same operation as in Example 162-1 was carried out, and then Example 162-2, Example 163-1 and [16- (trifluoromethoxy) phenyl] boric acid were used. The title compound was obtained by the same procedures as in Example 164-2.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.43 (6H, s), 2.27 (3H, s), 3.05 to 3.10 (5H, m), 3.80-3 .86 (2H, m), 7.43 (2H, d, J = 8.7 Hz), 7.77 (2H, d, J = 8.7 Hz), 8.73 (2H, s).
MS: 513 (M ⁺⁺ 1).
[Example 213]
2-methyl-2-({4- [2-({6- [4- (trifluoromethoxy) phenyl] pyridazin-3-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid (Example 213-1)
2-[(4- {2-[(6-chloropyridazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 5.0 g and 3,6- Dichloropyridazine (4.92 g) was dissolved in N-methylpyrrolidone (25 mL), diisopropylethylamine (4.27 g) was added, and the mixture was heated with stirring at 130 ° C. for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 1: 1) to give 5.5 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.60 (6H, s), 3.04 (2H, t, J = 6.0 Hz), 3.80-3 .86 (2H, m), 5.76 (1H, brs), 6.94-6.97 (2H, m), 7.09 (1H, d, J = 9.0 Hz).
(Example 213-2)
2-methyl-2-({4- [2-({6- [4- (trifluoromethoxy) phenyl] pyridazin-3-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid tert-butyl ester

  2-[(4- {2-[(6-Chloropyridazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] synthesized in Example 213-1 under nitrogen atmosphere 2-methylpropionic acid tert-butyl ester 500 mg and 4-trifluoromethoxyphenylboric acid 300 mg were dissolved in dioxane 6 mL and 2 mol / L sodium carbonate 3 mL, and tetrakis (triphenylphosphine) palladium 70 mg was added and refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 2) to give 520 mg of the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.62 (6H, s), 3.11 (2H, t, J = 6.0 Hz), 3.90-3 .96 (2H, m), 5.81 (1H, brs), 6.97 (1H, s), 7.07 (1H, d, J = 9.3 Hz), 7.30-7.32 (2H , M), 7.55 (1H, d, J = 9.3 Hz), 7.97-8.00 (2H, m).
(Example 213-3)
2-methyl-2-({4- [2-({6- [4- (trifluoromethoxy) phenyl] pyridazin-3-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-Methyl-2-({4- [2-({6- [4- (trifluoromethoxy) phenyl] pyridazin-3-yl} amino) ethyl] -1,3 obtained in Example 213-2 -Thiazol-2-yl} thio) propionic acid tert-butyl ester 520 mg was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 233 mg of the title compound as a white amorphous.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.70 (6H, s), 3.08 (2H, t, J = 5.9 Hz), 3.54 (2H, brs), 6.96 (1H , D, J = 9.4 Hz), 7.03 (1H, s), 7.27-7.31 (2H, m), 7.59 (1H, brs), 7.70 (1H, d, J = 9.4 Hz), 7.91-7.95 (2H, m).
MS: 485 (M ⁺⁺ 1).
[Example 214]
2-Methyl-2-({4- [2- (methyl {6- [4- (trifluoromethoxy) phenyl] pyridazin-3-yl} amino) ethyl] -1,3-thiazol-2-yl} thio ) Propionic acid

  2-Methyl-2-({4- [2-({6- [4- (trifluoromethoxy) phenyl] pyridazin-3-yl} amino) ethyl] -1,3 synthesized in Example 213-2 -Thiazol-2-yl} thio) propionic acid tert-butyl ester was used as a starting material, and the title compound was obtained in the same manner as in Example 163.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 3.12 (3H, s), 3.18 (2H, t, J = 6.9 Hz), 4.11 (2H , T, J = 6.9 Hz), 6.86 (1H, d, J = 9.3 Hz), 7.02 (1H, s), 7.29-7.32 (2H, m), 7.62 (1H, d, J = 9.3 Hz), 7.9-8.02 (2H, m).
MS: 499 (M ⁺⁺ 1).
[Example 215]
2-{[4- (2-{[6- (4-Fluorophenyl) pyridazin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 213-1 The title compound was obtained in the same manner as in Example 213-2 and Example 213-3 using propionic acid tert-butyl ester and 4-fluorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.70 (6H, s), 3.07 (2H, t, J = 5.7 Hz), 3.54 (2H, brs), 6.97 (1H , D, J = 9.5 Hz), 7.03 (1H, s), 7.11-7.17 (2H, m), 7.62 (1H, brs), 7.69 (1H, d, J = 9.5 Hz), 7.86-7.91 (2H, m).
MS: 419 (M ⁺⁺ 1).
[Example 216]
2-{[4- (2-{[6- (4-Chlorophenyl) pyridazin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 213-1 The title compound was obtained in the same manner as in Example 213-2 and Example 213-3 using propionic acid tert-butyl ester and 4-chlorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.07 (2H, t, J = 6.0 Hz), 3.57-3.61 (2H, m), 7 .03 (1H, s), 7.09 (1H, d, J = 9.6 Hz), 7.39-7.43 (2H, m), 7.75 (1H, d, J = 9.6 Hz) , 7.79-7.82 (2H, m).
MS: 435 (M ⁺⁺ 1).
[Example 217]
2-[(4- {2-[[6- (4-Chlorophenyl) pyridazin-3-yl] (methyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 213-1 The title compound was obtained in the same manner as in Example 213-2 and Example 214 using propionic acid tert-butyl ester and 4-chlorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 3.12 (3H, s), 3.18 (2H, t, J = 6.6 Hz), 4.11 (2H , T, J = 6.6 Hz), 6.86 (1H, d, J = 9.6 Hz), 7.02 (1H, s), 7.42-7.45 (2H, m), 7.62 (1H, d, J = 9.6 Hz), 7.91-7.93 (2H, m).
MS: 449 (M ⁺⁺ 1).
[Example 218]
2-methyl-2-({4- [2-({6- [4- (trifluoromethyl) phenyl] pyridazin-3-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 213-1 The title compound was obtained in the same manner as in Example 213-2 and Example 213-3 using propionic acid tert-butyl ester and 4- (trifluoromethyl) phenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.11 (2H, t, J = 6.0 Hz), 3.61 to 3.65 (2H, m), 7 .06 (1H, s), 7.12 (1H, d, J = 9.6 Hz), 7.71 (2H, d, J = 8.4 Hz), 7.84 (1H, d, J = 9. 6 Hz), 8.01 (2H, d, J = 8.4 Hz).
MS: 469 (M ⁺⁺ 1).
[Example 219]
2-Methyl-2-({4- [2- (methyl {6- [4- (trifluoromethyl) phenyl] pyridazin-3-yl} amino) ethyl] -1,3-thiazol-2-yl} thio ) Propionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 213-1 The title compound was obtained in the same manner as in Example 213-2 and Example 214 using propionic acid tert-butyl ester and 4- (trifluoromethyl) phenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 3.14 (3H, s), 3.19 (2H, t, J = 6.9 Hz), 4.13 (2H , T, J = 6.9 Hz), 6.84 (1H, d, J = 9.3 Hz), 7.03 (1H, s), 7.67-7.74 (3H, m), 8.10 (2H, d, J = 7.8 Hz).
MS: 483 (M ⁺⁺ 1).
[Example 220]
2-{[4- (2-{[6- (4-Chloro-2-fluorophenyl) pyridazin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 213-1 Using the propionic acid tert-butyl ester and 4-chloro-2-fluorophenylboric acid synthesized in Reference Example 3 as starting materials, the title compound was obtained in the same manner as in Example 213-2 and Example 213-3. .

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.70 (6H, s), 3.08 (2H, t, J = 5.7 Hz), 3.52-3.57 (2H, m), 6 .92 (1H, d, J = 9.6 Hz), 7.04 (1H, s), 7.16-7.24 (2H, m), 7.58 (1H, brs), 7.75-7 .79 (1H, m), 7.98-8.04 (1H, m).
MS: 453 (M ⁺⁺ 1).
[Example 221]
2-[(4- {2-[[6- (4-Chloro-2-fluorophenyl) pyridazin-3-yl] (methyl) amino] ethyl} -1,3-thiazol-2-yl) thio]- 2-Methylpropionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 213-1 The title compound was obtained in the same manner as in Example 213-2 and Example 214 using propionic acid tert-butyl ester and 4-chloro-2-fluorophenylboric acid synthesized in Reference Example 3 as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 3.11 (3H, s), 3.18 (2H, t, J = 6.9 Hz), 4.11 (2H , T, J = 6.9 Hz), 6.83 (1H, d, J = 9.6 Hz), 7.02 (1H, s), 7.17-7.28 (2H, m), 7.68 -7.72 (1H, m), 8.06-8.11 (1H, m).
MS: 467 (M ⁺⁺ 1).
[Example 222]
2-{[4- (2-{[6- (2,4-dichlorophenyl) pyridazin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 213-1 The title compound was obtained in the same manner as in Example 213-2 and Example 213-3 using propionic acid tert-butyl ester and 2,4-dichlorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.08 (2H, t, J = 5.4 Hz), 3.52 to 3.57 (2H, m), 6 .90-6.93 (1H, m), 7.05 (1H, s), 7.33-7.37 (1H, m), 7.48 (1H, d, J = 1.8 Hz), 7 61-7.72 (2H, m).
MS: 469 (M ⁺⁺ 1).
[Example 223]
2-[(4- {2-[[6- (2,4-Dichlorophenyl) pyridazin-3-yl] (methyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 213-1 The title compound was obtained in the same manner as in Example 213-2 and Example 214 using propionic acid tert-butyl ester and 2,4-dichlorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 3.12 (3H, s), 3.18 (2H, t, J = 6.9 Hz), 4.11 (2H , T, J = 6.9 Hz), 6.82 (1H, d, J = 9.6 Hz), 7.03 (1H, s), 7.36 (1H, dd, J = 2.1, 8.). 4 Hz), 7.48 (1 H, d, J = 2.1 Hz), 7.63 (1 H, d, J = 9.6 Hz), 7.70 (1 H, d, J = 8.4 Hz).
MS: 483 (M ⁺⁺ 1).
[Example 224]
2-({4- [2-({6- [2-Fluoro-4- (trifluoromethyl) phenyl] pyridazin-3-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) -2-Methylpropionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 213-1 Using 2-fluoro-4- (trifluoromethyl) phenylboric acid synthesized in the same manner as in Reference Example 3 using propionic acid tert-butyl ester and 4-bromo-3-fluorobenzotrifluoride as starting materials, Example The title compound was obtained in the same manner as in 213-2 and Example 213-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.70 (6H, s), 3.09 (2H, t, J = 5.0 Hz), 3.55-3.57 (2H, m), 6 .93 (1H, d, J = 9.8 Hz), 7.05 (1H, s), 7.42 (1H, d, J = 11.4 Hz), 7.51-7.57 (2H, m) 7.82 (1H, d, J = 9.8 Hz), 8.21 (1H, t, J = 7.8 Hz).
MS: 487 (M ⁺⁺ 1).
[Example 225]
2-({4- [2-({6- [2-Chloro-4- (trifluoromethyl) phenyl] pyridazin-3-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) -2-Methylpropionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 213-1 Using 2-chloro-4- (trifluoromethyl) phenylboric acid synthesized in the same manner as in Reference Example 3 using propionic acid tert-butyl ester and 3-chloro-4-iodobenzotrifluoride as starting materials, Example The title compound was obtained in the same manner as in 213-2 and Example 213-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.10 (2H, t, J = 5.2 Hz), 3.54-3.59 (2H, m), 6 .93 (1H, d, J = 9.6 Hz), 7.06 (1H, s), 7.61-7.64 (2H, m), 7.72-7.76 (2H, m), 7 .84 (1H, d, J = 8.2 Hz).
MS: 503 (M ⁺⁺ 1).
[Example 226]
2-{[4- (2-{[5- (4-Chlorophenyl) pyrazin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (Examples) 226-1)
2-[(4- {2-[(5-Bromopyrazin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 12.1 g and 2,5- 9.5 g of bromopyrazine was dissolved in 10 mL of N-methyl-2-pyrrolidone, 5.16 g of N, N-diisopropylethylamine was added, and the mixture was stirred at 80 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1 to 2: 1) to give 11.2 g of the title compound as a yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.60 (6H, s), 3.00 (2H, t, J = 6.2 Hz), 3.67-3 .74 (2H, m), 5.77-5.80 (1H, m), 6.93 (1H, s), 7.89 (1H, s), 8.03 (1H, s).
(Example 226-2)
2-{[4- (2-{[5- (4-Chlorophenyl) pyrazin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  2-[(4- {2-[(5-Bromopyrazin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] synthesized in Example 226-1 under nitrogen atmosphere 2-methylpropionic acid tert-butyl ester (10.5 g) and 4-chlorophenylboric acid (5.36 g) were dissolved in dioxane (80 mL) and a 2 mol / L aqueous sodium carbonate solution (40 mL), and tetrakis (triphenylphosphine) palladium (1.32 g) was added. Reflux for hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 10.2 g of the title compound as a brown oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.62 (6H, s), 3.05 (2H, t, J = 6.0 Hz), 3.76-3 .82 (2H, m), 5.73-5.77 (1H, m), 6.96 (1H, s), 7.38 (2H, d, J = 8.7 Hz), 7.79 (2H) , D, J = 8.7 Hz), 8.14 (1H, d, J = 1.5 Hz), 8.40 (1H, d, J = 1.5 Hz).
(Example 226-3)
2-{[4- (2-{[5- (4-Chlorophenyl) pyrazin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-{[4- (2-{[5- (4-Chlorophenyl) pyrazin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} obtained in Example 226-2 2-methylpropionic acid tert-butyl ester (10 g) was dissolved in dichloromethane (80 mL), trifluoroacetic acid (30 mL) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed (neutralized) with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 6.6 g of the title compound as a pale yellow solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.09 (2H, t, J = 6.0 Hz), 3.57-3.61 (2H, m), 6 84-6.87 (1H, m), 7.04 (1H, s), 7.40 (2H, d, J = 8.6 Hz), 7.77 (2H, d, J = 8.6 Hz) , 8.10 (1H, s), 8.31 (1H, s).
MS: 435 (M ⁺⁺ 1).
[Example 227]
2-[(4- {2-[[5- (4-Chlorophenyl) pyrazin-2-yl] (methyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[[5- (4-Chlorophenyl) pyrazin-2-yl] (methyl) amino] ethyl} -1,3-thiazol-2-yl synthesized in Example 226-2 ) Thio] -2-methylpropionic acid tert-butyl ester as a starting material, and the title compound was obtained in the same manner as in Example 163.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.67 (6H, s), 3.09 (2H, t, J = 6.8 Hz), 3.12 (3H, s), 3.94 (2H , T, J = 6.8 Hz), 6.96 (1H, s), 7.40 (2H, d, J = 8.6 Hz), 7.77 (2H, d, J = 8.6 Hz), 8 .08 (1H, s), 8.45 (1H, s).
MS: 449 (M ⁺⁺ 1).
[Example 228]
2-methyl-2-({4- [2-({5- [4- (trifluoromethyl) phenyl] pyrazin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-[(4- {2-[(5-Bromopyrazin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 226-1 The title compound was obtained in the same manner as in Example 226-2 and Example 226-3, starting from propionic acid tert-butyl ester and [4- (trifluoromethyl) phenyl] boric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.72 (6H, s), 3.09-3.15 (2H, m), 3.60-3.66 (2H, m), 6.94 -6.96 (1H, m), 7.07 (1H, s), 7.70 (2H, d, J = 8.2 Hz), 7.98 (2H, d, J = 8.2 Hz), 8 .16 (1H, s), 8.41 (1H, s).
MS: 469 (M ⁺⁺ 1).
[Example 229]
2-Methyl-2-({4- [2- (methyl {5- [4- (trifluoromethyl) phenyl] pyrazin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio ) Propionic acid

  2-Methyl-2-({4- [2-({5- [4- (trifluoromethyl) phenyl] pyrazin-2-yl} amino) ethyl] -1 which is an intermediate synthesized in Example 228 , 3-thiazol-2-yl} thio) propionic acid tert-butyl ester as a starting material, and the title compound was obtained in the same manner as in Example 163.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.67 (6H, s), 3.11 (2H, t, J = 6.8 Hz), 3.15 (3H, s), 3.96 (2H , T, J = 6.8 Hz), 6.97 (1H, s), 7.69 (2H, d, J = 8.2 Hz), 7.95 (2H, d, J = 8.2 Hz), 8 .12 (1H, s), 8.52 (1H, s).
MS: 483 (M ⁺⁺ 1).
[Example 230]
2-methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrazin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-[(4- {2-[(5-Bromopyrazin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 226-1 The title compound was obtained in the same manner as in Example 226-2 and Example 226-3, starting from propionic acid tert-butyl ester and [4- (trifluoromethoxy) phenyl] boric acid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.10 (2H, t, J = 6.0 Hz), 3.57-3.62 (2H, m), 6 .85-6.87 (1H, m), 7.04 (1H, s), 7.27 (2H, d, J = 8.9 Hz), 7.86 (2H, d, J = 8.9 Hz) , 8.11 (1H, s), 8.32 (1H, s).
MS: 485 (M ⁺⁺ 1).
[Example 231]
2-Methyl-2-({4- [2- (methyl {5- [4- (trifluoromethoxy) phenyl] pyrazin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio ) Propionic acid

  2-Methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrazin-2-yl} amino) ethyl] -1 as an intermediate synthesized in Example 230 , 3-thiazol-2-yl} thio) propionic acid tert-butyl ester as a starting material, and the title compound was obtained in the same manner as in Example 163.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.70 (6H, s), 3.12 (2H, t, J = 6.8 Hz), 3.16 (3H, s), 3.97 (2H , T, J = 6.8 Hz), 6.99 (1H, s), 7.30 (2H, d, J = 8.7 Hz), 7.88 (2H, d, J = 8.7 Hz), 8 .12 (1H, s), 8.48 (1H, s).
MS: 499 (M ⁺⁺ 1).
[Example 232]
2-({4- [2-({5- [2-Fluoro-4- (trifluoromethyl) phenyl] pyrazin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) -2-Methylpropionic acid

  2-[(4- {2-[(5-Bromopyrazin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 226-1 Using 2-fluoro-4- (trifluoromethyl) phenylboric acid synthesized in the same manner as in Reference Example 3 using propionic acid tert-butyl ester and 4-bromo-3-fluorobenzotrifluoride as starting materials, Example The title compound was obtained in the same manner as in 226-2 and Example 226-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69 (6H, s), 3.07-3.12 (2H, m), 3.60-3.65 (2H, m), 6.97 -7.01 (1H, m), 7.04 (1H, s), 7.39-7.50 (2H, m), 8.09 (1H, t, J = 8.1 Hz), 8.15 (1H, s), 8.50 (1H, s).
MS: 487 (M ⁺⁺ 1).
[Example 233]
2-{[4- (2-{[6- (4-Chlorophenyl) -4-methylpyridazin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropion acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and non-patent literature [J. Med. Chem. 32, 528 (1989)], starting from 3-chloro-6- (4-chlorophenyl) -4-methylpyridazine synthesized in the same manner as in Example 162-1 and Example 162-3. Gave the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 2.18 (3H, s), 3.22 (2H, t, J = 6.3 Hz), 3.98-4 .04 (2H, m), 5.00-5.05 (1H, m), 7.03 (1H, s), 7.37-7.42 (3H, m), 7.88 (2H, d , J = 8.6 Hz).
MS: 449 (M ⁺⁺ 1).
[Example 234]
2-[(4- {2-[[6- (4-Chlorophenyl) -4-methylpyridazin-3-yl] (methyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2 -Methylpropionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and non-patent literature [J. Med. Chem. 32, 528 (1989)] as a starting material and 3-chloro-6- (4-chlorophenyl) -4-methylpyridazine as a starting material, and the same procedure as in Example 162-1 and Example 163 was performed. A compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.60 (6H, s), 2.35 (3H, s), 3.11-3.17 (5H, m), 3.84 (2H, t , J = 6.9 Hz), 6.97 (1H, s), 7.46 (2H, d, J = 8.6 Hz), 7.51 (1H, s), 7.92 (2H, d, J = 8.6 Hz).
MS: 463 (M ^<+> ).
[Example 235]
2-methyl-2-({4- [2-({4-methyl-6- [4- (trifluoromethyl) phenyl] pyridazin-3-yl} amino) ethyl] -1,3-thiazole-2- Il} thio) propionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and non-patent literature [J. Med. Chem. 32, 528 (1989)] and starting from 3-chloro-4-methyl-6- [4- (trifluoromethyl) phenyl] pyridazine synthesized in accordance with Example 162-1 and Example 162- The title compound was obtained in the same manner as in 3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.60 (6H, s), 2.43 (3H, s), 3.14-3.20 (2H, m), 4.05-4.11 (2H, m), 7.13 (1H, s), 7.63-7.69 (3H, m), 7.88 (2H, d, J = 7.9 Hz).
MS: 483 (M ⁺⁺ 1).
[Example 236]
2-methyl-2-({4- [2- (methyl {4-methyl-6- [4- (trifluoromethyl) phenyl] pyridazin-3-yl} amino) ethyl] -1,3-thiazole-2 -Il} thio) propionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and non-patent literature [J. Med. Chem. 32, 528 (1989)] as a starting material, and starting from 3-chloro-4-methyl-6- [4- (trifluoromethyl) phenyl] pyridazine synthesized in accordance with Example 162-1 and Example 163 The title compound was obtained by the same operation.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.59 (6H, s), 2.39 (3H, s), 3.12-3.19 (5H, m), 3.88 (2H, t , J = 6.9 Hz), 7.00 (1H, s), 7.58 (1H, s), 7.74 (2H, d, J = 8.2 Hz), 8.08 (2H, d, J = 8.2 Hz).
MS: 497 (M ⁺⁺ 1).
[Example 237]
2-Methyl-2-({4- [2-({4-methyl-6- [4- (trifluoromethoxy) phenyl] pyridazin-3-yl} amino) ethyl] -1,3-thiazole-2- Il} thio) propionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and non-patent literature [J. Med. Chem. 32, 528 (1989)] and starting from 3-chloro-4-methyl-6- [4- (trifluoromethoxy) phenyl] pyridazine synthesized in accordance with Example 162-1 and Example 162- The title compound was obtained in the same manner as in 3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.58 (6H, s), 2.41 (3H, s), 3.12-3.18 (2H, m), 4.03-4.09 (2H, m), 7.10 (1H, s), 7.24 (2H, d, J = 8.8 Hz), 7.56 (1H, s), 7.82 (2H, d, J = 8) .8 Hz).
MS: 499 (M ⁺⁺ 1).
[Example 238]
2-{[4- (2-{[3-Cyano-5- (4-fluorophenyl) pyridin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and patent document [WO0224694] and the like The same operation as in Example 162-1 was carried out using 5-bromo-2-chloronicotinonitrile synthesized as a starting material as the starting material, and then Example 162-2 and Example using 4-fluorophenylboric acid. The title compound was obtained by the same procedures as 162-3.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.04 (2H, t, J = 7.2 Hz), 3.71 to 3.78 (2H, m) , 7.24-7.37 (3H, m), 7.51 (1H, s), 7.67-7.72 (2H, m), 8.25 (1H, d, J = 2.7 Hz) , 8.63 (1H, d, J = 2.7 Hz).
MS: 443 (M ⁺⁺ 1).
[Example 239]
2-{[4- (2-{[5- (4-Chlorophenyl) -3-cyanopyridin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropion acid

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and patent document [WO0224694] and the like The same operation as in Example 162-1 was performed using 5-bromo-2-chloronicotinonitrile synthesized as a reference as a starting material, and then Example 162-2 and Example 162 using 4-chlorophenylboric acid. The title compound was obtained by carrying out the same operation as -3.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.51 (6H, s), 3.03 (2H, t, J = 7.2 Hz), 3.72 to 3.78 (2H, m) 7.39-7.51 (4H, m), 7.68-7.71 (2H, m), 8.29 (1H, d, J = 2.4 Hz), 8.66 (1H, d, J = 2.4 Hz).
MS: 459 (M ⁺⁺ 1).
[Example 240]
2-({4- [2-({3-cyano-5- [4- (trifluoromethyl) phenyl] pyridin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) -2-Methylpropionic acid

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and patent document [WO0224694] and the like The same operation as in Example 162-1 was performed using 5-bromo-2-chloronicotinonitrile synthesized as a reference as a starting material, and then Example 162-2 was performed using 4- (trifluoromethyl) phenylboric acid. The title compound was obtained by the same procedures as in Example 162-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.67 (6H, s), 3.14 (2H, t, J = 6.3 Hz), 3.95-4.01 (2H, m), 6 .03 (1H, brs), 7.02 (1H, s), 7.57 (2H, d, J = 8.4 Hz), 7.70 (2H, d, J = 8.4 Hz), 7.90 (1H, d, J = 2.7 Hz), 8.54 (1H, d, J = 2.7 Hz).
MS: 493 (M ⁺⁺ 1).
[Example 241]
2-({4- [2-({3-cyano-5- [4- (trifluoromethoxy) phenyl] pyridin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) -2-Methylpropionic acid

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and patent document [WO0224694] and the like The same operation as in Example 162-1 was performed using 5-bromo-2-chloronicotinonitrile synthesized as a reference as a starting material, and then Example 162-2 was performed using 4- (trifluoromethoxy) phenylboric acid. The title compound was obtained by the same procedures as in Example 162-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.67 (6H, s), 3.13 (2H, t, J = 6.3 Hz), 3.94-4.00 (2H, m), 5 .98 (1H, brs), 7.01 (1H, s), 7.28-7.31 (2H, m), 7.46-7.49 (2H, m), 7.85 (1H, d) , J = 2.4 Hz), 8.49 (1H, d, J = 2.4 Hz).
MS: 509 (M ⁺⁺ 1).
[Example 242]
2-{[4- (2-{[5- (4-chlorophenyl) pyridin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid hydrochloride ( Example 242-1)
2-[(4- {2-[(5-Bromopyridin-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  16 g of {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid obtained in Example 3 and 2-amino-5- 8.7 g of bromopyridine is dissolved in 100 mL of dichloromethane, and 14.5 g of N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) hydrochloride and 9.2 g of 4-dimethylaminopyridine (DMAP) are sequentially added. The mixture was added and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 22 g of the title compound as a white solid.

1H-NMR (CDCl ₃ , 300 MHz) δ: 1.41 (9H, s), 1.56 (6H, s), 3.87 (2H, s), 7.24 (1H, s), 7.74 -7.77 (1H, m), 8.11 (1H, d, J = 9.0 Hz), 8.30 (1H, d, J = 2.1 Hz), 9.07 (1H, brs).
(Example 242-2)
2-[(4- {2-[(5-Bromopyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-[(4- {2-[(5-Bromopyridin-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) thio]-obtained in Example 242-1 12.5 g of 2-methylpropionic acid tert-butyl ester was dissolved in 20 mL of tetrahydrofuran, and 100 mL of 1 mol / L-borane / tetrahydrofuran complex was added thereto under ice cooling, followed by stirring at room temperature for 12 hours. After cooling the reaction solution with ice, 100 mL of methanol was added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, 40 mL of 2-aminoethanol was added, and the mixture was stirred at 70 ° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1) to give 5.7 g of the title compound as a colorless oil.

1H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.60 (6H, s), 3.02 (2H, t, J = 6.3 Hz), 3.64-3. 70 (2H, m), 5.20 (1H, brs), 6.45 (1H, d, J = 8.7 Hz), 6.97 (1H, s), 7.40-7.44 (1H, m), 8.09 (1H, d, J = 2.1 Hz).
MS: 460 (M ⁺⁺ 1).
(Example 242-3)
2-{[4- (2-{[5- (4-Chlorophenyl) pyridin-2-yl] amino} -2-oxoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  2-[(4- {2-[(5-Bromopyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl obtained in Example 242-2 700 mg of propionic acid tert-butyl ester and 358 mg of 4-chlorophenylboric acid were dissolved in 8 mL of dioxane and 4 mL of 2 mol / L sodium carbonate, and 88 mg of tetrakis (triphenylphosphine) palladium was added and refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 2 to 2: 1) to give 450 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.61 (6H, s), 3.07 (2H, t, J = 6.3 Hz), 3.72-3 .78 (2H, m), 5.20 (1H, brs), 6.57 (1H, d, J = 8.4 Hz), 7.00 (1H, s), 7.35-7.43 (4H M), 7.56-7.60 (1H, m), 8.30 (1H, d, J = 2.4 Hz).
MS: 490 (M ⁺⁺ 1).
(Example 242-4)
2-{[4- (2-{[5- (4-Chlorophenyl) pyridin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid hydrochloride

2-{[4- (2-{[5- (4-Chlorophenyl) pyridin-2-yl] amino} -2-oxoethyl) -1,3-thiazol-2-yl obtained in Example 242-3 ] 145 mg of thio} -2-methylpropionic acid tert-butyl ester was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 20: 1). The obtained compound was dissolved in 4 mL of diethyl ether, 0.5 mL of 4 mol / L hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give 69 mg of the title compound as a white solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.09 (2H, t, J = 6.9 Hz), 3.69-3.77 (2H, m) 7.18 (1H, d, J = 9.6 Hz), 7.55-7.58 (2H, m), 7.63 (1H, s), 7.70-7.74 (2H, m) , 8.20-8.28 (2H, m).
MS: 434 (M ⁺⁺ 1).
[Example 243]
2-methyl-2-({4- [2-({5- [4- (trifluoromethyl) phenyl] pyridin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid hydrochloride

  2-[(4- {2-[(5-Bromopyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 242-2 The title compound was obtained in the same manner as in Example 242-3 and Example 242-4 using propionic acid tert-butyl ester and 4- (trifluoromethyl) phenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.10 (2H, t, J = 6.9 Hz), 3.79-3.81 (2H, m) , 7.21 (1H, d, J = 9.3 Hz), 7.64 (1H, s), 7.85 (2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz), 8.30-8.33 (2H, m).
MS: 468 (M ⁺⁺ 1).
[Example 244]
2-methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyridin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid hydrochloride

  2-[(4- {2-[(5-Bromopyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 242-2 The title compound was obtained in the same manner as in Example 242-3 and Example 242-4 using propionic acid tert-butyl ester and 4- (trifluoromethoxy) phenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.09 (2H, t, J = 6.9 Hz), 3.77-3.90 (2H, m) 7.18 (1H, d, J = 9.6 Hz), 7.48-7.51 (2H, m), 7.63 (1H, s), 7.79-7.82 (2H, m) , 8.21-8.28 (2H, m).
MS: 484 (M ⁺⁺ 1).
[Example 245]
2-Methyl-2-({4- [2- (methyl {5- [4- (trifluoromethyl) phenyl] pyridin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio ) Propionic acid hydrochloride

  2-[(4- {2-[(5-Bromopyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 242-2 The title compound was obtained in the same manner as in Example 242-3, Example 163-1 and Example 164-2, using propionic acid tert-butyl ester and 4- (trifluoromethyl) phenylboric acid as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.08 (2H, t, J = 6.6 Hz), 3.15 (3H, s), 4.01 (2H, t, J = 6.6 Hz), 7.18 (1H, brd, J = 9.6 Hz), 7.58 (1H, s), 7.84 (2H, d, J = 8.4 Hz) 7.92 (2H, d, J = 8.4 Hz), 8.26 (1H, brd, J = 9.6 Hz), 8.33 (1H, d, J = 2.1 Hz).
MS: 482 (M ⁺⁺ 1).
[Example 246]
2-{[4- (2-{[3- (4-Chlorophenyl) -1H-pyrazol-5-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  {2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid and 3- (4-chlorophenyl) synthesized in Example 3 The compound obtained by performing the same operation as in Example 242-1 and Example 242-2 using -1H-pyrazol-5-amine as a starting material was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. did. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into a saturated aqueous sodium hydrogen carbonate layer). A 10% aqueous citric acid solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. After washing with water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.74 (6H, s), 2.85 (2H, t, J = 5.8 Hz), 3.05 (2H, t, J = 5.8 Hz) , 5.52 (1H, s), 6.87 (1H, s), 7.12-7.15 (2H, m), 7.42-7.46 (2H, m).
MS: 423 (M ⁺⁺ 1).
[Example 247]
2-{[4- (2-{[3- (4-Chlorophenyl) -1-methyl-1H-pyrazol-5-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2 -Methylpropionic acid

  {2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid and 3- (4-chlorophenyl) synthesized in Example 3 The compound obtained by performing the same operation as in Example 242-1 and Example 242-2 using -1-methyl-1H-pyrazol-5-amine as a starting material was subjected to dichloromethane and trifluoroacetic acid, and room temperature. For 12 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (elution solvent; chloroform: methanol = 20: 1) to obtain the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.66 (6H, s), 3.04 (2H, t, J = 6.3 Hz), 3.37 (2H, t, J = 6.3 Hz) 3.64 (3H, s), 5.66 (1H, s), 7.00 (1H, s), 7.26-7.30 (2H, m), 7.60-7.65 (2H , M).
MS: 437 (M ⁺⁺ 1).
[Example 248]
2-[(4- {2-[(5-Chloro-1,3-benzoxazol-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  {2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid and 5-chloro-1,3 synthesized in Example 3 -The compound obtained by performing the same operation as Example 242-1 and Example 242-2 using benzoxazol-2-amine as a starting material was attached to dichloromethane and trifluoroacetic acid, and stirred at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 20: 1), ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was an ethyl acetate layer). To be extracted). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.67 (6H, s), 3.04 (2H, t, J = 5.7 Hz), 3.70 (2H, brs), 6.98-7 .02 (1H, m), 7.08 (1H, s), 7.17 (1H, d, J = 8.7 Hz), 7.29-7.30 (2H, m).
MS: 398 (M ⁺⁺ 1).
[Example 249]
2-methyl-2-({4- [2-({6- [4- (trifluoromethyl) phenyl] pyridin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  {2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid and 6-bromopyridin-2- synthesized in Example 3 The same procedure as in Example 242-1 was performed using amine as the starting material, and then Example 242-2, Example 242-2, and Example 242-4 using 4- (trifluoromethyl) phenyl boric acid. The title compound was obtained by carrying out the same operation as.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.52 (6H, s), 3.06 (2H, t, J = 6.9 Hz), 3.73 (2H, t, J = 6. 9 Hz), 6.83 (1 H, brs), 7.23 (1 H, d, J = 7.5 Hz), 7.56 (1 H, s), 7.76 (1 H, s), 7.88 (2 H) , D, J = 8.1 Hz), 8.19 (2H, d, J = 8.1 Hz).
MS: 468 (M ⁺⁺ 1).
[Example 250]
2-{[4- (2-{[4- (4-Fluorophenyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid hydrochloride

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and patent document [WO2004000762A2] The title compound was obtained in the same manner as in Example 162-1 and Example 164-2, using 4- (4-fluorophenyl) -2- (methylsulfonyl) pyrimidine synthesized by reference as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.07 (2H, t, J = 6.9 Hz), 3.81 (2H, brs), 7.39 -7.45 (3H, m), 7.57 (1H, s), 8.30 (2H, brs), 8.46 (1H, d, J = 6.0 Hz).
[Example 251]
MS: 419 (M ⁺⁺ 1).
2-methyl-2-({4- [2-({4- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid hydrochloride

2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and patent document [WO2004000762A2] Starting from 2- (methylsulfonyl) -4- [4- (trifluoromethyl) phenyl] pyrimidine synthesized as a reference, the title compound was obtained in the same manner as in Example 162-1 and Example 164-2. The
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.04 (2H, t, J = 7.2 Hz), 3.64-3.80 (2H, m) , 7.32-7.34 (1H, m), 7.53 (1H, s), 7.89-7.91 (2H, m), 8.36 (2H, brs), 8.46 (1H , D, J = 5.4 Hz).
MS: 469 (M ⁺⁺ 1).
[Example 252]
2-Methyl-2-({4- [2-({4- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid hydrochloride

2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and patent document [WO2004000762A2] Starting from 2- (methylsulfonyl) -4- [4- (trifluoromethoxy) phenyl] pyrimidine synthesized as a reference, the title compound was obtained in the same manner as in Example 162-1 and Example 164-2. The
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.05 (2H, t, J = 7.2 Hz), 3.85-3.90 (2H, m) 7.36 (1H, brs), 7.53-7.55 (3H, m), 8.30 (2H, brs), 8.44 (1H, d, J = 6.0 Hz).
MS: 485 (M ⁺⁺ 1).
[Example 253]
2-Methyl-2-({4- [2-({3-methyl-1- [4- (trifluoromethoxy) phenyl] -1H-pyrazol-5-yl} amino) ethyl] -1,3-thiazole -2-yl} thio) propionic acid hydrochloride (Example 253-1)
2-Methyl-2-({4- [2-({3-methyl-1- [4- (trifluoromethoxy) phenyl] -1H-pyrazol-5-yl} amino) ethyl] -1,3-thiazole -2-yl} thio) propionic acid tert-butyl ester

2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 was treated with N, N- It melt | dissolved in 50 mL of dimethylformamide, and 0.88 g of diketene was dripped under ice-cooling. The mixture was warmed to room temperature and stirred for 1 hour. Dilute with ethyl acetate, wash with saturated brine, and dry over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to give 2-({4- [2- (acetoacetylamino) ethyl] -1,3-thiazole-2. -Il} thio) -2-methylpropionic acid tert-butyl ester 3.4 g was obtained as a colorless oil. This compound was used in the next step without further purification. [4- (Trifluoromethoxy) phenyl] hydrazine hydrochloride (390 mg) was dissolved in ethanol (8 mL), and crushed sodium hydroxide (65 mg) was added at room temperature. The insoluble material was filtered through Celite, and the solvent was distilled off under reduced pressure. The residue was dissolved again in 8 mL of ethanol, and the previously obtained 2-({4- [2- (acetoacetylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert -600 mg of butyl ester was added at room temperature and stirred for 30 minutes. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 8 mL of tetrahydrofuran, 345 mg of diphosphorus pentasulfide and 329 mg of sodium carbonate were added, and the mixture was heated to reflux for 2 hours. The solvent was evaporated, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to give 690 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.40 (9H, s) 1.49 (6H, s), 2.24 (3H, s), 3.05 (2H, t, J = 6. 3Hz), 3.41-3.47 (2H, m), 4.45-4.49 (1H, m), 5.40 (1H, s), 7.01 (1H, s), 7.28. -7.31 (2H, m), 7.53-7.59 (2H, m).
(Example 253-2)
2-Methyl-2-({4- [2-({3-methyl-1- [4- (trifluoromethoxy) phenyl] -1H-pyrazol-5-yl} amino) ethyl] -1,3-thiazole -2-yl} thio) propionic acid hydrochloride

  2-Methyl-2-({4- [2-({3-methyl-1- [4- (trifluoromethoxy) phenyl] -1H-pyrazol-5-yl} amino synthesized in Example 253-1 ) Ethyl] -1,3-thiazol-2-yl} thio) propionic acid tert-butyl ester (690 mg) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 1: 1). The obtained compound was dissolved in 4 mL of diethyl ether, 0.5 mL of 4 mol / L hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give 461 mg of the title compound as a white solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.49 (6H, s), 2.20 (3H, s), 2.97 (2H, t, J = 6.9 Hz), 3.37 (2H, t, J = 6.9 Hz), 5.70 (1H, s), 7.52-7.56 (3H, m), 7.67-7.71 (2H, m).
MS: 487 (M ⁺⁺ 1).
[Example 254]
2-Methyl-2-[(4- {2-[(3-methyl-1-phenyl-1H-pyrazol-5-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid Hydrochloride

  Starting from 2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and phenylhydrazine synthesized in Example 7, The title compound was obtained in the same manner as in Example 253.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 2.25 (3H, s), 2.96 (2H, t, J = 6.9 Hz), 3.39 -3.43 (2H, m), 5.80 (1H, s), 7.52-7.63 (6H, m).
MS: 403 (M ⁺⁺ 1).
[Example 255]
2-Methyl-2-({4- [2-({3-methyl-1- [4- (trifluoromethyl) phenyl] -1H-pyrazol-5-yl} amino) ethyl] -1,3-thiazole -2-yl} thio) propionic acid hydrochloride

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and [4- (trifluoromethyl) synthesized in Example 7 ) Phenyl] hydrazine was used as a starting material, and the title compound was obtained in the same manner as in Example 253.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.49 (6H, s), 2.17 (3H, s), 2.99 (2H, t, J = 6.9 Hz), 3.34 (2H, t, J = 6.9 Hz), 5.61 (1H, s), 7.53 (1H, s), 7.78-7.87 (4H, m).
MS: 471 (M ⁺⁺ 1).
[Example 256]
2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloride Reference Example 4
N- (4-Bromophenyl) -2-nitrobenzenesulfonamide

15.1 g of 4-bromoaniline was dissolved in 300 mL of dichloromethane, and 7.73 g of pyridine and 20.7 g of 2-nitrobenzenesulfonyl chloride were added at room temperature, followed by stirring for 1 hour. Water was added and the organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ether was added to the residue for suspension washing, and the resulting solid was dried under reduced pressure to give 21.9 g of the title compound as a pale yellow solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 7.08-7.10 (2H, m), 7.38-7.41 (2H, m), 7.61-7.63 (1H, m) , 7.69-7.71 (1H, m), 7.82-7.87 (2H, m).
(Example 256-1)
2-{[4- (2-{(4-Bromophenyl) [(2-nitrophenyl) sulfonyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert- Butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and Reference Example 4 5.9 g of N- (4-bromophenyl) -2-nitrobenzenesulfonamide synthesized is dissolved in 80 mL of dichloromethane, and 6.5 g of triphenylphosphine and diethyl diazodicarboxylate (40% toluene solution) are added under ice cooling. 8 g was added and then stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1 to 2: 1) to give 8.4 g of the title compound as a colorless oil.

1H-NMR (CDCl ₃ , 300 MHz) δ: 1.41 (9H, s), 1.51 (6H, s), 2.99 (2H, t, J = 7.2 Hz), 4.09-4. 16 (2H, m), 7.02-7.05 (2H, m), 7.11 (1H, s), 7.41-7.44 (2H, m), 7.51-7.69 ( 4H, m).
(Example 256-2)
2-{[4- (2-{(4′-fluorobiphenyl-4-yl) [(2-nitrophenyl) sulfonyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2- Methylpropionic acid tert-butyl ester

  2-{[4- (2-{(4-Bromophenyl) [(2-nitrophenyl) sulfonyl] amino} ethyl) -1,3-thiazol-2-yl] thio synthesized in Example 256-1 } 1.2 g of 2-methylpropionic acid tert-butyl ester and 0.31 g of 4-fluorophenylboric acid are dissolved in 10 mL of dioxane and 5 mL of 2 mol / L sodium carbonate, and 0.11 g of tetrakis (triphenylphosphine) palladium is added. Refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1 to 2: 1) to give 1.1 g of the title compound as a colorless oil.

1H-NMR (CDCl ₃ , 300 MHz) δ: 1.40 (9H, s), 1.51 (6H, s), 3.04 (2H, t, J = 7.2 Hz), 4.15-4. 20 (2H, m), 7.13-7.23 (5H, m), 7.45-7.63 (8H, m).
(Example 256-6)
2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-{(4′fluorobiphenyl-4-yl) [(2-nitrophenyl) sulfonyl] amino} ethyl) -1,3-thiazole-2 synthesized in Example 256-2 -Il] thio} -2-methylpropionic acid tert-butyl ester (675 mg) and thiophenol (169 mg) were dissolved in N, N-dimethylformamide (5 mL), potassium carbonate (425 mg) was added, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 5: 1) to give 454 mg of the title compound as a colorless oil.

1H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.61 (6H, s), 3.07 (2H, t, J = 6.3 Hz), 3.53 (2H, t, J = 6.3 Hz), 6.70-6.73 (2H, m), 7.01-7.09 (3H, m), 7.34-7.38 (2H, m), 7. 44-7.49 (2H, m).
(Example 256-4)
2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloride

2-[(4- {2-[(4′fluorobiphenyl-4-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl obtained in Example 256-6 300 mg of propionic acid tert-butyl ester was dissolved in 4 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 1: 1). The obtained compound was dissolved in 4 mL of diethyl ether, 0.5 mL of 4 mol / L hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give the title compound (199 mg) as a white solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.53 (6H, s), 3.07 (2H, t, J = 7.3 Hz), 3.50 (2H, t, J = 7. 3 Hz), 7.09 (2H, brs), 7.22-7.28 (2H, m), 7.56-7.67 (5H, m).
MS: 417 (M ⁺⁺ 1).
[Example 257]
2-[(4- {2-[(4'-Fluorobiphenyl-4-yl) (methyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2- synthesized in Example 256-6 The title compound was obtained in the same manner as in Example 163, using methylpropionic acid tert-butyl ester as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 2.95 (3H, s), 3.06 (2H, t, J = 7.2 Hz), 3.74 (2H , T, J = 7.2 Hz), 6.74-6.77 (2H, m), 6.96 (1H, s), 7.05-7.11 (2H, m), 7.42-7 .51 (4H, m).
MS: 431 (M ⁺⁺ 1).
[Example 258]
2-Methyl-2-{[4- (2-{[4 '-(trifluoromethoxy) biphenyl-4-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} propionic acid hydrochloride

  2-{[4- (2-{(4-Bromophenyl) [(2-nitrophenyl) sulfonyl] amino} ethyl) -1,3-thiazol-2-yl] thio synthesized in Example 256-1 } -2-Methylpropionic acid tert-butyl ester and 4- (trifluoromethoxy) phenylboric acid as starting materials, and the title compound was prepared in the same manner as in Example 256-2, Example 256-3 and Example 256-6. Got.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.53 (6H, s), 3.02 (2H, t, J = 7.2 Hz), 3.45 (2H, t, J = 7. 2 Hz), 6.89-6.91 (2H, m), 7.37-7.39 (2H, m), 7.51-7.54 (3H, m), 7.68-7.71 ( 2H, m).
MS: 483 (M ⁺⁺ 1).
[Example 259]
2-{[4- (2-{[6- (4-Fluorophenyl) pyridin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid (reference Example 5)
N- (6-chloropyridin-3-yl) -2-nitrobenzenesulfonamide

3.0 g of 6-chloropyridin-3-amine was dissolved in 80 mL of dichloromethane, 2.0 g of pyridine and 5.4 g of 2-nitrobenzenesulfonyl chloride were added at room temperature, and the mixture was stirred overnight. The precipitated solid was collected by filtration to give 5.6 g of the title compound as a purple solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 7.48 (1H, d, J = 8.7 Hz), 7.56-7.60 (1H, m), 7.85-7.90 ( 2H, m), 8.00-8.03 (2H, m), 8.16 (1H, d, J = 2.7 Hz).
(Example 259-1)
2-{[4- (2-{[6- (4-Fluorophenyl) pyridin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert- Butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and Reference Example 5 The synthesized N- (6-chloropyridin-3-yl) -2-nitrobenzenesulfonamide (5.2 g) was dissolved in dichloromethane (70 mL) and tetrahydrofuran (70 mL). Under ice cooling, 6.5 g of triphenylphosphine and diethyl diazodicarboxylate ( 10.7 g of a 40% toluene solution) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 1: 1) to give 2-{[4- (2- {2- { (6-Chloropyridin-3-yl) [(2-nitrophenyl) sulfonyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester 8 g was obtained. 2.0 g of this compound and 0.47 g of 4-fluorophenylboric acid were dissolved in 16 mL of dioxane and 8 mL of 2 mol / L sodium carbonate, and 0.19 g of tetrakis (triphenylphosphine) palladium was added and refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1 to 3: 2) to give 2-{[4- (2-{[6- (4-fluorophenyl) containing impurities. ) Pyridin-3-yl] [(2-nitrophenyl) sulfonyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester 1.9 g was obtained. 1.9 g of this compound and 0.49 g of thiophenol were dissolved in 15 mL of N, N-dimethylformamide, 1.2 g of potassium carbonate was added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 5: 1) to give 0.7 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (9H, s), 1.61 (6H, s), 3.07 (2H, t, J = 6.2 Hz), 3.51-3 .57 (2H, m), 4.56 (1H, brs), 7.00-7.12 (4H, m), 7.49 (1H, d, J = 8.7 Hz), 7.83-7 .88 (2H, m), 8.14 (1H, d, J = 2.8 Hz).
(Example 259-2)
2-{[4- (2-{[6- (4-Fluorophenyl) pyridin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-{[4- (2-{[6- (4-Fluorophenyl) pyridin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio synthesized in Example 259-1 } -2-Methylpropionic acid tert-butyl ester (270 mg) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 1: 1) to give 183 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.68 (6H, s), 3.04 (2H, t, J = 6.3 Hz), 3.53 (2H, t, J = 6.3 Hz) , 6.95-6.99 (2H, m), 7.06-7.11 (2H, m), 7.42 (1H, d, J = 8.7 Hz), 7.75-7.80 ( 2H, m), 8.22 (1H, d, J = 3.0 Hz).
MS: 418 (M ⁺⁺ 1).
[Example 260]
2-{[4- (2-{[6- (4-Chlorophenyl) pyridin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-{[4- (2-{(6-chloropyridin-3-yl) [(2-nitrophenyl) sulfonyl] amino} ethyl) -1,3-thiazole synthesized in the middle of Example 259-1 2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-chlorophenylboric acid as starting materials, and the title compound was obtained in the same manner as in Example 259.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.68 (6H, s), 3.06 (2H, t, J = 6.3 Hz), 3.57 (2H, t, J = 6.3 Hz) , 6.95-6.99 (2H, m), 7.36-7.38 (2H, m), 7.47 (1H, d, J = 8.7 Hz), 7.76-7.78 ( 2H, m), 8.19 (1H, d, J = 3.0 Hz).
MS: 434 (M ⁺⁺ 1).
[Example 261]
2-methyl-2-({4- [2-({6- [4- (trifluoromethyl) phenyl] pyridin-3-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-{[4- (2-{(6-chloropyridin-3-yl) [(2-nitrophenyl) sulfonyl] amino} ethyl) -1,3-thiazole synthesized in the middle of Example 259-1 2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4- (trifluoromethyl) phenylboric acid were used as starting materials, and the title compound was obtained in the same manner as in Example 259.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.68 (6H, s), 3.07 (2H, t, J = 6.3 Hz), 3.56 (2H, t, J = 6.3 Hz) , 6.96-6.99 (2H, m), 7.54 (1H, d, J = 8.7 Hz), 7.65 (2H, d, J = 8.4 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.22 (1H, d, J = 3.0 Hz).
MS: 468 (M ⁺⁺ 1).
[Example 262]
2-methyl-2-({4- [2-({6- [4- (trifluoromethoxy) phenyl] pyridin-3-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) Propionic acid

  2-{[4- (2-{(6-chloropyridin-3-yl) [(2-nitrophenyl) sulfonyl] amino} ethyl) -1,3-thiazole synthesized in the middle of Example 259-1 -2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4- (trifluoromethoxy) phenylboric acid were used as starting materials, and the title compound was obtained in the same manner as in Example 259.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.68 (6H, s), 3.05 (2H, t, J = 6.3 Hz), 3.54 (2H, t, J = 6.3 Hz) 6.95-6.99 (2H, m), 7.22-7.26 (2H, m), 7.46 (1H, d, J = 8.6 Hz), 7.82-7.85 ( 2H, m), 8.21 (1H, d, J = 2.9 Hz).
MS: 484 (M ⁺⁺ 1).
[Example 263]
2-[(4- {2-[[6- (4-Fluorophenyl) pyridin-3-yl] (methyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropion acid

  2-{[4- (2-{[6- (4-Fluorophenyl) pyridin-3-yl] amino} ethyl) -1,3-thiazol-2-yl synthesized in the middle of Example 259-1 The title compound was obtained by the same procedures as in Example 163 using thio} -2-methylpropionic acid tert-butyl ester as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.72 (6H, s), 3.02-3.05 (5H, m), 3.80 (2H, t, J = 6.4 Hz), 6 .91 (1H, s), 7.02-7.14 (3H, m), 7.49 (1H, d, J = 8.9 Hz), 7.77-7.82 (2H, m), 8 .27 (1H, d, J = 3.0 Hz).
MS: 432 (M ⁺⁺ 1).
[Example 264]
2-[(4- {2-[[6- (4-Chlorophenyl) pyridin-3-yl] (methyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-{[6- (4-Chlorophenyl) pyridin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} synthesized in the middle of Example 260 The title compound was obtained by the same procedures as in Example 163, using -2-methylpropionic acid tert-butyl ester as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.72 (6H, s), 3.02-3.05 (5H, m), 3.80 (2H, t, J = 6.3 Hz), 6 .91 (1H, s), 7.03 (1H, dd, J = 3.0, 8.7 Hz), 7.37-7.41 (2H, m), 7.52 (1H, d, J = 8.7 Hz), 7.75-7.77 (2 H, m), 8.28 (1 H, d, J = 3.0 Hz).
MS: 448 (M ⁺⁺ 1).
[Example 265]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (Example 265) -1)
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and 2-chloro- 13.2 g of N, N-diisopropylethylamine was added to 13.2 g of 5-ethylpyrimidine, and the mixture was stirred at 130 ° C. for 20 hours. The reaction solution was directly purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 1: 1) to obtain 23.5 g of the title compound as a slightly yellow solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19 (3H, t, J = 7.8 Hz), 1.44 (9H, s), 1.59 (6H, s), 2.46 (2H , Q, J = 7.8 Hz), 3.06 (2H, t, J = 6.6 Hz), 3.74-3.81 (2H, m), 5.26-5.30 (1H, m) 7.02 (1H, s), 8.13 (2H, s).
(Example 265-2)
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 8.90 g of propionic acid tert-butyl ester and 5.92 g of heptyl iodide were dissolved in 100 mL of N, N-dimethylformamide, 2.94 g of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 7: 1) to give 6.20 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.9 Hz), 1.16-1.35 (11H, m), 1.45 (9H, s), 1 .48-1.57 (2H, m), 1.58 (6H, s), 2.45 (2H, q, J = 7.5 Hz), 3.08 (2H, t, J = 7.5 Hz) 3.43 (2H, t, J = 7.5 Hz), 3.87 (2H, t, J = 7.5 Hz), 7.02 (1H, s), 8.12 (2H, s).
(Example 265-3)
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio]-obtained in Example 265-2 6.20 g of 2-methylpropionic acid tert-butyl ester was dissolved in 60 mL of dichloromethane, 12 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give the title compound (4.50 g) as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.9 Hz), 1.16-1.34 (11H, m), 1.51-1.57 (2H, m), 1.66 (6H, s), 2.45 (2H, q, J = 7.5 Hz), 3.10 (2H, t, J = 7.2 Hz), 3.46 (2H, t, J = 7.2 Hz), 3.82 (2H, t, J = 7.2 Hz), 6.96 (1H, s), 8.16 (2H, s).
MS: 451 (M ⁺⁺ 1).
[Example 266]
2-[(4- {2- [Heptyl (pyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  Starting from 2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloropyrimidine synthesized in Example 7 In the same manner as in Example 265, the title compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 7.0 Hz), 1.22-1.32 (8H, m), 1.52-1.57 (2H, m), 1.66 (6H, s), 3.11 (2H, t, J = 7.4 Hz), 3.47 (2H, t, J = 7.6 Hz), 3.89 (2H, t, J = 7.4 Hz), 6.46 (1H, s), 6.96 (1H, s), 8.29 (2H, d, J = 4.8 Hz).
MS: 423 (M ⁺⁺ 1).
[Example 267]
2-[(4- {2- [Heptyl (5-propylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro-5-propyl synthesized in Example 7 The title compound was obtained in the same manner as in Example 265, using pyrimidine as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.9 Hz), 1.20-1.32 (11H, m), 1.48-1.60 (4H, m), 1.66 (6H, s), 2.38 (2H, t, J = 7.2 Hz), 3.10 (2H, t, J = 7.2 Hz), 3.46 (2H, t, J = 7.5 Hz), 3.82 (2H, t, J = 7.2 Hz), 6.96 (1H, s), 8.13 (2H, s).
MS: 465 (M ⁺⁺ 1).
[Example 268]
2-{[4- (2- {Heptyl [4- (trifluoromethyl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro-4- (synthesized in Example 7 The title compound was obtained in the same manner as in Example 265, using trifluoromethyl) pyrimidine as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.9 Hz), 1.23-1.37 (8H, m), 1.52-1.60 (2H, m), 1.65 (6H, s), 3.12 (2H, t, J = 7.5 Hz), 3.53 (2H, t, J = 7.2 Hz), 3.90 (2H, t, J = 7.5 Hz), 6.74 (1H, d, J = 5.1 Hz), 6.99 (1H, s), 8.48 (1H, d, J = 5.1 Hz).
MS: 491 (M ⁺⁺ 1).
[Example 269]
2-[(4- {2-[(5-Bromopyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 5-bromo-2-chloro synthesized in Example 7 The title compound was obtained in the same manner as in Example 265, using pyrimidine as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.9 Hz), 1.20-1.37 (8H, m), 1.46-1.58 (2H, m), 1.66 (6H, s), 3.08 (2H, t, J = 7.5 Hz), 3.44 (2H, t, J = 7.5 Hz), 3.85 (2H, t, J = 7.5 Hz), 6.96 (1H, s), 8.27 (2H, s).
MS: 503 (M ⁺⁺ 1).
[Example 270]
2-[(4- {2-[(6-chloropyrimidin-4-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4,6-dichloropyrimidine synthesized in Example 7 The title compound was obtained in the same manner as in Example 265, using as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.89 (3H, t, J = 6.9 Hz), 1.20-1.37 (8H, m), 1.47-1.60 (2H, m), 1.66 (6H, s), 3.07 (2H, t, J = 7.2 Hz), 3.25-3.33 (2H, m), 3.81-3.89 (2H, m), 6.36 (1H, s), 7.01 (1H, s), 8.35 (2H, s).
MS: 457 (M ⁺⁺ 1).
[Example 271]
2-[(4- {2-[(6-Chloropyridazin-3-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and 3,6-dichloropyridazine The title compound was obtained in the same manner as in Example 265, using as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.9 Hz), 1.20-1.36 (8H, m), 1.44-1.58 (2H, m), 1.64 (6H, s), 3.13 (2H, t, J = 6.9 Hz), 3.34 (2H, t, J = 7.5 Hz), 3.94 (2H, t, J = 6.9 Hz), 6.75 (1H, d, J = 9.3 Hz), 7.01 (1H, s), 7.18 (1H, d, J = 9.3 Hz).
MS: 457 (M ⁺⁺ 1).
[Example 272]
2-[(4- {2- [Heptyl (4-morpholin-4-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (reference Example 6)
4- (2-chloropyrimidin-4-yl) morpholine and 4- (4-chloropyrimidin-2-yl) morpholine

2,4-dichloropyrimidine (5.0 g) and triethylamine (4.07 g) were dissolved in 50 mL of tetrahydrofuran, and 2.92 g of morpholine was added dropwise thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 1: 3) to give 4- (2-chloropyrimidine-4 as a highly polar compound). -Yl) With 5.2 g of morpholine as a low polarity compound, 1.4 g of 4- (4-chloropyrimidin-2-yl) morpholine was obtained as a white solid.

4- (2-chloropyrimidin-4-yl) morpholine;
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 3.60-3.69 (4H, m), 3.75-3.81 (4H, m), 6.38 (1H, d, J = 6. 3 Hz), 8.07 (1H, d, J = 6.3 Hz).
4- (4-chloropyrimidin-2-yl) morpholine;
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 3.73-3.77 (4H, m), 3.78-3.83 (4H, m), 6.38 (1H, d, J = 5. 2 Hz), 8.07 (1H, d, J = 5.2 Hz).

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and synthesized in Reference Example 6 The title compound was obtained in the same manner as in Example 265, using 4- (2-chloropyrimidin-4-yl) morpholine as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 0.86 (3H, t, J = 6.6 Hz), 1.15-1.36 (8H, m), 1.43-1.56 ( 8H, m), 3.00-3.06 (2H, m), 3.35-3.40 (2H, m), 3.68-4.06 (10H, m), 6.54 (1H, d, J = 7.4 Hz), 7.55 (1H, s), 7.86 (1H, d, J = 7.4 Hz).
MS: 508 (M ⁺⁺ 1).
[Example 273]
2-[(4- {2- [Heptyl (2-morpholin-4-ylpyrimidin-4-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and synthesized in Reference Example 6 The title compound was obtained in the same manner as in Example 265, using 4- (4-chloropyrimidin-2-yl) morpholine as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 0.83 (3H, t, J = 6.6 Hz), 1.15 to 1.26 (8H, m), 1.41-1.54 ( 8H, m), 2.96-3.03 (2H, m), 3.36-4.00 (12H, m), 6.31-6.41 (1H, m), 7.50 (1H, s), 7.77-7.81 (1H, m).
MS: 508 (M ⁺⁺ 1).
[Example 274]
2-[(4- {2- [Heptyl (5-methylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (Reference Example 7)
5-Methylpyrimidine-2 (1H) -thione

  10.0 g of 3- (dimethylamino) -2-methylacrylaldehyde and 13.5 g of thiourea were dissolved in 200 mL of ethanol, 12.0 g of sodium ethoxide was added, and the mixture was refluxed for 8 hours. After cooling, the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in water, and 1 mol / L hydrochloric acid was added, and the precipitated solid was collected by filtration and dried under reduced pressure to give 7.2 g of the title compound as a yellow solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 2.07 (3H, s), 8.17 (2H, s), 13.7 (1H, brs).
(Reference Example 8)
5-Methyl-2- (methylthio) pyrimidine

  Dissolve 7.2 g of 5-methylpyrimidine-2 (1H) -thione obtained in Reference Example 7 in 60 mL of methanol and 60 mL of 1 mol / L sodium hydroxide aqueous solution, add 8.1 g of methyl iodide and stir at room temperature for 1 hour. did. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.6 g) as a pale yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.24 (3H, s), 2.56 (3H, s), 8.37 (2H, s).
(Reference Example 9)
5-Methyl-2- (methylsulfonyl) pyrimidine

6.0 g of 5-methyl-2- (methylthio) pyrimidine obtained in Reference Example 8 was dissolved in 100 mL of dichloromethane, and after cooling with ice, 30 g of m-chloroperbenzoic acid was added and stirred at 0 ° C. for 3 hours. A 10% aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 7.3 g of the title compound as a white solid.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.47 (3H, s), 3.35 (3H, s), 8.76 (2H, s).

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and synthesized in Reference Example 9 The title compound was obtained in the same manner as in Example 265, using 5-methyl-2- (methylsulfonyl) pyrimidine as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 7.2 Hz), 1.18-1.32 (8H, m), 1.45-1.58 (2H, m), 1.66 (6H, s), 2.11 (3H, s), 3.10 (2H, t, J = 6.9 Hz), 3.45 (2H, t, J = 7.2 Hz) 3.87 (2H, t, J = 6.9 Hz), 6.95 (1H, s), 8.14 (2H, s).
MS: 437 (M ⁺⁺ 1).
[Example 275]
2-[(4- {2-[(4-Ethoxypyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (Reference Example 10 )
4-Ethoxy-2- (methylthio) pyrimidine

3.0 g of 4-chloro-2- (methylthio) pyrimidine was dissolved in 30 mL of ethanol, 2.54 g of sodium ethoxide was added, and the mixture was stirred at 60 ° C. for 10 hours. The reaction mixture was cooled, the solvent was concentrated under reduced pressure, water was added, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.0 g) as a pale yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.39 (3H, t, J = 7.5 Hz), 2.54 (3H, s), 4.42 (2H, q, J = 7.5 Hz) 6.36 (1H, d, J = 6.0 Hz), 8.20 (1H, d, J = 6.0 Hz).
(Reference Example 11)
5-Ethoxy-2- (methylsulfonyl) pyrimidine

Dissolve 3.0 g of 4-ethoxy-2- (methylthio) pyrimidine obtained in Reference Example 10 in 100 mL of dichloromethane, add ice-cooled 12.2 g of m-chloroperbenzoic acid, and stir at 0 ° C. for 5 hours. did. A 10% aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 3.2 g of the title compound as a white solid.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.44 (3H, t, J = 7.1 Hz), 3.34 (3H, s), 4.55 (2H, q, J = 7.1 Hz) 6.89 (1H, d, J = 5.9 Hz), 8.54 (1H, d, J = 5.9 Hz).

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and synthesized in Reference Example 11 The title compound was obtained in the same manner as in Example 265, using 4-ethoxy-2- (methylsulfonyl) pyrimidine as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.6 Hz), 1.16-1.35 (8H, m), 1.40 (3H, t, J = 7.2 Hz), 1.61 (6H, s), 3.12-3.17 (2H, m), 3.53 (2H, t, J = 7.5 Hz), 3.94-3.99 ( 2H, m), 4.40 (2H, q, J = 7.2 Hz), 6.10 (1H, d, J = 6.0 Hz), 7.00 (1H, s), 8.16 (1H, d, J = 6.0 Hz).
MS: 467 (M ⁺⁺ 1).
[Example 276]
2-{[4- (2- {Heptyl [4- (2,2,2-trifluoroethoxy) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2 -Methylpropionic acid (Reference Example 12)
2- (Methylthio) -4- (2,2,2-trifluoroethoxy) pyrimidine

  2.74 g of 2,2,2-trifluoroethanol was dissolved in 50 mL of N, N-dimethylformamide, 1.37 g of sodium hydride (approximately 60% oily) was added under ice cooling, and the mixture was stirred at room temperature for 20 minutes. After cooling with ice again, 5.0 g of 4-chloro-2- (methylthio) pyrimidine was added and stirred at 0 ° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 5.1 g of the title compound as a slightly yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.55 (3H, s), 4.79 (2H, q, J = 8.3 Hz), 6.53 (1H, d, J = 5.8 Hz) , 8.33 (1H, d, J = 5.8 Hz).
(Reference Example 13)
2- (Methylsulfonyl) -4- (2,2,2-trifluoroethoxy) pyrimidine

5.1 g of 2- (methylthio) -4- (2,2,2-trifluoroethoxy) pyrimidine obtained in Reference Example 12 was dissolved in 100 mL of dichloromethane, and after ice cooling, 21.0 g of m-chloroperbenzoic acid. Was added and stirred at 0 ° C. for 5 hours. A 10% aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.8 g) as a colorless oil.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 3.36 (3H, s), 4.92 (2H, q, J = 8.2 Hz), 7.10 (1H, d, J = 5.6 Hz) , 8.69 (1H, d, J = 5.6 Hz).

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and synthesized in Reference Example 13 The title compound was obtained in the same manner as in Example 265, using 2- (methylsulfonyl) -4- (2,2,2-trifluoroethoxy) pyrimidine as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.9 Hz), 1.19-1.34 (8H, m), 1.50-1.59 (2H, m), 1.65 (6H, s), 3.10 (2H, t, J = 6.9 Hz), 3.45 (2H, t, J = 7.4 Hz), 3.87 (2H, t, J = 6.9 Hz), 4.72 (2H, q, J = 8.5 Hz), 6.07 (1H, d, J = 5.5 Hz), 6.97 (1H, s), 8.12 ( 1H, d, J = 5.5 Hz).
MS: 521 (M ⁺⁺ 1).
[Example 277]
2-[(4- {2-[(3,4-Dicyanophenyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  Starting with 2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-fluorophthalonitrile synthesized in Example 7 The compounds obtained by the same operations as in Example 265-1 and Example 265-2 as raw materials were subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile) to give the title compound.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.86 (3H, t, J = 7.0 Hz), 1.15 to 1.49 (10H, m), 1.53 (6H, s), 2 .96 (2H, t, J = 7.0 Hz), 3.73 (2H, t, J = 7.0 Hz), 7.00 (1H, dd, J = 2.2, 8.9 Hz), 7. 27 (1H, d, J = 2.2 Hz), 7.49 (1H, s), 7.73 (1H, d, J = 8.9 Hz).
MS: 471 (M ⁺⁺ 1).
[Example 278]
2-[(4- {2-[(3-Chloro-4-cyanophenyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro-4-fluoro synthesized in Example 7 The compound obtained by the same procedure as in Example 265-1 and Example 265-2 using benzonitrile as a starting material was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 50: 1) to give the title compound.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.89 (3H, t, J = 7.0 Hz), 1.18-1.60 (10 H, m), 1.65 (6H, s), 3 .03 (2H, t, J = 7.6 Hz), 3.23 (2H, t, J = 7.6 Hz), 3.69 (2H, t, J = 7.0 Hz) 6.51 (1H, dd , J = 2.4, 8.9 Hz), 6.60 (1 H, d, J = 2.4 Hz), 7.99 (1 H, s), 7.42 (1 H, d, J = 8.9 Hz) .
MS: 480 (M ⁺⁺ 1).
[Example 279]
2-[(4- {2-[(2-Chloro-4-cyanophenyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 3-chloro-4-fluoro synthesized in Example 7 The compound obtained by the same procedure as in Example 265-1 and Example 265-2 using benzonitrile as a starting material was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 50: 1) to give the title compound.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.86 (3H, t, J = 7.0 Hz), 1.10-1.53 (10 H, m), 1.61 (6H, s), 2 .97 (2H, t, J = 7.6 Hz), 3.19 (2H, t, J = 7.6 Hz), 3.59 (2H, t, J = 7.0 Hz) 6.90 (1H, s) ), 7.05 (1H, d, J = 8.4 Hz), 7.45 (1H, dd, J = 2.2, 8.4 Hz), 7.59 (1H, d, J = 2.2 Hz) .
MS: 480 (M ⁺⁺ 1).
[Example 280]
2-[(4- {2-[[3-Chloro-5- (trifluoromethyl) pyridin-2-yl] (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2 -Methylpropionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2,3-dichloro-5 synthesized in Example 7 Using-(trifluoromethyl) pyridine as a starting material, compounds obtained by the same procedures as in Example 265-1 and Example 265-2 were subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 50: 1) to give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 7.0 Hz), 1.14-1.38 (8H, m), 1.45-1.72 (8H, m), 3.09 (2H, t, J = 7.0 Hz), 3.47 (2H, t, J = 7.0 Hz), 3.85 (2H, t, J = 7.0 Hz) 6.92 (1H, s), 7.69 (1H, d, J = 2.2 Hz), 8.33 (1H, d, J = 2.2 Hz).
MS: 524 (M ⁺⁺ 1).
[Example 281]
2-[(4- {2-[(5-carbamoyl-3-chloropyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride (Example 281-1)
2-[(4- {2-[(3-Chloro-5-methoxycarbonylpyridin-2-yl) (peptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropion Acid tert-butyl ester

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and 2,3-dichloro- Starting with 3.41 g of 5- (methoxycarbonyl) pyridine, 2-[(4- {2-[(3-chloro-5-methoxycarbonylpyridin-2-yl)] was prepared in the same manner as in Example 265-1. Amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester 5.14 g was obtained. 5.14 g of the obtained compound and 1.86 mL of heptyl iodide were dissolved in 40 mL of N, N-dimethylformamide, 1.34 g of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 9: 1) to give 2.59 g of the title compound as a yellow oil.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.87 (3H, t, J = 7.0 Hz), 1.14-1.38 (8H, m), 1.50-1.72 (14H, m), 3.09 (2H, t, J = 7.0 Hz), 3.51 (2H, t, J = 7.0 Hz), 3.85-3.97 (4H, m), 6.97 ( 1H, s), 8.04 (1H, d, J = 1.9 Hz), 8.67 (1H, d, J = 1.9 Hz).
MS: 570 (M ⁺⁺ 1).
(Example 281-2)
2-[(4- {2-[(5-carbamoyl-3-chloropyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl} thio} -2-methylpropionic acid tert-butyl ester

2-[(4- {2-[[3-Chloro-5- (methoxycarbonyl) pyridin-2-yl] (heptyl) amino] ethyl} -1,3-thiazole-2 obtained in Example 281-1 -Il) thio] -2-methylpropionic acid 2.50 g of tert-butyl ester was dissolved in 25 mL of ethanol, 5 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was allowed to stand for 12 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 50: 1) to give 2-[(4- {2-[(5-carboxy-3-chloropyridin-2-yl) (heptyl)]. 2.5 g of amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester was obtained as a colorless oil. This compound was dissolved in 20 mL of dichloromethane without purification, and 0.72 g of WSCD and an ammonia / methanol solution (7 M, 1 mL) were added, followed by stirring for 12 hours at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 2) to give 0.86 g of the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.90 (3H, t, J = 7.0 Hz), 1.15 to 1.37 (8H, m), 1.40 (9H, s), 1 .51-1.70 (8H, m), 3.07 (2H, t, J = 7.6 Hz), 3.49 (2H, t, J = 7.6 Hz), 3.89 (2H, t, J = 7.6 Hz), 5.77 (2H, brs), 6.95 (1H, s), 7.97 (1H, d, J = 2.2 Hz), 8.47 (1H, d, J = 2.2 Hz).
(Example 281-3)
2-[(4- {2-[(5-carbamoyl-3-chloropyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride

2-[(4- {2-[(5-carbamoyl-3-chloropyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl obtained in Example 281-2 ) 300 mg of thio] -2-methylpropionic acid tert-butyl ester was dissolved in 5 mL of trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ether, and 4N hydrochloric acid / ethyl acetate was added. The precipitated crystals were collected by filtration to give 243 mg of the title compound as white crystals.
¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.84 (3H, t, J = 7.0 Hz), 1.12-1.30 (8H, m), 1.40-1.55 ( 8H, m), 1.40-1.55 (8H, m), 2.99 (2H, t, J = 6.7 Hz), 3.76 (2H, t, J = 6.7 Hz), 7. 35 (1H, brs), 7.43 (1H, brs), 8.08 (1H, d, J = 1.9 Hz), 8.59 (1H, d, J = 1.9 Hz).
MS: 499 (M ⁺⁺ 1).
[Example 282]
2-[(4- {2-[(3-Chloro-5-cyanopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride (Example 282-1)
2-[(4- {2-[(3-Chloro-5-cyanopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

2-[(4- {2-[(5-carbamoyl-3-chloropyridin-2-yl) (heptyl) amino) ethyl) -1,3-thiazol-2-yl synthesized in Example 281-2 ) 0.85 g of thio) -2-methylpropionic acid tert-butyl ester was dissolved in 10 mL of dichloromethane, 0.26 mL of triethylamine and 0.24 mL of trifluoroacetic anhydride were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 9: 1) to give 0.37 g of the title compound.
¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.88 (3H, t, J = 7.0 Hz), 1.12-1.85 (28H, m), 3.09 (2H, t, J = 8.6 Hz), 3.53 (2H, t, J = 8.6 Hz), 3.93 (2H, t, J = 8.6 Hz), 6.97 (1H, s), 7.65 (1H, d, J = 1.9 Hz), 8.30 (1H, d, J = 2.2 Hz).
(Example 282-2)
2-[(4- {2-[(3-Chloro-5-cyanopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride

2-[(4- {2-[(3-Chloro-5-cyanopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl obtained in Example 282-1 ) 0.37 g of thio] -2-methylpropionic acid tert-butyl ester was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ether, and 4N hydrochloric acid / ethyl acetate was added. The precipitated crystals were collected by filtration to give 280 mg of the title compound as white crystals.
¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.83 (3H, t, J = 7.6 Hz), 1.11-1.34 (8H, m), 1.42-1.61 ( 8H, m), 3.01 (2H, t, J = 6.7 Hz), 3.87 (2H, t, J = 6.7 Hz), 7.43 (1H, s), 8.11 (1H, d, J = 2.2 Hz), 8.47 (1H, d, J = 2.2 Hz).
MS: 481 (M ⁺⁺ 1).
[Example 283]
2-[(4- {2-[(5-Chloro-3-cyanopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and non-patent literature [Liebigs Ann. Chem. , 487, 127 (1931)] and the like, and a compound obtained by carrying out the same operations as in Example 265-1 and Example 265-2 using 2,5-dichloronicotinonitrile synthesized as a starting material. Was dissolved in dioxane, an excessive amount of 4 mol / L hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 10: 1) to give the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.9 Hz), 1.28-1.30 (8H, m), 1.65 (8H, brs), 3 .13 (2H, t, J = 7.8 Hz), 3.59 (2H, t, J = 7.8 Hz), 3.90-3.95 (2H, m), 7.04 (1H, s) 7.67 (1H, d, J = 2.7 Hz), 8.24 (1H, d, J = 2.7 Hz).
MS: 481 (M ⁺⁺ 1).
[Example 284]
2-[(4- {2-[(5-Bromo-3-cyanopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and patent document [WO0224694] and the like Starting from 5-bromo-2-chloronicotinonitrile synthesized as a reference, the compounds obtained by the same procedures as in Example 265-1 and Example 265-2 were dissolved in dioxane, and 4 mol / An excess amount of L hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, diethyl ether was added and azeotroped, and the precipitated solid was collected by filtration to give the title compound as a white solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 0.85 (3H, t, J = 6.9 Hz), 1.24 (8H, brs), 1.50 (8H, brs), 3.03 (2H, t, J = 6.9 Hz), 3.49 (2H, t, J = 7.8 Hz), 3.91 (2H, t, J = 6.9 Hz), 7.47 (1H, s) , 8.22 (1H, d, J = 2.4 Hz), 8.41 (1H, d, J = 2.4 Hz).
MS: 527 (M ⁺⁺ 1).
[Example 285]
2-[(4- {2- [Heptyl (pyrazin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  Starting from 2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloropyrazine synthesized in Example 7 Then, a compound obtained by carrying out the same operations as in Example 265-1 and Example 265-2 was dissolved in dioxane, an excessive amount of 4 mol / L hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; ethyl acetate) to give the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.9 Hz), 1.26-1.31 (8H, m), 1.58-1.60 (2H, m), 1.67 (6H, s), 3.05 (2H, t, J = 7.2 Hz), 3.41-3.47 (2H, m), 3.81 (2H, t, J = 7.2 Hz), 6.93 (1 H, s), 7.71 (1 H, d, J = 2.7 Hz), 8.03 (1 H, brs), 8.08 (1 H, s).
MS: 423 (M ⁺⁺ 1).

[Example 286]
2-[(4- {2-[(4-Chlorophenyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (Reference Example 14)
N- (4-Chlorophenyl) -2-nitrobenzenesulfonamide

2.0 g of 4-chloroaniline was dissolved in 70 mL of dichloromethane, and 1.39 mL of pyridine and 3.65 g of 2-nitrobenzenesulfonyl chloride were added at room temperature, followed by stirring for 1 hour. Water was added and the organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ether was added to the residue for suspension washing, and the resulting solid was dried under reduced pressure to obtain 5.4 g of the title compound as a pale yellow solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 7.13-7.16 (2H, m), 7.23-7.27 (3H, m), 7.58-7.62 (1H, m) , 7.70-7.74 (1H, m), 7.81-7.88 (2H, m).
(Example 286-1)
2-{[4- (2-{(4-chlorophenyl) [(2-nitrophenyl) sulfonyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 and 788 mg synthesized in Reference Example 14 812 mg of N- (4-chlorophenyl) -2-nitrobenzenesulfonamide was dissolved in 13 mL of dichloromethane, and 1.0 g of triphenylphosphine and diethyl diazodicarboxylate (40% toluene solution) were added under ice cooling. Thereafter, the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 1.2 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.41 (9H, s), 1.51 (6H, s), 2.99 (2H, t, J = 7.2 Hz), 4.13 (2H , T, J = 7.2 Hz), 7.08-7.16 (3H, m), 7.23-7.28 (2H, m), 7.50-7.52 (2H, m), 7 .62-7.67 (2H, m).
(Example 286-2)
2-[(4- {2-[(4-Chlorophenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (2-{(4-chlorophenyl) [(2-nitrophenyl) sulfonyl] amino} ethyl) -1,3-thiazol-2-yl] thio} synthesized in Example 286-1 2-methylpropionic acid tert-butyl ester 1.2 g and thiophenol 0.26 mL were dissolved in N, N-dimethylformamide 12 mL, potassium carbonate 0.88 g was added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1-3: 1) to give 0.52 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.60 (6H, s), 3.03 (2H, t, J = 6.3 Hz), 3.45 (2H , T, J = 6.3 Hz), 6.56-6.59 (2H, m), 6.98 (1H, s), 7.08-7.12 (2H, m).
(Example 286-3)
2-[(4- {2-[(4-Chlorophenyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-[(4- {2-[(4-chlorophenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 286-2 tert-butyl 1.03 g of ester and 0.34 g of heptylaldehyde were dissolved in 15 mL of dichloroethane, 171 μL of acetic acid and 0.79 g of tri (acetoxy) boric acid hydride were sequentially added, and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1) to give the title compound (1.07 g) as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.86-0.90 (3H, m), 1.24-1.27 (8H, m), 1.45 (9H, s), 1.48 -1.53 (2H, m), 1.60 (6H, s), 2.97 (2H, t, J = 7.5 Hz), 3.17 (2H, t, J = 7.5 Hz), 3 .62 (2H, t, J = 7.5 Hz), 6.58-6.61 (2H, m), 6.97 (1H, s), 7.13-7.16 (2H, m).
(Example 286-4)
2-[(4- {2-[(4-Chlorophenyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(4-Chlorophenyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid obtained in Example 286-3 1.1 g of tert-butyl ester was dissolved in 20 mL of dichloromethane, 4.0 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1 to 1: 1) to give 0.99 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.84 (3H, t, J = 6.7 Hz), 1.21-1.29 (8H, m), 1.45 (2H, brs), 1 .63 (6H, s), 2.94 (2H, t, J = 7.4 Hz), 3.45 (2H, t, J = 8.1 Hz), 3.88 (2H, t, J = 7. 4 Hz), 6.96 (1 H, s), 7.38-7.48 (4 H, m).
MS: 455 (M ⁺⁺ 1).
[Example 287]
2-[(4- {2-[(2-chlorophenyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  Starting from 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloroaniline synthesized in Example 4 In the same manner as in Example 286, the title compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.83 (3H, t, J = 6.6 Hz), 1.19-1.32 (8H, m), 1.41-1.45 (2H, m), 1.64 (6H, s), 2.96 (2H, t, J = 6.9 Hz), 3.83 (2H, t, J = 8.1 Hz), 4.23 (2H, t, J = 6.9 Hz), 7.07 (1H, s), 7.51-7.59 (3H, m), 7.70-7.73 (1H, m).
MS: 455 (M ⁺⁺ 1).
[Example 288]
2-[(4- {2- [Heptyl (4-methoxyphenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-methoxyaniline synthesized in Example 4 (p- The title compound was obtained in the same manner as in Example 286, using anisidine) as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.83 (3H, t, J = 6.8 Hz), 1.19-1.29 (8H, m), 1.43-1.45 (2H, m), 1.62 (6H, s), 2.92 (2H, t, J = 6.9 Hz), 3.43 (2H, brs), 3.85-3.91 (5H, m), 6 .94-7.01 (3H, m), 7.42-7.46 (2H, m).
MS: 451 (M ⁺⁺ 1).
[Example 289]
2-[(4- {2-[(4-Cyanophenyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  Starting from 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-aminobenzonitrile synthesized in Example 4 The title compound was obtained in the same manner as in Reference Example 14, Example 286-1, Example 286-2, Example 265-2 and Example 265-3, using the starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.6 Hz), 1.23-1.31 (8H, m), 1.51-1.58 (2H, m), 1.65 (6H, s), 3.03 (2H, t, J = 7.3 Hz), 3.25 (2H, t, J = 7.5 Hz), 3.70 (2H, t, J = 7.5 Hz), 6.59-6.63 (2H, m), 6.98 (1H, s), 7.42-7.46 (2H, m).
MS: 446 (M ⁺⁺ 1).
[Example 290]
2-[(4- {2-[(3-Cyanophenyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  Starting from 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 3-aminobenzonitrile synthesized in Example 4 The title compound was obtained in the same manner as in Reference Example 14, Example 286-1, Example 286-2, Example 265-2 and Example 265-3, using the starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.89 (3H, t, J = 6.6 Hz), 1.29 (8H, brs), 1.47-1.54 (2H, m), 1 .65 (6H, s), 3.02 (2H, t, J = 7.2 Hz), 3.21 (2H, t, J = 7.4 Hz), 3.67 (2H, t, J = 7. 4 Hz), 6.82-6.93 (3 H, m), 6.97 (1 H, s), 7.24-7.29 (1 H, m).
MS: 446 (M ⁺⁺ 1).
[Example 291]
2-[(4- {2-[(2-Cyanophenyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  Starting with 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-aminobenzonitrile synthesized in Example 4 The title compound was obtained in the same manner as in Reference Example 14, Example 286-1, Example 286-2, Example 265-2 and Example 265-3, using the starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.86 (3H, t, J = 6.6 Hz), 1.26 (8H, brs), 1.50-1.52 (2H, m), 1 .62 (6H, s), 3.06 (2H, t, J = 7.3 Hz), 3.29 (2H, t, J = 7.6 Hz), 3.68 (2H, t, J = 7. 6 Hz), 6.91 (1H, t, J = 7.5 Hz), 6.98-7.03 (2H, m), 7.41-7.53 (2H, m).
MS: 446 (M ⁺⁺ 1).
[Example 292]
2-[(4- {2- [Heptyl (pyridin-4-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloride

  Starting from 2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-aminopyridine synthesized in Example 4 The compounds obtained by the same operations as in Reference Example 14, Example 286-1, Example 286-2, and Example 265-2 were dissolved in dioxane, and an excess amount of 4 mol / L hydrochloric acid-dioxane was added. Stir for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 10: 1) to give the title compound as an amorphous solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.89 (3H, t, J = 6.6 Hz), 1.24-1.32 (8H, m), 1.59 (2H, brs), 1 .70 (6H, s), 2.98 (2H, t, J = 6.9 Hz), 3.33-3.39 (2H, m), 3.77 (2H, t, J = 6.9 Hz) 6.62 (2H, d, J = 7.2 Hz), 6.91 (1H, s), 8.23 (2H, d, J = 7.2 Hz).
MS: 422 (M ⁺⁺ 1).
[Example 293]
2-[(4- {2-[(5-Bromopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloride Example 293-1)
2-[(4- {2-[(5-Bromopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  In Example 242, 2-amino-5-bromopyridine and {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazole- obtained in Example 3 2-[(4- {2-[(5-Bromopyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized from 4-yl} acetic acid 4.78 g of propionic acid tert-butyl ester and 3.54 g of heptyl iodide were dissolved in 50 mL of N, N-dimethylformamide, 1.75 g of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 1.72 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.86-0.91 (3H, m), 1.27 (8H, brs), 1.45 (9H, s), 1.53-1.56 (2H, m), 1.59 (6H, s), 3.02 (2H, t, J = 7.3 Hz), 3.28 (2H, t, J = 7.5 Hz), 3.75-3 .80 (2H, m), 6.38 (1 H, d, J = 9.4 Hz), 6.99 (1 H, s), 7.43-7.47 (1 H, m), 8.14 (1 H , D, J = 2.2 Hz).
(Example 293-2)
2-[(4- {2-[(5-Bromopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Bromopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio]-synthesized in Example 293-1 1.72 g of 2-methylpropionic acid tert-butyl ester was dissolved in 5 mL of dioxane, 25 mL of 4 mol / L hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, diethyl ether was added and azeotroped, and the precipitated solid was collected by filtration to give the title compound (1.0 g) as a white solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 0.85 (3H, t, J = 7.2 Hz), 1.24 (8H, brs), 1.46 to 1.55 (8H, m) , 2.98 (2H, t, J = 6.6 Hz), 3.35 (2H, t, J = 7.2 Hz), 3.80 (2H, t, J = 6.6 Hz), 6.80 ( 1H, d, J = 9.3 Hz), 7.51 (1H, s), 7.76-7.80 (1H, m), 8.11 (1H, brs).
MS: 502 (M ⁺⁺ 1).
[Example 294]
2-[(4- {2- [Heptyl (pyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  Starting from {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid and 2-aminopyridine synthesized in Example 3 The compound obtained by the same operation as in Example 293-1 was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile = 85: 15-40: 60). The title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.6 Hz), 1.28-1.37 (8H, m), 1.62-1.64 (8H, m), 3.14 (2H, t, J = 6.9 Hz), 3.48-3.53 (2H, m), 3.96 (2H, t, J = 6.9 Hz), 6.79- 6.82 (2H, m), 7.19 (1H, s), 7.77-7.82 (1H, m), 8.12-8.14 (1H, m).
MS: 422 (M ⁺⁺ 1).
[Example 295]
2-[(4- {2-[(5-chloropyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid trifluoroacetate

  {2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid and 2-amino-5-chloro synthesized in Example 3 The compound obtained by the same procedure as in Example 293-1 using pyridine as a starting material was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile = 50: 50 to 5:95). The title compound was obtained as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.6 Hz), 1.24-1.28 (8H, m), 1.49-1.53 (2H, m), 1.64 (6H, s), 3.06 (2H, t, J = 7.2 Hz), 3.28 (2H, t, J = 7.5 Hz), 3.81 (2H, t, J = 7.5 Hz), 6.39 (1H, d, J = 9.0 Hz), 6.96 (1H, s), 7.34-7.38 (1H, m), 8.05 (1H, d, J = 2.7 Hz).
MS: 456 (M ⁺⁺ 1).
[Example 296]
2-[(4- {2- [Heptyl (pyridin-3-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid trifluoroacetate

  Starting from {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid and 3-aminopyridine synthesized in Example 3 The compound obtained by the same operation as in Example 293-1 was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, diethyl ether was added and azeotroped, and the precipitated solid was collected by filtration to give the title compound.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 0.86 (3H, t, J = 6.6 Hz), 1.26 (8H, brs), 1.46 (2H, brs), 1.52 (6H, s), 2.97 (2H, t, J = 6.6 Hz), 3.25-3.28 (2H, m), 3.73 (2H, t, J = 6.6 Hz), 7 .51 (1H, s), 7.62 (2H, brs), 7.98-8.00 (1H, m), 8.13 (1H, brs).
MS: 422 (M ⁺⁺ 1).
[Example 297]
2-[(4- {2- [Heptyl (5-nitro-1,3-thiazol-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-bromo-5-nitro synthesized in Example 7 The title compound was obtained in the same manner as in Example 265, using -1,3-thiazole as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.89 (3H, t, J = 6.9 Hz), 1.20-1.36 (8H, m), 1.58-1.66 (8H, m), 3.17 (2H, t, J = 6.9 Hz), 3.35 (2H, t, J = 7.5 Hz), 3.90 (2H, t, J = 6.9 Hz), 7. 05 (1H, s), 8.12 (1H, s).
MS: 473 (M ⁺⁺ 1).
[Example 298]
2-[(4-{[(5-Ethylpyrimidin-2-yl) (heptyl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (aminomethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro-5-ethylpyrimidine synthesized in Example 13 The title compound was obtained in the same manner as in Example 265, using as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.9 Hz), 1.16-1.38 (11H, m), 1.52-1.63 (8H, m), 2.46 (2H, q, J = 7.5 Hz), 3.63 (2H, t, J = 7.5 Hz), 4.91 (2H, s), 7.08 (1H, s) , 8.18 (2H, s).
MS: 437 (M ⁺⁺ 1).
[Example 299]
2-[(5-{[(5-Ethylpyrimidin-2-yl) (heptyl) amino] methyl} -4-methyl-1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[5- (2-Aminoethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro synthesized in Example 30 The title compound was obtained in the same manner as in Example 265, using -5-ethylpyrimidine as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 7.2 Hz), 1.18-1.36 (11H, m), 1.54-1.65 (8H, m), 2.04-2.52 (5H, m), 3.57 (2H, t, J = 7.4 Hz), 4.79 (2H, s), 8.20 (2H, s).
MS: 451 (M ⁺⁺ 1).
[Example 300]
2-[(4- {3-[(5-Ethylpyridin-2-yl) (heptyl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloride

  2-{[4- (3-Aminopropyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro-5-ethyl synthesized in Example 33 Using pyrimidine as a starting material, the compound obtained by the same procedures as in Example 265-1 and Example 265-2 was subjected to formic acid and 4 mol / L hydrochloric acid-ethyl acetate, and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.83 (3H, t, J = 7.3H), 1.11 (3H, t, J = 7.6 Hz), 1.14-1. 35 (8H, m), 1.41-1.60 (8H, m), 1.80-1.99 (2H, m), 2.35-2.50 (2H, m), 2.71 ( 2H, t, J = 7.0 Hz), 7.46 (1H, s), 8.25 (2H, s).
MS: 465 (M ⁺⁺ 1).
[Example 301]
2-[(4- {3-[(3-Cyanopyridin-2-yl) (heptyl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid trifluoroacetate

  2-{[4- (3-aminopropyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 33 and 2-chloronicotinonitrile The compounds obtained as starting materials in the same manner as in Example 265-1 and Example 265-2 were subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 50: 1) to give the title compound.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.77-0.98 (3H, m), 1.17-1.44 (8H, m), 1.50-1.79 (8H, m) , 2.03-2.21 (2H, m), 2.88 (2H, t, J = 7.0 Hz). 6.81 ((1H, dd, J = 5.9, 3.8 Hz), 6.83 (1H, brs), 7.09 (1H, s), 7.99 (1H, dd, J = 5. 9 Hz), 8.44 (1H, dd, J = 3.8 Hz)
MS: 461 (M ⁺⁺ 1).
[Example 302]
2-[(4- {3-[(5-Cyanopyridin-2-yl) (heptyl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid trifluoroacetate

  2-{[4- (3-aminopropyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 33 and 6-chloronicotinonitrile The compounds obtained as starting materials in the same manner as in Example 265-1 and Example 265-2 were subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 50: 1) to give the title compound.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.89 (3H, t, J = 7.0 Hz), 1.18-1.42 (8H, m), 1.55-1.75 (8H, m), 2.00-2.17 (2H, m), 2.87 (2H, t, J = 7.0 Hz). 3.44-3.60 (2H, m), 6.79 (1H, d, J = 9.7 Hz), 7.14 (1H, s), 7.75 (1H, dd, J = 9.7) , 2.2 Hz), 8.54 (1H, d, J = 2.2 Hz)
MS: 461 (M ⁺⁺ 1).
[Example 303]
2-[(4- {2- [Heptyl (4-nitrophenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (Example 303-1)
2-({4- [2- (Heptylamino) -2-oxoethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester

  9. 25.0 g of {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid synthesized in Example 3 and heptylamine 0 g was dissolved in 250 mL of dichloromethane, and 18.0 g of hydrochloride of N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) and 16.6 g of monohydrate of hydroxybenzotriazole (HOBT) were sequentially added. And stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give the title compound (30.0 g) as a pale yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.9 Hz), 1.23-1.35 (8H, m), 1.44 (9H, s), 1 .45-1.55 (2H, m), 1.58 (6H, s), 3.25 (2H, q, J = 6.9 Hz), 3.67 (2H, s), 6.82 (1H) , Brs), 7.10 (1H, s).
(Example 303-2)
2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester

  2-({4- [2- (Heptylamino) -2-oxoethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester obtained in Example 303-1 12.0 g was dissolved in 120 mL of tetrahydrofuran, 100 mL of 1M-borane / tetrahydrofuran complex was added under ice-cooling, and then the mixture was stirred at room temperature for 12 hours. After cooling the reaction solution with ice, 400 mL of methanol was added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, 120 mL of piperidine was added, and the mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; dichloromethane: methanol = 20: 1 to 10: 1) to give 5.5 g of the title compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 7.1 Hz), 1.20-1.35 (8H, m), 1.42-1.50 (11H, m), 1.58 (6H, s), 2.62 (2H, t, J = 7.1 Hz), 2.95-2.97 (4H, m), 7.02 (1H, s).
(Example 303-3)
2-[(4- {2- [Heptyl (4-nitrophenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 0.40 g Then, 0.14 g of 1-fluoro-4-nitrobenzene was dissolved in 10 mL of N, N-dimethylformamide, 0.52 mL of N, N-diisopropylethylamine was added, and the mixture was stirred at 80 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 7: 3) to give the title compound (0.20 g) as a yellow oil.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.89 (3H, t, J = 7.0 Hz), 1.19-1.47 (8H, m), 1.41 (9H, s), 1 .49-1.68 (8H, m), 3.03 (2H, t, J = 7.3 Hz), 3.29 (2H, t, J = 7.3 Hz), 3.77 (2H, t, J = 7.0 Hz), 6.62 (2H, d, J = 9.2 Hz), 6.99 (1H, s), 8.11 (2H, d, J = 9.2 Hz).
(Example 303-4)
2-[(4- {2- [Heptyl (4-nitrophenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2- [Heptyl (4-nitrophenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid obtained in Example 303-3 tert -200 mg of butyl ester was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and hexane was added to the residue to give 108 mg of the title compound as a pale yellow solid.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.83-0.97 (3H, m), 1.20-1.43 (8H, m), 1.50-1.75 (8H, m) , 3.09 (2H, t, J = 7.0 Hz), 3.33 (2H, t, J = 7.5 Hz), 3.78 (2H, t, J = 7.5 Hz), 6.59 ( 2H, d, J = 7.0 Hz), 7.00 (1H, s), 8.13 (2H, d, J = 7.0 Hz).
MS: 466 (M ⁺⁺ 1).
[Example 304]
2-[(4- {2- [1,3-Benzothiazol-2-yl (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2- The title compound was obtained in the same manner as in Examples 303-3 and 303-4 using chloro-1,3-benzothiazole as a starting material.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.88 (3H, t, J = 7.0 Hz), 1.15 to 1.39 (8H, m), 1.53-1.75 (8H, m), 3.22 (2H, t, J = 7.0 Hz), 3.36 (2H, t, J = 7.5 Hz), 3.92 (2H, t, J = 7.5 Hz), 6. 98-7.09 (2H, m), 7.20-7.34 (1H, m), 7.50-7.62 (2H, m).
MS: 478 (M ⁺⁺ 1).
[Example 305]
2-[(4- {2-[(5-Cyanopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid trifluoroacetate

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 6- Using chloronicotinonitrile as a starting material, the compound obtained by the same procedure as in Example 303-3 was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 50: 1) to give the title compound.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: ¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.85 (3H, t, J = 7.0 Hz), 1.13 to 1.35 (8H) M), 1.40-1.61 (8H, m), 2.98 (2H, t, J = 7.0 Hz), 3.37 (2H, t, J = 7.3 Hz), 3.81 (2H, t, J = 7.0 Hz), 6.67 (1H, d, J = 9.2 Hz), 7.48 (1H, s), 7.78 (1H, dd, J = 9.2) 2.2 Hz), 8.46 (1H, d, J = 2.2 Hz).
MS: 447 (M ⁺⁺ 1).

[Example 306]
2-[(4- {2- [Heptyl ([1,3] oxazolo [4,5-b] pyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2 -Methylpropionic acid trifluoroacetate

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2- Starting from chloro [1,3] oxazolo [4,5-b] pyridine, the compound obtained by the same procedure as in Example 303-3 was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.78-0.96 (3H, m), 1.16-1.42 (8H, m), 1.53-1.78 (8H, m) 3.12-3.28 (2H, m), 3.50-3.67 (2H, m), 3.90-4.07 (2H, m), 7.08-7.25 (2H, m), 7.83 (1H, d, J = 7.3 Hz), 7.90-8.32 (2H, m)
MS: 478 (M ⁺⁺ 1).
[Example 307]
2-[(4- {2- [1,3-Benzoxazol-2-yl (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloride

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2- The title compound was prepared by dissolving chloro-1,3-benzoxazole as a starting material and dissolving the compound obtained in the same manner as in Examples 303-3 and 303-4 in diethyl ether and reacting with 4 mol / L hydrochloric acid-ethyl acetate. A compound was obtained.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.88 (3H, t, J = 6.5 Hz), 1.13 to 1.35 (8H, m), 1.40 to 1.61 ( 8H, m), 2.98 (2H, t, J = 7.0 Hz), 3.37 (2H, t, J = 7.3 Hz), 3.81 (2H, t, J = 7.0 Hz), 6.67 (1H, d, J = 9.2 Hz), 7.48 (1H, s), 7.78 (1H, dd, J = 9.2, 2.2 Hz), 8.46 (1H, d , J = 2.2 Hz).
MS: 462 (M ⁺⁺ 1).
[Example 308]
2-[(4- {2-[(6-Chloro-1,3-benzothiazol-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid hydrochloride

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2, Using 6-dichloro-1,3-benzothiazole as a starting material, the compound obtained by the same procedure as in Example 303-3 was subjected to formic acid and 4 mol / L hydrochloric acid-ethyl acetate, and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.86 (3H, t, J = 6.5 Hz), 1.17-1.39 (8H, m), 1.45 to 1.65 ( 8H, m), 3.11 (2H, t, J = 6.8 Hz), 3.37 (2H, t, J = 6.8 Hz), 6.67 (1H, d, J = 9.2 Hz), 7.28 (1H, dd, J = 8.9, 2.2 Hz), 7.42 (1H, d, J = 8.9 Hz) 7.55 (1H, s), 7.88 (1H, d, J = 2.2 Hz).
MS: 462 (M ⁺⁺ 1).
[Example 309]
2-[(4- {2-[(3-Cyanopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloride

2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2- Using chloronicotinonitrile as a starting material, the compound obtained by the same procedure as in Examples 303-3 and 303-4 was dissolved in diethyl ether, and the title compound was obtained by reacting with 4 mol / L hydrochloric acid-ethyl acetate. .
¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.85 (3H, t, J = 7.0 Hz), 1.13-1.36 (8H, m), 1.42-1.62 ( 8H, m), 3.04 (2H, t, J = 6.7 Hz), 3.52 (2H, t, J = 6.7 Hz), 6.74 (1H, dd, J = 7.6, 4 .6 Hz), 7.47 (1H, s), 7.95 (1H, dd, J = 7.6, 2.2 Hz) 8.35 (1H, dd, J = 4.6, 2.2 Hz).
MS: 447 (M ⁺⁺ 1).
[Example 310]
2-[(4- {2-[(4-Cyanopyridin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloride

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2- Using chloroisonicotinonitrile as a starting material, the compound obtained by the same procedure as in Examples 303-3 and 303-4 was dissolved in diethyl ether, and the title compound was obtained by reacting with 4 mol / L hydrochloric acid-ethyl acetate. It was.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.85 (3H, t, J = 7.0 Hz), 1.10-1.60 (16H, m), 2.98 (2H, t, J = 6.7 Hz), 3.35 (2H, t, J = 6.7 Hz), 6.89 (1H, d, J = 5.4 Hz), 7.16 (1H, s), 7.50 ( 1H, s), 8.22 (1H, d, J = 5.4 Hz).
MS: 447 (M ⁺⁺ 1).
[Example 311]
2-[(3- {2- [1,3-Benzoxazol-2-yl (heptyl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (Examples) 311-1)
2-({4- [3- (Heptylamino) propyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester

2-{[4- (3-Aminopropyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 33 3.16 g and 1.68 mL of triethylamine Was dissolved in 50 mL of dichloromethane, 1.62 mL of heptanoyl chloride was added by ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 10 mL of tetrahydrofuran, and 26.6 mL of 1M-borane / tetrahydrofuran complex was added under ice cooling, followed by stirring at room temperature for 12 hours. After cooling the reaction solution with ice, 30 mL of methanol was added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, 30 mL of piperidine was added, and the mixture was stirred at 60 ° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 50: 1) to give 2.86 g of the title compound as a colorless oil.
(Example 311-2)
2-[(3- {2- [1,3-Benzoxazol-2-yl (heptyl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-({4- [3- (Heptylamino) propyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 311-1 and 2- Using chloro-1,3-benzoxazole as a starting material, the compound obtained by the same procedure as in Example 303-3 was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 50: 1) to give the title compound.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.89 (3H, t, J = 7.0 Hz), 1.18-1.43 (8H, m), 1.52-1.78 (8H, m), 2.09-2.25 (2H, m), 2.86 (2H, t, J = 7.6 Hz), 3.58 (2H, t, J = 7.6 Hz), 3.67 ( 2H, t, J = 7.6 Hz), 6.47 (1H, brs), 7.02 (1H, s), 7.01-7.54 (4H, m).
MS: 476 (M ⁺⁺ 1).
[Example 312]
2-[(4- {2-[[(5-Chloro-1H-indol-2-yl) carbonyl] (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid
(Example 312-1)
2-[(4- {2-[[(5-Chloro-1H-indol-2-yl) carbonyl] (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid tert-butyl ester

2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester 400 mg and 5 obtained in Example 303-2 196 mg of chloro-1H-indole-2-carboxylic acid was dissolved in 5 mL of N, N-dimethylformamide, 211 mg of N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) hydrochloride, hydroxybenzotriazole (HOBT) 168 mg was sequentially added, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ether was added to the residue to give the title compound as a white powder.
(Example 312-2)
2-[(4- {2-[[(5-Chloro-1H-indol-2-yl) carbonyl] (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid

  2-[(4- {2-[[(5-Chloro-1H-indol-2-yl) carbonyl] (heptyl) amino] ethyl} -1,3-thiazole-2 obtained in Example 312-1 -Il) thio] -2-methylpropionic acid tert-butyl ester (270 mg) was dissolved in formic acid (5 mL), and 4N hydrochloric acid / ethyl acetate solution (5 mL) was added. The reaction mixture was concentrated under reduced pressure, and ether was added to the residue to give 192 mg of the title compound as a white solid.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.72-0.95 (3H, m), 1.10-1.66 (16H, m), 2.99-4.00 (6H, m), 6.65-6.96 (1H, m), 7.18 (1H, dd, J = 8.9, 2.2 Hz), 7.43 (1H, d, J = 8.9 Hz), 7.55 (1H, s), 7.67 (1H, d, J = 2.2 Hz), 11.75 (1H, s).
MS: 522 (M ⁺⁺ 1).
[Example 313]
2-[(4- {2-[(4-Chlorobenzoyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 4- The title compound was obtained in the same manner as in Example 312 using chlorobenzoic acid as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.86-0.88 (3H, m), 1.14 to 1.64 (16H, m), 2.90-3.80 (6H, m) , 6.87-7.12 (1H, m), 7.26-7.38 (4H, m).
MS: 483 (M ⁺⁺ 1).
[Example 314]
2-[(4- {2-[[(2E) -3- (4-chlorophenyl) prop-2-noyl] (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2 -Methylpropionic acid

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and (2E ) -3- (4-Chlorophenyl) acrylic acid was used as a starting material, and the title compound was obtained in the same manner as in Example 312.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.72-0.92 (3H, m), 1.11-1.60 (16H, m), 2.90-3.06 (2H, m), 3.20-3.87 (4H, m), 6.98-7.38 (1H, m), 7.42-7.53 (4H, m), 7.66-7.80 ( 4H, m), 12.91 (1H, s).
MS: 509 (M ⁺⁺ 1).
[Example 315]
2-[(4- {2- [Heptyl (quinolin-3-ylcarbonyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester and quinoline- synthesized in Example 303-2 The title compound was obtained in the same manner as in Example 312 using 3-carboxylic acid as a starting material.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.60-1.12 (7H, m), 1.11-1.70 (14H, m), 2.90-3.52 (4H, m), 3.57-3.85 (2H, m), 6.39-7.62 (1H, m), 7.75-8.34 (5H, m), 9.47 (1H, s) .
MS: 500 (M ⁺⁺ 1).
[Example 316]
2-[(4- {2- [Heptyl (quinoxalin-2-ylcarbonyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester and quinoxaline- synthesized in Example 303-2 A compound obtained by the same procedure as in Example 312-1 using 2-carboxylic acid as a starting material was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 50: 1) to give the title compound.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.63-1.14 (13H, m), 1.21-1.42 (8H, m), 3.00-3.85 (6H, m), 7.38-7.72 (3H, m), 7.78-7.90 (1H, m), 7.96-8.10 (2H, m), 8.41-8.52 ( 1H, m).
MS: 500 (M ⁺⁺ 1).
[Example 317]
2-{[4- (2- {Heptyl [(2-phenyl-1,3-thiazol-4-yl) carbonyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2- The title compound was obtained in the same manner as in Example 312 using phenyl-1,3-thiazole-4-carboxylic acid as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.82-0.89 (3H, m), 1.24-1.35 (8H, m), 1.58-1.67 (8H, m) 3.24-3.26 (2H, m), 3.47-3.70 (2H, m), 3.87-4.16 (2H, m), 6.90-7.15 (1H, m), 7.45-7.47 (3H, m), 7.88-7.99 (3H, m).
MS: 532 (M ⁺⁺ 1).
[Example 318]
2-[(4- {2-[(biphenyl-2-ylcarbonyl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester and biphenyl- synthesized in Example 303-2 A compound obtained by the same procedure as in Example 312-1 using 2-carboxylic acid as a starting material was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile) to give the title compound.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.70-1.37 (13H, m), 1.62 (6H, m), 2.33-3.96 (5H, m), 3.13 -4.02 (3H, m), 6.65-6.77 (1H, m), 7.03-7.52 (9H, m).
MS: 525 (M ⁺⁺ 1).
[Example 319]
2-[(4- {2- [3- (2,4-Difluorophenyl) -1-heptylureido] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid (Examples) 319-1)
2-[(4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

1.2 g of 2-({4- [2- (heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 2,4-difluoroisocyanate 0.40 mL and pyridine 0.25 mL were added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography (elution solvent hexane-ethyl acetate = 4: 1) to give the title compound (0.77 g) as a pale brown oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (2H, t, J = 6.6 Hz), 1.24-1.30 (8H, m), 1.43 (9H, s), 1 .56 (3H, s), 1.57 (3H, s), 1.55-1.58 (2H, m), 3.08 (2H, t, J = 7.2 Hz), 3.22 (2H , T, J = 7.2 Hz), 3.70 (2H, t, J = 7.5 Hz), 6.62 (1H, brs), 6.81-6.87 (2H, m), 7.09 (1H, s), 7.95-8.00 (1H, m).
MS: 556 (M ⁺⁺ 1).
(Example 319-2)
2-[(4- {2- [3- (2,4-Difluorophenyl) -1-heptylureido] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethyl} -1,3-thiazol-2-yl) thio]-obtained in Example 319-1 10 mL of formic acid was added to 0.67 g of 2-methylpropionic acid tert-butyl ester, and the mixture was stirred overnight at room temperature, and further stirred at 50 ° C. for 3 hours and at 70 ° C. for 4 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography (elution solvent hexane-ethyl acetate = 1: 1) to give the title compound (0.55 g) as a pale brown oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.89 (2H, t, J = 7.2 Hz), 1.24-1.32 (8H, m), 1.57-1.64 (2H, m), 1.64 (6H, s), 3.09 (2H, t, J = 7.2 Hz), 3.24 (2H, t, J = 7.2 Hz), 3.70 (2H, t, J = 7.2 Hz), 6.45 (1H, d, J = 3.0 Hz), 6.80-6.88 (2H, m), 7.07 (1H, s), 7.94-8. 01 (1H, m).
MS: 500 (M ⁺⁺ 1).
[Example 320]
2-({4- [2- (3-cyclohexyl-1-heptylureido) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid dicyclohexylamine salt

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester and cyclohexyl isocyanate synthesized in Example 303-2 Using narate as a starting material, the title compound was obtained by the same procedures as in Example 319 and reacting with dicyclohexylamine.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.85 (3H, t, J = 6.8 Hz), 0.96-2.04 (46H, m), 2.77-3.72 ( 9H, m), 7.26 (1H, s)
MS: 470 (M ⁺⁺ 1).
[Example 321]
2-({4- [3- (3-cyclohexyl-1-peptylureido) propyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid dicyclohexylamine salt

  2-({4- [3- (Heptylamino) propyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester and cyclohexyl isocyanate synthesized in Example 311-1 Using narate as a starting material, the title compound was obtained by the same procedures as in Example 319 and reacting with dicyclohexylamine.

¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.88 (3H, t, J = 6.7 Hz), 1.02-2.12 (36H, m), 2.77 (2H, t, J = 7.0 Hz), 2.88-3.06 (2H, m), 3.14 (2H, t, J = 7.6 Hz), 3.27 (2H, t, J = 7.6 Hz), 3. 54-3.72 (1H, m), 4.40 (1H, d, J = 7.6 Hz), 6.96 (1H, s)
MS: 484 (M ⁺⁺ 1).
[Example 322]
2- [4- (2-{[3-cyclohexyl-1- (4-cyclohexylbutyl) ureido] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid dicyclohexylamine salt Example 322-1)
2-({4- [2- (4-cyclohexylbutylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester

2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 1.51 g and 4-cyclohexylbutane 0.85 g of acid was dissolved in 10 mL of N, N-dimethylformamide, 1.05 g of hydrochloride of N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC), 1 water of hydroxybenzotriazole (HOBT) 0.85 g of the Japanese product was sequentially added and stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to purify the reaction mixture directly by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1). Gave 2.2 g of 2-({4- [2- (4-cyclohexylbutanoylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester as a colorless oil. Obtained as a thing. 2.2 g of the obtained compound was dissolved in 10 mL of tetrahydrofuran, 19.5 mL of 1M-borane / tetrahydrofuran complex was added under ice cooling, and then the mixture was stirred at room temperature for 12 hours. After cooling the reaction solution with ice, 30 mL of methanol was added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, 30 mL of piperidine was added, and the mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 50: 1) to give 1.2 g of the title compound as a colorless oil.
(Example 322-2)
2- [4- (2-{[3-cyclohexyl-1- (4-cyclohexylbutyl) ureido] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid dicyclohexylamine salt

  2-({4- [2- (4-cyclohexylbutylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester obtained in Example 322-1 and Using cyclohexyl isocyanate as a starting material, a compound obtained by the same procedure as in Example 319-1 was subjected to dichloromethane and trifluoroacetic acid and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile) to give the title compound.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 0.75-1.99 (33H, m), 2.94-3.18 (4H, m), 3.50-3.70 (3H, m), 4.24 (1H, m), 7.04 (1H, s)
MS: 510 (M ⁺⁺ 1).
[Example 323]
2- [4- (2-{[1-Heptyl-3- (3-pyridyl) ureido] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

148 mg of nicotinic acid was dissolved in 8 mL of toluene, 0.2 mL of triethylamine and 0.28 mL of diphenyl phosphate azide were added, and the mixture was refluxed for 1 hour to prepare 3-pyridyl isocyanate. The reaction solution was cooled to room temperature and 2-({4- [2- (heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropion synthesized in Example 303-2. 400 mg of acid tert-butyl ester was added and stirred for 1 hour. The reaction solution was diluted with ethyl acetate and washed with water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; ethyl acetate: hexane = 1: 9) to give 2- [4- (2-{[1-heptyl-3- (3-pyridyl) ureido] ethyl} -1 , 3-Thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester 0.43 g was obtained as a colorless oil.

  0.43 g of the obtained compound was dissolved in 5 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 380 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.88 (3H, t, J = 6.9 Hz), 1.18-1.35 (8H, m), 1.52-1.68 (8H, m), 3.11 (2H, t, J = 6.8 Hz), 3.34 (2H, t, J = 6.8 Hz), 3.76 (2H, t, J = 6.8 Hz), 7. 18 (1H, s), 7.76 (1H, dd, J = 5.6, 8.8 Hz), 8.32 (1H, d, J = 5.6 Hz), 8.76 (1H, brs), 8.86 (1H, d, J = 8.8 Hz), 9.22 (1H, s).
MS: 465 (M ⁺⁺ 1).
[Example 324]
2- [4- (2-{[1-Heptyl-3- (4-pyridyl) ureido] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

Isonicotinic acid and 2-({4- [2- (heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid synthesized in Example 303-2 tert-butyl Purification by high performance liquid chromatography (elution solvent: 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile) using the ester as a starting material and the same procedure as in Example 323 Gave the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.88 (3H, t, J = 6.9 Hz), 1.19-1.37 (8H, m), 1.50-1.65 (8H, m), 3.10 (2H, t, J = 6.4 Hz), 3.33 (2H, t, J = 6.8 Hz), 3.82 (2H, t, J = 6.8 Hz), 7. 15 (1H, s), 8.09 (1H, d, J = 6.8 Hz), 8.33 (1H, d, J = 8.8 Hz), 9.93 (1H, s).
MS: 465 (M ⁺⁺ 1).
[Example 325]
2- [4- (2-{[1-Heptyl-3- (5-methylthiophen-2-yl) ureido] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

5-methylthiophenecarboxylic acid and 2-({4- [2- (heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropion synthesized in Example 303-2 The compound obtained by the same procedure as in Example 323 using acid tert-butyl ester as the starting material was subjected to high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile). To give the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.80-0.91 (3H, m), 1.10-1.35 (8H, m), 1.50-1.70 (8H, m) , 2.37 (3H, s), 3.06 (2H, t, J = 6.8 Hz), 3.22 (2H, t, J = 7.6 Hz), 3.67 (2H, t, J = 6.8 Hz), 6.36 (1 H, d, J = 3.6 Hz), 6.43 (1 H, d, J = 3.6 Hz), 7.01 (1 H, s), 7.06 (1 H, s).
MS: 484 (M ⁺⁺ 1).
[Example 326]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl ] Thio} -2-methylpropionic acid (Reference Example 15)
3-Amino-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester

  2- (Ethoxymethylene) -2-cyanoacetic acid ethyl ester (78.2 g) and phenylhydrazine (50.0 g) were dissolved in ethanol (500 mL) and refluxed for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure, and 500 mL of hexane was added to the residue for suspension washing, and the solid obtained by filtration was dried under reduced pressure to obtain 86.0 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.36 (3H, t, J = 7.5 Hz), 4.31 (2H, q, J = 7.5 Hz), 5.31 (2H, brs) , 7.38-7.54 (5H, m), 7.79 (1H, s).
(Reference Example 16)
1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester

  64.8 g of 3-amino-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester synthesized in Reference Example 15 was dissolved in 500 mL of tetrahydrofuran, 98.5 g of isoamyl nitrite was added, and the mixture was stirred at 65 ° C. for 3 hours. did. After cooling, the reaction solution was concentrated under reduced pressure, and 500 mL of hexane was added to the residue for suspension washing, and the solid obtained by filtration was dried under reduced pressure to obtain 43.0 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.38 (3H, t, J = 7.5 Hz), 4.35 (2H, q, J = 7.5 Hz), 7.36 (1H, t, J = 7.7 Hz), 7.49 (2H, t, J = 7.7 Hz), 7.71 (2H, d, J = 7.7 Hz), 8.11 (1H, s), 8.41 ( 1H, s).
(Reference Example 17)
(1-Phenyl-1H-pyrazol-4-yl) methanol

  Suspend 3.51 g of lithium aluminum hydride in 200 mL of tetrahydrofuran, add 20 g of 1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester synthesized in Reference Example 16 under ice cooling, and then add 1. Stir for 5 hours. After the reaction solution was ice-cooled, 7 mL of water and 3.5 mL of a 1 mol / L sodium hydroxide aqueous solution were sequentially added dropwise, and the mixture was warmed to room temperature and stirred for 30 minutes. Anhydrous sodium sulfate was added to the reaction solution and filtered through celite, and the filtrate was concentrated under reduced pressure. 30 mL of diethyl ether and 30 mL of hexane were added to the residue for suspension washing, and the solid obtained by filtration was dried under reduced pressure to obtain 14.8 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (1H, t, J = 4.8 Hz), 4.68 (2H, d, J = 4.8 Hz), 7.29 (1H, t, J = 7.7 Hz), 7.45 (2H, t, J = 7.7 Hz), 7.67 (2H, d, J = 7.7 Hz), 7.72 (1H, s), 7.93 ( 1H, s).
(Reference Example 18)
4- (Chloromethyl) -1-phenyl-1H-pyrazole

  6.3 g of (1-phenyl-1H-pyrazol-4-yl) methanol synthesized in Reference Example 17 was dissolved in 100 mL of dichloromethane, and after cooling with ice, 5.59 g of thionyl chloride was added and stirred at 0 ° C. for 2 hours. did. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to give 7.4 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.62 (2H, s), 7.30 (1H, t, J = 8.4 Hz), 7.46 (2H, t, J = 8.4 Hz) 7.66 (2H, d, J = 8.4 Hz), 7.74 (1H, s), 7.96 (1H, s).
Hereinafter, by using various substituted phenylhydrazines in the same manner, 4- (chloromethyl) -1- (4-methylphenyl) -1H-pyrazole, 4- (chloromethyl) -1- (3- Methylphenyl) -1H-pyrazole, 4- (chloromethyl) -1- (2-methylphenyl) -1H-pyrazole, 4- (chloromethyl) -1- (4-chlorophenyl) -1H-pyrazole, 4- ( 4- (chloromethyl) -1-cyclohexyl-1H-pyrazole by using chloromethyl) -1- (4-fluorophenyl) -1H-pyrazole and cyclohexylhydrazine and 4- (chloromethyl) by using pyridylhydrazine ) -1- (2-pyridyl) -1H-pyrazole was obtained.
(Example 326-1)
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl ] Thio} -2-methylpropionic acid tert-butyl ester

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 7.0 g of propionic acid tert-butyl ester and 3.47 g of 4- (chloromethyl) -1-phenyl-1H-pyrazole synthesized in Reference Example 18 were dissolved in 80 mL of N, N-dimethylformamide, and potassium tert-butoxide was dissolved. 2.32 g was added and stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1-3: 1) to give 7.30 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.5 Hz), 1.44 (9H, s), 1.58 (6H, s), 2.49 (2H , Q, J = 7.5 Hz), 3.11 (2H, t, J = 7.5 Hz), 3.95 (2H, t, J = 7.5 Hz), 4.61 (2H, s), 7 0.00 (1H, s), 7.24 (1 H, t, J = 7.6 Hz), 7.41 (2H, t, J = 7.6 Hz), 7.63-7.66 (3H, m) , 7.90 (1H, s), 8.22 (2H, s).
(Example 326-2)
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl ] Thio} -2-methylpropionic acid

  2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl)-obtained in Example 326-1 7.3 g of 1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester was dissolved in 80 mL of dichloromethane, and 20 mL of trifluoroacetic acid was added and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 5.0 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.5 Hz), 1.62 (6H, s), 2.49 (2H, q, J = 7.5 Hz) 3.09 (2H, t, J = 7.1 Hz), 3.93 (2H, t, J = 7.1 Hz), 4.70 (2H, s), 6.94 (1H, s), 7 21-7.26 (1H, m), 7.39-7.45 (2H, m), 7.64-7.68 (3H, m), 7.95 (1H, s), 8.22 (2H, s).
MS: 509 (M ⁺⁺ 1).
[Example 327]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(6-phenylpyridin-3-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-Methylpropionic acid hydrochloride (Reference Example 19)
6-Phenylnicotinic acid ethyl ester

  Under a nitrogen atmosphere, 24.0 g of 6-chloronicotinic acid ethyl ester and 23.6 g of phenylboric acid were dissolved in 200 mL of dioxane and 100 mL of 2M aqueous sodium carbonate solution, 7.0 g of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed for 8 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 7: 1 to 5: 1) to give 25.5 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (3H, t, J = 7.0 Hz), 4.43 (2H, q, J = 7.0 Hz), 7.45-7.53 ( 3H, m), 7.81 (1H, d, J = 8.3 Hz), 8.04-8.07 (2H, m), 8.34 (1H, dd, J = 2.2, 8.3 Hz) ), 9.29 (1H, s).
(Reference Example 20)
(6-Phenylpyridin-3-yl) methanol

  3.50 g of lithium aluminum hydride was suspended in 200 mL of tetrahydrofuran, and 21.0 g of 6-phenylnicotinic acid ethyl ester synthesized in Reference Example 19 was added under ice cooling, followed by stirring at room temperature for 12 hours. After the reaction solution was ice-cooled, 5 mL of water and 10 mL of a 1 mol / L sodium hydroxide aqueous solution were sequentially added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. Anhydrous sodium sulfate was added to the reaction solution and filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 1: 3) to give 17.0 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.21 (1H, brs), 4.75 (2H, s), 7.41-7.48 (3H, m), 7.70-7.79 (2H, m), 7.95-7.99 (2H, m), 8.64 (1H, s).
(Reference Example 21)
5- (Chloromethyl) -2-phenylpyridine

  15.0 g of (6-phenylpyridin-3-yl) methanol synthesized in Reference Example 20 was dissolved in 150 mL of dichloromethane, and after ice cooling, 12.5 g of thionyl chloride was added and stirred at 0 ° C. for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to give 13.5 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.64 (2H, s), 7.42-7.51 (3H, m), 7.72-7.80 (2H, m), 7.97 −8.01 (2H, m), 8.69 (1H, s).
(Example 327-1)
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(6-phenylpyridin-3-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-Methylpropionic acid tert-butyl ester

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 600 mg of propionic acid tert-butyl ester and 360 mg of 5- (chloromethyl) -2-phenylpyridine synthesized in Reference Example 21 were dissolved in 10 mL of N, N-dimethylformamide, and 200 mg of potassium tert-butoxide was added at room temperature. Stir for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 2 to 2: 1) to give 740 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.6 Hz), 1.42 (9H, s), 1.57 (6H, s), 2.49 (2H , Q, J = 7.5 Hz), 3.13 (2H, t, J = 6.9 Hz), 3.98 (2H, t, J = 6.9 Hz), 4.78 (2H, s), 7 0.00 (1H, s), 7.38-7.48 (3H, m), 7.60-7.63 (2H, m), 7.93-7.97 (2H, m), 8.20 (2H, s), 8.58 (1H, s).
(Example 327-2)
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(6-phenylpyridin-3-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-Methylpropionic acid hydrochloride

  2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(6-phenylpyridin-3-yl) methyl] amino} ethyl) -1,3 obtained in Example 327-1 -Thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester (740 mg) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1). The obtained compound was dissolved in 10 mL of diethyl ether, 2 mL of 4 mol / L hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give 220 mg of the title compound as a white solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.16 (3H, t, J = 7.2 Hz), 1.50 (6H, s), 2.48 (2H, q, J = 7. 2 Hz), 3.08 (2H, t, J = 7.2 Hz), 4.03 (2H, t, J = 7.2 Hz), 4.92 (2H, s), 7.49 (1H, s) 7.57-7.61 (3H, m), 8.08-8.11 (2H, m), 8.19 (2H, s), 8.34 (2H, s), 8.66 (1H) , S).
MS: 520 (M ⁺⁺ 1).
[Example 328]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (pentyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrobromic acid salt

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Starting from propionic acid tert-butyl ester and 1-iodopentane, the compound obtained by the same procedure as in Example 326 was dissolved in diethyl ether, and the title compound was reacted with 30% hydrobromic acid-acetic acid. Obtained.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 0.86 (3H, t, J = 6.9 Hz), 1.16 (3H, t, J = 7.5 Hz), 1.20-1. 30 (4H, m), 1.43-1.58 (8H, m), 2.47-2.53 (2H, m), 3.03 (2H, t, J = 7.0 Hz), 3. 44 (2H, t, J = 7.6 Hz), 3.89 (2H, t, J = 7.0 Hz), 7.50 (1H, s), 8.39 (2H, s).
MS: 423 (M ⁺⁺ 1).
[Example 329]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (hexyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrobromic acid salt

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained by dissolving propionic acid tert-butyl ester and 1-iodohexane as starting materials, dissolving the compound obtained in the same manner as in Example 326 in diethyl ether and reacting with 30% hydrobromic acid-acetic acid. Got.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 0.856 (3H, t, J = 7.0 Hz), 1.16 (3H, t, J = 7.7 Hz), 1.20-1. 30 (6H, m), 1.42-1.54 (8H, m), 2.44-2.53 (2H, m), 3.03 (2H, t, J = 6.8 Hz), 3. 40-3.47 (2H, m), 3.90 (2H, t, J = 6.8 Hz), 7.50 (1H, s), 8.40 (2H, s).
MS: 437 (M ⁺⁺ 1).
[Example 330]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (octyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrobromic acid salt

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Starting from propionic acid tert-butyl ester and 1-iodooctane, the compound obtained by the same procedure as in Example 326 was dissolved in diethyl ether, and the title compound was reacted with 30% hydrobromic acid-acetic acid. Obtained.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 0.87 (3H, t, J = 7.2 Hz), 1.17-1.45 (10H, m), 1.62-1.81 ( 8H, m), 2.65 (2H, t, J = 7.2 Hz), 3.54-3.65 (2H, m), 4.05-4.25 (4H, m), 8.29 ( 1H, s), 8.67 (1H, s), 9.05 (1H, s).
MS: 465 (M ⁺⁺ 1).
[Example 331]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (nonyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrobromic acid salt

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Starting from propionic acid tert-butyl ester and 1-iodononane, the compound obtained by the same procedure as in Example 326 is dissolved in diethyl ether, and the title compound is obtained by reacting with 30% hydrobromic acid-acetic acid. It was.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 0.87 (3H, t, J = 7.2 Hz), 1.19-1.44 (12H, m), 1.60-1.81 ( 8H, m), 2.65 (2H, t, J = 7.2 Hz), 3.55-3.68 (2H, m), 4.03-4.25 (4H, m), 8.29 ( 1H, s), 8.67 (1H, s), 8.98 (1H, s).
MS: 479 (M ⁺⁺ 1).
[Example 332]
2-[(4- {2-[(5-ethylpyrimidin-2-yl) (4-methylpentyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Odor Hydride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Using 1-iodo-4-methylpentane synthesized with reference to non-patent literature [Tetrahedron, 38, 11461 (1998)] using propionic acid tert-butyl ester and 4-methylpentanol as starting materials The title compound was obtained by dissolving the compound obtained in the same manner as in 326 in diethyl ether and reacting with 30% hydrobromic acid-acetic acid.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 0.87 (3H, t, J = 7.0 Hz), 1.10-1.18 (5H, m), 1.48-1.55 ( 9H, m), 2.47-2.55 (9H, m), 3.03 (2H, t, J = 7.0 Hz), 3.41 (2H, t, J = 7.0 Hz), 3. 90 (2H, t, J = 7.0 Hz), 7.52 (1H, s), 8.41 (1H, s).
MS: 437 (M ⁺⁺ 1).
[Example 333]
2-[(4- {2-[(5-ethylpyrimidin-2-yl) (5-methylhexyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Odor Hydride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Using 1-iodo-5-methylhexane synthesized with reference to non-patent literature [Tetrahedron, 38, 11461 (1998)] using propionic acid tert-butyl ester and 5-methylhexanol as starting materials, Example 326 The title compound was obtained by dissolving the compound obtained by the same procedure as in diethyl ether and reacting with 30% hydrobromic acid-acetic acid.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 0.84 (3H, t, J = 7.0 Hz), 1.10-1.29 (7H, m), 1.46-1.51 ( 9H, m), 2.48-2.55 (2H, m), 3.03 (2H, t, J = 7.0 Hz), 3.44 (2H, t, J = 7.0 Hz), 3. 91 (2H, t, J = 7.0 Hz), 7.53 (1H, s), 8.44 (1H, s).
MS: 451 (M ⁺⁺ 1).
[Example 334]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (6-methylheptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Odor Hydride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Using 6-methyl-1-iodoheptane synthesized with reference to non-patent literature [Tetrahedron, 38, 11461 (1998)] using propionic acid tert-butyl ester and 6-methylheptanol as starting materials The title compound was obtained by dissolving the compound obtained in the same manner as in 326 in diethyl ether and reacting with 30% hydrobromic acid-acetic acid.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 0.82-0.95 (8H, m), 0.97-1.60 (16H, m), 2.50-2.54 (2H, m), 3.03 (2H, t, J = 7.0 Hz), 3.37-3.46 (2H, m), 3.85-3.91 (2H, m), 7.52 (1H, s), 8.40 (1H, s), 8.47 (1H, s).
MS: 465 (M ⁺⁺ 1).
[Example 335]
2-({4- [2-((5-Ethylpyrimidin-2-yl) {[1- (4-fluorophenyl) -1H-pyrazol-4-yl] methyl} amino) ethyl] -1,3- Thiazol-2-yl} thio) -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Propionic acid tert-butyl ester and 4- (chloromethyl) -1- (4-fluorophenyl) -1H-pyrazole synthesized in the same manner as in Reference Examples 16 to 18 were used as starting materials, and the same operation as in Example 327 was performed. The title compound was obtained.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.16 (3H, t, J = 7.7 Hz), 1.50 (6H, s), 2.47 (2H, q, J = 7. 7 Hz), 3.05 (2H, t, J = 7.1 Hz), 3.92 (2H, t, J = 7.1 Hz), 4.64 (2H, s), 7.28-7.34 ( 2H, m), 7.50 (1H, s), 7.67 (1H, s), 7.79-7.83 (2H, m), 8.35 (2H, s), 8.39 (1H , S).
MS: 527 (M ⁺⁺ 1).
[Example 336]
2-[(4- {2-[{[1- (4-Chlorophenyl) -1H-pyrazol-4-yl] methyl} (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazole -2-yl) thio] -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Propionic acid tert-butyl ester and 4- (chloromethyl) -1- (4-chlorophenyl) -1H-pyrazole synthesized in the same manner as in Reference Examples 16 to 18 were used as starting materials in the same manner as in Example 327. A compound was obtained.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.15 (3H, t, J = 7.6 Hz), 1.50 (6H, s), 2.45 (2H, q, J = 7. 6 Hz), 3.03 (2 H, t, J = 7.0 Hz), 3.90 (2 H, t, J = 7.0 Hz), 4.62 (2 H, s), 7.48 (1 H, s) 7.53 (2H, d, J = 7.0 Hz), 7.68 (1 H, s), 7.82 (2H, d, J = 7.0 Hz), 8.31 (2H, s), 8 .41 (1H, s).
MS: 534 (M ⁺⁺ 1).
[Example 337]
2-({4- [2-((5-Ethylpyrimidin-2-yl) {[1- (4-methylphenyl) -1H-pyrazol-4-yl] methyl} amino) ethyl] -1,3- Thiazol-2-yl} thio) -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Propionic acid tert-butyl ester and 4- (chloromethyl) -1- (4-methylphenyl) -1H-pyrazole synthesized in the same manner as in Reference Examples 16 to 18 were used as starting materials in the same manner as in Example 327. The title compound was obtained.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.50 (6H, s), 2.32 (3H, s), 2.46 (2H, q, J = 7.5 Hz), 3.03 (2H, t, J = 7.0 Hz), 3.90 (2H, t, J = 7.0 Hz), 4.62 (2H, s) 7.26 (2H, d, J = 8.4 Hz), 7.49 (1H, s), 7.63 (1H, s), 7.65 (2H, d, J = 8.4 Hz), 8 .32 (2H, s).
MS: 523 (M ⁺⁺ 1).
[Example 338]
2-({4- [2-((5-Ethylpyrimidin-2-yl) {[1- (3-methylphenyl) -1H-pyrazol-4-yl] methyl} amino) ethyl] -1,3- Thiazol-2-yl} thio) -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Propionic acid tert-butyl ester and 4- (chloromethyl) -1- (3-methylphenyl) -1H-pyrazole synthesized in the same manner as in Reference Examples 16 to 18 were used as starting materials, and the same operation as in Example 327 was performed. The title compound was obtained.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.50 (6H, s), 2.36 (3H, s), 2.47 (2H, q, J = 7.5 Hz), 3.04 (2H, t, J = 7.1 Hz), 3.92 (2H, t, J = 7.1 Hz), 4.63 (2H, s) 7.08-7.10 (1 H, m), 7.34 (1 H, t, J = 7.8 Hz), 7.50 (1 H, s), 7.56-7.65 (3 H, m) , 8.34 (2H, s), 8.38 (1H, s).
MS: 523 (M ⁺⁺ 1).
[Example 339]
2-({4- [2-((5-ethylpyrimidin-2-yl) {[1- (2-methylphenyl) -1H-pyrazol-4-yl] methyl} amino) ethyl] -1,3- Thiazol-2-yl} thio) -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Propionic acid tert-butyl ester and 4- (chloromethyl) -1- (2-methylphenyl) -1H-pyrazole synthesized in the same manner as in Reference Examples 16 to 18 were used as starting materials, and the same operation as in Example 327 was performed. The title compound was obtained.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.16 (3H, t, J = 7.9 Hz), 1.50 (6H, s), 2.17 (3H, s), 2.46 −2.51 (2H, m), 3.04 (2H, t, J = 7.0 Hz), 3.93 (2H, t, J = 7.0 Hz), 4.69 (2H, s), 7 .30-7.38 (4H, m), 7.51 (1H, s), 7.67 (1H, s), 8.00 (1H, s), 8.39 (2H, s).
MS: 523 (M ⁺⁺ 1).
[Example 340]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(1-pyridin-2-yl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole -2-yl] thio} -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Propionic acid tert-butyl ester and 2- [4- (chloromethyl) -1H-pyrazol-1-yl] pyridine synthesized in the same manner as in Reference Examples 16 to 18 were used as starting materials, and the same operation as in Example 327 was performed. The title compound was obtained.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.16 (3H, t, J = 7.7 Hz), 1.50 (6H, s), 2.46-2.51 (2H, m) , 3.05 (2H, t, J = 7.0 Hz), 3.94 (2H, t, J = 7.0 Hz), 4.68 (2H, s), 7.33 (2H, dd, J = 4.7, 7.0 Hz), 7.51 (1H, s), 7.77 (1H, s), 8.37-8.54 (4H, m).
MS: 510 (M ⁺⁺ 1).
[Example 341]
2-[(4- {2-[[(1-cyclohexyl-1H-pyrazol-4-yl) methyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl ) Thio] -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, starting from propionic acid tert-butyl ester and 4- (chloromethyl) -1-cyclohexyl-1H-pyrazole synthesized in the same manner as in Reference Examples 16 to 18. .

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.08-1.41 (6H, m), 1.50 (6H, s), 1.58-2.00 (7H, m), 2 .47-2.54 (2H, m), 2.99 (2H, t, J = 6.5 Hz), 3.86 (2H, t, J = 6.5 Hz), 4.05 (1H, s) , 4.57 (2H, s), 7.39 (1H, s), 7.49 (1H, s), 7.72 (2H, s).
MS: 515 (M ⁺⁺ 1).
[Example 342]
2-({4- [2-((5-ethylpyrimidin-2-yl) {[1- (2-thienyl) -1H-pyrazol-4-yl] methyl} amino) ethyl] -1,3-thiazole -2-yl} thio) -2-methylpropionic acid hydrochloride (Reference Example 22)
4- (Chloromethyl) -1- (2-thienyl) -1H-pyrazole

7.0 g of 1H-pyrazole-4-carboxylic acid ethyl ester and 10.5 g of 2-iodothiophene were dissolved in 50 mL of DMSO, 6.91 g of potassium carbonate and 31.7 mg of copper powder were added, and the mixture was stirred at 150 ° C. for 6 hours. The reaction solution was cooled to 80 ° C., 2 mL of bromoethane was added and stirred for 2 hours, and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 9: 1) to give 2.23 g of 1- (2-thienyl) -1H-pyrazole-4-carboxylic acid ethyl ester as a white solid. It was. The obtained compound was subjected to the same reaction as in Reference Examples 17 to 18 to give the title compound.

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 4- (chloromethyl) -1- (2-thienyl) -1H-pyrazole synthesized in Reference Example 22 as starting materials. .

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.16 (3H, t, J = 7.4 Hz), 1.51 (6H, s), 2.49 (2H, q, J = 7. 4 Hz), 3.06 (2H, t, J = 7.0 Hz), 3.94 (2H, t, J = 7.0 Hz), 4.64 (2H, s), 6.96-7.00 ( 1H, m), 7.23-7.26 (1H, m), 7.52 (1H, s), 7.64 (1H, s), 8.33 (1H, s), 8.39 (2H) , S).
MS: 515 (M ⁺⁺ 1).
[Example 343]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(1-isobutyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl ] Thio} -2-methylpropionic acid hydrochloride (Reference Example 23)
4- (Chloromethyl) -1- (2-methylpropyl) -1H-pyrazole

  Dissolve 5.0 g of 1H-pyrazole-4-carboxylic acid ethyl ester in 50 mL of DMF, add 1.57 g of 60% sodium hydride, stir at 0 ° C. for 30 minutes, and then add 4.7 mL of isobutyl iodide. Stir for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 8: 2) to give 6.0 g of 1- (2-methylpropyl) -1H-pyrazole-4-carboxylic acid ethyl ester as an oil. Obtained. The obtained compound was subjected to the same reaction as in Reference Examples 17 to 18 to give the title compound.

  Similarly, using 1H-pyrazole-4-carboxylic acid ethyl ester and butyl iodide, 4- (chloromethyl) -1- (2-methylpropyl) -1H-pyrazole was converted to ethyl 1H-pyrazole-4-carboxylate. 4- (Chloromethyl) -1- (phenylmethyl) -1H-pyrazole was obtained using ester and benzyl bromide.

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 4- (chloromethyl) -1-isobutyl-1H-pyrazole synthesized in Reference Example 23 as starting materials.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 0.78 (6H, d, J = 6.6 Hz), 1.16 (3H, t, J = 7.4 Hz), 1.51 (6H, s), 2.00-2.08 (1H, m), 2.46-2.55 (2H, m), 3.00 (2H, t, J = 7.4 Hz), 3.83-3. 89 (4H, m), 4.60 (2H, s), 7.43 (1H, s), 7.50 (1H, s), 7.69 (1H, s), 8.39 (2H, s) ).
MS: 489 (M ⁺⁺ 1).
[Example 344]
2-[(4- {2-[[(1-Butyl-1H-pyrazol-4-yl) methyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl ) Thio] -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 1-butyl-4- (chloromethyl) -1H-pyrazole synthesized in the same manner as in Reference Example 23 as starting materials.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 0.84 (3H, t, J = 7.0 Hz), 1.13-2.26 (5H, m), 1.34 (6H, s) , 1.64-1.72 (2H, m), 2.47-2.68 (2H, m), 2.99 (2H, m), 2.85 (2H, m) 4.02 (2H, t, J = 7.0 Hz), 4.57 (2H, s), 7.39 (1H, s), 7.48 (1H, s), 7.68 (1H, s), 8.36 (2H) , S).
MS: 515 (M ⁺⁺ 1).
[Example 345]
2-[(4- {2-[[(1-Benzyl-1H-pyrazol-4-yl) methyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl ) Thio] -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 1-benzyl-4- (chloromethyl) -1H-pyrazole synthesized in the same manner as in Reference Example 23 as starting materials.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.15 (3H, t, J = 7.8 Hz), 1.56 (6H, s), 2.50 (2H, t, J = 7. 8 Hz), 2.90-3.03 (2H, m), 3.80-3.88 (2H, m), 4.56 (2H, s), 5.26 (2H, s), 7.16. -7.45 (7H, m), 7.77 (1H, s), 8.34 (2H, s).
MS: 523 (M ⁺⁺ 1).
[Example 346]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(2E) -3-phenylprop-2-en-1-yl] amino} ethyl) -1,3-thiazole-2 -Yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326 using propionic acid tert-butyl ester and cinnamyl bromide as starting materials.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.21 (3H, t, J = 7.9 Hz), 1.63 (6H, s), 2.48 (2H, t, J = 7.9 Hz) 3.13 (2H, t, J = 7.0 Hz), 3.93 (2H, t, J = 7.0 Hz), 4.33 (2H, d, J = 4.7 Hz), 6.17− 6.25 (1H, m), 6.50 (1 H, d, J = 16.4 Hz), 6.96 (1 H, s), 7.18-7.37 (6H, m), 8.20 ( 2H, s).
MS: 469 (M ⁺⁺ 1).
[Example 347]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(2E) -3- (4-fluorophenyl) prop-2-en-1-yl] amino} ethyl) -1, 3-Thiazol-2-yl] thio} -2-methylpropionic acid
(Reference Example 24)
(2E) -3- (4-Fluorophenyl) prop-2-en-1-ol

10 g of 4-fluorocinnamic acid was dissolved in 120 mL of tetrahydrofuran, and 10.12 mL of triethylamine and 6.92 mL of ethyl chloroformate were added dropwise under ice cooling, followed by stirring for 1 hour. To the reaction solution, a solution of sodium borohydride (6.87 g) in water (60 mL) was added dropwise and stirred overnight at room temperature. 200 mL of 1 mol / L hydrochloric acid aqueous solution was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogen carbonate solution and water and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1 to 1: 1) to give 9.36 g of the title compound as a white solid.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.31-4.33 (2H, m), 6.24-6.33 (1H, m), 6.59 (1H, d, J = 15. 9 Hz), 6.98-7.04 (2H, m), 7.33-7.38 (2H, m).
(Reference Example 25)
1-[(1E) -3-Chloroprop-1-en-1-yl] -4-fluorobenzene

1.36 g of (2E) -3- (4-fluorophenyl) prop-2-en-1-ol synthesized in Reference Example 24 was dissolved in 45 mL of dichloromethane, and 0.78 g of pyridine and thionyl chloride were added under ice cooling. .72 mL was added and stirred for 30 minutes. The mixture was diluted with dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane) to give 1.1 g of the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.23 (2H, d, J = 6.3 Hz), 6.19-6.29 (1H, m), 6.62 (1H, d, J = 15.6 Hz), 6.99-7.05 (2H, m), 7.33-7.38 (2H, m).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Operation similar to that in Example 326 using propionic acid tert-butyl ester and 1-[(1E) -3-chloroprop-1-en-1-yl] -4-fluorobenzene synthesized in Reference Example 25 as starting materials Gave the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.26 (3H, t, J = 7.6 Hz), 1.61 (6H, s), 2.57 (2H, q, J = 7.6 Hz) 3.15 (2H, t, J = 7.0 Hz), 4.02 (2H, t, J = 7.0 Hz), 4.40 (2H, d, J = 6.1 Hz), 6.04- 6.14 (1H, m), 6.57 (1H, d, J = 15.8 Hz), 6.96-7.01 (2H, m), 7.07 (1H, s), 7.26- 7.36 (2H, m), 8.39 (2H, s).
MS: 487 (M ⁺⁺ 1).
[Example 348]
2-[(4- {2-[[(2E) -3- (4-chlorophenyl) prop-2-en-1-yl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3 -Thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 1-Chloro-4-[(1E) -3-chloroprop-1 synthesized by the same procedure as in Reference Example 24 and Reference Examples 24 to 25 using propionic acid tert-butyl ester and 4-chlorocinnamic acid as starting materials The title compound was obtained in the same manner as in Example 326 using -en-1-yl] benzene.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.63 (6H, s), 2.48 (2H, q, J = 7.5 Hz) , 3.13 (2H, t, J = 7.2 Hz), 3.92 (2H, t, J = 7.2 Hz), 4.32 (2H, d, J = 6.0 Hz), 6.13− 6.22 (1H, m), 6.46 (1 H, d, J = 15.9 Hz), 6.96 (1 H, s), 7.22-7.29 (4 H, m), 8.20 ( 2H, s).
MS: 503 (M ⁺⁺ 1).
[Example 349]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [4- (trifluoromethyl) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2- Methyl propionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and 1- (bromomethyl) -4- (trifluoromethyl) benzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.6 Hz), 1.62 (6H, s), 2.49 (2H, q, J = 7.6 Hz) , 3.09 (2H, t, J = 6.9 Hz), 3.92 (2H, t, J = 6.9 Hz), 4.86 (2H, s), 6.93 (1H, s), 7 .33 (2H, d, J = 8.1 Hz), 7.53 (2H, d, J = 8.1 Hz), 8.20 (2H, s).
MS: 511 (M ⁺⁺ 1).
[Example 350]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [4- (trifluoromethoxy) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2- Methyl propionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and 1- (bromomethyl) -4- (trifluoromethoxy) benzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.5 Hz), 1.62 (6H, s), 2.50 (2H, q, J = 7.5 Hz) , 3.08 (2H, t, J = 6.9 Hz), 3.91 (2H, t, J = 6.9 Hz), 4.82 (2H, s), 6.95 (1H, s), 7 .13 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.4 Hz), 8.23 (2H, s).
MS: 527 (M ⁺⁺ 1).
[Example 351]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-phenoxybutyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and (4-bromobutoxy) benzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.20 (3H, t, J = 7.8 Hz), 1.65 (6H, s), 1.68-1.83 (4H, m), 2 .46 (2H, q, J = 7.8 Hz), 3.11 (2H, t, J = 6.9 Hz), 3.56 (2H, t, J = 6.9 Hz), 3.91 (2H, t, J = 6.9 Hz), 3.98 (2H, t, J = 6.0 Hz), 6.80-6.96 (4H, m), 7.24-7.30 (2H, m), 8.17 (2H, s).
MS: 515 (M ⁺⁺ 1).
[Example 352]
2-[(4- {2-[(biphenyl-4-ylmethyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 4- (bromomethyl) biphenyl as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.31 (3H, t, J = 7.5 Hz), 1.66 (6H, s), 2.66 (2H, q, J = 7.5 Hz) 3.49-3.58 (2H, m), 4.11-4.18 (2H, m), 5.31 (2H, s), 7.30-7.56 (10H, m), 8 .47 (2H, brs).
MS: 519 (M ⁺⁺ 1).
[Example 353]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [4- (1H-pyrazol-1-yl) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio } -2-Methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 1- [4- (bromomethyl) phenyl] -1H-pyrazole as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.29 (3H, t, J = 7.5 Hz), 1.61 (6H, s), 2.62 (2H, q, J = 7.5 Hz) 3.13 (2H, t, J = 6.9 Hz), 4.13 (2H, t, J = 6.9 Hz), 5.05 (2H, s), 6.47 (1H, s), 7 39-7.42 (3H, m), 7.66-7.72 (3H, m), 7.92 (1H, d, J = 2.4 Hz), 8.46 (2H, s).
MS: 509 (M ⁺⁺ 1).
[Example 354]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [4- (1H-1,2,4-triazol-1-yl) benzyl] amino} ethyl) -1,3-thiazole -2-yl] thio} -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 1- [4- (bromomethyl) phenyl] -1H-1,2,4-triazole as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.30 (3H, t, J = 7.5 Hz), 1.63 (6H, s), 2.65 (2H, q, J = 7.5 Hz) 3.30 (2H, t, J = 7.2 Hz), 4.20 (2H, t, J = 7.2 Hz), 5.18 (2H, s), 7.52 (2H, d, J = 8.4 Hz), 7.68-7.72 (3 H, m), 8.17 (1 H, s), 8.50 (2 H, s), 8.95 (1 H, s).
MS: 510 (M ⁺⁺ 1).
[Example 355]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (2-naphthylmethyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloric acid salt

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 2- (bromomethyl) naphthalene as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.13 (3H, t, J = 7.5 Hz), 1.46 (6H, s), 2.44 (2H, q, J = 7. 5 Hz), 3.02 (2H, t, J = 6.9 Hz), 3.90 (2H, t, J = 6.9 Hz), 4.90 (2H, s), 7.33-7.45 ( 4H, m), 7.66 (1H, s), 7.79-7.86 (3H, m), 8.30 (2H, s).
MS: 493 (M ⁺⁺ 1).
[Example 356]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (1-naphthylmethyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloric acid salt

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 1- (chloromethyl) naphthalene as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.16 (3H, t, J = 7.5 Hz), 1.46 (6H, s), 2.47 (2H, q, J = 7. 5 Hz), 3.04 (2 H, t, J = 7.2 Hz), 3.91 (2 H, t, J = 7.2 Hz), 5.25 (2 H, s), 7.22 (1 H, d, J = 7.2 Hz), 7.39-7.46 (2H, m), 7.52-7.56 (2H, m), 7.83 (1H, d, J = 8.4 Hz), 7. 94-7.97 (1H, m), 8.03-8.06 (1H, m), 8.33 (2H, s).
MS: 493 (M ⁺⁺ 1).
[Example 357]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(2-phenyl-1,3-oxazol-4-yl) methyl] amino} ethyl) -1,3-thiazole-2 -Yl] thio} -2-methylpropionic acid hydrochloride (Reference Example 26)
4- (Chloromethyl) -2-phenyl-1,3-oxazole

Benzamide 10.0 g and 1,3-dichloroacetone 10.5 g were dissolved in ethanol 100 mL and refluxed for 8 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 7: 1) to give 4.6 g of the title compound as a white solid.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.58 (2H, s), 7.45-7.47 (3H, m), 7.71 (1H, s), 8.01-8.06 (2H, m).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 4- (chloromethyl) -2-phenyl-1,3-oxazole synthesized in Reference Example 26 as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.27 (3H, t, J = 7.6 Hz), 1.68 (6H, s), 2.62 (2H, q, J = 7.5 Hz) 3.27 (2H, t, J = 6.3 Hz), 4.43 (2H, t, J = 6.3 Hz), 4.89 (2H, s), 7.17 (1H, s), 7 .43-7.47 (3H, m), 7.9-8.04 (2H, m), 8.16 (1H, brs), 8.48 (2H, s).
MS: 510 (M ⁺⁺ 1).
[Example 358]
2-({4- [2-((5-ethylpyrimidin-2-yl) {[2- (4-methylphenyl) -1,3-oxazol-4-yl] methyl} amino) ethyl] -1, 3-thiazol-2-yl} thio) -2-methylpropionic acid hydrochloride (Reference Example 27)
4- (Chloromethyl) -2- (4-methylphenyl) -1,3-oxazole

10.0 g of 4-methylbenzamide and 9.4 g of 1,3-dichloroacetone were dissolved in 100 mL of ethanol and refluxed for 8 hours. After cooling, the reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 7: 1) to give 7.8 g of the title compound as a white solid. It was.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.40 (3H, s), 4.57 (2H, s), 7.26 (2H, d, J = 8.1 Hz), 7.67 (1H , S), 7.92 (2H, d, J = 8.1 Hz).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 4- (chloromethyl) -2- (4-methylphenyl) -1,3-oxazole synthesized in Reference Example 27 as starting materials. Got.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.50 (6H, s), 2.36 (3H, s), 2.47 (2H, q, J = 7.5 Hz), 3.08 (2H, t, J = 7.2 Hz), 3.99 (2H, t, J = 7.2 Hz), 4.71 (2H, s) , 7.32 (2H, d, J = 8.1 Hz), 7.50 (1H, s), 7.82 (2H, d, J = 8.1 Hz), 7.97 (1H, s), 8 .33 (2H, s).
MS: 524 (M ⁺⁺ 1).
[Example 359]
2-({4- [2-((5-ethylpyrimidin-2-yl) {[2- (4-fluorophenyl) -1,3-oxazol-4-yl] methyl} amino) ethyl] -1, 3-thiazol-2-yl} thio) -2-methylpropionic acid hydrochloride (Reference Example 28)
4- (Chloromethyl) -2- (4-fluorophenyl) -1,3-oxazole

10.0 g of 4-fluorobenzamide and 9.5 g of 1,3-dichloroacetone were dissolved in 100 mL of ethanol and refluxed for 8 hours. After cooling, the reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1-7: 1) to give 4.3 g of the title compound as a white solid. It was.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.56 (2H, s), 7.11-7.17 (2H, m), 7.69 (1H, s), 8.00-8.05 (2H, m).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 4- (chloromethyl) -2- (4-fluorophenyl) -1,3-oxazole synthesized in Reference Example 28 as starting materials. Got.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.16 (3H, t, J = 7.5 Hz), 1.51 (6H, s), 2.49 (2H, q, J = 7. 5 Hz), 3.11 (2H, t, J = 7.2 Hz), 4.03 (2H, t, J = 7.2 Hz), 4.75 (2H, s), 7.33-7.39 ( 2H, m), 7.53 (1H, s), 7.96-8.01 (2H, m), 8.07 (1H, s), 8.39 (2H, s).
MS: 528 (M ⁺⁺ 1).
[Example 360]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(2-phenyl-1,3-thiazol-4-yl) methyl] amino} ethyl) -1,3-thiazol-2 -Yl] thio} -2-methylpropionic acid hydrochloride (Reference Example 29)
4- (Chloromethyl) -2-phenyl-1,3-thiazole

10.0 g of thiobenzamide and 9.25 g of 1,3-dichloroacetone were dissolved in 200 mL of acetone and stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, 200 mL of methanol was added, and the mixture was refluxed for 1.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 7: 1) to give 5.1 g of the title compound as a brown oil.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.75 (2H, s), 7.31 (1H, s), 7.41-7.46 (3H, m), 7.93-8.03 (2H, m).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 4- (chloromethyl) -2-phenyl-1,3-thiazole synthesized in Reference Example 29 as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.27 (3H, t, J = 7.5 Hz), 1.65 (6H, s), 2.61 (2H, q, J = 7.5 Hz) 3.28 (2H, t, J = 6.3 Hz), 4.46 (2H, t, J = 6.3 Hz), 5.08 (2H, s), 7.19 (1H, s), 7 .43-7.45 (3H, m), 7.76 (1H, brs), 7.89-7.93 (2H, m), 8.47 (2H, s).
MS: 526 (M ⁺⁺ 1).
[Example 361]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(4-methyl-2-phenyl-1,3-oxazol-5-yl) methyl] amino} ethyl) -1,3 -Thiazol-2-yl] thio} -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Similar to Example 327, starting from propionic acid tert-butyl ester and 5- (chloromethyl) -4-methyl-2-phenyl-1,3-oxazole synthesized with reference to patent document [WO0100603] and the like To give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.30 (3H, t, J = 7.5 Hz), 1.62 (6H, s), 2.53 (3H, s), 2.67 (2H , Q, J = 7.5 Hz), 3.42-3.52 (2H, m), 4.31-4.37 (2H, m), 5.27 (2H, s), 7.48-7 .57 (3H, m), 7.94 (1H, brs), 8.19-18.22 (2H, m), 8.52 (2H, brs).
MS: 524 (M ⁺⁺ 1).
[Example 362]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(4-methyl-2-phenyl-1,3-thiazol-5-yl) methyl] amino} ethyl) -1,3 -Thiazol-2-yl] thio} -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Similar to Example 327, starting from propionic acid tert-butyl ester and 5- (chloromethyl) -4-methyl-2-phenyl-1,3-thiazole synthesized with reference to patent document [WO0100603] and the like To give the title compound.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.17 (3H, t, J = 7.5 Hz), 1.51 (6H, s), 2.44-2.51 (5H, m) , 3.02 (2H, t, J = 7.5 Hz), 3.90 (2H, t, J = 7.5 Hz), 4.88 (2H, s), 7.41-7.49 (4H, m), 7.81-7.85 (2H, m), 8.35 (2H, s).
MS: 540 (M ⁺⁺ 1).
[Example 363]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(5-methyl-2-phenyl-1,3-thiazol-4-yl) methyl] amino} ethyl) -1,3 -Thiazol-2-yl] thio} -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 4- (chloromethyl) -5-methyl-2-phenyl-1,3-thiazole as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.51 (6H, s), 2.47 (2H, q, J = 7. 5 Hz), 2.53 (3 H, s), 3.10 (2 H, t, J = 7.2 Hz), 4.06 (2 H, t, J = 7.2 Hz), 4.83 (2 H, s) , 7.43-7.48 (3H, m), 7.51 (1H, s), 7.78-7.82 (2H, m), 8.36 (2H, s).
MS: 540 (M ⁺⁺ 1).
[Example 364]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(2-phenylpyrimidin-5-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-Methylpropionic acid hydrochloride (Reference Example 30)
(2-Phenylpyrimidin-5-yl) methanol

  2.0 g of 2-phenylpyrimidine-5-carbaldehyde was dissolved in 20 mL of ethanol, and 411 mg of sodium borohydride was added under ice cooling, followed by stirring at 0 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of ammonium chloride and subsequently with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.75 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.19 (1H, t, J = 5.1 Hz), 4.77 (2H, t, J = 5.1 Hz), 7.47-7.52 ( 3H, m), 8.39-8.44 (2H, m), 8.80 (2H, s).
(Reference Example 31)
5- (Chloromethyl) -2-phenylpyrimidine

1.75 g of (2-phenylpyrimidin-5-yl) methanol synthesized in Reference Example 30 was dissolved in 20 mL of dichloromethane, and after ice cooling, 1.45 g of thionyl chloride was added and stirred at 0 ° C. for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 1.83 g of the title compound as a white solid.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.61 (2H, s), 7.49-7.53 (3H, m), 8.43-8.47 (2H, m), 8.82 (2H, s).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 5- (chloromethyl) -2-phenylpyrimidine synthesized in Reference Example 31 as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.50 (6H, s), 2.46 (2H, q, J = 7. 5 Hz), 3.08 (2H, t, J = 6.6 Hz), 4.02 (2H, t, J = 6.6 Hz), 4.77 (2H, s), 7.47-7.53 ( 4H, m), 8.33-8.37 (4H, m), 8.77 (2H, s).
MS: 521 (M ⁺⁺ 1).
[Example 365]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-phenoxybenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloric acid Salt (Reference Example 32)
1- (Chloromethyl) -4-phenoxybenzene

Using 4-phenoxybenzaldehyde as the starting material, the title compound was obtained in the same manner as in Reference Example 30 and Reference Example 31.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.61 (2H, s), 7.49-7.53 (3H, m), 8.43-8.47 (2H, m), 8.82 (2H, s).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 1- (chloromethyl) -4-phenoxybenzene synthesized in Reference Example 32 as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.28 (3H, t, J = 7.5 Hz), 1.61 (6H, s), 2.62 (2H, q, J = 7.5 Hz) 3.18 (2H, t, J = 7.2 Hz), 4.12 (2H, t, J = 7.2 Hz), 4.99 (2H, s), 6.94-7.00 (4H, m), 7.11 (1H, t, J = 7.5 Hz), 7.25-7.36 (5H, m), 8.46 (2H, s).
MS: 535 (M ⁺⁺ 1).
[Example 366]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (quinolin-3-ylmethyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride (Reference Example 33)
3- (Chloromethyl) quinoline

The title compound was obtained in the same manner as in Reference Example 30 and Reference Example 31, using quinoline-3-carbaldehyde as a starting material.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.79 (2H, s), 7.58 (1H, t, J = 7.2 Hz), 7.71-7.78 (1H, m), 7 .83 (1H, d, J = 7.2 Hz), 8.10-8.17 (2H, m), 8.94 (1H, d, J = 2.1 Hz).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 3- (chloromethyl) quinoline synthesized in Reference Example 33 as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.46 (6H, s), 2.47 (2H, q, J = 7. 5Hz), 3.12 (2H, t, J = 6.9 Hz), 4.10 (2H, t, J = 6.9 Hz), 5.04 (2H, s), 7.50 (1H, s) , 7.92 (1H, t, J = 7.8 Hz), 8.10 (1H, t, J = 7.8 Hz), 8.29-8.43 (4H, m), 8.92 (1H, s), 9.21 (1H, s).
MS: 494 (M ⁺⁺ 1).
[Example 367]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (quinolin-2-ylmethyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride (Reference Example 34)
2- (Chloromethyl) quinoline

5.0 g of 2-methylquinoline was dissolved in 25 mL of carbon tetrachloride, 6.2 g of N-bromosuccinimide and 57 mg of 2,2′-azobisisobutyronitrile (AIBN) were added, and the mixture was refluxed for 4 hours. After cooling with ice, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 3.7 g of the title compound as a pale yellow solid.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.72 (2H, s), 7.53-7.59 (2H, m), 7.70-7.76 (1H, m), 7.81 (1H, d, J = 8.1 Hz), 8.07 (1H, d, J = 8.7 Hz), 8.18 (1H, d, J = 8.7 Hz).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 2- (chloromethyl) quinoline synthesized in Reference Example 34 as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.09 (3H, t, J = 7.5 Hz), 1.44 (6H, s), 2.40 (2H, q, J = 7. 5Hz), 3.11 (2H, t, J = 6.9 Hz), 4.12 (2H, t, J = 6.9 Hz), 5.18 (2H, s), 7.50 (1H, s) , 7.64 (1H, d, J = 7.8 Hz), 8.02 (1H, d, J = 7.8 Hz), 8.18-8.32 (4H, m), 8.79 (1H, d, J = 8.4 Hz).
MS: 494 (M ⁺⁺ 1).
[Example 368]
2-[(4- {2-[[(6-Chloroquinolin-2-yl) methyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-Methylpropionic acid hydrochloride (Reference Example 35)
6-Chloro-2- (chloromethyl) quinoline

The title compound was obtained in the same manner as in Reference Example 34 using 6-chloro-2-methylquinoline as a starting material.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.69 (2H, s), 7.59 (1H, d, J = 8.7 Hz), 7.66 (1H, dd, J = 2.4) 9.0 Hz), 7.79 (1H, d, J = 2.4 Hz), 8.00 (1H, d, J = 9.0 Hz), 8.08 (1H, d, J = 8.7 Hz).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and 6-chloro-2- (chloromethyl) quinoline synthesized in Reference Example 35 as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.13 (3H, t, J = 7.5 Hz), 1.47 (6H, s), 2.45 (2H, q, J = 7. 5Hz), 3.12 (2H, t, J = 7.2 Hz), 4.10 (2H, t, J = 7.2 Hz), 5.12 (2H, s), 7.52 (1H, s) 7.57 (1H, d, J = 8.7 Hz), 7.91 (1H, d, J = 9.3 Hz), 8.18 (1H, d, J = 9.3 Hz), 8.25 ( 1H, s), 8.30 (2H, s), 8.53 (1H, d, J = 8.7 Hz).
MS: 528 (M ⁺⁺ 1).
[Example 369]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-propylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid
(Reference Example 36)
(4-Propylphenyl) methanol

  1.16 g of lithium aluminum hydride was suspended in 100 mL of diethyl ether, 50 mL of a diethyl ether solution of 5.0 g of 4-propylbenzoic acid was added under ice cooling, and the mixture was heated to reflux for 2.5 hours. After cooling the reaction solution with ice, 3.0 mL of water and 12 mL of a 1 mol / L sodium hydroxide aqueous solution were sequentially added dropwise, and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction solution was directly filtered through Celite, and the filtrate was concentrated under reduced pressure to give 4.9 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.94 (3H, t, J = 7.4 Hz), 1.58-1.70 (3H, m), 2.59 (2H, t, J = 7.4 Hz), 4.66 (2H, d, J = 5.6 Hz), 7.16-7.19 (2H, m), 7.26-7.30 (2H, m).
(Reference Example 37)
1- (chloromethyl) -4-propylbenzene

4.93 g of (4-propylphenyl) methanol synthesized in Reference Example 36 was dissolved in 65 mL of carbon tetrachloride, 9.5 g of triphenylphosphine was added, and the mixture was heated to reflux for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in hexane, insoluble matters were filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane) to give 2.24 g of the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.94 (3H, t, J = 7.3 Hz), 1.57-1.70 (2H, m), 2.59 (2H, t, J = 7.5 Hz), 4.58 (2H, s), 7.16-7.18 (2H, m), 7.29-7.31 (2H, m).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and 1- (chloromethyl) -4-propylbenzene synthesized in Reference Example 37 as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.92 (3H, t, J = 7.4 Hz), 1.21 (3H, t, J = 7.5 Hz), 1.57-1.63 ( 8H, m), 2.44-2.56 (4H, m), 3.05 (2H, t, J = 7.2 Hz), 3.88 (2H, t, J = 7.2 Hz), 4. 79 (2H, s), 6.89 (1H, s), 7.07-7.15 (4H, m), 8.19 (2H, s).
MS: 485 (M ⁺⁺ 1).
[Example 370]
2-[(4- {2-[(4-Butylbenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Using 1-butyl-4- (chloromethyl) benzene synthesized by the same procedure as in Reference Examples 36 to 37 using propionic acid tert-butyl ester and 4-butylbenzoic acid as starting materials, the same as in Example 326 The title compound was obtained by manipulation.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.90 (3H, t, J = 7.3 Hz), 1.21 (3H, t, J = 7.5 Hz), 1.26 to 1.37 ( 2H, m), 1.53-1.59 (2H, m), 1.63 (6H, s), 2.46-2.59 (4H, m), 3.05 (2H, t, J = 7.2 Hz), 3.88 (2H, t, J = 7.2 Hz), 4.79 (2H, s), 6.89 (1H, s), 7.07-7.15 (4H, m) , 8.19 (2H, s).
MS: 499 (M ⁺⁺ 1).
[Example 371]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-isopropylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and 1- (chloromethyl) -4-isopropylbenzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.18-1.23 (9H, m), 1.63 (6H, s), 2.48 (2H, q, J = 7.5 Hz), 2 84-2.89 (1H, m), 3.07 (2H, t, J = 7.2 Hz), 3.89 (2H, t, J = 7.2 Hz), 4.79 (2H, s) 6.90 (1H, s), 7.14 (4H, s), 8.19 (2H, s).
MS: 485 (M ⁺⁺ 1).
[Example 372]
2-[(4- {2-[(4-tert-Butylbenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropion acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and 1- (bromomethyl) -4-tert-butylbenzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.29 (9H, s), 1.63 (6H, s), 2.48 (2H , Q, J = 7.5 Hz), 3.07 (2H, t, J = 7.2 Hz), 3.89 (2H, t, J = 7.2 Hz), 4.79 (2H, s), 6 .90 (1H, s), 7.14-7.16 (2H, m), 7.28-7.31 (2H, m), 8.19 (2H, s).
MS: 499 (M ⁺⁺ 1).
[Example 373]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-isobutylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Using 1- (chloromethyl) -4-isobutylbenzene synthesized by the same procedure as in Reference Examples 36 to 37 using propionic acid tert-butyl ester and 4-isobutylbenzoic acid as starting materials, the same as in Example 326 The title compound was obtained by manipulation.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (6H, d, J = 6.6 Hz), 1.21 (3H, t, J = 7.5 Hz), 1.63 (6H, s) , 1.77-1.84 (1H, m), 2.41-2.52 (4H, m), 3.05 (2H, t, J = 7.2 Hz), 3.88 (2H, t, J = 7.2 Hz), 4.79 (2H, s), 6.89 (1H, s), 7.05 (2H, t, J = 8.1 Hz), 7.13 (2H, t, J = 8.1 Hz), 8.19 (2H, s).
MS: 499 (M ⁺⁺ 1).
[Example 374]
2-[(4- {2-[[4- (Ethoxymethyl) benzyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid (Reference Example 38)
4- (Ethoxymethyl) benzoic acid methyl ester

  4- (Hydroxymethyl) benzoic acid methyl ester (2.0 g) and ethyl iodide (3.8 g) are dissolved in N, N-dimethylformamide (60 mL). Under ice-cooling, 2.8 g of potassium tert-butoxide is added, and 1 at room temperature is added. Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 10: 1 to 5: 1) to give 2.0 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.27 (3H, t, J = 6.9 Hz), 3.57 (2H, q, J = 6.9 Hz), 3.92 (3H, s) 4.56 (2H, s), 7.40-7.43 (2H, m), 8.01-8.03 (2H, m).
(Reference Example 39)
[4- (Ethoxymethyl) phenyl] methanol

  0.39 g of lithium aluminum hydride was suspended in 10 mL of tetrahydrofuran, and under ice cooling, a solution of 2.0 g of 4- (ethoxymethyl) benzoic acid methyl ester synthesized in Reference Example 38 in 50 mL of tetrahydrofuran was added, and then at room temperature. Stir for 12 hours. After cooling the reaction solution with ice, 1.0 mL of water and 4.0 mL of a 1 mol / L aqueous sodium hydroxide solution were sequentially added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give 1.52 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.24 (3H, t, J = 7.1 Hz), 3.54 (2H, q, J = 7.1 Hz), 4.51 (2H, s) , 4.69 (2H, d, J = 5.7 Hz), 7.35 (4H, s).
(Reference Example 40)
1- (Chloromethyl) -4- (ethoxymethyl) benzene

1.54-g of [4- (ethoxymethyl) phenyl] methanol synthesized in Reference Example 39 was dissolved in 20 mL of carbon tetrachloride, 2.64 g of triphenylphosphine was added, and the mixture was heated to reflux for 2.5 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in hexane, insoluble matters were filtered, and the filtrate was collected under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 20: 1) to give 1.07 g of the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.25 (3H, t, J = 7.0 Hz), 3.54 (2H, q, J = 7.0 Hz), 4.50 (2H, s) , 4.58 (2H, s), 7.29-7.38 (4H, m).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and 1- (chloromethyl) -4- (ethoxymethyl) benzene synthesized in Reference Example 40 as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.18-1.25 (6H, m), 1.63 (6H, s), 2.48 (2H, q, J = 7.5 Hz), 3 .05 (2H, t, J = 7.2 Hz), 3.52 (2H, q, J = 6.9 Hz), 3.88 (2H, t, J = 7.2 Hz), 4.47 (2H, s), 4.82 (2H, s), 6.90 (1H, s), 7.19-7.28 (4H, m), 8.20 (2H, s).
MS: 501 (M ⁺⁺ 1).
[Example 375]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [4- (methoxymethyl) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Using (4-methoxymethyl) phenylmethyl chloride obtained by the same procedure as in Reference Examples 38 to 40 using propionic acid tert-butyl ester and methyl iodide as starting materials, the title compound was prepared in the same manner as in Example 326. Obtained.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.21 (3H, t, J = 7.8 Hz), 1.63 (6H, s), 2.48 (2H, q, J = 7.8 Hz) , 3.05 (2H, t, J = 7.0 Hz), 3.37 (3H, s), 3.88 (2H, t, J = 7.0 Hz), 4.42 (2H, s), 4 .82 (2H, s), 6.91 (1H, s), 7.20-7.27 (4H, m), 8.20 (2H, s).
MS: 487 (M ⁺⁺ 1).
[Example 376]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [4- (2-methoxyethyl) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2 -Methylpropionic acid (Reference Example 41)
1-Bromo-4- (2-methoxyethyl) benzene

2.0 g of 2- (4-bromophenyl) ethanol was dissolved in 50 mL of N, N-dimethylformamide, and 0.44 g of sodium hydride (60% oily) was added under ice cooling. The temperature was gradually raised to room temperature, and after stirring for 2 hours, 2.1 g of methyl iodide was added again under ice cooling. The temperature was gradually raised to room temperature and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 20: 1-10: 1) to give 1.2 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.83 (2H, t, J = 6.9 Hz), 3.34 (3H, s), 3.57 (2H, t, J = 6.9 Hz) 7.08-7.11 (2H, m), 7.39-7.43 (2H, m).
(Reference Example 42)
[4- (2-methoxyethyl) phenyl] methanol

  1.15 g of 1-bromo-4- (2-methoxyethyl) benzene obtained in Reference Example 41 was dissolved in 30 mL of tetrahydrofuran, cooled to −78 ° C., and 1.56 mol / L n-butyllithium- under a nitrogen atmosphere. 3.6 mL of hexane was added dropwise and stirred as it was for 1 hour. After dropwise addition of 0.621 mL of N, N-dimethylformamide, the mixture was stirred for 30 minutes, saturated aqueous ammonium chloride solution was added, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4- (2-methoxyethyl) benzaldehyde. This compound was used in the next step without further purification. This compound was dissolved in 25 mL of ethanol, 0.202 g of sodium borohydride was added, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give the title compound (0.415 g) as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.89 (2H, t, J = 6.9 Hz), 3.36 (3H, s), 3.60 (2H, t, J = 6.9 Hz) 4.67 (2H, d, J = 6.2 Hz), 7.22 (2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.0 Hz).
(Reference Example 43)
1- (Chloromethyl) -4- (2-methoxyethyl) benzene

415 mg of [4- (2-methoxyethyl) phenyl] methanol synthesized in Reference Example 42 was dissolved in 8 mL of carbon tetrachloride, 720 mg of triphenylphosphine was added, and the mixture was heated to reflux for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in hexane, insoluble matter was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 20: 1) to give 225 mg of the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.89 (2H, t, J = 6.9 Hz), 3.35 (3H, s), 3.60 (2H, t, J = 6.9 Hz) 4.57 (2H, s), 7.21-7.24 (2H, m), 7.31-7.33 (2H, m).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and 1- (chloromethyl) -4- (2-methoxyethyl) benzene obtained in Reference Example 43 as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.63 (6H, s), 2.48 (2H, q, J = 7.5 Hz) , 2.84 (2H, t, J = 7.2 Hz), 3.05 (2H, t, J = 7.2 Hz), 3.34 (3H, s), 3.57 (2H, t, J = 7.2 Hz), 3.88 (2H, t, J = 7.2 Hz), 4.79 (2H, s), 6.89 (1H, s), 7.11-7.17 (4H, m) , 8.19 (2H, s).
MS: 501 (M ⁺⁺ 1).
[Example 377]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-propoxybenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloric acid salt

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was prepared in the same manner as in Example 327 using (4-propoxyphenyl) methyl chloride obtained by the same procedure as in Reference Examples 42 to 43 using propionic acid tert-butyl ester and 4-propoxybenzaldehyde as starting materials. Obtained.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.95 (3H, t, J = 7.3 Hz), 1.15 (3H, t, J = 7.8 Hz), 1.50 (6H, s) , 1.67-1.75 (2H, m), 2.46 (2H, q, J = 7.6 Hz), 2.98 (2H, t, J = 7.1 Hz), 3.82 (2H, t, J = 7.1 Hz), 3.87 (2H, t, J = 7.1 Hz), 4.69 (2H, s), 6.84 (2H, d, J = 6.5 Hz), 7. 14 (2H, d, J = 6.5 Hz), 8.31 (2H, s).
MS: 501 (M ⁺⁺ 1).
[Example 378]
2-[(4- {2-[(4-Benzoylbenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloric acid salt

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, using propionic acid tert-butyl ester and [4- (bromomethyl) phenyl] (phenyl) methanone as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.49 (6H, s), 2.44-2.46 (2H, m) , 3.04 (2H, brs), 3.92 (2H, brs), 4.84 (2H, s), 7.35 (2H, d, J = 8.1 Hz), 7.48 (1H, s) ), 7.55-7.57 (2H, m), 7.67-7.73 (5H, m), 8.29 (2H, s).
MS: 547 (M ⁺⁺ 1).
[Example 379]
2-[(4- {2-[(3-butoxypropyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid ( Reference Example 44)
3-Butoxypropan-1-ol

Non-patent literature [J. Am. Chem. Soc. 249 (1939)], 2.13 g of sodium metal was added little by little to 15.75 g of 1,3-propanediol and 10.3 g of 1-bromobutane. After the addition, the mixture was stirred at 40 ° C. for 1 hour and further stirred at 60 ° C. for 1 hour. The precipitated inorganic substance was filtered and then distilled under reduced pressure to obtain 3.15 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.92 (3H, t, J = 7.2 Hz), 1.33-1.40 (2H, m), 1.53-1.58 (2H, m), 1.82-1.87 (2H, m), 3.44 (2H, t, J = 6.6 Hz), 3.62 (2H, t, J = 5.7 Hz), 3.76- 3.81 (2H, m).
(Reference Example 45)
3-Butoxypropyl 4-methylbenzenesulfonic acid

3.15 g of 3-butoxypropan-1-ol synthesized in Reference Example 44 was dissolved in 80 mL of dichloromethane, and 6.6 mL of triethylamine, 6.82 g of p-toluenesulfonyl chloride and 0.29 g of 4-dimethylaminopyridine were added. Stir at room temperature overnight. Water was added to the reaction solution, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to give 4.46 g of the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.89 (3H, t, J = 7.2 Hz), 1.24-1.33 (2H, m), 1.43-1.48 (2H, m), 1.87-1.91 (2H, m), 2.45 (3H, s), 3.31 (2H, t, J = 6.6 Hz), 3.41 (2H, t, J = 6.0 Hz), 4.13 (2H, t, J = 6.3 Hz), 7.33-7.36 (2H, m), 7.77-7.81 (2H, m).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and 3-butoxypropyl 4-methylbenzenesulfonic acid synthesized in Reference Example 45 as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.91 (3H, t, J = 7.5 Hz), 1.19 (3H, t, J = 7.5 Hz), 1.34-1.36 ( 2H, m), 1.54-1.57 (2H, m), 1.68 (6H, s), 1.75-1.85 (2H, m), 2.44-2.47 (2H, m), 3.08 (2H, t, J = 6.6 Hz), 3.44-3.51 (6H, m), 3.91 (2H, t, J = 6.6 Hz), 6.87 ( 1H, s), 8.16 (2H, s).
MS: 467 (M ⁺⁺ 1).
[Example 380]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (3-propoxypropyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Using 3-propoxypropyl 4-methylbenzenesulfonic acid synthesized by the same procedure as in Reference Examples 44 to 45 using propionic acid tert-butyl ester and 1-bromopropane as starting materials, the same procedure as in Example 326 was performed. The title compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.91 (3H, t, J = 7.2 Hz), 1.19 (3H, t, J = 7.5 Hz), 1.57-1.62 ( 2H, m), 1.68 (6H, s), 1.75-1.85 (2H, m), 2.44-2.47 (2H, m), 3.08 (2H, t, J = 6.6 Hz), 3.40-3.51 (6 H, m), 3.91 (2 H, t, J = 6.6 Hz), 6.87 (1 H, s), 8.16 (2 H, s) .
MS: 453 (M ⁺⁺ 1).
[Example 381]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (2-phenoxyethyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and (2-bromoethoxy) benzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.20 (3H, t, J = 7.6 Hz), 1.66 (6H, s), 2.48 (2H, q, J = 7.6 Hz) 3.17 (2H, t, J = 7.1 Hz), 3.90 (2H, t, J = 5.5 Hz), 4.06 (2H, t, J = 7.1 Hz), 4.17 ( 2H, t, J = 5.5 Hz), 6.88-6.95 (4H, m), 7.23-7.28 (2H, m), 8.19 (2H, s).
MS: 473 (M ⁺⁺ 1).
[Example 382]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [2- (4-fluorophenoxy) ethyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2 -Methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and 1- (2-bromoethoxy) -4-fluorobenzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.20 (3H, t, J = 7.5 Hz), 1.66 (6H, s), 2.47 (2H, q, J = 7.5 Hz) 3.16 (2H, t, J = 7.1 Hz), 3.87 (2H, t, J = 5.5 Hz), 4.03 (2H, t, J = 7.1 Hz), 4.12 ( 2H, t, J = 5.5 Hz), 6.81-6.86 (2H, m), 6.92-6.97 (3H, m), 8.17 (2H, s).
MS: 491 (M ⁺⁺ 1).
[Example 383]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [2- (4-methylphenoxy) ethyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2 -Methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Propionic acid tert-butyl ester and non-patent literature [Russ. J. et al. Org. Chem. 36,254 (2000)], and the title compound was obtained in the same manner as in Example 326 using 1- (2-bromoethoxy) -4-methylbenzene synthesized as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19 (3H, t, J = 7.5 Hz), 1.66 (6H, s), 2.26 (3H, s), 2.46 (2H , Q, J = 7.5 Hz), 3.16 (2H, t, J = 7.2 Hz), 3.87 (2H, t, J = 5.4 Hz), 4.04 (2H, t, J = 7.2 Hz), 4.13 (2H, t, J = 5.4 Hz), 6.79 (2H, d, J = 8.4 Hz), 6.94 (1H, s), 7.05 (2H, d, J = 8.4 Hz), 8.16 (2H, s).
MS: 487 (M ⁺⁺ 1).
[Example 384]
2-[(4- {2-[[2- (4-Chlorophenoxy) ethyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2 -Methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326 using propionic acid tert-butyl ester and 1- (2-bromoethoxy) -4-chlorobenzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.20 (3H, t, J = 7.5 Hz), 1.65 (6H, s), 2.47 (2H, q, J = 7.5 Hz) 3.15 (2H, t, J = 7.2 Hz), 3.88 (2H, t, J = 5.4 Hz), 4.02 (2H, t, J = 7.2 Hz), 4.12 ( 2H, t, J = 5.4 Hz), 6.81-6.84 (2H, m), 6.95 (1H, s), 7.19-7.22 (2H, m), 8.17 ( 2H, s).
MS: 507 (M ⁺⁺ 1).
[Example 385]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [2- (4-methoxyphenoxy) ethyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2 -Methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Propionic acid tert-butyl ester and non-patent literature [Russ. J. et al. Org. Chem. 36,254 (2000)], and the title compound was obtained in the same manner as in Example 326 using 1- (2-bromoethoxy) -4-methoxybenzene synthesized as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19 (3H, t, J = 7.5 Hz), 1.66 (6H, s), 2.46 (2H, q, J = 7.5 Hz) 3.16 (2H, t, J = 7.2 Hz), 3.75 (3H, s), 3.86 (2H, t, J = 5.4 Hz), 4.03 (2H, t, J = 7.2 Hz), 4.11 (2 H, t, J = 5.4 Hz), 6.78-6.86 (4 H, m), 6.94 (1 H, s), 8.17 (2 H, s) .
MS: 503 (M ⁺⁺ 1).

[Example 386]
2-[(4- {2-[[2- (4-Ethylphenoxy) ethyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2 -Methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Propionic acid tert-butyl ester and non-patent literature [Russ. J. et al. Org. Chem. 36, 254 (2000)], and the title compound was obtained in the same manner as in Example 326, using 1- (2-bromoethoxy) -4-ethylbenzene synthesized as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.16 to 1.21 (6H, m), 1.66 (6H, s), 2.46 (2H, q, J = 7.5 Hz), 2 .57 (2H, q, J = 7.5 Hz), 3.16 (2H, t, J = 7.2 Hz), 3.87 (2H, t, J = 5.4 Hz), 4.04 (2H, t, J = 7.2 Hz), 4.14 (2H, t, J = 5.4 Hz), 6.81-6.85 (2H, m), 6.94 (1H, s), 7.06- 7.10 (2H, m), 8.16 (2H, s).
MS: 501 (M ⁺⁺ 1).
[Example 387]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [2- (4-propylphenoxy) ethyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2 -Methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Propionic acid tert-butyl ester and non-patent literature [Russ. J. et al. Org. Chem. 36,254 (2000)], and the title compound was obtained in the same manner as in Example 326 using 1- (2-bromoethoxy) -4-propylbenzene synthesized as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.91 (3H, t, J = 7.5 Hz), 1.19 (3H, t, J = 7.5 Hz), 1.54-1.62 ( 2H, m), 1.66 (6H, s), 2.42-2.53 (4H, m), 3.17 (2H, t, J = 7.2 Hz), 3.87 (2H, t, J = 5.4 Hz), 4.04 (2H, t, J = 7.2 Hz), 4.13 (2H, t, J = 5.4 Hz), 6.80-6.84 (2H, m), 6.94 (1H, s), 7.04-7.07 (2H, m), 8.16 (2H, s).
MS: 515 (M ⁺⁺ 1).
[Example 388]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (3-phenoxypropyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and (3-bromopropoxy) benzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19 (3H, t, J = 7.5 Hz), 1.64 (6H, s), 2.04-2.10 (2H, m), 2 .45 (2H, q, J = 7.5 Hz), 3.11 (2H, t, J = 7.2 Hz), 3.68 (2H, t, J = 7.2 Hz), 3.91 (2H, t, J = 7.2 Hz), 4.00 (2H, t, J = 6.0 Hz), 6.88-6.95 (4H, m), 7.24-7.30 (2H, m), 8.15 (2H, s).
MS: 487 (M ⁺⁺ 1).
[Example 389]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [3- (4-fluorophenoxy) propyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2 -Methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326 using propionic acid tert-butyl ester and 1- (3-chloropropoxy) -4-fluorobenzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19 (3H, t, J = 7.5 Hz), 1.64 (6H, s), 2.02-2.11 (2H, m), 2 .45 (2H, q, J = 7.5 Hz), 3.11 (2H, t, J = 6.9 Hz), 3.67 (2H, t, J = 6.9 Hz), 3.88-3. 97 (4H, m), 6.80-6.85 (2H, m), 6.93-6.98 (3H, m), 8.15 (2H, s).
MS: 505 (M ⁺⁺ 1).
[Example 390]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [3- (4-methylphenoxy) propyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2 -Methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The same procedure as in Example 327, starting from propionic acid tert-butyl ester and 1- (3-chloropropoxy) -4-methylbenzene synthesized with reference to non-patent literature [Synthesis, 1069 (1990)] Gave the title compound.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.13 (3H, t, J = 7.5 Hz), 1.50 (6H, s), 1.91-1.98 (2H, m) 2.21 (3H, s), 2.45 (2H, q, J = 7.5 Hz), 3.01 (2H, t, J = 6.9 Hz), 3.60 (2H, t, J = 6.9 Hz), 3.85-3.95 (4 H, m), 6.79 (2 H, d, J = 8.2 Hz), 7.06 (2 H, d, J = 8.2 Hz), 7. 47 (1H, s), 8.30 (2H, s).
MS: 501 (M ⁺⁺ 1).
[Example 391]
2-[(4- {2-[[3- (4-Chlorophenoxy) propyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2 -Methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The same operation as in Example 326, starting from propionic acid tert-butyl ester and 1-chloro-4- (3-chloropropoxy) benzene synthesized with reference to non-patent literature [Synthesis, 1069 (1990)] Gave the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19 (3H, t, J = 7.8 Hz), 1.64 (6H, s), 2.05 to 2.09 (2H, m), 2 .45 (2H, q, J = 7.8 Hz), 3.11 (2H, t, J = 7.2 Hz), 3.67 (2H, t, J = 6.9 Hz), 3.87-3. 98 (4H, m), 6.80-6.83 (2H, m), 6.93 (1H, s), 7.20-7.23 (2H, m), 8.15 (2H, s) .
MS: 521 (M ⁺⁺ 1).
[Example 392]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [3- (4-methoxyphenoxy) propyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2 -Methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The same operation as in Example 326, starting from propionic acid tert-butyl ester and 1- (3-chloropropoxy) -4-methoxybenzene synthesized with reference to non-patent literature [Synthesis, 1069 (1990)] Gave the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19 (3H, t, J = 7.5 Hz), 1.64 (6H, s), 2.01-2.10 (2H, m), 2 .45 (2H, q, J = 7.5 Hz), 3.11 (2H, t, J = 7.2 Hz), 3.67 (2H, t, J = 7.2 Hz), 3.76 (3H, s), 3.89-3.97 (4H, m), 6.79-6.86 (4H, m), 6.91 (1H, s), 8.15 (2H, s).
MS: 517 (M ⁺⁺ 1).
[Example 393]
2-[(4- {2-[[3- (4-Cyanophenoxy) propyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2 -Methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 327, starting from propionic acid tert-butyl ester and 4- (3-chloropropoxy) benzonitrile synthesized with reference to non-patent literature [Synthesis, 1069 (1990)]. Got.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.12 (3H, t, J = 7.5 Hz), 1.49 (6H, s), 1.99-2.01 (2H, m) , 2.43 (2H, q, J = 7.5 Hz), 3.00 (2H, t, J = 6.6 Hz), 3.60 (2H, t, J = 6.6 Hz), 3.86 ( 2H, t, J = 7.5 Hz), 4.07 (2H, t, J = 6.0 Hz), 7.07 (2H, d, J = 8.7 Hz), 7.46 (1H, s), 7.75 (2H, d, J = 8.7 Hz), 8.25 (2H, s).
MS: 512 (M ⁺⁺ 1).
[Example 394]
2-[(4- {2-[(5-ethylpyrimidin-2-yl) (3-phenylpropyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Odor Hydride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 By using propionic acid tert-butyl ester and (3-bromopropyl) benzene as starting materials, a compound obtained by the same procedure as in Example 326 was dissolved in diethyl ether and reacted with 30% hydrobromic acid-acetic acid. The title compound was obtained.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.16 (3H, t, J = 7.5 Hz), 1.51 (6H, s), 1.82-1.85 (2H, m) , 2.46-2.61 (4H, m), 3.02 (2H, t, J = 7.0 Hz), 3.51 (2H, t, J = 7.5 Hz), 3.90 (2H, t, J = 7.0 Hz), 7.17-7.29 (5H, m), 7.50 (1H, s), 8.41 (2H, s).
MS: 471 (M ⁺⁺ 1).
[Example 395]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-phenylbutyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326 using propionic acid tert-butyl ester and (4-chlorobutyl) benzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19 (3H, t, J = 7.5 Hz), 1.60-1.64 (10H, m), 2.45 (2H, q, J = 7.5 Hz), 2.63 (2H, brs), 3.07 (2H, t, J = 7.2 Hz), 3.51 (2H, brs), 3.85 (2H, t, J = 7. 2Hz), 6.93 (1H, s), 7.16-7.18 (3H, m), 7.24-7.28 (2H, m), 8.16 (2H, s).
MS: 485 (M ⁺⁺ 1).
[Example 396]
2-[(4- {2-[[3- (cyclohexyloxy) propyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid hydrobromide (Reference Example 46)
1,5-Dioxaspiro [5,5] undecane

Dissolve 7.94 g of cyclohexanone in 200 mL of toluene, add 12.3 g of 1,3-propanediol and 0.1 g of p-toluenesulfonic acid monohydrate, and heat to reflux for 1.5 hours while removing the generated water did. After returning to room temperature, it was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 12.4 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.38-1.58 (6H, m), 1.69-1.79 (6H, m), 3.89-3.92 (4H, m) .
(Reference Example 47)
3- (Cyclohexyloxy) propan-1-ol

Non-patent literature [J. Am. Chem. Soc. 2371 (1962)], 1.71 g of aluminum chloride was dissolved in 10 mL of diethyl ether, and 0.121 g of lithium aluminum hydride was added under ice cooling. After stirring for 20 minutes, a solution of 1.0 g of 1,5-dioxaspiro [5,5] undecane obtained in Reference Example 46 in 5.0 mL of diethyl ether was added dropwise. The temperature was gradually raised to room temperature and stirred for 2 hours. Under ice cooling, 20 mL of 10% sulfuric acid was added, and the mixture was extracted with diethyl ether. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 0.82 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21-1.90 (12H, m), 3.25-3.28 (1H, m), 3.66 (2H, t, J = 5. 5 Hz), 3.79 (2H, t, J = 5.5 Hz).
(Reference Example 48)
3- (Cyclohexyloxy) propyl 4-methylbenzenesulfonic acid

820 mg of 3- (cyclohexyloxy) propan-1-ol synthesized in Reference Example 47 is dissolved in 20 mL of dichloromethane, 1.1 mL of triethylamine, 1.2 g of p-toluenesulfonyl chloride and 63 mg of 4-dimethylaminopyridine are added, Stir overnight at room temperature. Water was added to the reaction solution, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 1.0 g of the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.12-1.92 (12H, m), 2.45 (3H, s), 3.07-3.10 (1H, m), 3.45 (2H, t, J = 6.0 Hz), 4.14 (2H, t, J = 6.0 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.80 (2H, d, J = 8.4 Hz).

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Starting from propionic acid tert-butyl ester and 3- (cyclohexyloxy) propyl 4-methylbenzenesulfonic acid synthesized in Reference Example 48, the compound obtained by the same procedure as in Example 326 was dissolved in diethyl ether, The title compound was obtained by the action of 30% hydrobromic acid-acetic acid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.07-1.20 (9H, m), 1.51 (6H, s), 1.73-1.75 (6H, m), 2 .45-2.50 (2H, m), 2.95-3.05 (2H, m), 3.36-3.41 (3H, m), 3.49 (2H, t, J = 7. 2 Hz), 3.86 (2H, t, J = 7.2 Hz), 7.48 (1H, s), 8.33 (2H, s).
MS: 493 (M ⁺⁺ 1).
[Example 397]
2-[(4- {2-[[2- (Benzyloxy) ethyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and [(2-bromoethoxy) methyl] benzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19 (3H, t, J = 7.5 Hz), 1.66 (6H, s), 2.46 (2H, q, J = 7.5 Hz) , 3.09 (2H, t, J = 6.6 Hz), 3.67 (4H, s), 3.99 (2H, t, J = 6.6 Hz), 4.54 (2H, s), 6 .84 (1H, s), 7.25-7.31 (5H, m), 8.15 (2H, s).
MS: 487 (M ⁺⁺ 1).
[Example 398]
2-[(4- {2-[[3- (Benzyloxy) propyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and [(3-bromopropoxy) methyl] benzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.86 (3H, t, J = 7.5 Hz), 1.65 (6H, s), 1.83-1.92 (2H, m), 2 .45 (2H, q, J = 7.5 Hz), 3.07 (2H, t, J = 6.7 Hz), 3.47-3.54 (4H, m), 3.88 (2H, t, J = 6.7 Hz), 4.55 (2H, s), 6.87 (1H, s), 7.26-7.35 (5H, m), 8.15 (2H, s).
MS: 501 (M ⁺⁺ 1).
[Example 399]
2-[(4- {2-[(biphenyl-4-ylmethyl) (5-cyanopyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro-5-cyano synthesized in Example 7 The same operation as in Example 265-1 was carried out using pyridine as the starting material, and then the compound obtained by the same operation as in Example 265-2 using biphenyl-4-ylmethyl chloride as the starting material was converted into dichloromethane and trifluoroacetic acid. And stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile) to give the title compound.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 1.51 (6H, s), 2.95-3.12 (2H, m), 3.80-4.03 (2H, m), 4 .79 (2H, s), 6.74 (1H, d, J = 8.9 Hz), 7.23-7.71 (10H, m), 7.82 (1H, d, J = 8.9 Hz) 8.52 (1H, s).
MS: 515 (M ⁺⁺ 1).
[Example 400]
2-[(4- {2-[(4-Bromophenylmethyl) (5-cyanopyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro-5-cyano synthesized in Example 7 The same operation as in Example 265-1 was carried out using pyridine as the starting material, and then the compound obtained by the same operation as in Example 265-2 using 4-bromobenzyl bromide as the starting material was subjected to dichloromethane and trifluoroacetic acid. And stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile) to give the title compound.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 1.50 (6H, s), 3.02 (2H, t, J = 7.3 Hz), 3.88 (2H, t, J = 7. 3 Hz), 4.72 (2H, s), 6.71 (1H, d, J = 9.2 Hz), 7.14, (1H, d, J = 8.4 Hz), 7.40-7.52. (3H, m), 7.82 (1H, dd, J = 9.2, 2.0 Hz), 8.50 (1H, d, J = 2.0 Hz).
MS: 519 (M ⁺⁺ 1).
[Example 401]
2-[(4- {3-[(biphenyl-4-ylmethyl) (5-ethylpyridin-2-yl) amino] propyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Hydrochloride

  2-{[4- (3-Aminopropyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro-5-cyano synthesized in Example 33 The title compound was obtained by the same procedures as in Example 265-1 using pyridine as a starting material, and then the same operations as in biphenyl-4-ylmethyl chloride Example 327.

¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 1.49 (6H, s), 1.88-2.09 (2H, m), 2.77 (2H, t, J = 7.3 Hz) , 4.87 (2H, s), 6.75 (1H, d, J = 9.2 Hz), 7.21-7.51 (6H, m), 7.58-7.68 (4H, m) 7.81 (1H, dd, J = 9.2, 2.4 Hz), 7.50 (1H, d, J = 2.4 Hz).
MS: 529 (M ⁺⁺ 1).
[Example 402]
2-[(4- {2-[(4-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid ( Example 402-1)
2-[(4- {2-[(4-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert -Butyl ester

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 4.0 g of propionic acid tert-butyl ester and 2.94 g of 1-bromo-4- (bromomethyl) benzene are dissolved in 40 mL of N, N-dimethylformamide, 1.32 g of potassium tert-butoxide is added, and the mixture is stirred at room temperature for 8 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to give 4.65 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.42 (9H, s), 1.56 (6H, s), 2.48 (2H , Q, J = 7.5 Hz), 3.08 (2H, t, J = 6.9 Hz), 3.90 (2H, t, J = 6.9 Hz), 4.70 (2H, s), 6 .98 (1H, s), 7.09 (2H, d, J = 8.1 Hz), 7.38 (2H, d, J = 8.1 Hz), 8.19 (2H, s).
(Example 402-2)
2-[(4- {2-[(4-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(4-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) obtained in Example 402-1 350 mg of thio] -2-methylpropionic acid tert-butyl ester was dissolved in 6 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 240 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.63 (6H, s), 2.48 (2H, q, J = 7.5 Hz) 3.06 (2H, t, J = 6.9 Hz), 3.89 (2H, t, J = 6.9 Hz), 4.76 (2H, s), 6.91 (1H, s), 7 .11 (2H, d, J = 8.4 Hz), 7.39 (2H, d, J = 8.4 Hz), 8.20 (2H, s).
MS: 523 (M ⁺⁺ 1).
[Example 403]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-pyrazin-2-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid hydrochloride (Example 403-1)
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-pyrazin-2-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid tert-butyl ester

  2-[(4- {2-[(4-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazole- synthesized in Example 402-1 under nitrogen atmosphere 2-yl) thio] -2-methylpropionic acid tert-butyl ester (800 mg) and 2-tributylstannylpyrazine (672 mg) were dissolved in dioxane (10 mL), tetrakis (triphenylphosphine) palladium (140 mg) was added, and the mixture was refluxed for 8 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 180 mg of the title compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.6 Hz), 1.42 (9H, s), 1.57 (6H, s), 2.48 (2H , Q, J = 7.6 Hz), 3.13 (2H, t, J = 7.0 Hz), 3.98 (2H, t, J = 7.0 Hz), 4.85 (2H, s), 7 .01 (1H, s), 7.36 (2H, d, J = 8.1 Hz), 7.94 (2H, d, J = 8.1 Hz), 8.21 (2H, s), 8.47 (1H, s), 8.60 (1H, s), 9.00 (1H, s).
(Example 403-2)
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-pyrazin-2-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid hydrochloride

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-pyrazin-2-ylbenzyl) amino] ethyl} -1,3-thiazole-2 obtained in Example 403-1 -Yl) thio] -2-methylpropionic acid tert-butyl ester (180 mg) was dissolved in 6 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; dichloromethane: methanol = 10: 1). The obtained compound was dissolved in 5 mL of diethyl ether, 1 mL of 4 mol / L hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give 140 mg of the title compound as a white solid.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.30 (3H, t, J = 7.6 Hz), 1.62 (6H, s), 2.65 (2H, q, J = 7. 6 Hz), 3.24 (2H, t, J = 7.5 Hz), 4.19 (2H, t, J = 7.5 Hz), 5.16 (2H, s), 7.48 (2H, d, J = 8.1 Hz), 7.60 (1H, s), 8.00 (2H, d, J = 8.1 Hz), 8.50-8.54 (3H, m), 8.66 (1H, s), 9.02 (1H, s).
MS: 521 (M ⁺⁺ 1).
[Example 404]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-pyrimidin-2-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid hydrochloride

  2-[(4- {2-[(4-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) synthesized in Example 402-1 The title compound was obtained in the same manner as in Example 403 using thio] -2-methylpropionic acid tert-butyl ester and 2-tributylstannylpyrimidine as starting materials.

1H-NMR (CDCl ₃ , 300 MHz) δ: 1.32 (3H, t, J = 7.5 Hz), 1.64 (6H, s), 2.67 (2H, q, J = 7.5 Hz), 3.39 (2H, brs), 4.21 (2H, brs), 5.29 (2H, s), 7.59-7.63 (3H, m), 8.02 (2H, s), 8 .49 (1H, brs), 8.60 (2H, d, J = 8.1 Hz), 9.11 (2H, d, J = 4.8 Hz).
MS: 521 (M ⁺⁺ 1).
[Example 405]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [4- (1,3-thiazol-2-yl) benzyl] amino} ethyl) -1,3-thiazol-2-yl ] Thio} -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(4-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) synthesized in Example 402-1 The title compound was obtained in the same manner as in Example 403, using thio] -2-methylpropionic acid tert-butyl ester and 2-tributylstannyl thiazole as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.50 (6H, s), 2.46 (2H, q, J = 7. 5 Hz), 3.03 (2H, t, J = 6.6 Hz), 3.91 (2H, t, J = 6.6 Hz), 4.81 (2H, s), 7.32 (2H, d, J = 8.4 Hz), 7.48 (1H, s), 7.77 (1H, d, J = 3.0 Hz), 7.86-7.91 (3H, m), 8.31 (2H, s).
MS: 526 (M ⁺⁺ 1).
[Example 406]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-pyridin-2-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid hydrochloride

  2-[(4- {2-[(4-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) synthesized in Example 402-1 The title compound was obtained in the same manner as in Example 403 using thio] -2-methylpropionic acid tert-butyl ester and 2-tributylstannylpyridine as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.31 (3H, t, J = 7.5 Hz), 1.61 (6H, s), 2.66 (2H, q, J = 7.5 Hz) 3.16 (2H, t, J = 6.9 Hz), 4.18 (2H, t, J = 6.9 Hz), 5.14 (2H, s), 7.45 (1H, brs), 7 .63 (2H, d, J = 7.8 Hz), 7.80-7.84 (1H, m), 8.16-8.24 (3H, m), 8.41-8.48 (1H, m), 8.93 (1H, d, J = 5.7 Hz).
MS: 520 (M ⁺⁺ 1).
[Example 407]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-pyridin-3-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid trifluoroacetate salt (Example 407-1)
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-pyridin-3-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid tert-butyl ester

  2-[(4- {2-[(4-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazole- synthesized in Example 402-1 under nitrogen atmosphere 2-yl) thio] -2-methylpropionic acid tert-butyl ester 300 mg and (3-diethylboryl) pyridine 76 mg were dissolved in dioxane 2.6 mL and 2 mol / L sodium carbonate 1.3 mL, and tetrakis (triphenylphosphine) palladium. 30 mg was added and refluxed for 2 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 1: 1) to give 223 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.5 Hz), 1.42 (9H, s), 1.57 (6H, s), 2.49 (2H , Q, J = 7.5 Hz), 3.13 (2H, t, J = 7.2 Hz), 3.96 (2H, t, J = 7.2 Hz), 4.83 (2H, s), 7 .01 (1H, s), 7.31-7.36 (3H, m), 7.48-7.50 (2H, m), 7.82-7.86 (1H, m), 8.21 (2H, s), 8.55-8.57 (1H, m), 8.81-8.82 (1H, m).
(Example 407-2)
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-pyridin-3-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid trifluoroacetate

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-pyridin-3-ylbenzyl) amino] ethyl} -1,3-thiazole-2 synthesized in Example 407-1 -Yl) thio] -2-methylpropionic acid tert-butyl ester was subjected to dichloromethane and trifluoroacetic acid. The reaction solution is concentrated under reduced pressure, and the residue is purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile = 75: 25-30: 70). The title compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.24 (3H, t, J = 7.5 Hz), 1.62 (6H, s), 2.53 (2H, q, J = 7.5 Hz) 3.10 (2H, t, J = 7.2 Hz), 3.98 (2H, t, J = 7.2 Hz), 4.91 (2H, s), 6.97 (1H, s), 7 .40 (2H, d, J = 8.1 Hz), 7.54 (2H, d, J = 8.1 Hz), 7.76-7.80 (1H, m), 8.28 (2H, s) , 8.34-8.37 (1H, m), 8.70-8.72 (1H, m), 9.04 (1H, brs).
MS: 520 (M ⁺⁺ 1).
[Example 408]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-morpholin-4-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid (Example 408-1)
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-morpholin-4-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid tert-butyl ester

  To a 20 mL screw-cap test tube purged with nitrogen was added 32 mg of tris (dibenzylideneacetone) dipalladium, 21 mg of 2- (di-tert-butylphosphino) biphenyl and 73 mg of sodium tert-butoxide, to which Example 402-1 2-[(4- {2-[(4-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized Toluene (1.4 mL) solution of propionic acid tert-butyl ester 400 mg and morpholine 91 mg was added. The lid was closed and the mixture was stirred at 110 ° C. for 8 hours. After cooling to room temperature, the solution was directly loaded onto silica gel chromatography and purified (elution solvent; hexane: ethyl acetate = 3: 1 to 2: 1) to give 200 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.43 (9H, s), 1.62 (6H, s), 2.47 (2H , Q, J = 7.5 Hz), 3.05-3.12 (6H, m), 3.83-4.14 (6H, m), 4.70 (2H, s), 6.82 (2H) , D, J = 8.4 Hz), 6.98 (1H, s), 7.15 (2H, d, J = 8.4 Hz), 8.19 (2H, s).
(Example 408-2)
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-morpholin-4-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (4-morpholin-4-ylbenzyl) amino] ethyl} -1,3-thiazole-2 synthesized in Example 408-1 -Yl) thio] -2-methylpropionic acid tert-butyl ester 200 mg Dissolved in 2 mL of dichloromethane, added 2 mL of trifluoroacetic acid, and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 20: 1) to give 111 mg of the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.63 (6H, s), 2.48 (2H, q, J = 7.5 Hz) , 3.02 (2H, t, J = 7.2 Hz), 3.11-3.14 (4H, m), 3.83-3.88 (6H, m), 4.75 (2H, s) 6.84 (2H, d, J = 8.4 Hz), 6.90 (1H, s), 7.17 (2H, d, J = 8.4 Hz), 8.19 (2H, s).
MS: 528 (M ⁺⁺ 1).
[Example 409]
2-[(4- {2-[[(4′-cyanobiphenyl-4-yl) methyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio ] -2-Methylpropionic acid hydrochloride

  2-[(4- {2-[(4-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) synthesized in Example 402-1 Using thio] -2-methylpropionic acid tert-butyl ester and 4-cyanophenylboric acid as starting materials, the compound obtained in the same manner as in Example 407 was dissolved in diethyl ether, and 4 mol / L hydrochloric acid-ethyl acetate was added. The title compound was obtained by acting.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.50 (6H, s), 2.45 (2H, q, J = 7. 5 Hz), 3.04 (2H, t, J = 7.2 Hz), 3.90 (2H, t, J = 7.2 Hz), 4.80 (2H, s), 7.32 (2H, d, J = 8.1 Hz), 7.48 (1H, s), 7.68 (2H, d, J = 8.1 Hz), 7.85 (2H, d, J = 8.4 Hz), 7.91 ( 2H, d, J = 8.4 Hz), 8.29 (2H, s).
MS: 544 (M ⁺⁺ 1).
[Example 410]
2-[(4- {2-[[(3′-cyanobiphenyl-4-yl) methyl] (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio ] -2-Methylpropionic acid hydrochloride

  2-[(4- {2-[(4-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) synthesized in Example 402-1 Using thio] -2-methylpropionic acid tert-butyl ester and 3-cyanophenylboric acid as starting materials, a compound obtained in the same manner as in Example 407 was dissolved in diethyl ether, and 4 mol / L hydrochloric acid-ethyl acetate was added. The title compound was obtained by acting.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.50 (6H, s), 2.46 (2H, q, J = 7. 5 Hz), 3.04 (2H, t, J = 6.9 Hz), 3.90 (2H, t, J = 6.9 Hz), 4.80 (2H, s), 7.31 (2H, d, J = 8.2 Hz), 7.48 (1H, s), 7.62-7.69 (3H, m), 7.81 (1H, d, J = 8.8 Hz), 7.99 (1H, d, J = 8.0 Hz), 8.12 (1H, s), 8.30 (2H, s).
MS: 544 (M ⁺⁺ 1).
[Example 411]
2-[(4- {2-[(3-bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid ( Example 411-1)
2-[(4- {2-[(3-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert -Butyl ester

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Dissolve 5.5 g of propionic acid tert-butyl ester and 4.04 g of 1-bromo-3- (bromomethyl) benzene in 55 mL of N, N-dimethylformamide and add 1.82 g of potassium tert-butoxide for 1 hour at room temperature. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to give 6.3 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.42 (9H, s), 1.57 (6H, s), 2.48 (2H , Q, J = 7.5 Hz), 3.09 (2H, t, J = 6.9 Hz), 3.92 (2H, t, J = 6.9 Hz), 4.23 (2H, s), 6 .98 (1H, s), 7.11-7.14 (2H, m), 7.31-7.35 (2H, m), 8.19 (2H, s).
(Example 411-2)
2-[(4- {2-[(3-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(3-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) obtained in Example 411-1 300 mg of thio] -2-methylpropionic acid tert-butyl ester was dissolved in 6 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 280 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.63 (6H, s), 2.49 (2H, q, J = 7.5 Hz) , 3.07 (2H, t, J = 6.9 Hz), 3.91 (2H, t, J = 6.9 Hz), 4.79 (2H, s), 6.93 (1H, s), 7 .14-7.17 (2H, m), 7.33-7.35 (2H, m), 8.21 (2H, s).
MS: 523 (M ⁺⁺ 1).
[Example 412]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (3-pyrimidin-2-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid hydrochloride

  2-[(4- {2-[(3-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) synthesized in Example 411-1 The title compound was obtained in the same manner as in Example 403 using thio] -2-methylpropionic acid tert-butyl ester and 2-tributylstannylpyrimidine as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.48 (6H, s), 2.46 (2H, q, J = 7. 5 Hz), 3.04 (2H, t, J = 6.3 Hz), 3.90 (2H, t, J = 6.3 Hz), 4.78 (2H, s), 7.36 (1H, d, J = 7.2 Hz), 7.42-7.49 (3H, m), 8.25-8.27 (2H, m), 8.31 (2H, s), 8.88 (2H, d, J = 4.8 Hz).
MS: 521 (M ⁺⁺ 1).
[Example 413]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) (3-pyrazin-2-ylbenzyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid hydrochloride

  2-[(4- {2-[(3-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) synthesized in Example 411-1 The title compound was obtained in the same manner as in Example 403 using thio] -2-methylpropionic acid tert-butyl ester and 2-tributylstannylpyrazine as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.16 (3H, t, J = 7.5 Hz), 1.48 (6H, s), 2.49 (2H, q, J = 7. 5 Hz), 3.07 (2H, t, J = 7.2 Hz), 3.95 (2H, t, J = 7.2 Hz), 4.90 (2H, s), 7.35 (1H, d, J = 7.7 Hz), 7.45-7.51 (2H, m), 8.00-8.02 (2H, m), 8.37 (2H, s), 8.62 (1H, d, J = 2.5 Hz), 8.70-8.73 (1 H, m), 9.22 (1 H, d, J = 1.4 Hz).
MS: 521 (M ⁺⁺ 1).
[Example 414]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [3- (1,3-thiazol-2-yl) benzyl] amino} ethyl) -1,3-thiazol-2-yl ] Thio} -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(3-Bromobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) synthesized in Example 411-1 The title compound was obtained in the same manner as in Example 403, using thio] -2-methylpropionic acid tert-butyl ester and 2-tributylstannyl thiazole as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.49 (6H, s), 2.46 (2H, q, J = 7. 5Hz), 3.04 (2H, t, J = 6.9 Hz), 3.91 (2H, t, J = 6.9 Hz), 4.84 (2H, s), 7.30 (1H, d, J = 7.8 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.48 (1H, s), 7.77-7.81 (3H, m), 7.91 (1H, d, J = 3.3 Hz), 8.32 (2H, s).
MS: 526 (M ⁺⁺ 1).
[Example 415]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -5-methyl-1,3-thiazole -2-yl] thio} -2-methylpropionic acid

  2-{[4- (2-Aminoethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro synthesized in Example 19 -The title compound was obtained by performing the same operation as in Example 265-1 using ethylpyrimidine as a starting material, and then performing the same operation as in Example 326.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.5 Hz), 1.61 (6H, s), 2.28 (3H, s), 2.49 (2H , Q, J = 7.5 Hz), 3.00 (2H, t, J = 6.9 Hz), 3.86 (2H, t, J = 6.9 Hz), 4.68 (2H, s), 7 .22-7.26 (1H, m), 7.39-7.45 (2H, m), 7.65-7.69 (3H, m), 7.95 (1H, s), 8.22 (2H, s).
MS: 523 (M ⁺⁺ 1).
[Example 416]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(6-phenylpyridin-3-yl) methyl] amino} ethyl) -5-methyl-1,3-thiazol-2- Yl] thio} -2-methylpropionic acid

  2-{[4- (2-Aminoethyl) -5-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro synthesized in Example 19 The title compound was obtained by conducting the same operation as in Example 265-1 using ethylpyrimidine as a starting material, followed by the same operation as in Examples 327-1 and 326-2.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.23 (3H, t, J = 7.5 Hz), 1.64 (6H, s), 2.19 (3H, s), 2.52 (2H , Q, J = 7.5 Hz), 3.08 (2H, t, J = 6.6 Hz), 3.97 (2H, t, J = 6.6 Hz), 4.78 (2H, s), 7 .55-7.57 (3H, m), 7.81-7.89 (3H, m), 8.18-8.25 (3H, m), 9.22 (1H, s).
MS: 534 (M ⁺⁺ 1).
[Example 417]
2-{[5- (2-{(5-Ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -4-methyl-1,3-thiazole -2-yl] thio} -2-methylpropionic acid

  2-{[5- (2-Aminoethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro synthesized in Example 24 -The title compound was obtained by performing the same operation as in Example 265-1 using ethylpyrimidine as a starting material, and then performing the same operation as in Example 326.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.23 (3H, t, J = 7.5 Hz), 1.60 (6H, s), 2.33 (3H, s), 2.50 (2H , Q, J = 7.5 Hz), 3.05 (2H, t, J = 7.2 Hz), 3.79 (2H, t, J = 7.2 Hz), 4.70 (2H, s), 7 .24-7.29 (1H, m), 7.29-7.45 (2H, m), 7.61-7.64 (3H, m), 7.85 (1H, s), 8.24 (2H, s).
MS: 523 (M ⁺⁺ 1).
[Example 418]
2-{[5- (2-{(5-Ethylpyrimidin-2-yl) [(6-phenylpyridin-3-yl) methyl] amino} ethyl) -4-methyl-1,3-thiazol-2- Yl] thio} -2-methylpropionic acid

  2-{[5- (2-Aminoethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro synthesized in Example 24 The title compound was obtained by conducting the same operation as in Example 265-1 using ethylpyrimidine as a starting material, followed by the same operation as in Examples 327-1 and 326-2.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.15 (3H, t, J = 7.5 Hz), 1.46 (6H, s), 2.24 (3H, s), 2.45 (2H , Q, J = 7.5 Hz), 3.07 (2H, t, J = 7.6 Hz), 3.80 (2H, t, J = 7.6 Hz), 4.82 (2H, s), 7 .42-7.51 (3H, m), 7.71-7.75 (1H, m), 7.90 (1H, d, J = 8.0 Hz), 8.01-8.05 (2H, m), 8.30 (2H, s), 8.56 (1H, s).
MS: 534 (M ⁺⁺ 1).
[Example 419]
2-{[5-({(5-Ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} methyl) -4-methyl-1,3-thiazole-2 -Yl] thio} -2-methylpropionic acid

  2-{[5- (Aminomethyl) -4-methyl-1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro-ethyl synthesized in Example 30 The title compound was obtained by the same procedures as in Example 265-1 using pyrimidine as a starting material, and then by the same procedures as in Example 326.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.59 (6H, s), 2.42 (3H, s), 2.53 (2H , Q, J = 7.5 Hz), 4.77 (2H, s), 4.84 (2H, s), 7.25-7.30 (1H, m), 7.40-7.46 (2H M), 7.60-7.63 (3H, m), 7.81 (1H, s), 8.27 (2H, s).
MS: 509 (M ⁺⁺ 1).
[Example 420]
2-[(4-{[(biphenyl-4-ylmethyl) (5-ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloride (Example 420-1)
2-[(4-{[(5-Ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (Aminomethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 13 and 2-chloro-5- 2.24 g of N, N-diisopropylethylamine was added to 2.47 g of ethylpyrimidine and stirred at 130 ° C. for 8 hours. The reaction mixture was directly purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give 5.0 g of the title compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19 (3H, t, J = 7.5 Hz), 1.42 (9H, s), 1.59 (6H, s), 2.47 (2H , Q, J = 7.5 Hz), 4.73 (2H, d, J = 6.0 Hz), 5.51-5.54 (1H, m), 7.20 (1H, s), 8.16 (2H, s).
(Example 420-2)
2-[(4-{[(biphenyl-4-ylmethyl) (5-ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloride

  2-[(4-{[(5-Ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 420-1 The title compound was obtained by the same procedures as in Example 326 using tert-butyl ester and 4- (bromomethyl) biphenyl as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.6 Hz), 1.59 (6H, s), 2.50 (2H, q, J = 7.6 Hz) , 4.93 (2H, s), 5.01 (2H, s), 7.08 (1H, s), 7.31-7.36 (3H, m), 7.40-7.45 (2H M), 7.50-7.58 (4H, m), 8.24 (2H, s).
MS: 505 (M ⁺⁺ 1).
[Example 421]
2-{[4-({(5-Ethylpyrimidin-2-yl) [4- (trifluoromethyl) benzyl] amino} methyl) -1,3-thiazol-2-yl] thio} -2-methylpropion acid

  2-[(4-{[(5-Ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 420-1 The title compound was obtained in the same manner as in Example 326, using tert-butyl ester and 1- (bromomethyl) -4- (trifluoromethyl) benzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.58 (6H, s), 2.50 (2H, q, J = 7.5 Hz) , 4.90 (2H, s), 5.02 (2H, s), 7.12 (1H, s), 7.36 (2H, d, J = 7.8 Hz), 7.54 (2H, d , J = 7.8 Hz), 8.22 (2H, s).
MS: 497 (M ⁺⁺ 1).
[Example 422]
2-{[4-({(5-Ethylpyrimidin-2-yl) [4- (trifluoromethoxy) benzyl] amino} methyl) -1,3-thiazol-2-yl] thio} -2-methylpropion acid

  2-[(4-{[(5-Ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 420-1 The title compound was obtained in the same manner as in Example 326, using tert-butyl ester and 1- (bromomethyl) -4- (trifluoromethoxy) benzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.20 (3H, t, J = 7.5 Hz), 1.59 (6H, s), 2.49 (2H, q, J = 7.5 Hz) , 4.88 (2H, s), 4.96 (2H, s), 7.09 (1H, s), 7.13 (2H, d, J = 8.4 Hz), 7.29 (2H, d , J = 8.4 Hz), 8.22 (2H, s).
MS: 513 (M ⁺⁺ 1).
[Example 423]
2-{[4-({(5-Ethylpyrimidin-2-yl) [(6-phenylpyridin-3-yl) methyl] amino} methyl) -1,3-thiazol-2-yl] thio} -2 -Methylpropionic acid hydrochloride

  2-[(4-{[(5-Ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 420-1 The title compound was obtained by the same procedures as in Example 327 using tert-butyl ester and 5- (chloromethyl) -2-phenylpyridine as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.29 (3H, t, J = 7.5 Hz), 1.57 (6H, s), 2.65 (2H, q, J = 7.5 Hz) , 5.08 (2H, s), 5.48 (2H, s), 7.62-7.65 (3H, m), 7.80 (1H, s), 8.06 (1H, d, J = 8.4 Hz), 8.12-8.16 (2H, m), 8.49 (2H, s), 8.59 (1 H, d, J = 8.4 Hz), 9.46 (1 H, s) ).
MS: 506 (M ⁺⁺ 1).
[Example 424]
2-{[4-({(5-Ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} methyl) -1,3-thiazol-2-yl] thio } -2-Methylpropionic acid hydrochloride

  2-[(4-{[(5-Ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 420-1 The title compound was obtained by the same procedures as in Example 327 using tert-butyl ester and 4- (chloromethyl) -1-phenyl-1H-pyrazole as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.29 (3H, t, J = 7.5 Hz), 1.57 (6H, s), 2.64 (2H, q, J = 7.5 Hz) , 5.06 (2H, s), 5.17 (2H, s), 7.28-7.33 (1H, m), 7.42-7.48 (3H, m), 7.65-7. .68 (3H, m), 8.24 (1H, s), 8.50 (2H, s).
MS: 495 (M ⁺⁺ 1).
[Example 425]
2-({4-[((5-ethylpyrimidin-2-yl) {[1- (4-fluorophenyl) -1H-pyrazol-4-yl] methyl} amino) methyl] -1,3-thiazole- 2-yl} thio) -2-methylpropionic acid hydrochloride

  2-[(4-{[(5-Ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 420-1 The same operation as in Example 327 is performed using tert-butyl ester and 4- (chloromethyl) -1- (4-fluorophenyl) -1H-pyrazole synthesized in the same manner as in Reference Examples 16 to 18 as starting materials. Gave the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.28 (3H, t, J = 7.5 Hz), 1.57 (6H, s), 2.63 (2H, q, J = 7.5 Hz) , 5.03 (2H, s), 5.14 (2H, s), 7.09-7.16 (2H, m), 7.41 (1H, brs), 7.59-7.64 (3H M), 8.13 (1H, brs), 8.47 (2H, s).
MS: 513 (M ⁺⁺ 1).
[Example 426]
2-{[4-({(5-Ethylpyrimidin-2-yl) [(2-phenyl-1,3-oxazol-4-yl) methyl] amino} methyl) -1,3-thiazol-2-yl ] Thio} -2-methylpropionic acid hydrochloride

  2-[(4-{[(5-Ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 420-1 The title compound was obtained by the same procedures as in Example 327, using tert-butyl ester and 4- (chloromethyl) -2-phenyl-1,3-oxazole synthesized in Reference Example 26 as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.28 (3H, t, J = 7.5 Hz), 1.58 (6H, s), 2.64 (2H, q, J = 7.5 Hz) 5.19 (2H, s), 5.39 (2H, s), 7.47-7.53 (3H, m), 7.59 (1H, s), 8.08-8.12 (2H M), 8.16 (1H, s), 8.49 (2H, s).
MS: 496 (M ⁺⁺ 1).
[Example 427]
2-({4-[((5-Ethylpyrimidin-2-yl) {[2- (4-fluorophenyl) -1,3-oxazol-4-yl] methyl} amino) methyl] -1,3- Thiazol-2-yl} thio) -2-methylpropionic acid hydrochloride

  2-[(4-{[(5-Ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 420-1 The title was obtained by carrying out the same operations as in Example 327 using tert-butyl ester and 4- (chloromethyl) -2- (4-fluorophenyl) -1,3-oxazole synthesized in Reference Example 28 as starting materials. A compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.28 (3H, t, J = 7.5 Hz), 1.58 (6H, s), 2.64 (2H, q, J = 7.5 Hz) , 5.13 (2H, s), 5.37 (2H, s), 7.13-7.19 (2H, m), 7.52 (1H, s), 8.03-8.10 (3H , M), 8.49 (2H, s).
MS: 514 (M ⁺⁺ 1).
[Example 428]
2-[(4-{[[(6-Chloroquinolin-2-yl) methyl] (5-ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2 -Methylpropionic acid hydrochloride

  2-[(4-{[(5-Ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 420-1 The title compound was obtained by the same procedures as in Example 327 using tert-butyl ester and 6-chloro-2- (chloromethyl) quinoline synthesized in Reference Example 35 as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.20 (3H, t, J = 7.5 Hz), 1.59 (6H, s), 2.53 (2H, q, J = 7.5 Hz) , 5.30 (2H, s), 5.90 (2H, s), 7.73-7.78 (2H, m), 7.95 (1H, dd, J = 2.1, 9.0 Hz) , 8.02 (1H, d, J = 2.1 Hz), 8.29 (2H, s), 8.55 (1H, d, J = 8.7 Hz), 8.94 (1H, d, J = 9.0 Hz).
MS: 514 (M ⁺⁺ 1).
[Example 429]
2-[(4-{[(5-Ethylpyrimidin-2-yl) (2-phenoxyethyl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloride

  2-[(4-{[(5-Ethylpyrimidin-2-yl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 420-1 The title compound was obtained by the same procedures as in Example 327 using tert-butyl ester and (2-bromoethoxy) benzene as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.13 (3H, t, J = 7.5 Hz), 1.49 (6H, s), 2.45 (2H, q, J = 7. 5 Hz), 4.00 (2H, t, J = 6.0 Hz), 4.17 (2H, t, J = 6.0 Hz), 4.99 (2H, s), 6.89-6.93 ( 3H, m), 7.24-7.29 (2H, m), 7.47 (1H, s), 8.31 (2H, s).
MS: 459 (M ⁺⁺ 1).
[Example 430]
2-Methyl-2-[(4- {2-[[(1-phenyl-1H-pyrazol-4-yl) methyl] (5-propylpyrimidin-2-yl) amino] ethyl} -1,3-thiazole -2-yl) thio] propionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro-5-propyl synthesized in Example 7 The title compound was obtained by the same procedures as in Example 265-1 using pyrimidine as a starting material, and then by the same procedures as in Example 326.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.96 (3H, t, J = 7.5 Hz), 1.56-1.64 (8H, m), 2.43 (2H, t, J = 7.2 Hz), 3.09 (2H, t, J = 6.9 Hz), 3.94 (2H, t, J = 6.9 Hz), 4.70 (2H, s), 6.96 (1H, s), 7.22-7.27 (1H, m), 7.39-7.45 (2H, m), 7.65-7.69 (3H, m), 7.96 (1H, s) , 8.21 (2H, s).
MS: 523 (M ⁺⁺ 1).
[Example 431]
2-{[4- (2-{(5-isopropylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl ] Thio} -2-methylpropionic acid (Reference Example 49)
5-Isopropyl-2- (methylsulfonyl) pyrimidine

The title compound was obtained in the same manner as in Reference Examples 7 to 9, using 3- (dimethylamino) -2-isopropylacrylaldehyde as a starting material.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.38 (6H, d, J = 6.9 Hz), 3.03-3.13 (1H, m), 3.36 (3H, s), 8 .79 (2H, s).

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and Reference Example 49 The title compound was obtained by performing the same operation as in Example 265-1 using 5-isopropyl-2- (methylsulfonyl) pyrimidine as a starting material, and then performing the same operation as in Example 326.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.26 (6H, d, J = 7.2 Hz), 1.62 (6H, s), 2.75-2.85 (1H, m), 3 .10 (2H, t, J = 6.9 Hz), 3.93 (2H, t, J = 6.9 Hz), 4.71 (2H, s), 6.95 (1H, s), 7.22 -7.26 (1H, m), 7.39-7.45 (2H, m), 7.66-7.69 (3H, m), 7.95 (1H, s), 8.25 (2H) , S).
MS: 523 (M ⁺⁺ 1).
[Example 432]
2-{[4- (2-{(5-isobutylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl ] Thio} -2-methylpropionic acid (Reference Example 50)
5-Isobutyl-2- (methylsulfonyl) pyrimidine

Using 3- (dimethylamino) -2-isobutylacrylaldehyde as a starting material, the title compound was obtained in the same manner as in Reference Examples 7-9.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.97 (6H, d, J = 6.3 Hz), 1.89-1.99 (1H, m), 2.60 (2H, d, J = 6.9 Hz), 3.36 (3H, s), 8.71 (2H, s).

  2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and synthesized in Reference Example 50 The title compound was obtained by performing the same operation as in Example 265-1 using 5-isobutyl-2- (methylsulfonyl) pyrimidine as a starting material, and then performing the same operation as in Example 326.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.92 (6H, d, J = 6.6 Hz), 1.63 (6H, s), 1.73-1.83 (1H, m), 2 .31 (2H, d, J = 6.9 Hz), 3.09 (2H, t, J = 6.9 Hz), 3.92 (2H, t, J = 6.9 Hz), 4.71 (2H, s), 6.95 (1H, s), 7.22-7.27 (1H, m), 7.38-7.45 (2H, m), 7.64-7.69 (3H, m) , 7.96 (1H, s), 8.17 (2H, s).
MS: 537 (M ⁺⁺ 1).
[Example 433]
2-{[4- (2-{(4,6-Dimethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole-2 -Yl] thio} -2-methylpropionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro-4,6 synthesized in Example 7 The title compound was obtained by performing the same operation as in Example 265-1 using dimethylpyrimidine as a starting material and subsequently performing the same operation as in Example 326.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 2.31 (6H, s), 3.10 (2H, t, J = 7.0 Hz), 3.94 (2H , T, J = 7.0 Hz), 4.71 (2H, s), 6.31 (1H, s), 6.95 (1H, s), 7.22-7.26 (1H, m), 7.43 (2H, t, J = 7.8 Hz), 7.65-7.68 (3H, m), 7.95 (1H, s).
MS: 509 (M ⁺⁺ 1).
[Example 434]
2-{[4- (2-{(4,6-dimethoxypyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole-2 -Yl] thio} -2-methylpropionic acid

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 2-chloro-4,6 synthesized in Example 7 The title compound was obtained by performing the same operation as in Example 265-1 using -dimethoxypyrimidine as a starting material, and then performing the same operation as in Example 326.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.61 (6H, s), 3.11 (2H, t, J = 6.9 Hz), 3.89-3.94 (8H, m), 4 .70 (2H, s), 5.44 (1H, s), 6.93 (1H, s), 7.23-7.28 (1H, m), 7.40-7.46 (2H, m ), 7.66-7.69 (3H, m), 7.96 (1H, s).
MS: 541 (M ⁺⁺ 1).
[Example 435]
2-{[4- (2-{(5-Bromopyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl ] Thio} -2-methylpropionic acid hydrochloride

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained by the same procedures as in Example 327 using propionic acid tert-butyl ester and 4- (chloromethyl) -1-phenyl-1H-pyrazole synthesized in Reference Example 18 as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.04 (2H, t, J = 7.2 Hz), 3.89 (2H, t, J = 7. 2 Hz), 4.60 (2H, s), 7.28-7.31 (1H, m), 7.44-7.50 (3H, m), 7.68 (1H, s), 7.78. (2H, d, J = 8.1 Hz), 8.40 (1H, s), 8.49 (2H, s).
MS: 561 (M ⁺⁺ 1).
[Example 436]
2-[(4- {2-[(5-Bromopyrimidin-2-yl) (2-phenoxyethyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained by the same procedures as in Example 326 using propionic acid tert-butyl ester and (2-bromoethoxy) benzene as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.66 (6H, s), 3.15 (2H, t, J = 7.2 Hz), 3.88 (2H, t, J = 5.4 Hz) 4.02 (2H, t, J = 7.2 Hz), 4.15 (2H, t, J = 5.4 Hz), 6.87-6.96 (4H, m), 7.24-7. 29 (2H, m), 8.29 (2H, s).
MS: 525 (M ⁺⁺ 1).
[Example 437]
2-[(4- {2-[{4-[(Ethylamino) carbonyl] benzyl} (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio]- 2-Methylpropionic acid
(Example 437-1)
4-{[(2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethyl) (5-ethylpyrimidine-2 -Yl) amino] methyl} benzoic acid methyl ester

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Dissolve 3.0 g of propionic acid tert-butyl ester and 2.0 g of 4- (bromomethyl) benzoic acid methyl ester in 37 mL of N, N-dimethylformamide, add 0.91 g of potassium tert-butoxide, and stir at room temperature for 8 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 2.2 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.42 (9H, s), 1.56 (6H, s), 2.48 (2H , Q, J = 7.5 Hz), 3.10 (2H, t, J = 7.2 Hz), 3.89-3.96 (5H, m), 4.80 (2H, s), 6.99 (1H, s), 7.25-7.27 (2H, m), 7.92-7.95 (2H, m), 8.19 (2H, s).
(Example 437-2)
4-{[(2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} ethyl) (5-ethylpyrimidine-2 -Yl) amino] methyl} benzoic acid

4-{[(2- {2-[(2-tert-Butyl-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} synthesized in Example 437-1 Ethyl) (5-ethylpyrimidin-2-yl) amino] methyl} benzoic acid methyl ester (2.2 g) was dissolved in methanol (50 mL) and tetrahydrofuran (50 mL). A 10% aqueous citric acid solution was added, and the mixture was extracted with chloroform. The insoluble material was filtered, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.0 g of the title compound as an oil.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.42 (9H, s), 1.56 (6H, s), 2.49 (2H , Q, J = 7.5 Hz), 3.12 (2H, t, J = 7.2 Hz), 3.95 (2H, t, J = 7.2 Hz), 4.82 (2H, s), 7 .01 (1H, s), 7.26-7.29 (2H, m), 7.96-7.99 (2H, m), 8.21 (2H, s).
(Example 437-3)
2-[(4- {2-[{4-[(Ethylamino) carbonyl] benzyl} (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio]- 2-Methylpropionic acid tert-butyl ester

  4-{[(2- {2-[(2-tert-Butyl-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} synthesized in Example 437-2 Ethyl) (5-ethylpyrimidin-2-yl) amino] methyl} benzoic acid 261 mg and ethylamine hydrochloride 47 mg were dissolved in 2.5 mL of N, N-dimethylformamide, and 80 μL of triethylamine, N- (3-dimethylaminopropyl) ) -N'-ethylcarbodiimide (EDC) hydrochloride (110 mg) and 1-hydroxybenztriazole (HOBt) monohydrate (86 mg) were sequentially added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give 268 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19-1.26 (6H, m), 1.42 (9H, s), 1.56 (6H, s), 2.48 (2H, q , J = 7.5 Hz), 3.09 (2H, t, J = 7.2 Hz), 3.46-3.53 (2H, m), 3.93 (2H, t, J = 7.2 Hz) , 4.79 (2H, s), 6.05 (1H, brs), 6.99 (1H, s), 7.24-7.26 (2H, m), 7.65-7.67 (2H) , M), 8.19 (2H, s).
(Example 437-4)
2-[(4- {2-[{4-[(Ethylamino) carbonyl] benzyl} (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio]- 2-Methylpropionic acid

  2-[(4- {2-[{4-[(Ethylamino) carbonyl] benzyl} (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-synthesized in Example 437-3 268 mg of thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester was dissolved in 2.0 mL of dichloromethane, and 2.0 mL of trifluoroacetic acid was added and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give 159 mg of the title compound as a white amorphous solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19-1.27 (6H, m), 1.61 (6H, s), 2.49 (2H, q, J = 7.5 Hz), 3 .01 (2H, t, J = 7.2 Hz), 3.44-3.53 (2H, m), 3.88 (2H, t, J = 7.2 Hz), 4.87 (2H, s) 6.17 (1H, brs), 6.93 (1H, s), 7.27-7.30 (2H, m), 7.66-7.68 (2H, m), 8.21 (2H) , S).
MS: 514 (M ⁺⁺ 1).
[Example 438]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [4- (pyrrolidin-1-ylcarbonyl) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-Methylpropionic acid

  4-{[(2- {2-[(2-tert-Butyl-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} synthesized in Example 437-2 The title compound was obtained in the same manner as in Example 437-3 and Example 437-4 using ethyl) (5-ethylpyrimidin-2-yl) amino] methyl} benzoic acid and pyrrolidine as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.5 Hz), 1.62 (6H, s), 1.84 to 1.98 (4H, m), 2 .49 (2H, q, J = 7.5 Hz), 3.01 (2H, t, J = 7.2 Hz), 3.42 (2H, t, J = 6.6 Hz), 3.64 (2H, t, J = 6.6 Hz), 3.90 (2H, t, J = 7.2 Hz), 4.86 (2H, s), 6.93 (1H, s), 7.24-7.26 ( 2H, m), 7.44-7.46 (2H, m), 8.21 (2H, s).
MS: 540 (M ⁺⁺ 1).
[Example 439]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [4- (propionylamino) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid hydrochloride (Example 439-1)
2-[(4- {2-[{4-[(tert-butoxycarbonyl) amino] benzyl} (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio ] -2-Methylpropionic acid tert-butyl ester

  4-{[(2- {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} synthesized in Example 437-2 Ethyl) (5-ethylpyrimidin-2-yl) amino] methyl} benzoic acid (2.2 g) is dissolved in tert-butanol (20 mL), triethylamine (0.85 mL) and diphenylphosphinoazide (1.31 g) are sequentially added, and the mixture is heated for 2 hours. Refluxed. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1-3: 1) to give 1.4 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.20 (3H, t, J = 7.5 Hz), 1.42 (9H, s), 1.50 (9H, s), 1.56 (6H , S), 2.47 (2H, q, J = 7.5 Hz), 3.07 (2H, t, J = 7.2 Hz), 3.89 (2H, t, J = 7.2 Hz), 4 .71 (2H, s), 6.39 (1H, brs), 6.96 (1H, s), 7.13-7.16 (2H, m), 7.23-7.26 (2H, m ), 8.18 (2H, s).
(Example 439-2)
2-[(4- {2-[(4-aminobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert -Butyl ester

  2-[(4- {2-[{4-[(tert-butoxycarbonyl) amino] benzyl} (5-ethylpyrimidin-2-yl) amino] ethyl} -1, synthesized in Example 439-1 3-Thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester 1.2 g was dissolved in 20 mL of dichloromethane, and 3.64 g of p-toluenesulfonic acid monohydrate was added little by little at room temperature. . After 2.5 hours, the reaction mixture was diluted with dichloromethane, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1 to 1: 1) to give the title compound (0.78 g) as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.20 (3H, t, J = 7.5 Hz), 1.43 (9H, s), 1.57 (6H, s), 2.47 (2H , Q, J = 7.5 Hz), 3.06 (2H, t, J = 7.5 Hz), 3.87 (2H, t, J = 7.5 Hz), 4.66 (2H, s), 6 58-6.61 (2H, m), 6.97 (1H, s), 7.02-7.05 (2H, m), 8.18 (2H, s).
(Example 439-3)
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [4- (propionylamino) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid tert-butyl ester

  2-[(4- {2-[(4-aminobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) synthesized in Example 439-2 120 mg of thio] -2-methylpropionic acid tert-butyl ester was dissolved in 2.5 mL of tetrahydrofuran, 40 μL of triethylamine and 22 μL of propionyl chloride were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was directly purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give 100 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.18-1.26 (6H, m), 1.43 (9H, s), 1.56 (6H, s), 2.37 (2H, q , J = 7.5 Hz), 2.48 (2H, q, J = 7.5 Hz), 3.08 (2H, t, J = 7.5 Hz), 3.89 (2H, t, J = 7. 5Hz), 4.72 (2H, s), 6.98 (1H, s), 7.06 (1H, brs), 7.16-7.19 (2H, m), 7.40-7.42. (2H, m), 8.18 (2H, s).
(Example 439-4)
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [4- (propionylamino) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid hydrochloride

  2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [4- (propionylamino) benzyl] amino} ethyl) -1,3-thiazole-2 synthesized in Example 439-3 -Il] thio} -2-methylpropionic acid tert-butyl ester (100 mg) was dissolved in formic acid (2.5 mL), 4 mol / L hydrochloric acid-ethyl acetate (0.5 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was evaporated under reduced pressure, and the residue was heated and dried at 60 ° C. to give 98 mg of the title compound as a white amorphous solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.21 (3H, t, J = 7.5 Hz), 1.30 (3H, t, J = 7.5 Hz), 1.65 (6H, s) , 2.46 (2H, q, J = 7.5 Hz), 2.65 (2H, q, J = 7.5 Hz), 3.28 (2H, brs), 4.03 (2H, brs), 5 .06 (2H, brs), 7.23-7.26 (2H, m), 7.54-7.57 (2H, m), 8.04 (1H, s), 8.41 (2H, brs) ).
MS: 514 (M ⁺⁺ 1).
[Example 440]
2-[(4- {2-[{4-[(Cyclopentylcarbonyl) amino] benzyl} (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio]- 2-Methylpropionic acid hydrochloride

  2-[(4- {2-[(4-aminobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) synthesized in Example 439-2 The title compound was obtained in the same manner as in Example 439-3 and Example 439-4 using thio] -2-methylpropionic acid tert-butyl ester and cyclopentanecarbonyl chloride as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.29 (3H, t, J = 7.5 Hz), 1.63 (6H, s), 1.76-1.92 (8H, m), 2 .64 (2H, q, J = 7.5 Hz), 2.75-2.81 (1H, m), 3.21 (2H, brs), 4.05 (2H, brs), 5.03 (2H , S), 7.21-7.26 (2H, m), 7.54-7.57 (2H, m), 7.95 (2H, brs), 8.48 (2H, brs).
MS: 554 (M ⁺⁺ 1).
[Example 441]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [4- (propylamino) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid hydrochloride (Example 441-1)
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [4- (propylamino) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid tert-butyl ester

2-[(4- {2-[(4-aminobenzyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) synthesized in Example 439-2 Thio] -2-methylpropionic acid tert-butyl ester (175 mg) was dissolved in dichloroethane (2.0 mL), propionylaldehyde (24 mg), acetic acid (20 μL) and sodium triacetoxyborohydride (100 mg) were sequentially added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to give 68 mg of the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.98 (3H, t, J = 7.5 Hz), 1.20 (3H, t, J = 7.5 Hz), 1.43 (9H, s) , 1.57-1.65 (8H, s), 2.47 (2H, q, J = 7.5 Hz), 3.07 (2H, t, J = 7.4 Hz), 3.87 (2H, t, J = 7.4 Hz), 4.66 (2H, s), 6.50-6.54 (2H, m), 6.97 (1H, s), 7.04-7.07 (2H, m), 8.18 (2H, s).
(Example 441-2)
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [4- (propylamino) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid hydrochloride

  2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [4- (propylamino) benzyl] amino} ethyl) -1,3-thiazole-2 synthesized in Example 441-1 -Il] thio} -2-methylpropionic acid tert-butyl ester (68 mg) was dissolved in formic acid (2.5 mL), 4 mol / L hydrochloric acid-ethyl acetate (0.5 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was evaporated under reduced pressure, and the residue was heated and dried at 60 ° C. to obtain 77 mg of the title compound as a white amorphous solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.98 (3H, t, J = 7.2 Hz), 1.30 (3H, t, J = 7.5 Hz), 1.69 (6H, s) , 1.84-1.92 (2H, m), 2.67 (2H, q, J = 7.5 Hz), 3.21-3.31 (6H, m), 5.10 (2H, brs) 7.30-7.32 (2H, m), 7.59-7.62 (2H, m), 8.07 (1H, s), 8.59 (2H, brs).
MS: 500 (M ⁺⁺ 1).
[Example 442]
2-[(4- {2- [Heptyl (5-morpholin-4-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Example 442-1)
2-[(4- {2-[(5-Bromopyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 3.27 g of propionic acid tert-butyl ester and 1.77 g of heptyl iodide were dissolved in 36 mL of N, N-dimethylformamide, 0.80 g of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 2.80 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.8 Hz), 1.24-1.29 (8H, m), 1.45 (9H, s), 1 .53 (2H, brs), 1.58 (6H, s), 3.06 (2H, t, J = 7.3 Hz), 3.40 (2H, t, J = 7.3 Hz), 3.84 (2H, t, J = 7.3 Hz), 7.01 (1H, s), 8.27 (2H, s).
(Example 442-2)
2-[(4- {2- [Heptyl (5-morpholin-4-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert- Butyl ester

  To a 20 mL screw-cap test tube purged with nitrogen was added 45 mg of tris (dibenzylideneacetone) dipalladium, 29 mg of 2- (di-tert-butylphosphino) biphenyl and 104 mg of sodium tert-butoxide, to which Example 442-1 was added. 2-[(4- {2-[(5-Bromopyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized tert -A solution of 550 mg of butyl ester and 129 mg of morpholine in toluene (2.0 mL) was added. The lid was closed and the mixture was stirred at 110 ° C. for 8 hours. After cooling to room temperature, the solution was directly loaded on silica gel chromatography and purified (elution solvent; hexane: ethyl acetate = 3: 1 to 2: 1) to give 300 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.6 Hz), 1.24-1.28 (8H, m), 1.45 (9H, s), 1 .51-1.53 (2H, m), 1.60 (6H, s), 2.97-3.00 (4H, m), 3.07 (2H, t, J = 7.5 Hz), 3 .42 (2H, t, J = 7.5 Hz), 3.83-3.87 (6H, m), 7.01 (1H, s), 8.09 (2H, s).
(Example 442-3)
2-[(4- {2- [Heptyl (5-morpholin-4-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2- [Heptyl (5-morpholin-4-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio obtained in Example 442-2 ] 710 mg of 2-methylpropionic acid tert-butyl ester was dissolved in 4 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 300 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.6 Hz), 1.28 (8H, brs), 1.53 (2H, brs), 1.65 (6H , S), 2.98-3.01 (4H, m), 3.09 (2H, t, J = 7.2 Hz), 3.45 (2H, t, J = 7.2 Hz), 3.83 -3.87 (6H, m), 6.95 (1H, s), 8.09 (2H, s).
MS: 508 (M ⁺⁺ 1).
[Example 443]
2-{[4- (2- {Heptyl [5- (4-methylpiperazin-1-yl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2- Methylpropionic acid trifluoroacetate

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio]-synthesized in Example 442-1 Using 2-methylpropionic acid tert-butyl ester and 1-methylpiperazine as starting materials, the compound obtained in the same manner as in Example 442-2 was subjected to dichloromethane and trifluoroacetic acid. The reaction solution is concentrated under reduced pressure, and the residue is purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile = 65: 35-15: 85). The title compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.9 Hz), 1.27-1.37 (8H, m), 1.55 (2H, brs), 1 .63 (6H, s), 2.18 (4H, m), 2.88 (3H, s), 3.10 (2H, t, J = 6.9 Hz), 3.36 (4H, brs), 3.45-3.50 (2H, m), 3.89 (2H, t, J = 6.9 Hz), 6.98 (1H, s), 8.17 (2H, s).
MS: 521 (M ⁺⁺ 1).
[Example 444]
2-[(4- {2- [Heptyl (5-pyrrolidin-1-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid trifluoro Acetate

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio]-synthesized in Example 442-1 Using 2-methylpropionic acid tert-butyl ester and pyrrolidine as starting materials, the compound obtained by the same procedure as in Example 442-2 was subjected to dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 10: 1) to give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.85-0.87 (3H, m), 1.27 (8H, brs), 1.52 (2H, brs), 1.65 (6H, s ), 1.99-2.01 (4H, m), 3.09 (2H, t, J = 6.9 Hz), 3.19-3.21 (4H, m), 3.42 (2H, t , J = 7.5 Hz), 3.84 (2H, t, J = 6.9 Hz), 6.95 (1H, s), 7.87 (2H, s).
MS: 492 (M ⁺⁺ 1).
[Example 445]
2-methyl-2-{[4- (2-{(5-morpholin-4-ylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1 , 3-Thiazol-2-yl] thio} propionic acid hydrochloride

2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 Starting from propionic acid tert-butyl ester and 4- (chloromethyl) -1-phenyl-1H-pyrazole synthesized in Reference Example 18, the compound obtained by the same procedure as in Example 442 was dissolved in diethyl ether. The title compound was obtained by reacting 4 mol / L hydrochloric acid-ethyl acetate.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 3.04 (2H, t, J = 7.2 Hz), 3.14 (4H, brs), 3.79 (4H, brs), 3.90 (2H, t, J = 7.2 Hz), 4.63 (2H, s), 7.25-7.30 (1H, m), 7.44-7.49 (3H, m), 7.66 (1H, s), 7.77-7.79 (2H, m), 8.40 (3H, brs).
MS: 566 (M ⁺⁺ 1).

[Example 446]
2-[(4- {2- [Heptyl (3-methyl-1H-pyrazol-5-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid trifluoroacetic acid Salt (Example 446-1)
2-[(4- {2- [Heptyl (3-methyl-1H-pyrazol-5-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 3.41 g Was dissolved in 43 mL of N, N-dimethylformamide, and 0.75 g of diketene was added dropwise under ice cooling. The mixture was warmed to room temperature and stirred for 1 hour. Dilute with ethyl acetate, wash with saturated brine, and dry over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to give 2-[(4- {2- [acetoacetyl (heptyl) amino] ethyl} -1,3- 3.4 g of thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester was obtained as a colorless oil. This compound was used in the next step without further purification. 1.0 g of this compound was dissolved in 10 mL of ethanol, 0.103 g of hydrazine monohydrate was added at room temperature, and the mixture was stirred overnight. The solvent was distilled off under reduced pressure, the residue was dissolved in 10 mL of tetrahydrofuran, 0.459 g of diphosphorus pentasulfide and 0.437 g of sodium carbonate were added, and the mixture was heated to reflux for 2 hours. The solvent was distilled off, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 1: 2) to give 0.54 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.6 Hz), 1.26-1.32 (8H, m), 1.44 (9H, s), 1 .52 (2H, brs), 1.58 (6H, s), 2.22 (3H, s), 3.02 (2H, t, J = 7.5 Hz), 3.13 (2H, t, J = 7.5 Hz), 3.55 (2H, t, J = 7.5 Hz), 5.35 (1H, s), 7.05 (1H, s).
(Example 446-2)
2-[(4- {2- [Heptyl (3-methyl-1H-pyrazol-5-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid trifluoroacetic acid salt

  2-[(4- {2- [Heptyl (3-methyl-1H-pyrazol-5-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] synthesized in Example 446-1 540 mg of -2-methylpropionic acid tert-butyl ester was dissolved in 1.0 mL of dioxane, 4.0 mL of 4 mol / L hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water: 0.05% trifluoroacetic acid-acetonitrile = 85: 15-40: 60). Gave 229 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87-0.91 (3H, m), 1.29-1.31 (8H, m), 1.62 (8H, brs), 2.34 (3H, s), 2.99 (2H, t, J = 7.7 Hz), 3.23 (2H, t, J = 7.5 Hz), 3.56 (2H, t, J = 7.7 Hz) , 5.37 (1H, s), 7.06 (1H, s).
MS: 425 (M ⁺⁺ 1).
[Example 447]
2-[(4- {2-[(1,3-Dimethyl-1H-pyrazol-5-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropion acid

  2-[(4- {2- [acetoacetyl (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in the middle of Example 446-1 -The title compound was obtained by refine | purifying the compound obtained by the operation similar to Example 446 by silica gel chromatography (elution solvent; chloroform: methanol = 10: 1) using butyl ester and methylhydrazine.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.8 Hz), 1.22-1.27 (8H, m), 1.36-1.41 (2H, m), 1.64 (6H, s), 2.21 (3H, s), 2.81-2.88 (4H, m), 3.27 (2H, t, J = 6.9 Hz), 3 .51 (3H, s), 5.69 (1H, s), 6.84 (1H, s).
MS: 439 (M ⁺⁺ 1).
[Example 448]
2-[(4- {2-[[1- (4-Fluorophenyl) -3-methyl-1H-pyrazol-5-yl] (heptyl) amino] ethyl} -1,3-thiazol-2-yl) Thio] -2-methylpropionic acid

  2-[(4- {2- [acetoacetyl (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in the middle of Example 446-1 -The compound obtained by the same operation as in Example 446 using the hydrochloride of butyl ester and (4-fluorophenyl) hydrazine and sodium acetate for neutralization (elution solvent; chloroform: methanol = 10 The title compound was obtained by purification in 1).

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.86 (3H, t, J = 7.2 Hz), 1.12 to 1.26 (8H, m), 1.37 to 1.41 (2H, m), 1.61 (6H, s), 2.27 (3H, s), 2.77 (2H, t, J = 7.8 Hz), 2.91 (2H, t, J = 7.2 Hz) 3.25 (2H, t, J = 7.2 Hz), 5.77 (1H, s), 6.80 (1H, s), 7.00-7.06 (2H, m), 7.46. -7.50 (2H, m).
MS: 519 (M ⁺⁺ 1).
[Example 449]
2-[(4- {2-[(3-Ethyl-1H-pyrazol-5-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Tri Fluoroacetate

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 3.0 g Then, 1.46 g of methyl ester of 3-keto-n-valeric acid was dissolved in 10 mL of xylene and stirred at 135 degrees for 8 hours. After cooling to room temperature, the solution was directly packed in silica gel chromatography and purified (elution solvent; hexane: ethyl acetate = 1: 1) to give 2-[(4- {2- [heptyl (3-oxopenta 1.6 g of noyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester was obtained as a colorless oil. This compound was used in the next step without further purification. The title compound was obtained by conducting the same procedure as in Example 446 for the previous step from the cyclization reaction using hydrazine monohydrate.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.89 (3H, t, J = 6.6 Hz), 1.27-1.32 (11H, m), 1.56-1.65 (8H, m), 2.69 (2H, q, J = 7.5 Hz), 3.00 (2H, t, J = 7.5 Hz), 3.24 (2H, t, J = 7.5 Hz), 3. 57 (2H, t, J = 7.5 Hz), 5.38 (1H, s), 7.06 (1H, s).
MS: 439 (M ⁺⁺ 1).
[Example 450]
2-[(4- {2- [Heptyl (3-propyl-1H-pyrazol-5-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid trifluoroacetic acid salt

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 3- The title compound was obtained in the same manner as in Example 449 using keto-n-hexanoic acid methyl ester as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87-0.91 (3H, m), 0.99 (3H, t, J = 7.2 Hz), 1.29 (8H, brs), 1 .62 (8H, brs), 1.66-1.74 (2H, m), 2.62 (2H, t, J = 7.5 Hz), 3.00 (2H, t, J = 7.5 Hz) , 3.23 (2H, t, J = 7.5 Hz), 3.57 (2H, t, J = 7.5 Hz), 5.36 (1H, s), 7.06 (1H, s).
MS: 453 (M ⁺⁺ 1).
[Example 451]
2-methyl-2-{[4- (2-{(3-methyl-1H-pyrazol-5-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1, 3-thiazol-2-yl] thio} propionic acid hydrochloride (Example 451-1)
2-methyl-2-{[4- (2-{[(1-phenyl-1H-pyrazol-4-yl) carbonyl] amino} ethyl) -1,3-thiazol-2-yl] thio} propionic acid tert -Butyl ester

  4.1 g of 1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester synthesized in Reference Example 16 was dissolved in 40 mL of methanol and 40 mL of tetrahydrofuran, and 40 mL of 1 mol / L aqueous sodium hydroxide solution was added. Stir for hours. The reaction solution was concentrated under reduced pressure, 50 ml of 1 mol / L hydrochloric acid aqueous solution was added, and the precipitated solid was filtered. After dissolving in ethyl acetate and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2.5 g of 1-phenyl-1H-pyrazole-4-carboxylic acid as a white solid. 8.72 g of this carboxylic acid and 14 g of 2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 Is dissolved in 225 mL of N, N-dimethylformamide, and 10.65 g of N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) hydrochloride, 1-hydroxybenztriazole (HOBt) monohydrate 10 .62 g was sequentially added and stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give the title compound (16.2 g) as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.45 (9H, s), 1.57 (6H, s), 3.05 (2H, t, J = 6.0 Hz), 3.80-3 .86 (2H, m), 7.02 (1H, s), 7.05 (1H, brs), 7.29-7.35 (1H, m), 7.43-7.48 (2H, m ), 7.69-7.72 (2H, m), 8.12 (1H, s), 8.49 (1H, s).
(Example 451-2)
2-methyl-2-{[4- (2-{[(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl] thio} propionic acid tert -Butyl ester

  2-Methyl-2-{[4- (2-{[(1-phenyl-1H-pyrazol-4-yl) carbonyl] amino} ethyl) -1,3-thiazole- obtained in Example 451-1 2-yl] thio} propionic acid tert-butyl ester (16.2 g) was dissolved in 20 mL of tetrahydrofuran, and 160 mL of 1 mol / L-borane / tetrahydrofuran complex was added thereto under ice-cooling, followed by stirring at room temperature for 12 hours. After cooling the reaction solution with ice, 200 mL of methanol was added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, 60 mL of piperidine was added, and the mixture was stirred at 60 ° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; dichloromethane: methanol = 20: 1 to 10: 1) to give 9.5 g of the title compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.57 (6H, s), 2.98-3.06 (4H, m), 3.79 (2H, s) ), 7.02 (1H, s), 7.24-7.29 (1H, m), 7.41-7.46 (2H, m), 7.64-7.68 (3H, m), 7.89 (1H, s).
(Example 451-3)
2-methyl-2-{[4- (2-{(3-methyl-1H-pyrazol-5-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1, 3-thiazol-2-yl] thio} propionic acid hydrochloride

2-methyl-2-{[4- (2-{[(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole- synthesized in Example 451-2 2-yl] thio} propionic acid tert-butyl ester was used to dissolve the compound obtained by the same procedure as in Example 446 in diethyl ether, and the title compound was obtained by reacting with 4 mol / L hydrochloric acid-ethyl acetate. It was.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 2.24 (3H, s), 3.04 (2H, t, J = 6.9 Hz), 3.67 (2H, t, J = 6.9 Hz), 4.40 (2H, s), 5.85 (1H, s), 7.28-7.33 (1H, m), 7.49 (2H, t , J = 7.8 Hz), 7.58 (1H, s), 7.75-7.81 (3H, m), 8.54 (1H, s).
MS: 483 (M ⁺⁺ 1).
[Example 452]
2-[(4- {2-[(biphenyl-4-ylmethyl) (3-methyl-1H-pyrazol-5-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2- Methyl propionic acid

  Starting from 2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester and 4-phenylbenzoic acid synthesized in Example 7 The compounds obtained by the same operations as in Example 451-1, Example 451-2 and Example 446-1 as raw materials were subjected to dichloromethane and trifluoroacetic acid. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (at this time, the target product was extracted into the ethyl acetate layer). The extract was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 2.21 (3H, s), 3.00 (2H, t, J = 7.2 Hz), 3.59 (2H , T, J = 7.2 Hz), 4.41 (2H, s), 5.33 (1H, s), 6.93 (1H, s), 7.27-7.58 (9H, m).
MS: 493 (M ⁺⁺ 1).
[Example 453]
2-Methyl-2-{[4- (2-{(3-methyl-1H-pyrazol-5-yl) [(6-phenylpyridin-3-yl) methyl] amino} ethyl) -1,3-thiazole -2-yl] thio} propionic acid hydrochloride

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 and Reference Example 21 The title compound was obtained in the same manner as in Example 451 using 6-phenylnicotinic acid ethyl ester.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 2.24 (3H, s), 3.04 (2H, t, J = 6.9 Hz), 3.74 (2H, t, J = 6.9 Hz), 4.64 (2H, s), 5.84 (1H, s), 7.50-7.57 (4H, m), 7.91-7.94. (1H, m), 8.05-8.09 (3H, m), 8.63 (1H, d, J = 1.8 Hz).
MS: 494 (M ⁺⁺ 1).
[Example 454]
2-{[4- (2-{(3-Ethyl-1H-pyrazol-5-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole- 2-yl] thio} -2-methylpropionic acid hydrochloride

  2-methyl-2-{[4- (2-{[(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole- synthesized in Example 451-2 2-yl] thio} propionic acid tert-butyl ester and 3-keto-n-hexanoic acid methyl ester were dissolved in diethyl ether by the same procedure as in Example 449, and 4 mol / L hydrochloric acid- The title compound was obtained by the action of ethyl acetate.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.20 (3H, t, J = 7.5 Hz), 1.50 (6H, s), 2.59 (2H, q, J = 7. 5Hz), 3.04 (2H, t, J = 6.9 Hz), 3.68 (2H, t, J = 6.9 Hz), 4.42 (2H, s), 5.88 (1H, s) 7.28-7.33 (1H, m), 7.49 (2H, t, J = 7.8 Hz), 7.58 (1 H, s), 7.76-7.81 (3H, m) 8.55 (1H, s).
MS: 497 (M ⁺⁺ 1).
[Example 455]
2-methyl-2-({4-[({[4 '-(trifluoromethyl) biphenyl-4-yl] carbonyl} amino) ethyl] -1,3-thiazol-2-yl} thio) propionic acid ( Example 455-1)
2-[(4-{[(4-Bromobenzoyl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  2-{[4- (Aminomethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 13 and 4-bromobenzoic acid 2 .51 g was dissolved in 50 mL of dichloromethane, and 2.99 g of N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) hydrochloride and 2.39 g of monohydrate of hydroxybenzotriazole (HOBT) were sequentially added. The mixture was added and stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 3.5 g of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.38 (9H, s), 1.59 (6H, s), 4.67 (2H, d, J = 5.4 Hz), 6.90-6 .94 (1H, m), 7.22 (1H, s), 7.58 (2H, d, J = 8.6 Hz), 7.74 (2H, d, J = 8.6 Hz).
(Example 455-2)
2-methyl-2-({4-[({[4 '-(trifluoromethyl) biphenyl-4-yl] carbonyl} amino) methyl] -1,3-thiazol-2-yl} thio) propionic acid tert -Butyl ester

  2-[(4-{[(4-Bromobenzoyl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid synthesized in Example 455-1 under nitrogen atmosphere 600 mg of tert-butyl ester and 363 mg of 4-trifluoromethylphenylboric acid were dissolved in 8 mL of dioxane and 4 mL of 2M aqueous sodium carbonate solution, and 73 mg of tetrakis (triphenylphosphine) palladium was added and refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1 to 1: 1) to give 590 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.64 (6H, s), 4.76 (2H, d, J = 5.3 Hz), 6.98-7 .02 (1H, m), 7.29 (1H, s), 7.69-7.81 (6H, m), 8.00 (2H, d, J = 8.2 Hz).
(Example 455-3)
2-Methyl-2-({4-[({[4 '-(trifluoromethyl) biphenyl-4-yl] carbonyl} amino) ethyl] -1,3-thiazol-2-yl} thio) propionic acid

  2-Methyl-2-({4-[({[4 ′-(trifluoromethyl) biphenyl-4-yl] carbonyl} amino) methyl] -1,3-thiazole- obtained in Example 455-2 2-yl} thio) propionic acid tert-butyl ester (580 mg) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 330 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 4.66 (2H, d, J = 5.6 Hz), 7.37 (1H, s), 7.49-7 .54 (3H, m), 6.64-7.72 (4H, m), 7.78 (2H, d, J = 8.3 Hz).
MS: 481 (M ⁺⁺ 1).
[Example 456]
2-{[4-({[(4′-Fluorobiphenyl-4-yl) carbonyl] amino} methyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4-{[(4-Bromobenzoyl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester synthesized in Example 455-1 Using 4-fluorophenylboric acid as a starting material, the title compound was obtained in the same manner as in Example 455-2 and Example 455-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.66 (6H, s), 4.68 (2H, d, J = 5.4 Hz), 7.13-7.29 (3H, m), 7 .35 (1H, s), 7.52-7.58 (4H, m), 7.82 (2H, d, J = 8.2 Hz).
MS: 431 (M ⁺⁺ 1).
[Example 457]
2-{[4-({[(4′-Chlorobiphenyl-4-yl) carbonyl] amino} methyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4-{[(4-Bromobenzoyl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester synthesized in Example 455-1 Using 4-chlorophenylboric acid as a starting material, the title compound was obtained in the same manner as in Example 455-2 and Example 455-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 4.61 (2H, d, J = 5.5 Hz), 7.35 (1H, s), 7.39-7 .53 (7H, m), 7.76 (2H, d, J = 8.2 Hz).
MS: 447 (M ⁺⁺ 1).
[Example 458]
2-methyl-2-{[4- (2-oxo-2-{[4 '-(trifluoromethyl) biphenyl-4-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} Propionic acid (Example 458-1)
2-[(4- {2-[(4-Bromophenyl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester

  {2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid (3.0 g) synthesized in Example 3 and 4-bromoaniline 1.63 g is dissolved in 50 mL of dichloromethane, and N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) hydrochloride (2.72 g) and 4-dimethylaminopyridine (DMAP) (1.73 g) are sequentially added. And stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 4.5 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.42 (9H, s), 1.61 (6H, s), 3.81 (2H, s), 7.15 (1H, s), 7. 41 (2H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.8 Hz), 8.75 (1H, brs).
(Example 458-2)
2-methyl-2-{[4- (2-oxo-2-{[4 '-(trifluoromethyl) biphenyl-4-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} Propionic acid tert-butyl ester

  2-[(4- {2-[(4-Bromophenyl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) thio]-synthesized in Example 458-1 under nitrogen atmosphere 2-methylpropionic acid tert-butyl ester (600 mg) and 4-trifluoromethylphenylboric acid (363 mg) were dissolved in dioxane (8 mL) and 2M aqueous sodium carbonate solution (4 mL), tetrakis (triphenylphosphine) palladium (73 mg) was added, and the mixture was refluxed for 4 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 550 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.47 (9H, s), 1.67 (6H, s), 3.89 (2H, s), 7.22 (1H, s), 7. 59 (2H, d, J = 8.8 Hz), 7.70 (4H, s), 7.79 (2H, d, J = 8.8 Hz), 8.86 (1 H, brs).
(Example 458-3)
2-methyl-2-{[4- (2-oxo-2-{[4 '-(trifluoromethyl) biphenyl-4-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} Propionic acid

  2-Methyl-2-{[4- (2-oxo-2-{[4 '-(trifluoromethyl) biphenyl-4-yl] amino} ethyl) -1,3 obtained in Example 458-2 -Thiazol-2-yl] thio} propionic acid tert-butyl ester (540 mg) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1 to 0: 1) to give 290 mg of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.66 (6H, s), 3.84 (2H, s), 7.30-7.66 (9H, m), 8.70 (1H, brs) ).
MS: 481 (M ⁺⁺ 1).
[Example 459]
2-[(4- {2-[(4'-Fluorobiphenyl-4-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(4-Bromophenyl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) thio] -2-methylpropion synthesized in Example 458-1 The title compound was obtained in the same manner as in Example 458-2 and Example 458-3 using acid tert-butyl ester and 4-fluorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.66 (6H, s), 3.84 (2H, s), 7.05-7.11 (2H, m), 7.23-7.54 (7H, m), 8.47 (1H, brs).
MS: 431 (M ⁺⁺ 1).
[Example 460]
2-[(4- {2-[(4′-Chlorobiphenyl-4-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4-{[(4-Bromobenzoyl) amino] methyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester synthesized in Example 458-1 Using 4-chlorophenylboric acid as a starting material, the title compound was obtained in the same manner as in Example 458-2 and Example 458-3.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.66 (6H, s), 3.84 (2H, s), 7.31-7.55 (9H, m), 8.46 (1H, brs) ).
MS: 447 (M ⁺⁺ 1).
[Example 461]
2-[(4- {2- [Heptyl (3-nitropyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

(Example 461-1)
2-({4- [2- (9H-Fluoren-9-ylmethoxy) -2-oxoethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester

  To a solution of 160 g of {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid obtained in Example 3 in dichloromethane (500 ml) 98 g of 9H-fluoren-9-ylmethanol and 3.1 g of 4-dimethylaminopyridine were added, and 78 ml of diisopropylcarbodiimide was added dropwise under ice cooling, followed by stirring at 0 ° C. for 1 hour and further stirring at room temperature for 2 hours. . The precipitate was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure and subjected to silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to obtain 260 g of the title compound as a yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.55 (6H, s), 3.91 (2H, s), 4.20 (1H, t, J = 6) .9 Hz), 4.44 (2H, d, J = 6.9 Hz), 7.15 (1H, s), 7.30 (2H, dt, J = 7.5, 1.2 Hz), 7.39. (2H, t, J = 7.5 Hz), 7.51 (2H, d, J = 7.5 Hz), 7.76 (2H, d, J = 7.5 Hz).
MS: 496 (M ⁺⁺ 1).
(Example 461-2)
2-({4- [2- (9H-Fluoren-9-ylmethoxy) -2-oxoethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid

  2-({4- [2- (9H-Fluoren-9-ylmethoxy) -2-oxoethyl] -1,3-thiazol-2-yl} thio) -2-methylpropion obtained in Example 461-1 To a solution of 260 g of acid tert-butyl ester in dichloromethane (400 ml) was added 100 ml of trifluoroacetic acid, and the mixture was stirred overnight at room temperature and then heated and stirred at 45 ° C. for 8 hours. The reaction mixture was concentrated, ethyl acetate was added, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give the title compound (250 g) as a yellow oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 3.52 (1H, bs), 3.89 (2H, s), 4.22 (1H, t, J = 6) 0.9 Hz), 4.50 (2H, d, J = 6.9 Hz), 7.08 (1H, s), 7.31 (2H, dt, J = 7.5, 1.2 Hz), 7.41. (2H, t, J = 7.5 Hz), 7.52 (2H, d, J = 7.5 Hz), 7.76 (2H, d, J = 7.5 Hz).
MS: 440 (M ⁺⁺ 1).
(Example 461-3)
2-({4- [2- (9H-Fluoren-9-ylmethoxy) -2-oxoethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid resin

  In a suspension of 100 g of Wangresin dimethylformamide (500 ml), 42 ml of pyridine and 2-({4- [2- (9H-fluoren-9-ylmethoxy) -2-oxoethyl] -1, obtained in Example 461-2, 3-Thiazol-2-yl} thio) -2-methylpropionic acid (130 g) was added, and 42 ml of 2,6-dichlorobenzoyl chloride was added dropwise under ice cooling, followed by stirring overnight at room temperature. The resin was collected from the reaction solution by filtration, washed three times with methanol and dimethyl rumamide, then twice with tetrahydrofuran and methanol, and finally once with tetrahydrofuran, and air-dried to obtain 150 g of the title pale yellow resin. .

IR (KBr) cm ⁻¹ : 3060, 3024, 2926, 1730.
(Example 461-4)
2-{[4- (Carboxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid resin

  2-({4- [2- (9H-Fluoren-9-ylmethoxy) -2-oxoethyl] -1,3-thiazol-2-yl} thio) -2-methylpropion obtained in Example 461-3 To a suspension of 150 g of acid resin in dimethylformamide (500 ml), 100 ml of piperidine was added and stirred overnight at room temperature. The resin was filtered from the reaction solution, washed once with dimethylformamide, methanol and water, then three times with dimethylformamide and methanol, and finally twice with dichloromethane, and dried under reduced pressure to give the title pale yellow resin. 130 g was obtained.

IR (KBr) cm ⁻¹ : 3058, 3025, 2922, 1728, 1677.
(Example 461-5)
2-({4- [2- (Heptylamino) -2-oxoethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid resin

  2-{[4- (Carboxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid synthesized in Example 461-4 5.0 g of dimethylformamide (20 ml) in resin To the liquid, 1.2 ml of pyridine and 2.3 ml of 4 mol / L-hydrochloric acid-dioxane solution were added and stirred gently at room temperature for 30 minutes, and then the resin was collected by filtration and washed with dimethylformamide three times. To this resin, 20 ml of dimethylformamide, 0.75 ml of pyridine and 1.6 g of 2-chloro-1,3-dimethylimidazolinium chloride were added and stirred at room temperature for 30 minutes. To this reaction solution, 1.4 ml of heptylamine was added and stirred overnight at room temperature. The resin was filtered from the reaction solution, washed with dimethylformamide three times, once with water and methanol, once with tetrahydrofuran, once with methanol, and finally three times with dichloromethane and dried under reduced pressure. The title pale yellow resin (5.2 g) was obtained.

  A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 359 (M ⁺⁺ 1).
(Example 461-6)
2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid resin

  2-({4- [2- (Heptylamino) -2-oxoethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid synthesized in Example 461-5 Resin 5.2 g 18 ml of 1 mol / L borane-tetrahydrofuran complex was added to a suspension of 20 ml of tetrahydrofuran, stirred at room temperature for 30 minutes, and then stirred at 50 ° C. for 16 and a half hours. The resin was collected from the reaction mixture by filtration, washed with tetrahydrofuran and methanol three times each, and dried under reduced pressure to obtain 4.0 g of the title pale yellow resin.

  A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 345 (M ⁺⁺ 1).
(Example 461-7)
2-[(4- {2- [Heptyl (3-nitropyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid synthesized in Example 461-6 0.15 g of acetonitrile ( 1.5 ml) To the suspension were added 0.16 ml of triethylamine and 0.089 g of 2-chloro-3-nitropyridine, and the mixture was stirred overnight at room temperature. The resin was collected from the reaction solution by filtration, washed with dimethylformamide, tetrahydrofuran and methanol three times each and dried under reduced pressure. To the obtained resin, 2.0 ml of trifluoroacetic acid was added and left at room temperature for 2 hours. Next, the resin was filtered off from the reaction solution, and the filtrate was blown with nitrogen gas, concentrated, dried under reduced pressure, and purified by HPLC fractionation to obtain 1.5 mg of the title compound as a light brown oil.

MS: 467 (M ⁺⁺ 1).

  The following compounds were obtained in the same manner as in Example 461.

[Example 483]
2-Methyl-2-[(4- {2-[(8-methylnonyl) (5-nitropyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

(Example 483-1)
2-{[4- (2-{[(9H-Fluoren-9-ylmethoxy) carbonyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester

  To a solution of 19 g of 2-{[4- (2-aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 7 in tetrahydrofuran (60 ml) , 23 g of N- (9H-fluoren-9-ylmethyloxycarbonyl) succinimide was added and stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The deposited precipitate was filtered off and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and silica gel chromatography (elution solvent; hexane: Ethyl acetate = 2: 1) gave 33 g of the title compound as a light brown oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.60 (6H, s), 2.96 (2H, dd, J = 6.0, 5.4 Hz), 3 .59 (2H, q, J = 6.0 Hz), 4.21 (1H, t, J = 6.9 Hz), 4.37 (2H, d, J = 6.9 Hz), 5.50 (1H, bs), 6.98 (1H, s), 7.30 (2H, t, J = 7.2 Hz), 7.39 (2H, t, J = 7.2 Hz), 7.60 (2H, d, J = 7.5 Hz), 7.51 (2H, d, J = 7.5 Hz).
(Example 483-2)
2-{[4- (2-{[(9H-Fluoren-9-ylmethoxy) carbonyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-{[4- (2-{[(9H-Fluoren-9-ylmethoxy) carbonyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2 synthesized in Example 483-1 -To a solution of 33 g of methylpropionic acid tert-butyl ester in dichloromethane (30 ml), 50 ml of trifluoroacetic acid was added and stirred overnight at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and the solvent was concentrated under reduced pressure and subjected to silica gel chromatography (elution solvent; ethyl acetate). To give 38 g of the title compound as a light brown oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 2.74-3.07 (2H, m), 3.23-3.65 (2H, m), 4.09 -4.32 (1H, m), 4.40-4.59 (2H, m), 6.34 (1H, bs), 6.97 (1H, s), 7.32 (2H, t, J = 7.5 Hz), 7.41 (2H, t, J = 7.2 Hz), 7.58 (2H, d, J = 7.2 Hz), 7.77 (2H, d, J = 7.2 Hz) .
(Example 483-3)
2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid resin

  2-{[4- (2-{[(9H-Fluoren-9-ylmethoxy) carbonyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2 synthesized in Example 483-2 -Using methyl propionic acid as a starting material, the same operation as in Example 461-3 was performed, and 2-{[4- (2-{[(9H-fluoren-9-ylmethoxy) carbonyl] amino} ethyl) -1, 3-thiazol-2-yl] thio} -2-methylpropionic acid resin was obtained.

  A part of this resin was cut out with trifluoroacetic acid, and the introduction of the resin was confirmed.

MS: 469 (M ⁺⁺ 1).
Subsequently, the same operation as in Example 461-4 was performed to obtain 44 g of the title light brown resin.

  A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 247 (M ⁺⁺ 1).
(Example 483-4)
2-Methyl-2-[(4- {2-[(8-methylnonyl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid resin

  2-{[4- (2-Aminoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid synthesized in Example 483-3 0.30 g of dimethylformamide (4. 0 ml) HOBT monohydrate 0.092 g, diisopropylcarbodiimide 0.10 ml, and 8-methylnonanoic acid 0.10 g were added to the suspension and stirred overnight at room temperature. The resin was collected from the reaction solution by filtration, washed with dimethylformamide, tetrahydrofuran and methanol three times each, dried under reduced pressure, and 2-methyl-2-[(4- {2-[(8-methylnonanoyl) amino] ethyl}. A -1,3-thiazol-2-yl) thio] propionic acid resin was obtained.

  To this resin, 1.0 ml of tetrahydrofuran and 2.5 ml of 1 mol / L borane-tetrahydrofuran complex were added and stirred overnight at room temperature. The resin was filtered from the reaction solution, and the resin was washed once with tetrahydrofuran, three times with a solution of tetrahydrofuran-methanol (1: 1), and further twice with methanol. Next, 4.0 ml of a tetrahydrofuran-methanol-piperidine (1: 1: 2) solution was added to the resin and stirred overnight at room temperature. After the reaction, the resin was collected by filtration, washed 4 times with tetrahydrofuran and twice with methanol, and dried under reduced pressure to give 0.30 g of the title brown resin.

  A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 387 (M ⁺⁺ 1).
(Example 483-5)
2-Methyl-2-[(4- {2-[(8-methylnonyl) (5-nitropyridin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-methyl-2-[(4- {2-[(8-methylnonyl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid resin obtained in Example 483-4 and 2- The title compound (30 mg) was obtained as a pale-yellow oil by the same procedures as in Example 461-7 using chloro-5-nitroaniline as a starting material.

MS: 509 (M ⁺⁺ 1).

  The following compounds were obtained in the same manner as in Example 483.

[Example 487]
2-Methyl-2-[(4- {2- [methyl (phenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

(Example 487-1)
2-Methyl-2-[(4- {2- [methyl (phenyl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) thio] propionic acid resin

  2-{[4- (Carboxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid synthesized in Example 461-4 and 0.52 ml of N-methylaniline as starting materials In the same manner as in Example 461-5, 2.0 g of the title yellow resin was obtained.

  A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 351 (M ⁺⁺ 1).
(Example 487-2)
2-Methyl-2-[(4- {2- [methyl (phenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-methyl-2-[(4- {2- [methyl (phenyl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) thio] propionic acid resin obtained in Example 487-1 Trifluoroacetic acid (2.0 ml) was added to the resin obtained as a starting material in the same manner as in Example 461-6, and allowed to stand at room temperature for 2 hours. Next, the resin was filtered off from the reaction solution, and the filtrate was blown with nitrogen gas, concentrated, dried under reduced pressure, and purified by HPLC fractionation to give the title compound (30 mg) as a pale brown oil.

MS: 337 (M ⁺⁺ 1).
[Example 488]
2-Methyl-2-[(4- {2- [phenyl (3-phenylpropyl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

(Example 488-1)
2-{[4- (2-anilino-2-oxoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid resin

  2-{[4- (Carboxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid synthesized in Example 461-4 Starting from resin and aniline, Example 461- In the same manner as in No. 5, 2.9 g of the title yellow resin was obtained.

  A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 337 (M ⁺⁺ 1).
(Example 488-2)
2-{[4- (2-anilinoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid resin

2-{[4- (2-anilino-2-oxoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid obtained in Example 488-1 2.9 g of resin in tetrahydrofuran (30 ml) ) 24 ml of 1 mol / L borane-tetrahydrofuran complex was added to the suspension and stirred overnight at room temperature. Methanol was gradually added to the reaction mixture, and the mixture was stirred overnight at room temperature. The resin was collected by filtration, washed with methanol three times, and dried under reduced pressure to give 2.4 g of the title pale brown resin.
A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 323 (M ⁺⁺ 1).
(Example 488-3)
2-Methyl-2-[(4- {2- [phenyl (3-phenylpropyl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-{[4- (2-anilinoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid obtained in Example 488-2 0.20 g of resin in dichloroethane (3.0 ml) To the mixture, 0.027 g of 3-phenylpropionaldehyde, 0.084 g of sodium tri (acetoxy) borate, and 0.22 ml of acetic acid were added and stirred overnight. The resin was collected from the reaction solution by filtration, washed once with methanol and dimethylformamide, and then twice with methanol.

  To this resin, 2.0 ml of trifluoroacetic acid was added, left at room temperature for 1 hour, the resin was filtered off, nitrogen gas was blown into the solvent, the solvent was concentrated, and the residue was purified by HPLC fractionation to give the title compound ( 11 mg) as a colorless oil.

MS: 441 (M ⁺⁺ 1).

  The following compounds were obtained in the same manner as in Example 488.

[Example 504]
2-[(4- {2-[[4- (2-hydroxyethyl) phenyl] (3-phenylpropyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

(Example 504-1)
2-{[4- (2-{[4- (2-Ethoxy-2-oxoethyl) phenyl] amino} -2-oxoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid Resin

  Using 2-{[4- (carboxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid resin and 4-aminophenylacetic acid ethyl ester obtained in Example 461-4, The same operation as in Example 461-5 was performed 3 times. To the obtained dimethylformamide (30 ml) suspension of resin, 0.92 g of HOBT monohydrate, 0.93 ml of diisopropylcarbodiimide, and 1.1 g of 4-aminophenylacetic acid ethyl ester were added and stirred at room temperature overnight. did. The resin was filtered from the reaction solution, washed with dimethylformamide and methanol once, dimethylformamide twice, methanol once, tetrahydrofuran three times, and finally methanol once, and dried under reduced pressure. 3.1 g of a brown resin was obtained.

  A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 423 (M ⁺⁺ 1).
(Example 504-2)
2-{[4- (2-{[4- (2-hydroxyethyl) phenyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid resin

  2-{[4- (2-{[4- (2-Ethoxy-2-oxoethyl) phenyl] amino} -2-oxoethyl) -1,3-thiazol-2-yl] obtained in Example 504-1 Using 2.6 g of thio} -2-methylpropionic acid resin as a starting material, 2.6 g of the title light brown resin was obtained in the same manner as in Example 488-2.

  A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 423 (M ⁺⁺ 1).
(Example 504-3)
2-{[4- (2-{[4- (2-Ethoxy-2-oxoethyl) phenyl] amino} -2-oxoethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid Resin

  2-{[4- (2-{[4- (2-hydroxyethyl) phenyl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl obtained in Example 504-2 Using 0.3 g of propionic acid resin as a starting material, 8.5 mg of the title compound was obtained as a pale yellow oil by the same procedure as in Example 488-3.

MS: 581 (M ⁺⁺ 1).

  The following compounds were obtained in the same manner as in Example 504.

[Example 520]
2-[(4- {2-[(4-Fluorophenyl) (3-phenylpropyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

(Example 520-1)
2-[(4- {2-[(4-Fluorophenyl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid resin

  2-{[4- (Carboxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid synthesized in Example 461-4 3.0 g of dimethylformamide (30 ml) in resin To the solution were added 0.35 ml of pyridine and a 4 mol / L hydrochloric acid-dioxane solution (1.0 ml), and the mixture was lightly stirred at room temperature for 15 minutes, and then the resin was collected by filtration and washed three times with dimethylformamide. To this dimethylformamide (30 ml) suspension of resin, 0.92 g of HOBT monohydrate, 0.93 ml of diisopropylcarbodiimide, and 0.57 ml of 4-fluoroaniline were added and stirred overnight at room temperature. The resin was filtered from the reaction solution, washed with dimethylformamide and methanol once, dimethylformamide twice, methanol once, tetrahydrofuran three times, and finally methanol once, and dried under reduced pressure. As a result, 3.0 g of a brown resin was obtained.

  A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 355 (M ⁺⁺ 1).
(Example 520-2)
2-[(4- {2-[(4-Fluorophenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid resin

  2-[(4- {2-[(4-Fluorophenyl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) thio] -2-methylpropion synthesized in Example 520-1 The title yellow resin (2.6 g) was obtained in the same manner as in Example 488-2 using the acid resin as a starting material.

  A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 341 (M ⁺⁺ 1).
(Example 520-3)
2-[(4- {2-[(4-Fluorophenyl) (3-phenylpropyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(4-fluorophenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid resin synthesized in Example 520-2 The title compound (13 mg) was obtained as a colorless oil by the same procedures as in Example 488-3, using the starting material.

MS: 459 (M ⁺⁺ 1).

  The following compounds were obtained in the same manner as in Example 520.

[Example 629]
2-[(4- {2- [Heptyl (4-phenyl-1,3-thiazol-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloric acid salt

(Example 629-1)
2-{[4- (2- {3-[(9H-fluoren-9-ylmethoxy) carbonyl] -1-heptylthioureido} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid tert-butyl ester

  2-({4- [2- (Heptylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 2.5 g Into a dichloromethane (20 ml) solution, 2.5 g of 9H-fluoren-9-ylmethyloxycarbonyl isothiocyanate was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then subjected to silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to give the title compound (3.1 g) as a light brown solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.6 Hz), 1.13-1.35 (8H, m), 1.44 (9H, s), 1 .44-1.72 (2H, m), 1.56 (6H, s), 3.03-3.40 (4H, m), 3.70-4.00 (2H, m), 4.25 (1H, t, J = 6.8 Hz), 4.86 (2H, d, J = 6.8 Hz), 7.00-7.20 (1H, m), 7.31 (2H, t, J = 7.3 Hz), 7.41 (2H, t, J = 7.3 Hz), 7.60 (2H, d, J = 7.3 Hz), 7.77 (2H, d, J = 7.3 Hz).
MS: 682 (M ⁺⁺ 1).
(Example 629-2)
2-({4- [2- (1-Heptylthioureido) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester

  2-{[4- (2- {3-[(9H-fluoren-9-ylmethoxy) carbonyl] -1-heptylthioureido} ethyl) -1,3-thiazole-2 synthesized in Example 629-1 To a solution of 3.1 g of -yl] thio} -2-methylpropionic acid tert-butyl ester in methanol (40 ml) was added 20 ml of piperidine and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and then subjected to silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 2.0 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.6 Hz), 1.21-1.35 (8H, m), 1.43 (9H, s), 1 .53-1.75 (2H, m), 1.58 (6H, s), 3.10 (2H, bs), 3.40-4.00 (4H, m), 5.70-6.20. (2H, m), 7.06 (1H, s).
MS: 460 (M ⁺⁺ 1).
(Example 629-3)
2-[(4- {2- [Heptyl (4-phenyl-1,3-thiazol-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloric acid salt

  2-({4- [2- (1-Heptylthioureido) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 629-2 To a 1.0 g dioxane (20 ml) solution, 0.44 g of phenacyl bromide was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 20 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and subjected to silica gel chromatography (elution solvent; chloroform: methanol = 12: 1), and then silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1). Methanol and 1 mol / L hydrochloric acid-ether were added to the resulting residue, and the mixture was dried under reduced pressure. To this residue, 35 ml of methanol, 1.0 g of lithium hydroxide and 5 ml of water were added and stirred overnight at room temperature. Dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. To this residue was added 4 mol / L hydrochloric acid-dioxane, and the mixture was dried under reduced pressure to obtain 0.93 g of the title compound as a light brown amorphous.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 0.86 (3H, t, J = 6.6 Hz), 1.26 to 1.40 (8H, m), 1.40 to 1.70 ( 2H, m), 1.53 (6H, s), 3.11 (2H, t, J = 6.6 Hz), 3.71 (2H, t, J = 6.6 Hz), 3.72-3. 91 (2H, m), 7.16 (1H, s), 7.30 (1H, t, J = 7.2 Hz), 7.40 (2H, t, J = 7.2 Hz), 7.54 ( 1H, s), 7.83 (1H, d, J = 7.2 Hz).
MS: 504 (M ⁺⁺ 1).
[Example 630]
2-[(4- {2- [Heptyl (4-methyl-1,3-thiazol-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid hydrochloric acid salt

  2-({4- [2- (1-Heptylthioureido) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 629-2 The title compound was obtained as pale yellow crystals by the same procedure as in Example 629-3 using bromoacetone and bromoacetone as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 0.88 (3H, t, J = 6.6 Hz), 1.15 to 1.35 (8H, m), 1.58 (2H, t, J = 6.9 Hz), 1.65 (6H, s), 2.34 (3H, s), 3.13 (2H, t, J = 6.9 Hz), 3.25 (2H, t, J = 7.8 Hz), 3.80 (2H, t, J = 6.9 Hz), 6.26 (1H, s), 7.00 (1H, s).
MS: 442 (M ⁺⁺ 1).
[Example 631]
2-[(4- {2-[(4-Ethyl-1,3-thiazol-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropion Acid hydrochloride

  2-({4- [2- (1-Heptylthioureido) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 629-2 And the title compound (0.31 g) was obtained as a pale yellow oil by the same procedure as in Example 629-3 using 1-bromo-2-butanone as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 0.88 (3H, t, J = 7.2 Hz), 1.22 (3H, t, J = 7.5 Hz), 1.22-1. 30 (8H, m), 1.58 (2H, t, J = 6.3 Hz), 1.60 (6H, s), 2.59 (2H, dq, J = 7.2, 0.9 Hz), 3.14 (2H, t, J = 6.9 Hz), 3.26 (2H, t, J = 7.2 Hz), 3.80 (2H, t, J = 7.2 Hz), 6.03 (1H , S), 7.00 (1H, s).
MS: 456 (M ⁺⁺ 1).
[Example 632]
2-[(4- {2-[(4-tert-Butyl-1,3-thiazol-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2- Methylpropionic acid hydrochloride

  2-({4- [2- (1-Heptylthioureido) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid tert-butyl ester synthesized in Example 629-2 The title compound (0.51 g) was obtained as a pale purple oil by the same procedure as in Example 629-3 using 1-bromo-3,3-dimethyl-2-propanone as a starting material.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 0.84 (3H, t, J = 5.4 Hz), 1.32 (9H, s), 1.23-1.35 (8H, m) , 1.61-1.78 (2H, m), 1.61 (6H, s), 3.17 (2H, t, J = 6.9 Hz), 3.58 (2H, t, J = 7. 2 Hz), 4.07 (2H, t, J = 7.2 Hz), 6.10 (1H, s), 7.26 (1H, s).
MS: 456 (M ⁺⁺ 1).
[Example 633]
2-methyl-2-[(4- {2-[(4-methyl-1,3-thiazol-2-yl) (4-pentylphenyl) amino] ethyl} -1,3-thiazol-2-yl) Thio] propionic acid

(Example 633-1)
2-Methyl-2-[(4- {2-[(4-pentylphenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid resin

  2-{[4- (Carboxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid synthesized in Example 461-4 and 0.098 g of 4-amylaniline as starting materials And the same operation as in Example 520-1 was performed. To the obtained resin, 2.0 ml of tetrahydrofuran and 2.0 ml of 1 mol / L borane-tetrahydrofuran complex were added and stirred overnight at room temperature. The resin was filtered from the reaction solution, and the resin was washed once with tetrahydrofuran, twice with a solution of tetrahydrofuran / methanol = 1: 1, and further twice with methanol. Then, a solution of tetrahydrofuran-methanol-piperidine (1: 1: 2) (4.0 ml) was added to the resin and stirred at room temperature overnight. After completion of the reaction, the resin was collected by filtration, washed 4 times with tetrahydrofuran and twice with methanol, and dried under reduced pressure to give 0.30 g of the title pale yellow resin.

  A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 393 (M ⁺⁺ 1).
(Example 633-2)
2-methyl-2-[(4- {2-[(4-methyl-1,3-thiazol-2-yl) (4-pentylphenyl) amino] ethyl} -1,3-thiazol-2-yl) Thio] propionic acid

  2-Methyl-2-[(4- {2-[(4-pentylphenyl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid synthesized in Example 633-1 Resin 0 To a 30 g dichloromethane (4.0 ml) suspension, 2.5 g 9H-fluoren-9-ylmethyloxycarbonyl isothiocyanate was added dropwise and stirred at room temperature overnight. After completion of the reaction, the resin was collected by filtration, washed with dichloromethane, tetrahydrofuran and methanol three times each and dried under reduced pressure. To this resin, a solution (3 ml) of piperidine-dimethylformamide (1: 2) was added and allowed to stand for 3 hours with occasional stirring. The resin was collected by filtration, three times with dimethylformamide, once with methanol, and with tetrahydrofuran. The extract was washed three times, once with methanol and once with dioxane, and dried under reduced pressure. To the obtained resin, 0.035 ml of bromoacetone and 4.0 ml of dioxane were added and stirred overnight at room temperature. After completion of the reaction, the resin was collected by filtration, washed with dimethylformamide, tetrahydrofuran and methanol three times each and dried under reduced pressure. To this resin was added 2.0 ml of trifluoroacetic acid, and the mixture was allowed to stand for 1 hour, then the resin was filtered off, the residue was concentrated by blowing nitrogen gas, and purified by HPLC fractionation to give 0.029 g of the title compound as a pale brown oil. Obtained as a thing.

MS: 490 (M ⁺⁺ 1).

  The following compounds were obtained in the same manner as in Example 633.

[Example 675]
2-Methyl-2-[(4- {2-[(8-methylnonyl) (4-methyl-1,3-thiazol-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio ] Propionic acid

  2-methyl-2-[(4- {2-[(8-methylnonyl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid synthesized in Example 483-4 Using 3 g as a starting material, the title compound (0.031 g) was obtained as a pale yellow oil by the same procedure as in Example 633-2.

MS: 484 (M ⁺⁺ 1).

  The following compounds were obtained in the same manner as in Example 675.

[Example 680] 2-({4- [2- (biphenyl-3-ylamino) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid

  2-{[4- (Carboxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid synthesized in Example 461-4 was used starting from resin and 3-aminobiphenyl. The same operation as in Example 520-1 and Example 488-2 was performed. Trifluoroacetic acid was added to the resulting resin and allowed to stand overnight. The resin was filtered off, concentrated by blowing with nitrogen gas, and purified by HPLC fractionation to give 0.015 g of the title compound as a light brown oil.

MS: 399 (M ⁺⁺ 1).

  The following compounds were obtained in the same manner as in Example 680.

[Example 713]
2-({4- [2- (biphenyl-4-yloxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid

(Example 713-1)
2-{[4- (2-Hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid resin

  2-{[4- (Carboxymethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid synthesized in Example 461-4 To a tetrahydrofuran (50 ml) suspension of 10 g of resin, Under ice cooling, 25 ml of 1 mol / L borane-tetrahydrofuran complex was added and stirred overnight at room temperature. The resin was collected by filtration from the reaction mixture, washed twice with a tetrahydrofuran-methanol (1: 1) solution, three times with tetrahydrofuran, twice with methanol, once with piperidine, once with tetrahydrofuran, and once with methanol. And dried under reduced pressure. To this resin, 25 ml of 1 mol / L borane-tetrahydrofuran complex was again added and stirred overnight at room temperature. The resin was collected from the reaction solution by filtration, washed once with tetrahydrofuran, tetrahydrofuran-methanol (1: 1) solution, and tetrahydrofuran-piperidine (1: 1) solution in this order, and then with tetrahydrofuran and methanol three times. And dried under reduced pressure to obtain 8.6 g of the title pale yellow resin.

  A part of this resin was cut out with trifluoroacetic acid to confirm the structure.

MS: 262 (M ⁺⁺ 1).
(Example 713-2)
2-({4- [2- (biphenyl-4-yloxy) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid synthesized in Example 713-1 0.3 g of resin in tetrahydrofuran (3.0 ml) ) 0.12 g of triphenylphosphine and 0.17 g of 4-phenylphenol were added to the suspension and left for 15 minutes. To this was added 0.26 ml of diisopropyl azodicarboxylate (40% toluene solution), and the mixture was stirred at room temperature for 30 minutes. The resin was collected from the reaction solution by filtration and washed with tetrahydrofuran three times. This operation was repeated three times, and the resulting resin was washed three times with dimethylformamide, tetrahydrofuran and methanol, and dried under reduced pressure. Trifluoroacetic acid was added to this resin, and after standing at room temperature for 4 hours, the resin was filtered off, concentrated by blowing with nitrogen gas, and purified by HPLC fractionation to obtain 0.012 g of the title compound as a colorless oil. It was.

MS: 400 (M ⁺⁺ 1).

  The following compounds were obtained in the same manner as in Example 713.

[Example 733]
2-Methyl-2-[(4- {2-[(4′-nitrobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

(Example 733-1)
2-Methyl-2-[(4- {2-[(4′-nitrobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid tert-butyl ester

  2-{[4- (2-hydroxyethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid tert-butyl ester synthesized in Example 4 2.7 g of tetrahydrofuran (15 ml) To the solution, 2.5 g of triphenylphosphine and 2.1 g of 4- (4-nitrophenyl) phenol were added and stirred for 5 minutes under ice cooling. To this solution, 4.7 ml of diisopropyl azodicarboxylate (40% toluene solution) was added and stirred overnight at room temperature. To this solution were further added 1.2 g of triphenylphosphine and 2.4 ml of diisopropyl azodicarboxylate (40% toluene solution), and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated, extracted with ethyl acetate, washed with aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give 3.3 g of the title compound as a light brown solid.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.43 (9H, s), 1.58 (6H, s), 3.28 (2H, t, J = 6.6 Hz), 4.37 (2H , T, J = 6.6 Hz), 7.01 (2H, dd, J = 6.8, 2.0 Hz), 7.14 (1H, s), 7.57 (2H, dd, J = 6. 8, 2.0 Hz), 7.69 (2H, dd, J = 7.0, 1.9 Hz), 8.27 (2H, dd, J = 7.0, 1.9 Hz).
MS: 501 (M ⁺⁺ 1).
(Example 733-2)
2-Methyl-2-[(4- {2-[(4′-nitrobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-Methyl-2-[(4- {2-[(4′-nitrobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio synthesized in Example 733-1 ] To a solution of propionic acid tert-butyl ester 3.3 g in dichloromethane (10 ml), 30 ml of trifluoroacetic acid was added and stirred overnight at room temperature. The reaction mixture was concentrated, poured into water, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. Diisopropyl ether was added to this, and the resulting crystals were collected by filtration to give 2.4 g of the title compound as yellow crystals.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 3.30 (2H, t, J = 6.0 Hz), 4.36 (2H, t, J = 6.0 Hz) 7.01 (2H, ddd, J = 9.9, 3.0, 2.0 Hz), 7.13 (1H, s), 7.58 (2H, ddd, J = 9.9, 3.0 2.0 Hz), 7.68 (2H, ddd, J = 9.3, 2.7, 2.1 Hz), 8.27 (2H, ddd, J = 9.3, 2.7, 2.1 Hz) ).
MS: 445 (M ⁺⁺ 1).
[Example 734]
2-{[4- (2-{[6- (3,4-Dichlorophenyl) pyridazin-3-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl obtained in Example 123-1 The title compound was obtained in the same manner as in Example 123-2 and Example 123-3 using propionic acid tert-butyl ester and 3,4-dichlorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.64 (6H, s), 3.36 (2H, t, J = 6.0 Hz), 4.90 (2H, t, J = 6.0 Hz) , 7.08 (1H, s), 7.15 (1H, d, J = 9.3 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.76 (1H, d, J = 9.3 Hz), 7.83 (1H, dd, J = 2.1, 8.4 Hz), 8.13 (1H, d, J = 2.1 Hz).
MS: 470 (M ⁺⁺ 1).
[Example 735]
2-{[4- (2-{[6- (3-Chloro-4-fluorophenyl) pyridazin-3-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl obtained in Example 123-1 The title compound was obtained in the same manner as in Example 123-2 and Example 123-3 using propionic acid tert-butyl ester and 3-chloro-4-fluorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.36 (2H, t, J = 6.0 Hz), 4.89 (2H, t, J = 6.0 Hz) , 7.08 (1H, s), 7.15 (1H, d, J = 9.0 Hz), 7.23-7.29 (1H, m), 7.75 (1H, d, J = 9. 0 Hz), 7.85-7.89 (1H, m), 8.08-8.11 (1H, m).
MS: 454 (M ⁺⁺ 1).
[Example 736]
2-{[4- (2-{[6- (2,4-dichlorophenyl) pyridazin-3-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl obtained in Example 123-1 The title compound was obtained in the same manner as in Example 123-2 and Example 123-3 using propionic acid tert-butyl ester and 2,4-dichlorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.36 (2H, t, J = 6.0 Hz), 4.90 (2H, t, J = 6.0 Hz) 7.08-7.19 (2H, m), 7.37-7.41 (1H, m), 7.51 (1H, brs), 7.65 (1H, d, J = 8.4 Hz) , 7.76 (1H, d, J = 9.3 Hz).
MS: 470 (M ⁺⁺ 1).
[Example 737]
2-{[4- (2-{[6- (4-Chloro-2-fluorophenyl) pyridazin-3-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl obtained in Example 123-1 The title compound was obtained in the same manner as in Example 123-2 and Example 123-3 using propionic acid tert-butyl ester and 4-chloro-2-fluorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.36 (2H, t, J = 6.0 Hz), 4.90 (2H, t, J = 6.0 Hz) 7.08-7.13 (2H, m), 7.20-7.33 (2H, m), 7.83-7.87 (1H, m), 8.06 (1H, t, J = 8.4 Hz).
MS: 454 (M ⁺⁺ 1).
[Example 738]
2-({4- [2-({6- [2-Fluoro-4- (trifluoromethyl) phenyl] pyridazin-3-yl} oxy) ethyl] -1,3-thiazol-2-yl} thio) -2-Methylpropionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl obtained in Example 123-1 The title compound was obtained in the same manner as in Example 123-2 and Example 123-3 using propionic acid tert-butyl ester and 2-fluoro-4- (trifluoromethyl) phenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.37 (2H, t, J = 6.0 Hz), 4.92 (2H, t, J = 6.0 Hz) 7.09 (1H, s), 7.16 (1H, d, J = 9.3 Hz), 7.45-7.48 (1H, m), 7.56-7.59 (1H, m) , 7.89-7.93 (1H, m), 8.24 (1H, t, J = 8.1 Hz).
MS: 488 (M ⁺⁺ 1).
[Example 739]
2-{[4- (2-{[6- (3,5-dichlorophenyl) pyridazin-3-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid

  2-[(4- {2-[(6-Chloropyrazin-3-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl obtained in Example 123-1 The title compound was obtained in the same manner as in Example 123-2 and Example 123-3 using propionic acid tert-butyl ester and 3,5-dichlorophenylboric acid as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.65 (6H, s), 3.37 (2H, t, J = 6.0 Hz), 4.90 (2H, t, J = 6.0 Hz) , 7.09 (1H, s), 7.16 (1H, d, J = 9.0 Hz), 7.44-7.45 (1H, m), 7.76 (1H, d, J = 9. 0 Hz), 7.90 (2H, brs).
MS: 470 (M ⁺⁺ 1).
[Example 740]
[(4- {2-[(4′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] acetic acid

  (2-Mercapto-1,3-thiazol-4-yl) acetic acid ethyl ester and bromoacetic acid tert-butyl ester synthesized in Example 1 were used in the same manner as in Example 2 to perform {2-[(2 -Tert-Butoxy-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid ethyl ester was obtained, and then the same operations as in Examples 3, 4 and 34 were sequentially performed to obtain the title compound. Obtained.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 3.12 (2H, t, J = 6.3 Hz), 4.08 (2H, s), 4.31 (2H, t, J = 6. 3 Hz), 7.03 (2H, d, J = 8.7 Hz), 7.25 (2H, t, J = 8.7 Hz), 7.36 (1H, s), 7.56 (2H, d, J = 8.7 Hz), 7.61-7.66 (2H, m).
MS: 390 (M ⁺⁺ 1).
[Example 741]
{[4- (2-{[5- (4-Fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} acetic acid

  (2-Mercapto-1,3-thiazol-4-yl) acetic acid ethyl ester and bromoacetic acid tert-butyl ester synthesized in Example 1 were used in the same manner as in Example 2 to perform {2-[(2 -Tert-Butoxy-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid ethyl ester was obtained, and then the title compound was obtained by sequentially performing the same operations as in Examples 3, 4 and 100. It was.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 3.13 (2H, t, J = 6.1 Hz), 4.07 (2H, s), 4.58 (2H, t, J = 6. 1 Hz), 6.88 (1 H, d, J = 8.4 Hz), 7.30 (2 H, t, J = 8.8 Hz), 7.34 (1 H, s), 7.70 (2 H, t, J = 8.8 Hz), 7.99 (1H, d, J = 11.3 Hz), 8.47 (1H, s).
MS: 391 (M ⁺⁺ 1).
[Example 742]
[(4- {2-[(4′-Chlorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] acetic acid

  (2-Mercapto-1,3-thiazol-4-yl) acetic acid ethyl ester and bromoacetic acid tert-butyl ester synthesized in Example 1 were used in the same manner as in Example 2 to perform {2-[(2 -Tert-Butoxy-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid ethyl ester was obtained, and then the title compound was obtained in the same manner as in Examples 3, 4 and 38. It was.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 3.12 (2H, t, J = 6.6 Hz), 4.07 (2H, s), 4.31 (2H, t, J = 6. 6 Hz), 7.04 (2H, d, J = 8.1 Hz), 7.36 (1 H, s), 7.47 (2H, d, J = 8.1 Hz), 7.58-7.66 ( 4H, m).
MS: 406 (M ⁺⁺ 1).
[Example 743]
({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) acetic acid

  (2-Mercapto-1,3-thiazol-4-yl) acetic acid ethyl ester and bromoacetic acid tert-butyl ester synthesized in Example 1 were used in the same manner as in Example 2 to perform {2-[(2 -Tert-Butoxy-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid ethyl ester was obtained, and then the same operations as in Examples 3, 4, 5, 6, 7, and 162 were sequentially performed. This gave the title compound.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 2.94 (2H, t, J = 7.2 Hz), 3.61 (2H, dd, J = 6.9 Hz, 13.8 Hz), 4. 07 (2H, s), 7.28 (1H, s), 7.41-7.49 (3H, m), 7.75 (2H, t, d = 8.7 Hz), 8.65 (2H, s), 13.03 (1H, brs).
MS: 457 (M ⁺⁺ 1).
[Example 744]
({4- [2-({5- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl} thio) acetic acid

  (2-Mercapto-1,3-thiazol-4-yl) acetic acid ethyl ester and bromoacetic acid tert-butyl ester synthesized in Example 1 were used in the same manner as in Example 2 to perform {2-[(2 -Tert-Butoxy-2-oxoethyl) thio] -1,3-thiazol-4-yl} acetic acid ethyl ester was obtained, and then the same operations as in Examples 3, 4, 5, 6, 7, and 165 were sequentially performed. This gave the title compound.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 2.92 (2H, t, J = 7.4 Hz), 3.61 (2H, dd, J = 6.7 Hz, 13.3 Hz), 4. 05 (2H, s), 7.26 (1H, s), 7.54 (1H, t, J = 5.7 Hz), 7.75 (2H, d, J = 8.3 Hz), 7.85 ( 2H, d, J = 8.3 Hz), 8.70 (2H, s).
MS: 441 (M ⁺⁺ 1).
[Example 745]
2-[(4- {2-[(4′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-({2-mercapto-1,3-thiazol-4-yl) acetic acid ethyl ester and 2-bromopropionic acid tert-butyl ester synthesized in Example 1 were used in the same manner as in Example 2 to produce 2- { After obtaining [4- (2-ethoxy-2-oxoethyl) -1,3-thiazol-2-yl] thio} propionic acid tert-butyl ester, the same operations as in Examples 3, 4 and 34 were sequentially performed. This gave the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.59 (3H, d, J = 7.4 Hz), 3.26 (2H, d, J = 6.1 Hz), 4.08 (1H, q, J = 7.4 Hz), 4.32 (2H, d, J = 6.1 Hz), 6.96 (2H, d, J = 8.7 Hz), 7.07-7.12 (3H, m), 7.44-7.50 (4H, m).
MS: 404 (M ⁺⁺ 1).
[Example 746]
2-[(4- {2-[(4′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-butanoic acid

  Using 2-ethyl [2-mercapto-1,3-thiazol-4-yl) acetic acid ethyl ester and 2-bromobutanoic acid tert-butyl ester synthesized in Example 1, 2-{[ After obtaining 4- (2-ethoxy-2-oxoethyl) -1,3-thiazol-2-yl] thio} butanoic acid tert-butyl ester, the same operations as in Examples 3, 4 and 34 are sequentially performed. Gave the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.09 (3H, t, J = 7.5 Hz), 1.75-1.86 (1H, m), 2.10-2.20 (1H, m), 3.26 (2H, t, J = 6.0 Hz), 3.84 (1H, t, J = 7.5 Hz), 4.32 (2H, t, J = 6.0 Hz), 6. 97 (2H, d, J = 6.6 Hz), 7.07-7.13 (3H, m), 7.43-7.51 (4H, m).
MS: 418 (M ⁺⁺ 1).
(Reference Example 51)
(2-Mercapto-1,3-thiazol-4-yl) acetic acid

22.6 g of (2-mercapto-1,3-thiazol-4-yl) acetic acid ethyl ester synthesized in Example 1 was dissolved in 200 mL of methanol, and 222 mL of a 1 mol / L aqueous sodium hydroxide solution was added to it overnight at room temperature. Stir. The reaction solution was weakly acidified with 1 mol / L hydrochloric acid, methanol was distilled off, and the residue was extracted with ethyl acetate. After washing with a saturated aqueous sodium chloride solution, the solvent was distilled off and the resulting crystals were suspended and washed with diethyl ether to give 11.9 g of the title compound.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 3.55 (2H, s), 6.72 (1H, s), 13.08 (1H, brs).
[Example 747]
(2-{[1- (methoxycarbonyl) cyclohexyl] thio} -1,3-thiazol-4-yl) acetic acid

3.50 g of (2-mercapto-1,3-thiazol-4-yl) acetic acid synthesized in Reference Example 51 and 4.42 g of 2-bromocyclohexanecarboxylic acid methyl ester were dissolved in 80 mL of methanol, and sodium methoxide 2. 38 g was added and heated to reflux for 22 hours. The solvent was distilled off, and 50 mL of diethyl ether and 50 mL of water were added to the residue. After stirring, 1 mol / L hydrochloric acid was added to the aqueous layer obtained by liquid separation operation to adjust the pH to about 4. The mixture was extracted with 100 mL of ethyl acetate, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After evaporating the solvent, the solid obtained by purification by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 2 to 0: 1) was suspended and washed with hexane-ethyl acetate to give 663 mg of the title compound. Obtained.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.41-1.50 (4H, m), 1.78-1.86 (4H, m), 2.15-2.22 (2H, m) , 3.73 (3H, s), 3.88 (2H, s), 7.26 (1H, s).
[Example 748]
1-[(4- {2-[(4′-Fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -cyclohexanecarboxylic acid

  Using (2-{[1- (methoxycarbonyl) cyclohexyl] thio} -1,3-thiazol-4-yl) acetic acid synthesized in Example 747, operations similar to those in Examples 4 and 34-1 were sequentially performed. As a result, 892 mg of the methyl ester of the title compound was obtained. This was dissolved in 30 mL of methanol and 5 mL of tetrahydrofuran, 2 mL of a 1 mol / L aqueous sodium hydroxide solution was added, and the mixture was heated to reflux for 8 hours and 30 minutes. The reaction solution was allowed to cool, the solvent was distilled off, 10 mL of water and diethyl ether were added to the residue, and the mixture was stirred and then subjected to liquid separation operation. The aqueous layer was adjusted to pH 2 by adding 1 mol / L hydrochloric acid and the precipitated solid was collected by filtration and recrystallized using hexane and ethyl acetate to obtain 591 mg of the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.36 to 1.66 (6H, m), 1.82-1.88 (2H, m), 2.08-2.18 (2H, m) 3.28 (2H, t, J = 6.0 Hz), 4.33 (2H, t, J = 6.0 Hz), 6.94 (2H, d, J = 6.6 Hz), 7.07- 7.13 (3H, m), 7.43-7.51 (4H, m).
MS: 458 (M ⁺⁺ 1).
[Example 749]
2-methyl-2-{[4- (2-{(5-methylpyridin-2-yl) [4- (trifluoromethyl) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio } Propionic acid

  2-[(4- {2-[(5-methylpyridin-2-yl) amino] ethyl was prepared by the same procedure as in Example 242-1 and Example 242-2 using 2-amino-5-methylpyridine. } -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester was obtained. The title compound was obtained in the same manner as in Example 326 using this compound and 1- (bromomethyl) -4- (trifluoromethyl) benzene as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 2.12 (3H, s), 2.99 (2H, t, J = 7.2 Hz), 3.80 (2H, t, J = 7.2 Hz), 4.67 (2H, s), 6.53 (1H, d, J = 8.7 Hz), 7.27 (4H, s), 7.32 (1H , Dd, J = 2.4 Hz, 8.7 Hz), 7.44 (1H, s), 7.91 (1H, d, J = 2.4 Hz), 12.89 (1H, brs).
MS: 496 (M ⁺⁺ 1).
[Example 750]
2-Methyl-2-{[4- (2-{(5-methylpyridin-2-yl) [4- (trifluoromethoxy) benzyl] amino} ethyl) -1,3-thiazol-2-yl] thio } Propionic acid

  2-[(4- {2-[(5-methylpyridin-2-yl) amino] ethyl was prepared by the same procedure as in Example 242-1 and Example 242-2 using 2-amino-5-methylpyridine. } -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester was obtained. The title compound was obtained in the same manner as in Example 326 using this compound and 1- (bromomethyl) -4- (trifluoromethoxy) benzene as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.50 (6H, s), 2.13 (3H, s), 3.01 (2H, t, J = 7.1 Hz), 3.84 (2H, t, J = 7.1 Hz), 4.74 (2H, s), 6.59 (1H, brs), 7.35-7.39 (3H, m), 7.47 (1H, s ), 7.65 (2H, d, J = 8.1 Hz), 7.91 (1H, d, J = 1.8 Hz), 12.91 (1H, brs).
MS: 512 (M ⁺⁺ 1).
[Example 751]
2-methyl-2-{[4- (2-{(5-methylpyridin-2-yl) [(2E) -3-phenylprop-2-en-1-yl] amino} ethyl) -1,3 -Thiazol-2-yl] thio} propionic acid

2-[(4- {2-[(5-methylpyridin-2-yl) amino] ethyl} was prepared by the same procedure as in Example 242-1 and Example 242-2 using 2-amino5-methylpyridine. -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester was obtained. The title compound was obtained in the same manner as in Example 326 using this and cinnamyl bromide as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.49 (6H, s), 2.12 (3H, S), 2.99 (2H, t, J = 7.1 Hz), 3.80 (2H, t, J = 7.1 Hz), 4.17 (2H, d, J = 5.4 Hz), 6.20-6.28 (1H, m), 6.47 (1H, d, J = 16 Hz), 6.58 (1 H, d, J = 8.6 Hz), 7.18-7.39 (7 H, m), 7.93 (1 H, d, J = 1.9 Hz).
MS: 454 (M ⁺⁺ 1)
[Example 752]
2-methyl-2-{[4- (2-{(5-methylpyridin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole -2-yl] thio} propionic acid

2-[(4- {2-[(5-methylpyridin-2-yl) amino] ethyl was prepared by the same procedure as in Example 242-1 and Example 242-2 using 2-amino-5-methylpyridine. } -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester was obtained. This was combined with 4- (chloromethyl) -1-phenyl-1H-pyrazole synthesized in Reference Example 18 as a starting material to give the title compound by the same procedure as in Example 326.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.46 (6H, s), 2.27 (3H, s), 2.98 (2H, t, J = 7.2 Hz), 3.80 (2H, t, J = 7.2 Hz), 4.53 (2H, s), 6.63 (1H, d, J = 9.0 Hz), 7.24-7.34 (3H, m), 7 .46 (2H, t, J = 7.8 Hz), 7.61 (1H, s), 7.77 (2H, d, J = 8.4 Hz), 7.95 (1H, s), 8.36 (1H, s).
MS: 494 (M ⁺⁺ 1).
[Example 753]
2-Methyl-2-[(4- {2-[[(2E) -3-phenylprop-2-en-1-yl] (pyridin-2-yl) amino] ethyl] -1,3-thiazole- 2-yl} thio) propionic acid

2-[(4- {2-[(pyridin-2-yl) amino] ethyl} -1,3-thiazole was prepared by the same procedure as in Example 242-1 and Example 242-2 using 2-aminopyridine. -2-yl) thio] -2-methylpropionic acid tert-butyl ester was obtained. The title compound was obtained in the same manner as in Example 326 using this and cinnamyl bromide as starting materials.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.49 (6H, s), 3.01 (2H, t, J = 7.1 Hz), 3.83 (2H, t, J = 7. 1 Hz), 4.20 (2H, d, J = 5.4 Hz), 6.20-6.28 (1H, m), 6.46 (1H, s), 6.51-6.58 (1H, m), 6.65 (1H, d, J = 8.7 Hz), 7.18-7.23 (1H, m), 7.30 (2H, t, J = 7.8 Hz), 7.37- 7.40 (3H, m), 7.44-7.51 (1H, m), 8.08-8.11 (1H, m).
MS: 440 (M ⁺⁺ 1).
(Reference Example 52)
5-ethylpyridin-2-amine

Dissolve 2.51 g of 5-bromopyridin-2-amine in 150 mL of toluene, add 10.0 g of tributylvinyltin, 1.23 g of lithium chloride, and 160 mg of 2,6-di-tert-butyl-4-methylphenol to add 2 The mixture was heated to reflux for 30 minutes. The resulting solid was removed by filtration, the solvent was evaporated, the residue was dissolved in ethyl acetate, and the insoluble material was removed again by filtration. The filtrate was extracted with 0.2 mol / L hydrochloric acid (100 mL, 50 mL), and the resulting hydrochloric acid solution was basified (pH 12) with 1 mol / L sodium hydroxide, and then extracted with 200 mL of ethyl acetate, and saturated sodium chloride. After washing with an aqueous solution, it was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 1.00 g of 5-vinylpyridin-2-amine. This was dissolved in 80 mL of ethyl acetate, added with 330 mg of 10% palladium-carbon under a nitrogen atmosphere, changed to a hydrogen atmosphere, and stirred for 8 hours. The reaction vessel was purged with nitrogen, 300 mg of 10% -palladium carbon was added, and the mixture was again placed in a hydrogen atmosphere and stirred for 4 hours. The reaction vessel was purged with nitrogen, the catalyst was removed by filtration, the solvent was distilled off, and the residue was dissolved in 20 mL of 0.4 mol / L hydrochloric acid. The obtained hydrochloric acid solution was washed with ethyl acetate, made basic (pH 12) with a 1 mol / L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and further dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain 773 mg of the title compound.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.10 (3H, t, J = 7.6 Hz), 2.40 (2H, q, J = 7.6 Hz), 5.62 (2H, brs), 6.38 (1H, d, J = 8.4 Hz), 7.23 (1H, dd, J = 2.3 Hz, 8.4 Hz), 7.74 (1H, d, J = 2.3 Hz). ).
[Example 754]
2-{[4- (2-{(5-Ethylpyridin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl ] Thio} -2-methylpropionic acid

  Using 5-ethylpyridin-2-amine synthesized in Reference Example 52 in the same manner as in Example 242-1 and Example 242-2, 2-[(4- {2-[(5-ethylpyridine- 2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid tert-butyl ester was obtained. This was combined with 4- (chloromethyl) -1-phenyl-1H-pyrazole synthesized in Reference Example 18 as a starting material to give the title compound by the same procedure as in Example 326.

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 1.13 (3H, t, J = 7.5 Hz), 1.49 (6H, s), 2.45 (2H, q, J = 7. 5 Hz), 2.99 (2H, t, J = 7.1 Hz), 3.81 (2H, t, J = 7.1 Hz), 4.53 (2H, s), 6.65 (1H, d, J = 8.7 Hz), 7.27 (1H, t, J = 7.4 Hz), 7.36 (1H, dd, J = 2.4 Hz, 8.7 Hz), 7.41-7.49 (3H) , M), 7.63 (1H, m), 7.78 (2H, d, J = 8.9 Hz), 7.98 (1H, d, J = 2.1 Hz), 8.37 (1H, s) ).
MS: 508 (M ⁺⁺ 1).
[Example 755]
2-[(4- {2-[(5-ethylpyrimidin-2-yl) ({1- [4- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl} methyl) amino] ethyl}- 1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 4- (Chloromethyl) -1- (4-trifluoromethyl) phenyl- synthesized from [4- (trifluoromethyl) phenyl] hydrazine by the same procedure as in Protionic acid tert-butyl ester and Reference Examples 15-18 The title compound was obtained in the same manner as in Example 326 using 1H-pyrazole as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.5 Hz), 1.63 (6H, s), 2.50 (2H, q, J = 7.5 Hz) 3.10 (2H, t, J = 6.6 Hz), 3.92 (2H, t, J = 6.6 Hz), 4.70 (2H, s), 6.97 (1H, s), 7 .69 (2H, d, J = 8.7 Hz), 7.70 (1H, s), 7.84 (2H, d, J = 8.7 Hz), 8.07 (1H, s), 8.23 (2H, s).
MS: 577 (M ⁺⁺ 1).
[Example 756]
2-[(4- {2-[(5-ethylpyrimidin-2-yl) ({1- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl} methyl) amino] ethyl}- 1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 4- (Chloromethyl) -1- (3-trifluoromethyl) phenyl-synthesized from [3- (trifluoromethyl) phenyl] hydrazine by the same procedure as in propionic acid tert-butyl ester and Reference Examples 15-18 The title compound was obtained in the same manner as in Example 326 using 1H-pyrazole as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.5 Hz), 1.63 (6H, s), 2.50 (2H, q, J = 7.5 Hz) 3.10 (2H, t, J = 6.6 Hz), 3.93 (2H, t, J = 6.9 Hz), 4.70 (2H, s), 6.96 (1H, s), 7 .48-7.59 (3H, m), 7.70 (1H, m) 7.88 (2H, d, J = 8.1 Hz), 7.98 (1H, s), 8.01 (1H, s), 8.23 (2H, s).
MS: 577 (M ⁺⁺ 1).
[Example 757]
2-[(4- {2-[{[1- (3-Chlorophenyl) -1H-pyrazol-4-yl] methyl} (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazole -2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Propionic acid tert-butyl ester and 4- (chloromethyl) -1- (3-chlorophenyl) -1H-pyrazole synthesized from (3-chlorophenyl) hydrazine by the same operation as in Reference Examples 15 to 18 were carried out as starting materials. The title compound was obtained in the same manner as the Example 326.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.5 Hz), 1.64 (6H, s), 2.50 (2H, q, J = 7.5 Hz) 3.09 (2H, t, J = 6.9 Hz), 3.93 (2H, t, J = 6.9 Hz), 4.69 (2H, s), 6.96 (1H, s), 7 .22 (1H, d, J = 9.3 Hz), 7.35 (1H, t, J = 8.1 Hz), 7.57 (1H, d, J = 8.7 Hz), 7.67 (1H, s), 7.72 (1H, s), 7.94 (1H, s), 8.23 (2H, s).
MS: 543 (M ⁺⁺ 1).
[Example 758]
2-[(4- {2-[(5-Ethylpyrimidin-2-yl) ({1- [4- (trifluoromethoxy) phenyl] -1H-pyrazol-4-yl} methyl) amino] ethyl}- 1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 4- (Chloromethyl) -1- (4-trifluoromethoxy) phenyl- synthesized from [4- (trifluoromethoxy) phenyl] hydrazine by the same procedure as that of propionic acid tert-butyl ester and Reference Examples 15 to 18 The title compound was obtained in the same manner as in Example 326 using 1H-pyrazole as a starting material.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.5 Hz), 1.63 (6H, s), 2.50 (2H, q, J = 7.5 Hz) 3.09 (2H, t, J = 7.1 Hz), 3.92 (2H, t, J = 7.1 Hz), 4.69 (2H, s), 6.96 (1H, s), 7 .28 (2H, d, J = 9.0 Hz), 7.67 (1H, s), 7.73 (2H, d, J = 9.0 Hz), 7.97 (1H, s), 8.22 (2H, s).
MS: 593 (M ⁺⁺ 1).
[Example 759]
2-({4- [2-((5-Ethylpyrimidin-2-yl) {[1- (3-fluorophenyl) -1H-pyrazol-4-yl] methyl} amino) ethyl] -1,3- Thiazol-2-yl} thio) -2-methylpropionic acid

  2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 Starting from propionic acid tert-butyl ester and 4- (chloromethyl) -1- (3-fluorophenyl) -1H-pyrazole synthesized from (3-fluorophenyl) hydrazine by the same procedure as in Reference Examples 15 to 18 In the same manner as in Example 326, the title compound was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.5 Hz), 1.63 (6H, s), 2.50 (2H, q, J = 7.5 Hz) , 3.09 (2H, t, J = 7.8 Hz), 3.93 (2H, t, J = 7.8 Hz), 4.69 (2H, s), 6.91-6.97 (2H, m), 7.26-7.47 (3H, m), 7.67 (1H, s), 7.95 (1H, s), 8.23 (2H, s).
MS: 527 (M ⁺⁺ 1).
[Example 760]
2-{[4- (2-{(5-cyanopyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazol-2-yl ] Thio} -2-methylpropionic acid

2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 Starting from propionic acid tert-butyl ester and 4- (chloromethyl) -1-phenyl-1H-pyrazole synthesized in Reference Example 18 as a starting material, 500 mg of a compound obtained by the same procedure as in Example 442-1 was added to DMF2. It melt | dissolved in 5 mL, zinc cyanide 100 mg and tetrakis (triphenylphosphine) palladium 282 mg were added, and it heated at 100 degreeC for 6 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 4: 1 to 1: 1) to give a compound (300 mg) by the same procedure as in Example 442-3. A compound was obtained.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.63 (6H, s), 3.08 (2H, t, J = 7.5 Hz), 3.98 (2H, t, J = 7.5 Hz) , 4.77 (2H, s), 6.97 (1H, s), 7.26-7.30 (1H, m), 7.42-7.47 (2H, m), 7.67-7 .70 (3H, m), 8.02 (1H, s), 8.57 (2H, bd, J = 15.3 Hz).
MS: 506 (M ⁺⁺ 1).
[Example 761]
2-{[4- (2-{[5- (dimethylamino) pyrimidin-2-yl] [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole- 2-yl] thio} -2-methylpropionic acid

2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The same operation as in Example 442-1 was performed using propionic acid tert-butyl ester and 4- (chloromethyl) -1-phenyl-1H-pyrazole synthesized in Reference Example 18 as starting materials. Using the obtained compound and dimethylamine hydrochloride as starting materials, the same operation as in Example 442-2 (the solvent was changed to tert-butanol) was performed. The obtained compound was treated in the same manner as in Example 442-3 to give the title compound.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.62 (6H, s), 2.84 (6H, s), 3.09 (2H, t, J = 7.2 Hz), 3.90 (2H , T, J = 7.2 Hz), 4.67 (2H, s), 6.94 (1H, s), 7.22-7.28 (1H, m), 7.40-7.45 (2H) M), 7.65-7.68 (3H, m), 7.93 (1H, s), 8.09 (2H, s).
MS: 524 (M ⁺⁺ 1).
[Example 762]
2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(3-methyl-5-phenyl-isoxazol-4-yl) methyl] amino} ethyl) -1,3-thiazol-2 -Yl] thio} -2-methylpropionic acid

2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained in the same manner as in Example 326, using propionic acid tert-butyl ester and 4- (chloromethyl) -3-methyl-5-phenyl-isoxazole as starting materials.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.22 (3H, t, J = 7.5 Hz), 1.59 (6H, s), 2.21 (3H, s), 2.50 (2H , Q, J = 7.5 Hz), 2.85 (2H, t, J = 7.4 Hz), 3.66 (2H, t, J = 7.4 Hz), 4.92 (2H, s), 6 .64 (1H, s), 7.44-7.46 (3H, m), 7.63-7.67 (2H, m), 8.21 (2H, s).
MS: 524 (M ⁺⁺ 1).
[Example 763]
2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(5-phenyl-1,3-oxazol-4-yl) methyl] amino} ethyl) -1,3-thiazole-2 -Yl] thio} -2-methylpropionic acid

2-[(4- {2-[(5-Ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 265-1 The title compound was obtained by the same procedures as in Example 326 using propionic acid tert-butyl ester and 4- (chloromethyl) -5-phenyl-1,3-oxazole as starting materials.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.19 (3H, t, J = 7.5 Hz), 1.65 (6H, s), 2.46 (2H, q, J = 7.5 Hz) , 3.07 (2H, t, J = 6.9 Hz), 3.93 (2H, t, J = 6.9 Hz), 4.94 (2H, s), 6.86 (1H, s), 7 .32-7.38 (3H, m), 7.65-7.68 (2H, m), 7.95 (1H, s), 8.13 (2H, s).
MS: 510 (M ⁺⁺ 1).
[Example 764]
2-Methyl-2-[(4- {2-[(5-morpholin-4-ylpyrimidin-2-yl) (pentyl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 442 using propionic acid tert-butyl ester and pentyl iodide as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.89 (3H, t, J = 6.6 Hz), 1.26-1.32 (4H, m), 1.55 (2H, brs), 1 .65 (6H, s), 2.98-3.00 (4H, m), 3.09 (2H, t, J = 7.2 Hz), 3.45 (2H, t, J = 7.2 Hz) 3.84-3.88 (6H, m), 6.95 (1H, s), 8.09 (2H, s).
MS: 480 (M ⁺⁺ 1).
[Example 765]
2-[(4- {2- [Hexyl (5-morpholin-4-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 442 using propionic acid tert-butyl ester and hexyl iodide as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.85-0.88 (3H, m), 1.28 (6H, brs), 1.54 (2H, brs), 1.65 (6H, s ), 2.98-3.01 (4H, m), 3.09 (2H, t, J = 7.2 Hz), 3.45 (2H, t, J = 7.2 Hz), 3.84-3 .87 (6H, m), 6.96 (1H, s), 8.09 (2H, s).
MS: 494 (M ⁺⁺ 1).
[Example 766]
2-Methyl-2-[(4- {2-[(5-morpholin-4-ylpyrimidin-2-yl) (octyl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained by the same procedures as in Example 442 using propionic acid tert-butyl ester and octyl iodide as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.6 Hz), 1.26 to 1.27 (10H, m), 1.53-1.58 (2H, m), 1.65 (6H, s), 2.97-3.00 (4H, m), 3.09 (2H, t, J = 7.5 Hz), 3.45 (2H, t, J = 7.5 Hz), 3.83-3.88 (6H, m), 6.94 (1H, s), 8.09 (2H, s).
MS: 522 (M ⁺⁺ 1).
[Example 767]
2-Methyl-2-[(4- {2-[(5-morpholin-4-ylpyrimidin-2-yl) (nonyl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl synthesized in Example 162-1 The title compound was obtained in the same manner as in Example 442 using propionic acid tert-butyl ester and nonyl iodide as starting materials.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.87 (3H, t, J = 6.6 Hz), 1.26 (12H, brs), 1.54 (2H, brs), 1.65 (6H , S), 2.98-3.01 (4H, m), 3.09 (2H, t, J = 7.2 Hz), 3.45 (2H, t, J = 7.2 Hz), 3.84 -3.88 (6H, m), 6.95 (1H, s), 8.09 (2H, s).
MS: 536 (M ⁺⁺ 1).
[Example 768]
2-[(4- {2-[[5- (Dimethylamino) pyrimidin-2-yl] (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Tri Fluoroacetate

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio]-synthesized in Example 442-1 Using 2-methylpropionic acid tert-butyl ester and dimethylamine hydrochloride as starting materials, the compound obtained by the same procedure as in Example 442-2 (change the solvent to tert-butanol) was subjected to dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 10: 1) to give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.6 Hz), 1.26 to 1.29 (8H, m), 1.57 (2H, brs), 1 .62 (6H, s), 2.92 (6H, s), 3.10 (2H, t, J = 6.9 Hz), 3.51 (2H, t, J = 7.5 Hz), 3.92 (2H, t, J = 6.9 Hz), 7.05 (1H, s), 8.21 (2H, s).
MS: 466 (M ⁺⁺ 1).
[Example 769]
2-[(4- {2- [Heptyl (5-piperidin-1-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid trifluoro Acetate

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio]-synthesized in Example 442-1 Using 2-methylpropionic acid tert-butyl ester and piperidine as starting materials, the compound obtained by the same procedure as in Example 442-2 was subjected to dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 10: 1) to give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.6 Hz), 1.27-1.29 (8H, m), 1.56-1.59 (4H, m), 1.63 (6H, s), 1.85 to 1.88 (4H, m), 3.10 (2H, t, J = 7.2 Hz), 3.19 (4H, t, J = 5.4 Hz), 3.50 (2H, t, J = 7.7 Hz), 3.91 (2H, t, J = 7.2 Hz), 7.03 (1H, s), 8.36 (2H, s).
MS: 506 (M ⁺⁺ 1).
[Example 770]
2-{[4- (2- {Heptyl [5- (3-methoxypyrrolidin-1-yl) pyrimidin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2- Methylpropionic acid trifluoroacetate

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio]-synthesized in Example 442-1 Using 2-methylpropionic acid tert-butyl ester and 3-methoxypyrrolidine as starting materials, the compound obtained in the same manner as in Example 442-2 was subjected to dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 10: 1) to give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.88 (3H, t, J = 6.6 Hz), 1.26 to 1.29 (8H, m), 1.56 (2H, brs), 1 .62 (6H, s), 2.05-2.17 (2H, m), 3.09 (2H, t, J = 6.9 Hz), 3.28-3.53 (9H, m), 3 .91 (2H, t, J = 6.9 Hz), 4.10-4.11 (1H, m), 7.06 (1H, s), 8.02 (2H, s).
MS: 522 (M ⁺⁺ 1).
[Example 771]
2-[(4- {2-[[5- (Cyclopentylamino) pyrimidin-2-yl] (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid Tri Fluoroacetate

  2-[(4- {2-[(5-Bromopyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio]-synthesized in Example 442-1 Using 2-methylpropionic acid tert-butyl ester and cyclopentylamine as starting materials, the compound obtained in the same manner as in Example 442-2 was subjected to dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform: methanol = 10: 1) to give the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz) δ: 0.85-0.87 (3H, m), 1.28 (8H, brs), 1.55-1.78 (14H, m), 1.98 -2.04 (2H, m), 3.08 (2H, t, J = 7.2 Hz), 3.48 (2H, t, J = 7.5 Hz), 3.65-3.67 (1H, m), 3.88 (2H, t, J = 7.2 Hz), 7.01 (1H, s), 8.11 (2H, s).
MS: 506 (M ⁺⁺ 1).
[Pharmacological Test Example 1]
Plasma triglyceride (TG) and free fatty acid (FFA) lowering action in Zucker fatty rats Male Zucker fatty rat, a high TG model animal with insulin resistance (Japan Charles River, 10-24 weeks old, n = 4-5) The test was conducted using. Suspend a test compound or a control compound (Fenofibrate (isopropyl 2- [4- (4-chlorobenzoyl) phenoxy] -2-methylpropionate), purchased from Sigma-Aldrich) in 0.5 w / v% hydroxypropylmethyl cellurose (HPMC). The liquid prepared to a predetermined concentration was orally administered once a day for 4 days or 5 days. In addition, 0.5 w / v% HPMC was administered to the control group. After repeated administration, blood was collected from the tail vein under non-fasting conditions, and plasma was obtained by centrifugation (4 ° C., 3000 rpm × 10 min). Plasma TG was measured using Fuji Dry Chem (Fuji Film Medical), and FFA was measured using Determiner NEFA (Kyowa Medics).

  The results are shown in Table 28 to Table 31. From these results, it was clarified that the compound of the present invention exhibits an excellent plasma TG lowering action and an FFA lowering action in animals having insulin resistance as compared with the control group and the fenofibrate group.

  Mean ± SEM (n = 4-5). *: P <0.05, **: P <0.01 vs. control (Dunnett ’s method)

  Mean ± SEM (n = 5). *: P <0.05, **: P <0.01 vs. control (Dunnett ’s method)

  Mean ± SEM (n = 5). *: P <0.05, **: P <0.01 vs. control (Dunnett ’s method)

  Mean ± SEM (n = 5). *: P <0.05, **: P <0.01 vs. control (Dunnett ’s method).

[Pharmacological test example 2]
Serum HDL Cholesterol (HDL-C) Increase in Rats Treated with High Cholesterol Diet Male SD rats (Kudo, 8 weeks old) in standard diet CE-2 (Clea Japan) 1% cholesterol, 2% olive oil and 0.2% cholic acid The feed supplemented with was treated from 1 week before administration of the test compound until the end of administration. A test compound or a control compound (fenofibrate) was suspended in 0.5 w / v% HPMC, and a solution prepared to a predetermined concentration was orally administered once a day for 5 days. After repeated administration, blood was collected from the non-fasted jugular vein, and serum was obtained by centrifugation (4 ° C., 3000 rpm × 10 min). Serum HDL cholesterol was measured using Fuji Dry Chem (Fuji Film Medical). The rate of HDL-C increase is the value obtained by subtracting the average serum HDL-C concentration in the vehicle administration group (0.5 w / v% HPMC, n = 5) from the serum HDL-C concentration in the drug administration group (n = 5) It calculated by calculating | requiring the ratio with respect to the average serum HDL-C density | concentration of an administration group.

  The results are shown in Table 32. From these results, it was revealed that the compound of the present invention has an excellent serum HDL-C increasing action as compared with the fenofibrate group.

[Pharmacological test example 3]
Blood glucose and blood insulin lowering effect in 0b / ob mice Test compound 34 to 0.5 w / v% HPMC in male ob / ob mice (Nippon Charles River, 8 weeks old) with obesity, hyperglycemia and hyperinsulinemia The suspension and the liquid prepared to a predetermined concentration were orally administered once a day for 14 days. After completion of repeated administration, blood was collected from the non-fasted tail vein and plasma was obtained by centrifugation (4 ° C., 3000 rpm × 15 min). TG in plasma is Fuji Dry Chem (Fuji Film Medical), blood glucose level is glucose CII-Test Wako (Wako Pure Chemical Industries), insulin is ultrasensitive insulin measurement kit (Morinaga Biochemical Research Institute), FFA is Determiner NEFA (Kyowa Medics) ) Were used for measurement.

  Table 33 shows the results. From these results, it was clarified that the compound of the present invention has TG, FFA, blood glucose and insulin lowering effects in animals having obesity, hyperglycemia and hyperinsulinemia compared to the control group.

  Mean ± SEM (n = 7-8). *: P <0.05, **: P <0.01 vs. control (Dunnett ’s method)

  According to the present invention, a compound useful as a prophylactic and / or therapeutic agent for hyperlipidemia associated with diabetes can be provided.

  According to the present invention, a compound useful as a preventive and / or therapeutic agent for diabetic hyperlipidemia can be provided.

  ADVANTAGE OF THE INVENTION According to this invention, the compound useful as a prophylactic and / or therapeutic agent of hyperlipidemia for administering to the patient who shows hyperlipidemia complicated with diabetes can be provided.

  In addition, according to the present invention, a compound useful as a preventive and / or therapeutic agent for diabetes can be provided.

  In addition, this application was filed by claiming priority from Japanese Patent Application No. 2006-122804, which is incorporated by reference in its entirety.

Claims (18)

Formula (I ′) below

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom or an alkyl group, or R ¹ and R ² are bonded to each other to form a cycloalkyl group;
R ³ represents a hydrogen atom or an alkyl group;
R ⁴ represents a hydrogen atom, an alkyl group or an aryl group;
n represents an integer of 1 to 5;
Y represents an oxygen atom, a sulfur atom, —NR ⁵ —, —CONR ⁵ —, —NR ⁵ CO— or —NHCONR ⁵ — (wherein R ⁵ represents a hydrogen atom, an alkyl group, a cycloalkylalkyl group, an aryl group, an aryl group, An alkyl group, an arylalkenyl group, an aryloxyalkyl group, a heteroaryl group or a heteroarylalkyl group));
Z represents a cycloalkyl group, an aryl group, an arylalkyl group, an arylalkenyl group, an aryloxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
Of the above groups, each of the alkyl group, cycloalkyl group, cycloalkylalkyl group, aryl group, arylalkyl group, arylalkenyl group, aryloxyalkyl group, heteroaryl group or heteroarylalkyl group has a substituent. You may do it. And / or the prevention of hyperlipidemia associated with diabetes containing a carboxylic acid derivative containing a thiazole ring represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. Or a therapeutic agent. In the formula (I ′), n is an integer of 1 to 3, and Y is an oxygen atom, a sulfur atom, —NR ⁶ —, —CONR ⁶ —, —NR ⁶ CO— or —NHCONR ⁶ — (wherein R ⁶ represents a hydrogen atom, an alkyl group, a cycloalkylalkyl group, an arylalkyl group, an arylalkenyl group, an aryloxyalkyl group or a heteroarylalkyl group, and among these groups, an alkyl group, an arylalkyl group, an arylalkenyl group , An aryloxyalkyl group or a heteroarylalkyl group each may have a substituent), and Z may be a cycloalkyl group that may have a substituent or an aryl that may have a substituent. Carboxylic acid derivative containing thiazole ring which is a group, an arylalkyl group which may have a substituent or a heteroaryl group which may have a substituent The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to claim 1, comprising a body or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient. In formula (I ′), Y represents an oxygen atom, a sulfur atom, or —NR ⁷ — [wherein R ⁷ represents a hydrogen atom, an alkyl group, or —CH ₂ —W (wherein W represents an aryl group or a heteroaryl group. Show.) Of the above groups, the alkyl group, aryl group or heteroaryl group may have a substituent. Z is the following formula (II)

[Wherein, R ⁸ , R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a halogen atom, a haloalkyl group, a haloalkyloxy group, a cyano group, a nitro group, or —NR ^13. R ¹⁴ , —NR ¹⁵ COR ¹⁶ , —CONR ¹⁷ R ¹⁸ (wherein R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ may be the same or different and are each independently hydrogen; Represents an atom, an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group, or R ¹³ and R ¹⁴ , R ¹⁵ and R ¹⁶ are bonded to each other to form a carbon atom and a hetero atom; even when the have to form a good ^{heterocycle), -. oR 19, -COR} 20 or -C≡CR ²¹ (wherein R ^19, R ²⁰ and R ²¹ are respectively independently a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a) a heteroaryl group or a heteroaryl group.;
R ¹¹ represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a halogen atom, a haloalkyl group, a cyano group or a nitro group;
R ¹² represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group;
E ¹ represents an oxygen atom, a sulfur atom or —NR ²² — (wherein R ²² represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group or a heteroarylalkyl group). Indicates.
Of the above groups, each of the alkyl group, cycloalkyl group, cycloalkylalkyl group, aryl group, arylalkyl group, heteroaryl group, heteroarylalkyl group or heterocycle may have a substituent. A carboxylic acid derivative containing a thiazole ring represented by a substituent selected from the above or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. A prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes mellitus. In the formula (I ′), Y is an oxygen atom, a sulfur atom, or —NR ²³ — {wherein R ²³ is a hydrogen atom, an alkyl group which may have a substituent, or the following formula (III)

[Wherein, R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an arylcarbonyl group, a heteroaryl group, a halogen atom, a haloalkyl group, a haloalkyloxy group, —NR ²⁶ R ²⁷ , —NR ²⁸ COR ²⁹ , —CONR ³⁰ R ³¹ (wherein R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ and R ³¹ may be the same or different and are each independently a hydrogen atom) Represents an alkyl group, an aryl group or a heteroaryl group, or R ²⁶ and R ²⁷ , R ³⁰ and R ³¹ are bonded to each other to form a heterocycle which may have carbon and heteroatoms.) or a ^{-OR 32 (wherein, R 32} is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group A heteroaryl group or a heteroaryl group.) Shows a. Of the above groups, each of the alkyl group, cycloalkyl group, aryl group, arylalkyl group, heteroaryl group, heteroarylalkyl group and heterocycle may have a substituent. ] Is a substituent selected from the group consisting of the following formula (IV)

[Wherein, R ⁸ , R ⁹ and R ¹⁰ are as defined above. Any one of claims 1 to 3, comprising a carboxylic acid derivative containing a thiazole ring represented by a substituent selected from the group consisting of a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof as an active ingredient. A prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to any one of the above. (34) 2-[(4- {2-[(4′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(38) 2-[(4- {2-[(4′-chlorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(68) 2-[(4- {2-[(3′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(76) 2-[(4- {2-[(4′-fluorobiphenyl-4-yl) thio] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(79) 2-[(4- {2-[(3,4'-difluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(100) 2-{[4- (2-{[5- (4-Fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio-2-methylpropionic acid ,
(102) 2-Methyl-2-({4- [2-({5- [4- (trifluoromethyl) phenyl] pyridin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid,
(103) 2-Methyl-2-({4- [2-({5- [3- (trifluoromethyl) phenyl] pyridin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid,
(104) 2-Methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyridin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid,
(106) 2-{[4- (2-{[5- (4-Chlorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid ,
(107) 2-{[4- (2-{[5- (3-Chlorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid ,
(108) 2-{[4- (2-{[5- (3,4-Dichlorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid,
(109) 2-{[4- (2-{[5- (3-Chloro-4-fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio}- 2-methylpropionic acid,
(152) 2-methyl-2-{[4-({[4 '-(trifluoromethyl) biphenyl-4-yl] methoxy} methyl) -1,3-thiazol-2-yl] thio} propionic acid,
(162) 2-Methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid,
(220) 2-{[4- (2-{[6- (4-Chloro-2-fluorophenyl) pyridazin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio}- 2-methylpropionic acid,
(224) 2-({4- [2-({6- [2-Fluoro-4- (trifluoromethyl) phenyl] pyridazin-3-yl} amino) ethyl] -1,3-thiazol-2-yl } Thio) -2-methylpropionic acid,
(226) 2-{[4- (2-{[5- (4-Chlorophenyl) pyrazin-2-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid ,
(227) 2-[(4- {2-[[5- (4-Chlorophenyl) pyrazin-2-yl] (methyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2- Methyl propionic acid,
(229) 2-Methyl-2-({4- [2- (methyl {5- [4- (trifluoromethyl) phenyl] pyrazin-2-yl} amino) ethyl] -1,3-thiazole-2- Il} thio) propionic acid,
(231) 2-Methyl-2-({4- [2- (methyl {5- [4- (trifluoromethoxy) phenyl] pyrazin-2-yl} amino) ethyl] -1,3-thiazole-2- Il} thio) propionic acid,
(232) 2-({4- [2-({5- [2-Fluoro-4- (trifluoromethyl) phenyl] pyrazin-2-yl} amino) ethyl] -1,3-thiazol-2-yl } Thio) -2-methylpropionic acid,
(243) 2-Methyl-2-({4- [2-({5- [4- (trifluoromethyl) phenyl] pyridin-2-yl} amino) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid,
(260) 2-{[4- (2-{[6- (4-Chlorophenyl) pyridin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid ,
(261) 2-Methyl-2-({4- [2-({6- [4- (trifluoromethyl) phenyl] pyridin-3-yl} amino) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid,
(265) 2-[(4- {2-[(5-ethylpyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(267) 2-[(4- {2- [heptyl (5-propylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(319) 2-[(4- {2- [3- (2,4-Difluorophenyl) -1-heptylureido] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid ,
(320) 2-({4- [2- (3-cyclohexyl-1-peptylureido) ethyl] -1,3-thiazol-2-yl} thio) -2-methylpropionic acid,
(326) 2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole- 2-yl] thio} -2-methylpropionic acid,
(329) 2-[(4- {2-[(5-ethylpyrimidin-2-yl) (hexyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(346) 2-{[4- (2-{(5-Ethylpyrimidin-2-yl) [(2E) -3-phenylprop-2-en-1-yl] amino} ethyl) -1,3- Thiazol-2-yl] thio} -2-methylpropionic acid,
(379) 2-[(4- {2-[(3-Butoxypropyl) (5-ethylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid,
(430) 2-methyl-2-[(4- {2-[[(1-phenyl-1H-pyrazol-4-yl) methyl] (5-propylpyrimidin-2-yl) amino] ethyl} -1, 3-thiazol-2-yl) thio] propionic acid,
(442) 2-[(4- {2- [Heptyl (5-morpholin-4-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropion acid,
(449) 2-[(4- {2-[(3-Ethyl-1H-pyrazol-5-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid, and (450) 2-[(4- {2- [heptyl (3-propyl-1H-pyrazol-5-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2 5. A carboxylic acid derivative containing a thiazole ring selected from -methylpropionic acid, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. A prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes mellitus. In formula (I ′), Y is an oxygen atom, and Z is a carboxylic acid derivative containing a thiazole ring represented by an aryl group or a heteroaryl group, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to claim 1, comprising a product as an active ingredient. In formula (I ′), Y is an oxygen atom, Z is a carboxylic acid derivative containing a thiazole ring represented by an aryl group, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. 7. A prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to claim 1 or 6 which is contained as follows. (34) 2-[(4- {2-[(4′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(38) 2-[(4- {2-[(4′-chlorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(68) 2-[(4- {2-[(3′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(76) 2-[(4- {2-[(4′-fluorobiphenyl-4-yl) thio] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(79) 2-[(4- {2-[(3,4'-difluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(100) 2-{[4- (2-{[5- (4-Fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio-2-methylpropionic acid ,
(102) 2-Methyl-2-({4- [2-({5- [4- (trifluoromethyl) phenyl] pyridin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid,
(103) 2-Methyl-2-({4- [2-({5- [3- (trifluoromethyl) phenyl] pyridin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid,
(104) 2-Methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyridin-2-yl} oxy) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid,
(106) 2-{[4- (2-{[5- (4-Chlorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid ,
(107) 2-{[4- (2-{[5- (3-Chlorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methylpropionic acid ,
(108) 2-{[4- (2-{[5- (3,4-Dichlorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio} -2-methyl Propionic acid,
(109) 2-{[4- (2-{[5- (3-Chloro-4-fluorophenyl) pyridin-2-yl] oxy} ethyl) -1,3-thiazol-2-yl] thio}- 2-methylpropionic acid,
(152) 2-methyl-2-{[4-({[4 '-(trifluoromethyl) biphenyl-4-yl] methoxy} methyl) -1,3-thiazol-2-yl] thio} propionic acid,
(162) 2-Methyl-2-({4- [2-({5- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amino) ethyl] -1,3-thiazol-2-yl } Thio) propionic acid,
(220) 2-{[4- (2-{[6- (4-Chloro-2-fluorophenyl) pyridazin-3-yl] amino} ethyl) -1,3-thiazol-2-yl] thio}- 2-methylpropionic acid, and (224) 2-({4- [2-({6- [2-fluoro-4- (trifluoromethyl) phenyl] pyridazin-3-yl} amino) ethyl] -1, A carboxylic acid derivative containing a thiazole ring selected from 3-thiazol-2-yl} thio) -2-methylpropionic acid, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to any one of claims 1, 6, and 7. In formula (I ′), Y is —NR ^5a — (wherein R ^5a represents an alkyl group having 4 to 10 carbon atoms), and Z is a carboxylic acid containing a thiazole ring represented by a heteroaryl group. The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to claim 1, comprising a derivative or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient. In formula (I ′), Y represents —NR ^5b — (wherein R ^5b represents an alkyl group having 6 to 9 carbon atoms), and Z represents a carboxylic acid containing a thiazole ring represented by a heteroaryl group. 10. A prophylactic and / or therapeutic agent for hyperlipidemia associated with diabetes according to claim 1 or 9, comprising a derivative or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient. . (265) 2-[(4- {2-[(5-ethylpyrimidin-2-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(267) 2-[(4- {2- [heptyl (5-propylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(329) 2-[(4- {2-[(5-ethylpyrimidin-2-yl) (hexyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid,
(442) 2-[(4- {2- [Heptyl (5-morpholin-4-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropion acid,
(449) 2-[(4- {2-[(3-Ethyl-1H-pyrazol-5-yl) (heptyl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methyl Propionic acid,
(450) 2-[(4- {2- [Heptyl (3-propyl-1H-pyrazol-5-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid A carboxylic acid derivative containing a thiazole ring selected from the above, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient. A prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes mellitus. In formula (I ′), Y is —NR ^5c — (wherein R ^5c represents an arylalkyl group or a heteroarylalkyl group), and Z is a carboxylic acid containing a thiazole ring represented by a heteroaryl group. The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to claim 1, comprising a derivative or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient. In formula (I ′), Y is —NR ^5d — (wherein R ^5d represents a heteroarylalkyl group), and Z is a carboxylic acid derivative containing a thiazole ring represented by a heteroaryl group or a drug thereof The prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to claim 1 or 12, comprising the above-acceptable salt or a hydrate or solvate thereof as an active ingredient. (326) 2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole- 2-yl] thio} -2-methylpropionic acid, and (430) 2-methyl-2-[(4- {2-[[(1-phenyl-1H-pyrazol-4-yl) methyl] (5- Carboxylic acid derivatives containing a thiazole ring selected from propylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] propionic acid, or a pharmaceutically acceptable salt thereof, or a hydrate thereof Alternatively, the prophylactic and / or therapeutic drug for hyperlipidemia associated with diabetes according to any one of claims 1, 12, or 13, comprising a solvate as an active ingredient. (34) 2-[(4- {2-[(4′-fluorobiphenyl-4-yl) oxy] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropionic acid A prophylactic and / or therapeutic agent for hyperlipidemia associated with diabetes, comprising a thiazole ring-containing carboxylic acid derivative or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient. (442) 2-[(4- {2- [Heptyl (5-morpholin-4-ylpyrimidin-2-yl) amino] ethyl} -1,3-thiazol-2-yl) thio] -2-methylpropion Prevention and / or treatment of hyperlipidemia associated with diabetes containing a carboxylic acid derivative containing a thiazole ring represented by an acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient medicine. (326) 2-{[4- (2-{(5-ethylpyrimidin-2-yl) [(1-phenyl-1H-pyrazol-4-yl) methyl] amino} ethyl) -1,3-thiazole- Combining with diabetes containing a carboxylic acid derivative containing a thiazole ring represented by 2-yl] thio} -2-methylpropionic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient For preventing and / or treating hyperlipidemia. Formula (I ')

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom or an alkyl group, or R ¹ and R ² are bonded to each other to form a cycloalkyl group;
R ³ represents a hydrogen atom or an alkyl group;
R ⁴ represents a hydrogen atom, an alkyl group or an aryl group;
n represents an integer of 1 to 5;
Y represents an oxygen atom, a sulfur atom, —NR ⁵ —, —CONR ⁵ —, —NR ⁵ CO— or —NHCONR ⁵ — (wherein R ⁵ represents a hydrogen atom, an alkyl group, a cycloalkylalkyl group, an aryl group, an aryl group, An alkyl group, an arylalkenyl group, an aryloxyalkyl group, a heteroaryl group or a heteroarylalkyl group));
Z represents a cycloalkyl group, an aryl group, an arylalkyl group, an arylalkenyl group, an aryloxyalkyl group, a heteroaryl group or a heteroarylalkyl group.
Of the above groups, each of the alkyl group, cycloalkyl group, cycloalkylalkyl group, aryl group, arylalkyl group, arylalkenyl group, aryloxyalkyl group, heteroaryl group or heteroarylalkyl group has a substituent. You may do it. ] The preventive and / or therapeutic agent of diabetes which contains the carboxylic acid derivative containing the thiazole ring represented by these, its pharmaceutically acceptable salt, or those hydrates or solvates as an active ingredient.