TW201039827A - Indoline compound - Google Patents

Abstract

The present invention provides a compound or pharmaceutically acceptable salt thereof having novel structure and having excellent effect to lower blood glucose. The compound or pharmaceutically acceptable salt thereof is represented by the general formula (I):

Description

201039827 VI. Description of the Invention: [Technical Field] The present invention relates to a novel porphyrin compound having a hypoglycemic effect or a pharmaceutically acceptable salt thereof, and a compound containing the same or a pharmaceutically acceptable salt thereof A pharmaceutical composition as an active ingredient. [Prior Art] Diabetes is a metabolic disease characterized by chronic hyperglycemia caused by insufficient insulin action. In the treatment of diabetes, in general, drug therapy is administered concurrently with food therapy and exercise therapy. As an oral hypoglycemic agent for the treatment of diabetes, a guanidine-urea agent which promotes insulin resistance and a secretion of insulin from pancreatic β-cells is generally used as a biguanide agent or a thiazolidinedione which improves insulin resistance. Or a ginide-based drug, an α-glucosidase inhibitor that inhibits sugar absorption, and the like. However, it has been reported that bismuth steroids have lactic acidosis, thiazolidinedione has weight gain and edema, sulfonyl urea and glibenclamide have hypoglycemia or two times due to long-term use, (X-glucose) The glucosidase inhibitor has a Q side effect such as sputum, etc. Therefore, development of an oral hypoglycemic agent which is expected to solve such problems is being developed. In recent years, a pyridyl compound having a new structure, piperidine-1-carboxylic acid, is also being developed. An ester compound or the like is used as an oral hypoglycemic agent (for example, refer to Patent Documents 1 to 5, etc.). PRIOR ART DOCUMENT PATENT DOCUMENT Patent Document 1 International Publication No. 05/7647 Booklet Document 2 International Publication No. 05/121121 Patent Document 3 International Publication No. 06/83491 Booklet 201039827 Patent Document 4 International Publication No. 07/3 962 Booklet Patent Document 5 International Publication No. 9/51119 Booklet [Invention] The invention is to be solved by the invention However, the compounds described in the above Patent Documents 1 to 4 have a problem that it is difficult to obtain a sufficient blood sugar lowering action. On the other hand, Patent Document 5 discloses a porphyrin compound, but The patent document disclosed before the priority date is 0. The present invention provides a compound having the novel structure which is not described or suggested in the above Patent Documents 1 to 4 and which has excellent hypoglycemic action or a pharmaceutical thereof. The above-mentioned salt and the pharmaceutical composition having excellent therapeutic effects and/or preventive effects such as type 1 diabetes and type 2 diabetes which are caused by an increase in blood sugar abnormality due to abnormal glucose metabolism. = (1) A compound represented by the general formula (I) or a pharmaceutically acceptable Q salt thereof:

Wherein R1 is -S(0)-Rn, -S(0)2-Ru, -S(NH)(0)-R" or -C(0)-NR12R13; R11 is Cl~C6 alkyl ; 201039827

Rl2 or R13 are each independently a hydrogen atom, or may have *(a) a C1 to C6 alkyl group selected from the substituent group of the substituent group, or r12 and r13 together with the nitrogen atom bonded thereto form a morphine Substituent _α is a group consisting of a halogen atom, a meridine, and a C1 to C6 alkoxy group; m is an integer of 〇~5; r2 is the same or a different halogen atom; η is an integer of 0 to 4; R3 is a same or different halogen atom R4 is -C(0)-0-R4i, may have 丨~3 phenyl groups selected from substituents of substituent group p, may have one selected from substituent group 0 a pyridyl group of a substituent, or a pyrimidinyl group which may have a substituent selected from the substituent group p; R41 is a C1 to C6 substituent group which may be substituted by a halogen atom; and the substituent group β is a halogen atom and may pass through a halogen atom a group of C1 to C6 substituted groups, a C1-C6 alkoxy group which may be substituted by a halogen atom, and a cyano group; X is CH or hydrazine; 〇Υ is CH or Ν; Ζ is 0 or NR5; R5 is a hydrogen atom Or a C1-C6 alkyl group; however, where X and Υ are both Ν, Ζ is 〇, and _c(〇)_〇_R4i, R1 is -SiNHKCO-R11 or -C(〇)_NRi2Ri3]. (2) A compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein R1 is 4(0)-1111. (3) A compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein R1 is -SCOh-R11. (4) The compound according to the above (2) or (3), wherein R11 is a C1 to C3 alkyl group, or a pharmaceutically acceptable salt thereof. (5) A compound according to the above (2) or (3), or a pharmaceutically acceptable salt thereof, wherein R11 is a methyl group. (6) The compound of the above (1) or a pharmaceutically acceptable salt thereof, R1, is -C(0)-NR12R13. (7) The compound of the above (6) or a pharmaceutically acceptable salt thereof, R12 or R13, each independently a hydrogen atom or a C1 to C3 which may have 1 to 3 substituents selected from the substituent 0 group α alkyl. (8) The compound according to the above (6) or a pharmaceutically acceptable salt thereof, each of R12 or R13 is independently a hydrogen atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group C1-C3 alkyl group, or a hydroxyl group C1~ C3 alkyl or dihydroxy C1 to C3 alkyl. (9) The compound according to the above (6) or a pharmaceutically acceptable salt thereof, each of R12 or R13 is independently a hydrogen atom, a methyl group, -(CH2)2OCH3, -(ch2)2oh, -(ch2)3oh, -ch2ch(ch3)oh, -ch(ch3)ch2oh or -ch2ch(oh)ch2oh. The compound of the above (6) or a pharmaceutically acceptable salt thereof, R12 and R13, together with the nitrogen atom to which they are bonded, form a morpholinyl group. (11) A compound according to any one of the above (1) to (10), or a pharmaceutically acceptable salt thereof, wherein m is hydrazine or 1. (1) The compound according to any one of the above (1) to (1), or a pharmaceutically acceptable salt thereof, wherein m is hydrazine. (13) As in the above (1) to (10)! The compound of the formula or a pharmaceutically acceptable salt thereof, wherein m is 1, and R2 is a fluorine atom. (1) The compound according to any one of the above (1) to (1), or a pharmaceutically acceptable salt thereof, wherein η is 0 or 1. (1) The compound according to any one of the above (1) to (1), or a pharmaceutically acceptable salt thereof, wherein η is 0. (1) The compound according to any one of the above (1) to (1), or a pharmaceutically acceptable salt thereof, wherein η is 1 and R3 is a fluorine atom. (1) The compound according to any one of the above (1) to (16), or a pharmaceutically acceptable salt thereof, wherein R4 is a phenyl group which may have one substituent selected from the substituent group β, and may have 1 a pyridyl group selected from a substituent of the substituent group 0, 0 or a pyrimidinyl group which may have one substituent selected from the substituent group β. (1) The compound according to any one of the above (1) to (16), or a pharmaceutically acceptable salt thereof, wherein R4 is a pyridyl group which may have one substituent, and the substituent is selected from a halogen atom. A group consisting of a C1 to C3 alkyl group substituted by a halogen atom and a C1-C3 alkoxy group which may be substituted by a halogen atom. (19) The compound according to any one of the above (1) to (16) or a pharmaceutically acceptable salt thereof, wherein R4 is a pyridyl group which may have one substituent, and the substituent is selected from a fluorine atom, A A group consisting of ethyl, ethyl, propyl, isopropyl, trifluoromethylhydrazine and methoxy. (20) The compound according to any one of the above (1) to (6), or a pharmaceutically acceptable salt thereof, is a pyrimidyl group which may have one substituent, and the substituent is selected from a halogen atom. A group consisting of a C1 to C3 alkyl group which may be substituted by a halogen atom and a C1 to C3 alkoxy group which may be substituted by a halogen atom. (2) The compound according to any one of the above items (1) to (1), or a pharmaceutically acceptable salt thereof, is a pyrimidyl group which may have one substituent, and the substituent is selected from a fluorine atom. a group consisting of methyl, ethyl, propyl, isopropyl, trifluoromethyl and methoxy. The compound of any one of the above (1) to (16) or a pharmaceutically acceptable salt thereof, wherein R4 is -C(0)-0-R41. (23) A compound according to the above (22) or a pharmaceutically acceptable salt thereof, wherein R41 is a C1 to C3 alkyl group which may be substituted by a halogen atom. (24) A compound according to the above (22), wherein R41 is an ethyl group which may be substituted by a fluorine atom, or an isopropyl group which may be substituted with a fluorine atom, or a pharmaceutically acceptable salt thereof. (25) A compound according to any one of the above (1) to (24) or a pharmaceutically acceptable salt thereof, wherein X is N and Y is N. (26) A compound according to any one of the above (1) to (25), or a pharmaceutically acceptable salt thereof, wherein Z is 0. (27) A compound selected from the group consisting of pharmaceutically acceptable salts thereof: 1-(2-{[1-(5-ethylpyridin-2-yl)piperidin-4-yl]oxy Pyridyl-4-yl)-5-(methylsulfonyl)porphyrin; 1-(6-{[1-(5-ethylpyridin-2-yl)piperidin-4-yl]oxy }}pyrimidin-4-yl)-5-(methylsulfonyl)porphyrin; Q 1-(6-{[1-(5-isopropylpyridin-2-yl)piperidin-4-yl ]oxy}pyrimidine_4_yl)-5-(methylsulfonyl)porphyrin; 1-(6-{[1_(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy 5-(pyridin-4-yl)-5-(methylsulfinyl)porphyrin; 1-(6-{[1-(5-isopropylpyrimidin-2-yl)piperidin-4-yl ]oxy}pyrimidine_4_yl)-5-(methylsulfonyl)porphyrin; 1-(6-{[1-(5-trifluoromethylpyridin-2-yl)piperidine_4_ Methoxy]pyrimidin-4-yl)-5-(methylsulfonyl)indole;

I 1-(6-{[1-(5-methoxypyridin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-5-(methylsulfonyl)porphyrin 1-(6-{[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N-(2-methoxyethyl)indole Porphyrincarboxylic acid 201039827 amine; 1-(6-{[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N-(2-hydroxyethyl Porphyrin-5-carbamide; 1-(6-{[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N -[(2S)-2-hydroxypropyl]porphyrin-5-carboxamide; 1-(6-{[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy Pyrimidine-4-yl)-N-[(2R)-2-hydroxypropyl]porphyrin-5-carboxamide; and 1-(6-{[1-(5-ethylpyrimidine-2) -yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N-(2-hydroxyethyl)-N-methylporphyrin-5-carboxamide. (28) A pharmaceutical composition comprising the compound according to any one of the above items (1) to (27) or a pharmaceutically acceptable salt thereof as an active ingredient. (29) A pharmaceutical composition according to the above (28) for use in the treatment and/or prevention of type 1 diabetes, type 2 diabetes, diabetes related diseases or obesity. (30) The use of the compound according to any one of the above (1) to (27), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical composition. (31) A method for treating and/or preventing a disease, comprising administering a pharmacologically effective amount of the compound according to any one of the above (1) to (27) or a pharmaceutically acceptable salt thereof to a mammal; The method of (31), wherein the mammal is a human. Advantageous Effects of Invention According to the present invention, a porphyrin compound having an excellent hypoglycemic action, or a pharmaceutically acceptable salt thereof, and an excellent therapeutic effect and/or prevention for type 1 diabetes, type 2 diabetes, etc. which cause an increase in sugar can be provided. The pharmaceutical composition of the effect. [Embodiment] In order to carry out the invention, in the present specification, "C1 to C6 alkyl group" means a straight chain of a polymer having a carbon number of 1 to 6 201039827. Specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a second butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group and the like. The term "halogen atom" as used herein means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The term "C1 to C6 alkoxy group" as used herein means a group in which the above-mentioned "C1 to C6 alkyl group" is bonded to an oxygen atom. Specific examples thereof include a methoxy group, an ethoxy group 'propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group and the like. In the present specification, the term "pharmaceutically acceptable salt" means a salt formed by reacting a compound of the present invention with an acid. Examples of the salt include hydrogen halides such as hydrofluoric acid salts, hydrochloride salts, hydrobromide salts, and hydroiodides; and inorganic salts such as hydrochlorides, nitrates, perchlorates, sulfates, and phosphates. Acid salt; lower alkanesulfonate such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; arylsulfonate such as besylate or p-toluenesulfonate; acetate 'malic acid Salts, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, maleates, and the like. The compound of the present invention represented by the general formula (I) is hydrated, for example, by being placed in the atmosphere to absorb water and adhere to adsorbed water. Such a hydrate is also included in the salt of the present invention. The compound of the present invention represented by the general formula (I) has an optical isomer in the case where an asymmetric carbon atom is present in the molecule. These isomers and mixtures of such isomers are all represented by a single formula, i.e., represented by the general formula (I). Accordingly, the compound of the present invention represented by the general formula (I) contains all of a mixture of optical isomers and optical isomers in any ratio. -10-201039827 One or more of the atoms of the present invention or the compound constituting the present invention may include a compound substituted with an isotope of its atom. The isotope contains two types of radioisotopes and stable isotopes. Examples of isotopes include, for example, hydrogen isotopes (2H and 3H), carbon isotopes (Mc, 13c, and 14c), and nitrogen isotopes (13n and 15n). , oxygen isotope (15 〇, 17 〇 and 18 〇), fluorine isotope (18F) and so on. The composition containing the compound labeled with an isotope is used as, for example, a therapeutic agent, a prophylactic agent, a test drug, an analytical test drug, a diagnostic agent, an in vivo imaging diagnostic agent, and the like. The isotopically-labeled compound also includes a compound of the present invention, and a mixture of any of the isotopically-labeled compounds is also included in the compound of the present invention. Thus, the compounds of the present invention identified by isotopes can be produced by a method known in the art, for example, in the production method of the present invention described later, using an isotope-labeled starting material instead of a raw material. R1 is preferably -S(0)-Rn, 4(0)2-1111 or -C(0)-NR12R13. R11 is preferably a Cl~C3 alkyl group, more preferably a methyl group. R12 is preferably a hydrogen atom or a C1 to C3 alkyl group which may have 1 to 3 substituents selected from the substituent group α, more preferably a hydrogen atom, a C1 to C3 alkyl group, a hydroxyl group C1 to C3 alkyl group or C1. More preferably, the C3 alkoxy C1 to C3 alkyl group is a hydrogen atom, a methyl group, a 2-hydroxyethyl group or a 2-hydroxypropyl group. R13 is preferably a hydrogen atom or a C1 to C3 alkyl group which may have 3 to 3 substituents selected from the substituent group α, more preferably a hydrogen atom, a C1 to C3 alkyl group, a hydroxyl group C1 to C3 alkyl group or C1~ The C3 alkoxy group is a C1 to C3 alkyl group, more preferably a hydrogen atom, a methyl group, a 2-hydroxyethyl group or a 2-hydroxypropyl group. Further, it is also preferred that R12 and R13 together with the nitrogen atom to which they are combined form a wheylin. m is preferably 0 or 1. R2 is preferably a fluorine atom. -11- 201039827 η is preferably 0 or 1. R3 is preferably a fluorine atom. R4 is preferably a phenyl group which may have one substituent selected from the substituent group β, a pyridyl group which may have one substituent selected from the substituent group 、, or may have i selected from the substituent group β. The pyrimidyl group of the substituent is more preferably a substituent which may have a group consisting of a halogen atom, a C1 to C3 group which may be substituted by a halogen atom, and a C1 to C3 alkoxy group which may be substituted by a g atom. a pyridyl group; or a pyrimidyl group which may have a substituent selected from the group consisting of a halogen atom, a C1 to C3 alkyl group which may be substituted by a halogen atom, and a C1 to C3 alkoxy group which may be substituted by a halogen atom, and further a pyridyl group which may have a substituent selected from the group consisting of a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a trifluoromethyl group and a methoxy group; and may have one selected from a fluorine atom. a pyrimidinyl group having a substituent of a group consisting of a methyl group, an ethyl group, a propyl group, an isopropyl group, a trifluoromethyl group, and a methoxy group. R41 is preferably a C1 to C3 alkyl group which may be substituted by a halogen atom, more preferably an ethyl group which may be substituted by a fluorine atom, or an isopropyl group which may be substituted by a fluorine atom. X is preferably N° Y is preferably N. More preferably, X is N, and Y is 〇, preferably 〇. However, when ζ is 0 and R4 is -C(0)-0-R41, R1 is -SCNHKCO-R11 or -C(0)-NR12R13. R5 is preferably a hydrogen atom or a C1 to C3 alkyl group, more preferably a methyl group. The preferred combination of substituents in the compounds of the invention represented by the general formula (I) is: 111 is -8(0)-1111, -8(0)2-11" or -(:(0)411121113,111 is 0, η is 0, and R4 is a pyridyl group which may have one substituent selected from the substituent group β, or a pyrimidyl group which may have one substituent selected from the substituent group β, and X is CH or ruthenium, Υ Ν, and Ζ is a combination of 。. A combination of preferred substituents is iR1 is -S(0)2-RM, m is 〇, η is 0, -12-201039827 R is one having one substituent selected from a pyridyl group of a substituent of the group β, χ is CH' Y is Ν, and Ζ is a combination of Ο; melon is 〇, η is 0, and R is a pyridyl group which may have one substituent selected from the substituent group p , X is a combination of Ν 'Υ is Ν' and Ζ is 〇; 〇, η is O'R is a sprayed steep group which may have one substituent selected from the substituent group β, X is Ν, Υ is Ν 'and Ζ is a combination of ,, and 111 is _3(〇)_1111, m is 0, η is 0, and R4 is a pyrimidyl group 'X which may have one substituent selected from the substituent group β, X, Υ Is Ν, and Ζ is a combination of ;; R1 is Q -C(〇)-Nr12r13 '111 is 0, η is 0, and R4 is exemplified to have i selected from substituents a pyrimidyl group of a substituent of group β, X is hydrazine, γ is N, and hydrazine is a combination of hydrazine. Further preferred combinations of substituents are: R1 is methylsulfonyl, m is 0, and η is 0. R4 is a pyridyl group having 1 C1 to C6 alkyl group as a substituent, X is a combination of CH' Υ and Ζ, and Ζ is 0; R1 is methylsulfonyl, „1 is 0, η is 0, R4 A combination of a pyridine Q group having a C1 to C6 alkyl group which may be substituted by a halogen atom or a C1 to C6 alkoxy group which may be substituted by a halogen atom, X is N, Y is N, and Z is 0. R1 is a methylsulfinyl group, m is 0, η is 0, R4 is a pyrimidinyl group having 1 C1 to C6 alkyl group as a substituent, X is N, Y is N, and Z is a combination of ruthenium; R1 is -C(0)-NH-(CH2)2-0CH3, -C(0)-NH-(CH2)2-0H, -C(0)-NH-CH2CH2(CH3)-0H, m is 0 , η is 0, and R4 is a combination of a pyrimidyl group X having one substituent selected from the substituent group β, wherein X is N and Z is ruthenium. The compound of the present invention can be, for example, the following A~ Manufactured by the F method. Further, the porphyrin intermediate, the benzene intermediate, the pyridine system, the-13-201039827, and the pyrimidine system in the following production methods Interstitial and piperidine-based intermediates, for example, J. Med. Chem, 41, 1 998, 1 5 98- 1 6 1 2, Bioorg. Med. Chem. Lett., 2002, 12, 3105-3110, Chem Pharm. Bull·, 1993, 41, 529-538, J. Org Chem., 53, (1 98 8), 2047-2052, WO2003/47586, WO2006/76243, W02009/5 1 1 1 9 etc. . Further, as the above respective intermediates, commercially available porphyrin derivatives, benzene derivatives, pyridine derivatives, pyrimidine derivatives and piperidine derivatives can also be used. In the case where it is necessary to post-process each method, for example, it is preferable to perform post-processing in the following order. Water is added to the reaction mixture, and the product is extracted with an organic solvent such as ethyl acetate. The obtained organic layer is washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate and sodium sulfate. Next, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel chromatography or washed with an organic solvent, water, or the like. In the method A, the compound of the present invention can be produced in the general formula (I), X and Y are both N, Z is 0, and R1 is 4 (0)-1111 or 4 (0) 2-1111, or Formula (I), any of X and Y is N, the other is CH, Z is 0, and R1 is a compound of the invention of 4(0)-1111 or -S(0)2-Rn. In the QB method, the compound of the present invention can be produced in the general formula (I), X and Y are both N, z is NR5, and R1 is 4(0)-1111 or -SWh-R11, or in the general formula ( I), X and Y are those of the invention wherein N is the other, CH is Z, and R1 is -S(0)-Rn or -S(0)2-Rm. In the C method, the compound of the present invention can be produced by the formula (I) wherein both X and Y are CH, Z is fluorene, and R1 is -S(0)-Ru or -SiOh-R11. In the D method, the compound of the present invention can be produced by the formula (1) wherein both X and Y are CH, Z is NR5, and R1 is -S(0)-Rn or 4(0)2-1111. In the E method, a compound of the invention of the present invention can be produced by the general formula (I), and R1 is -SWHNHhR11. In the F method, a compound of the present invention which is of the general formula (I) and wherein R1 is -C(0)-NR12R13 can be produced. The description of each step in the A to F method will be described below. Method A

(where '8 and Ya are both Ν' or either is N, and the other is CH, the ruler is -3 (0)-foot" or - SCOh-R11, m, n, R" , r2, r3 and R4 are as defined above. The AI step is to produce a compound (3) by reacting a compound (?) with a compound (2) in the presence of a base. 〇 (4) (4) (4) Agent 'For example, tetrahydrofuran (THF), 1 , 4-dioxane, cyclopentyl methyl ether, dimethylformamide (DMF), dimethylacetamide, etc., preferably THF or DMF. As a base to be used, for example, third butoxide Potassium, sodium butoxide, carbonic acid planing, potassium carbonate, sodium hydride, N,N-diisopropylethylamine, etc., preferably potassium second potassium hydride, sodium hydride or N, N _ Isopropylethylamine. The reaction temperature is 0 to 150 ° C ' preferably 20 to 130 ° C. The reaction time is 30 minutes to 24 hours ' preferably 3 minutes to 6 hours. The A-Π step is The step of producing the compound (la) of the present invention by reacting the compound (3) obtained in the step A-Ι with the compound (4) by a Buchwald-Hartwig reaction using a palladium catalyst of -15 to 201039827. Catalyst, ligand The base and the reaction conditions are not particularly limited as long as they can be used for the reagents and conditions of the usual Buchwald-Hartwig reaction, and are described, for example, in AR Muci, SL Buchwald, Top. Curr. Chem. 2002, 219, p. Preferably, the palladium catalyst is palladium (II) acetate or palladium (yttrium) dibenzylideneacetone, more preferably palladium (II) acetate. 0 The preferred ligand is tricyclohexylphosphine, 1,3-double (phenylphosphonic acid) propane, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, 2-(dicyclohexylphosphonic acid)biphenyl or 2-dicyclohexyl Phosphono-2'-(N,N-dimethylamino)biphenyl, more preferably 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl. The base is sodium carbonate, potassium carbonate, carbonic acid planing, sodium third butoxide or potassium third butoxide, more preferably potassium carbonate. The preferred solvent is toluene or 1,4-dioxane, more preferably 1 , 4-dioxane. The reaction temperature is preferably from 20 to 150 ° C. The reaction time is preferably from 30 minutes to 12 〇 hours. -16 - 201039827 B method

(1)

(wherein Q is a halogen atom, m, n, Rla, R2, R4, R5,

Xa and Ya are as described above). The B-I step is a step of producing a compound (6) by reacting the compound (1) with the compound (5) in the presence of a base. The solvent to be used, the base to be used, the reaction temperature and the reaction time are the same as those of the A-step. The step B-II is a step of producing a compound (8) by reacting the compound (6) obtained in the step B-I with a halogenated alkyl group (7) in the presence of a base. As the solvent to be used, for example, THF, 1,4-diBf alkane, cyclopentylmethyl ether, DMF, dimethylacetamide or the like can be exemplified, and DMF is preferred. As the base to be used, for example, potassium t-butoxide, carbonic acid planer, potassium carbonate, sodium hydride 'N,N-diisopropylethylamine or the like can be exemplified, and sodium hydride is preferred. As the halogenated C1-C6 alkyl group to be used, methyl bromide, methyl iodide, ethyl bromide, methyl iodide or the like can be exemplified, and methyl iodide is preferred. -17- 201039827 The reaction temperature is 〇15 (TC, preferably 2〇~6 (TC. The reaction time is 30 minutes~24 hours, preferably 30 minutes~6 hours. B III step* is the step The obtained compound (8) is subjected to the step of producing the compound (Ib) of the present invention by reacting with the thiophene-Hartwig reaction using the Buchwald-Hartwig reaction.

The pin catalyst, ligand, base, solvent and reaction conditions used are the same as in the A-II procedure. C method

(wherein m, η, Q, Rla, R2, R3 and R4 are as defined above). The CI step is to produce a compound by reacting the compound (2) with the compound (2) according to the method described in Tetsuo Tsunoda, Fumie Ozaki and Sho Ito, Tetrahedron Lett., 1994, 35, p. 10) steps. As the solvent to be used, for example, benzene, toluene, xylene or the like can be exemplified as toluene. As the reagent to be used, for example, cyanomethylenetris-n-butylphosphine or the like. The reaction temperature is 30 to 150 ° C, preferably 100 to 130 ° C. The reaction time is -18 - 201039827 30 minutes to 12 hours, preferably 1 to 6 hours. The C-II step is a step of producing the compound (Ic) of the present invention by reacting the compound (10)' obtained in the C-oxime step with the compound (4) by a Buchwald-Hartwig reaction using a pin catalyst. The palladium catalyst, ligand, base, solvent and reaction conditions used are the same as in the step A11. D method

(wherein m, η, Q, Rla, R2, R3, R4 and R5 are as defined above). The D-oxime step is a step of producing a compound (13) by reacting the compound (11) with the compound (12) in the presence of a reducing agent. As the solvent to be used, for example, dichlorocarbyl, THF, acetonitrile (containing acetic acid) or the like can be exemplified, and THF is preferred. -19-201039827 As the reducing agent to be used, for example, sodium triethoxy borohydride, sodium cyanoborohydride or the like is preferred, and sodium triethyl sulfoxide is preferred. The reaction temperature is 0 to 5 (TC, preferably 20 to 30 ° C. The reaction time is 30 minutes to 12 hours, preferably 1 to 6 hours. The D-II step is obtained by D-Ι step骡a compound (13) which is produced by reacting a halogenated C1 to C6 alkyl group (7) in the presence of a base to produce a compound (14). A solvent, a base, a halogenated C1 to C6 alkyl group, a reaction temperature, And the reaction time is the same as that of the step B-II. The OD-III step is a process in which the compound (14) obtained in the step D-II is reacted with the compound (4) via a Buchwald-Hartwig reaction using a palladium catalyst to produce the present invention. Step of Compound (Id).

The palladium catalyst, ligand, base, solvent and reaction conditions used are the same as in the A-II step. E method

(wherein m, η, R11, R2, r3, r4, r5, X, γ and z are as described above). The E method is a compound of the Ri of the general formula (1) (2〇), by Carl R. johns〇n, R〇bert a Kirchh〇ff, H Gienn c〇rkins, j

A method of producing the compound (Ie) of the present invention by the method described in Org Chem.', 974, p. 245, et al. -20- 201039827 As the solvent to be used, for example, dichloromethane, dichloroethane or the like is preferably dichloromethane. As the reagent to be used, for example, hydrazine-sulfonylhydroxylamine or the like is exemplified. The reaction temperature is 0 to 40 ° C, preferably 10 to 30 ° C. The reaction time is from 3 to 36 hours, preferably from 2 to 24 hours. F method

(twenty four)

(wherein m, η, Q, R12, Ri3, r2 'r3, r4, χ, γ, and z are as described above). The F-I step is a step of producing a compound (24) by reacting the compound (22)' with a compound (23) via a Buchwald-Hartwig reaction using a palladium catalyst. The catalyst, ligand, base, solvent and reaction conditions used are the same as in the Α_π step. -21 - 201039827 The F-oxime step is a step of producing a compound (25) by subjecting the compound (24) obtained in the F-oxime step to hydrolysis. As the solvent to be used, for example, THF, ethanol, methanol, isopropyl alcohol or the like can be exemplified, and methanol is preferred. As the reagent to be used, for example, an aqueous sodium hydroxide solution, a potassium hydroxide aqueous solution, or a lithium hydroxide aqueous solution can be exemplified, and an aqueous sodium hydroxide solution is preferred. The reaction temperature is 〇~1 30 ° C, preferably 50 to 70 ° C. The reaction time is from 30 minutes to 12 hours, preferably from 30 minutes to 4 hours. 0 In the case of post-processing in this step, it is advisable to perform post-processing in the following order. After neutralizing the solution with 1 N hydrochloric acid, the compound (25) is extracted with an organic solvent, and the obtained organic layer is dried with a drying agent such as sodium sulfate or anhydrous magnesium sulfate. Next, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel chromatography. The solvent is distilled off under reduced pressure, and then aqueous sodium hydroxide is added, and the resulting precipitate is filtered and washed with water, ethyl acetate or the like. The step F-III is a step of producing a compound (If) of the present invention by reacting the compound (25) obtained in F-II with a compound (26) in the presence of a condensing agent. Q is a solvent to be used, for example, an alcohol, THF, 1,4-dioxane, DMF, dimethylacetamide or the like, preferably an alcohol or DMF, more preferably DMF. The condensing agent to be used is not particularly limited as long as it is a user of the guanidation reaction, but for example, RC Larock, Comprehensive Organic Transformations. Second Edition, 1999, John Wiley & Sons, Inc. The condensing agent described above. As a specific example, a phosphate such as diethylphosphonium cyanide may be exemplified: 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide '1-ethyl-3 -Carboxyimides such as -(3-dimethylaminopropyl)carbodiimide (WSC); imidazoles such as 1,1'-carbonyldiimidazole (CDI)-22-201039827; (4,6-dimethoxy 4,3,5-three-speaking _2-yl)_4_methylmorpholine oxime (DMT-MM); 0-(7-azabenzotriazole)〗 Base)_Ν,Ν,Νι,Ν,_ tetramethylurea hexafluorophosphate (hatu), 〇-benzotriazole-mN, N, N, _ tetramethylurea hexafluorophosphate (HBTU), etc. Phosphate esters and the like are preferably DMT-MM. The solvent to be used, for example, 'alcohol, THF, 1,4-dioxane, DMF, dimethylacetamide or the like' is preferably an alcohol or DMF, more preferably DMF. The reaction temperature is 0 to 100 ° C, preferably 〇 50 50 ° C. The reaction time is from 3 〇 0 minutes to 96 hours, preferably from 1 to 12 hours. The compound of the present invention represented by the above formula (I) obtained by the above method or a pharmaceutically acceptable salt thereof can be used as type 1 diabetes, type 2 diabetes, gestational diabetes, or the like because of its excellent hypoglycemic action. Caused by blood glucose, impaired glucose to erance (IGT), diabetes-related diseases (eg, obesity, hyperlipidemia, hypercholesterolemia, abnormal lipid metabolism, hypertension, fatty liver, metabolic syndrome) , edema, heart failure, angina, myocardial infarction, atherosclerosis, hyperuricemia, Q gout, etc.) or diabetes complications (eg, omental disease, nephropathy, neurological disorders, cataracts, foot gangrene, infections) An active ingredient of a pharmaceutical composition for use in the treatment and/or prevention of ketotoxicity, and the like. A pharmaceutical composition containing a compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof, when administered to a mammal (for example, human, horse, cow, pig, etc., preferably human) Full or partial oral or non-oral administration. The pharmaceutical composition of the present invention can be prepared by a modulation method using various preparations which are usually used, depending on the mode of administration. As a form of the pharmaceutical composition for oral administration, a tablet, nine doses, -23-201039827 powder, granules, capsules, a liquid, a suspension, an emulsion, a syrup, an expectorant, and the like can be exemplified. The preparation of the pharmaceutical composition of the form may be selected as appropriate, such as an excipient, a binder, a disintegrant, a lubricant, a swelling agent, a swelling adjuvant, a coating agent, a plasticizer, a stabilizer, a preservative, and the like. An antioxidant, a coloring agent, a dissolution aid, a suspending agent, an emulsifier, a sweetener, a preservative, a buffer, a diluent, a wetting agent and the like are used as an additive, and are produced by a usual method. Examples of the form of the pharmaceutical composition for parenteral use include injections, ointments, gels, creams, wet wipes, patches, sprays, inhalants, sputum sprays, eye drops, and nose. Agents, suppositories, inhalants, etc. The preparation of the pharmaceutical composition of the form, if necessary, the usual use of stabilizers, preservatives, dissolution aids, humectants, preservatives, antioxidants, perfumes, gelling agents, neutralizing agents, dissolution aids, A buffering agent, an isotonic agent, a surfactant, a coloring agent, a buffering agent, a tackifier, a wetting agent, a chelating agent, an absorption enhancer, a suspending agent, a binder, and the like are used as an additive, and are produced by a usual method. The administration amount of the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof varies depending on the symptoms, age, body weight, etc., orally, on occasion, 1 to several times per day, adult For each time, the amount of compound conversion is 1~200 mg, preferably l~400mg. For non-oral injection, 1~1 times a day, adult one person each time, the compound conversion amount is 0.01~ 5 00 mg, preferably 0.1 to 00 mg. Hereinafter, the present invention will be described in more detail by way of Reference Examples, Examples, Preparation Examples and Test Examples, but the scope of the present invention is not limited thereto. EXAMPLES (Reference Example 1) 4-[(6-Chloropyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester-24- 201039827 4,6-di-chloropyrimidine (1.55 g , 10.4 mmol), 4-aminopiperidine-l-decanoic acid, third vinegar (2.50 g, 12.5 mmol) in DMF (25.0 mL) solution, 'N,N-diisopropylethylamine (2.70) mL, .15.6 mmol) and stirred for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4:1 -1:1, v/v) to give the title compound (3.24 g, yield: 97%). ^-NMR (400MHz, CDCl3) 5ppm: 0 8.36 (1H, s), 6.34 (1H, s), 5.00 (1H, br), 4.25 -3.66 (3H, m), 3.01-2.84 (2H, m), 2.08- 1.96 (2H, m), 1.5 5 - 1.3 3 (2H, m), 1.47 (9H, s). (Reference Example 2) 4-[(6-chloropyrimidin-4-yl)(methyl)amine A solution of the compound (887 mg, 2.84 mmol) of DMF (10. OmL) obtained in Reference Example 1 was added with sodium hydride (63% dispersion of mineral oil, below, sometimes Sodium hydride (63%) (162 mg, 4.25 mmol) was stirred for 10 minutes at room temperature, then iodomethane (283 μί, 4.25 mmol) was added and stirred at room temperature for 20 min. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified to silica gel column chromatography (hexane: ethyl acetate=5:1 - 2:1, v/v) to afford the title compound (867mg, yield: 94%). ^-NMR (400MHz, CDCl3) 6ppm: 8.37 (1H, s), 6.41 (1H, s), 4.79 (1H, br), 4.36-4.15 (2H, m), 2.86 (3H, s), 2.90-2.76 (2H,m),1.71-1.62 (4H,m),i 48 -25- 201039827 (9H, s). (Reference Example 3) 4-Fluoro-5-isothiocyanate Porphyrin in 4-Fluorine To a solution of porphyrin (1.12 g, 8.17 mmol) and potassium thiocyanate (2-24 g, 24.4 mmol) in methanol (24.5 mL), bromo (43 7 μί, 17.1 mmol) of saturated sodium bromide-methanol (5.50 mL) solution, stirred for 1.5 hours. Water was added to the reaction mixture under cold ice, neutralized with sodium carbonate, and extracted three times with ethanol. The organic layer was washed with water and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (hexanes: ethyl acetate = 19:1 - 4:1, Wv) to afford the title compound (828 mg, yield: 52%). ^-NMR (400MHz, CDCl3) 6ppm: 7.25-7.20 ( 1 H, m), 6.37 (1H, d, J = 8Hz), 4.15 (1H, br), 3.72 (2H, t, J = 9Hz), 3.12 (2H, t, J = 9 Hz). (Reference Example 4) 4-Fluoro-5-(methylthio)porphyrin in water (1.60 mL) of sodium sulfide nonahydrate (1. 〇 2 g, 4.26 mmol) A solution of the compound (816 mg, 4.20 mm) obtained in Reference Example 3 in ethanol (7.50 mL) was added to the solution, and the mixture was stirred at 50 ° C for 2 hours. A solution of methyl iodide (670 μί, 5 -78 mmol) in ethanol (1._50 mL) was added to the mixture and stirred at 50 ° C for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with EtOAc (3 mL). The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9··1 -11:9, v/v) to give the title compound (70 3 mg, yield: 91%). ^-NMR (400MHz, CDCl3) 8ppm: 7.13-7.07 (1H, m), 6.35 (1H, d, J = 8Hz), 3.88 (1H, br), 3.63 (2H, t, J = 8Hz), 3.08 ( 2H, t, J = 8Hz), 2.37 (3H, s). -26- 201039827 (Reference Example 5) 4-Fluoro-5-(methylthio)porphyrin-1-carboxylic acid tert-butyl ester To a solution of the compound obtained in Example 4 (350 mg, 1.91 mmol) in methylene chloride (5.00 mL), bis(t-butyl ester) dicarbonate ( 790 ί, 3.44 mmol) and triethylamine (620 ί, 4.44 mmol), Stir at room temperature for 18 hours. Saturated sodium hydrogencarbonate water was added to the reaction mixture, and the mixture was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1 - 4:1, v/v) to give the title compound (743 mg, yield: 100%). iH-NMR (400MHz, CDCl3) Sppm: 7.57 (1H, br), 7.20-7.14 (1H, m), 4.03 (2H, t, J = 9Hz), 3.10 (2H, t, J = 9Hz), 2.42 ( 3H, s), 1.53 (9H, s). (Reference Example 6) 4-fluoro-5-(methylsulfonyl) porphyrin hydrochloride Compound obtained in Reference Example 5 (2.08 g, 7.34 mmol) In a solution of dichloromethane (20.0 mL), m-chloroperbenzoic acid (ca. 65 %, 3.38 g, 12.8 mmol) was poured under cold ice and stirred for 1 hour. To the reaction mixture, a 10% aqueous solution of sodium sulfite was added, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine and dried over anhydrous magnesium sulfate. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-3: 2, v/v). The compound was suspended in ethyl acetate (10 mL), and 4N hydrochloric acid ethyl acetate (10 mL) was evaporated. The reaction mixture was filtered, and the obtained crude product was washed with ethyl acetate and diisopropyl ether to afford the title compound (1.42 g, yield 61%). ^-NMR (400MHz, CD3〇D) 5ppm: -27- 201039827 7.5 9-7.5 3 ( 1 H, m), 6.58 (1H, d, J = 8Hz), 3.78 (2H, t, J = 9Hz), 3.17 (2H, t, J = 9 Hz), 3.16 (3H, s). (Reference Example 7) 4-[(4-chloropyridin-2-yl)oxy]piperidine-1-carboxylic acid tert-butyl ester To a solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.40 g, 16.9 mmol) in THF (50.0 mL), EtOAc (2. Stir at room temperature for 1 hour. The reaction solution was added to a solution of 2,4-dichloropyridine (1.82 mL, 16-9 mmol) in THF (50.0 mL), and the mixture was stirred at 70 ° C and stirred at the same temperature for 1 hour. Saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1-7:3, v/v) to give the title compound (3.29 g, yield: 62%). ^-NMR (500MHz, DMS Ο - άβ) δ pp m : 8.16 (1 Η, d, J = 5Hz), 7.10 (1H, dd, J = 5Hz, 2Hz), 6.96 (1H, d, J = 2Hz) 5,5,5,6,6 1.40 (9H, s). (Reference Example 8) 2-[4-({4-[5-(Methylsulfonyl)-2,3-dihydro-1H-inden-1-yl]pyridine- 2-(yloxy)piperidin-1-yl]pyridine-5-carbaldehyde in a solution of the compound obtained in Example 9 (2300 mg, 0.486 mm) in dichloromethane (2.30 mL) The mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and a part (178 mg) of Compound (181 mg), and N,N-diisopropylethylamine (378 pL ' 2.17 mmol), and 6-chloro-nicotinic aldehyde (61 mg, A solution of -28-201039827 〇.43 4 mmol) in ethanol (5.34 mL) was stirred at 80 ° C for 21 hours. A saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1 - 0:1, v/v) to give the title compound (140 mg, yield: 67%). ^-NMR (500MHz, CDCl3) 6ppm: 9.78 (1H, s), 8.56 (1Η, d, J = 2Hz), 8.06 (1H, d, J = 6Hz), 7.93 (1H, dd, J = 9Hz, 2Hz ), 7.73 (1H, d, J = 9Hz), 7.71 (1H, s), ❹ 7.35 (1H, d, J = 9Hz), 6.82 (1H, dd, J = 6Hz, 2Hz), 6.72 (1H, d , J = 9Hz), 6.46 (1H, d, J = 2Hz), 5.42-5.3 8 ( 1 H, m), 4.15-4.08 (4H, m), 3.70-3.65 (2H, m), 3.23 (2H, t, J=8 Hz), 3.04 (3H, s), 2.16-2.10 (2H, m), 1,91-1.85 (2H, m). (Reference Example 9) 5-(Methylsulfonyl)-l -(2-{[l-(5-vinylpyridin-2-yl)piperidin-4-yl]oxy}pteridine-4-yl)porphyrin in triphenyl iron iodide (118 mg, 0.293 Add THF ( 1.18 mL) in THF (1. 18 mL) at rt. EtOAc (EtOAc <RTI ID=0.0>> A solution of the compound (140 mg, 0.293 mmol), THF (1. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification by a column chromatography (hexane: ethyl acetate = 9:1 - 3:7, v/v) to give the title compound (44 mg, yield: 32%). W-NMR (500 MHz, CD? OD) : 7.17 (1H, d, J = 2Hz), 7.14 (1H, d, J = 6Hz), 6.86-6.84 ( 1 H, -29- 201039827 m), 6.78-6.74 ( 1 H, m), 6.69-6.74 (2H, m), 6.69-6.65 ( 1 H, m), 6.55 (1H, d, J = 9Hz), 6.08 (1H, dd, J = 6Hz, 2Hz), 5.99 (1H, d, J = 9Hz) , 5.76-5.71 (1H, m), 5.68 (1H, d, J = 2Hz), 4.74 (1H, d, J=18Hz), 4.37-4.33 (1 H, m), 4.23 (1H, d, J= LlHz), 3.24 (2H, t, J = 8Hz), 3.12-3.07 (2H, m), 2.59-2.54 (2H, m), 2.36 (2H, t, J = 8Hz), 2.19 (3H, s), 1.25-1.19 (2H, m), 0.96-0.89 (2H, m). (Reference Example 10) l-[3-(Benzyloxy)phenyl]-5-(methylsulfonyl)porphyrin 〇 5-(Methyloresinyl) Π 琳 ( (197mg, l.OOmmol), 3-hydroxy bromide (263mg, 1.000mmol), acetic acid network (22mg, O.lOOmmol), 2- Dicyclohexylphosphino-2',4',6--triisopropylbiphenyl (95 mg, 0.200 mmol) and sodium butoxide (241 mg, 2-50 mmol) of 1,4-dioxane (20 . OmL) solution, under heating and reflux For 2 hours. A saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was evaporated to ethyl ether. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4:1 - 3: 2, v/v) to give the title compound (3,07 mg, yield: 81%). W-NMR (400MHz, CDCl3) Sppm: 7.66-7.60 ( 1 H, m), 7.60-7.5 6 ( 1 H, m), 7.47-7.25 (6H, m), 6.93 (1H, d, J = 9Hz) , 6.8 8 -6.82 (2H, m), 6.77-6.70 ( 1 H, m), 5.09 (2H, s), 4.05 (2H, t, J = 9Hz), 3.17 (2H, t, J = 9Hz), 3.02 (3H, s). (Reference Example 11) 1-(5-Bromopyridin-2-yl)piperidin-4-ol 5-bromo-2-chloropyridine (1.50 g, 7 · 7 9 mm ο 1 ), 4-hydroxypiperidine (1·50 g, 11.7 mmol) and potassium carbonate (3.23 g, 23.4 mmol) in DMF (20.0 mL) -30-201039827 The solution was stirred at 100 ° C under nitrogen atmosphere. hour. Water was added to the reaction mixture to extract with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by chromatography (hexane: ethyl acetate = 2 : 1 - 1 : 1 , v / v) to afford the title compound (1.32 g, yield: 66%). 1 Η - NMR (4 0 0 Μ H z, CD C13) δ ppm : 8-18 (1Η, d, J = 2Hz), 7.5 1 (1H, dd, J = 9Hz, 2Hz), 6.58 (1H, d , J = 9Hz), 4.04-3.88 (3H, m), 3.20-3.11 (2H, m), 〇2.01-1.91 (2H, m), 1.62-1.51 (2H, m), 1.46 (1H, d, J (Reference Example 12) 1-(5-vinylpyridin-2-yl)piperidin-4-ol The compound obtained in Reference Example 11 (1.54 g, 5.99 mmol), vinyl boronic acid pinacol (Pinacol) ester (2.00 mL, 12.0 mmol), palladium acetate (130 mg, 0.599 mmol), 2-dicyclohexylphosphino-2(-(fluorene, dimethyl-dimethylamino)biphenyl (47〇11) ^, 1.2〇111111〇1) and a suspension of potassium carbonate (2.48§, 18.〇111111〇1) of 1,4-dioxane (80.0mL) and water (20.0mL), heated under reflux in a nitrogen atmosphere 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2:1 - 2:3, v/v) to afford crude product (1.30 g). W-NMR (400MHz, CDCl3) 6ppm: 8.15 (1H, d, J-2Hz), 7.59 (1H, dd, J = 9Hz, 2Hz), 6.66 (1H, d, J = 9Hz), 6.60 (1H, dd , J=18Hz, 11Hz), 5.55 (1H, d, J=18Hz), 5.10 (1H, d, J=llHz), 4.11-4.04 (2H, m), 3.97-3.89 (1H, m), 3.22- 3.14 (2H, m), 2.02- 1.93 (2H, m), 1.64- 1.53 (2H, -31- 201039827 m), 1.46 (1H, d, J = 4Hz). (Reference 13) 1-(5- Ethylpyridin-2-yl)piperidin-4-ol was added palladium-carbon (10% w/w, wet weight, 200 mg) to a solution of the crude product (1.30 g) obtained in Reference Example 12 in ethanol (25.0 mL). > Stir at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified to silica gel column chromatography (hexane: ethyl acetate = 2:1 to 2:3, v/v) to give the title compound (925mg, yield: 2 steps combined to 75%). 0 ^-NMR (400MHz, CDCl3) 6ppm: 8.04 (1H, d, J = 2Hz), 7.34 (1H, dd, J = 9Hz, 2Hz), 6.65 (1H, d, J = 9Hz), 4.07-3.99 ( 2H, m), 3.95 -3.86 ( 1 H, m), 3.15-3.06 (2H, m), 2.52 (2H, q, J = 7Hz), 2.03 - 1.95 (2H, m), 1.65 - 1.57 (2H, m), 1.44 (1H, d, J = 5Hz), 1.20 (3H, t, J = 7Hz). (Reference Example 14) 1-(5-methylpyridin-2-yl)piperidin-4-ol The compound obtained in Reference Example 11 (500 mg, 1.94 mmol), [bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex hydrazine (1 58 mg, 0·1 94 mmol) and potassium carbonate (804 mg, 5.82 mmol) of a mixture of 1,4-dioxane (6.00 mL) and water (600 μί) was added 'trymethyl boroxin (27 1 pL, 1.94 mmol), nitrogen The mixture was heated under reflux for 2.5 hours. Water was added to the reaction solution to extract with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue obtained was purified by silica gel column chromatography ((i)hexane: ethyl acetate = 3:1 - 1:3, v/v, (ii) dichloromethane: ethyl acetate = 2: 1-2: 3 , v/v), obtained the labeled compound 〇41 mg' yield: 38%). -32- 201039827 *H-NMR (400MHz, CDCl3) 6ppm: 8.01 (1H, d, J = 2Hz), 7.30 (1H, dd, J = 9Hz, 2Hz), 6.62 (1H, d, J = 9Hz ), 4.04-3.97 (2H, m), 3.94-3.84 (1H, m), 3.13-3.04 (2H, m), 2.19 (3H, s), 2.02-1.93 (2H, m), 1.64- 1.53 (2H , m), 1.47 (1H, d, J = 4Hz).

(Reference Example 15) 1-(5-isopropylpyrimidin-2-yl)piperidin-4-ol 4-hydroxypiperidine (247 mg, 2 to 44 mmol), 2-chloro-5-(1-methylethyl) ) Journal of Medicinal Chemistry., 1980, 23 volumes, p.93, 80 mg ' 2.44 mmol ) 'Acetic acid (55 mg, 0.244 mmol), 2-dicyclohexylphosphino-2'-( N,N-Dimethylamino)biphenyl (192 mg, 0.48 8 mmol) and potassium carbonate (6 · 7 5 g, 4 8.8 mmo 1 ) of 1,4-dioxane (1. 2 mL) in nitrogen The mixture was heated under reflux for 9 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography (hexane: ethyl acetate = 3:1 - 1:1, v/v). =3: 1-2: 1, v/v), the title compound (140 mg, yield: 26%) was obtained. *H-NMR (400MHz, CDCl3) 6ppm: 8.06 (1H, d, J = 2Hz), 7.36 (1H, dd, J = 9Hz, 2Hz), 6.65 (1H, d, J = 9Hz), 4.07-3.99 ( 2H, m), 3.94-3.86 (1H, m), 3.14-3.06 (2H, m), 2.81 (1H, sept, J = 7Hz), 2.02-1.94 (2H, m), 1.64- 1.53 (2H, m ), 1.44 (1H, d, J = 5Hz), 1.21 (6H, d, J = 7Hz). (Reference Example 16) 2-{4-[(6-chloropyrimidin-4-yl)oxy]piperidine -1-yl}-5-ethylpyrimidine in 1-(5-ethyl-2-pyrimidinyl)-4-piperidinol (W02008/008895, -33-201039827 368 mg, 1.78 mmol) in THF (20.0 mL) Potassium tert-butoxide (299 mg, 2.67 mmol) was added to the solution and stirred for 20 minutes. Further, 4,6-dichloropyrimidine (3 18 mg, 2.13 mmol) was added to the reaction mixture under cold ice water, and the mixture was stirred for 30 minutes while warming to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was evaporated to ethyl ether. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=19:1 - 4:1, v/v) to give the title compound (313 mg, yield: 55%) 〇Q^-NMR (400 MHz, CDCl3) 5ppm: 8.57 (1H, s), 8.19 (2H, s), 6.77 (1H, s), 5.45-5.3 7 ( 1 H, m), 4.31-4.20 (2H, m), 3.63 -3.52 (2H , m), 2.48 (2H, q, J = 7Hz), 2.13-2.03 (2H, m), 1.8 6- 1.72 (2H, m), 1.20 (3H, t, J = 7Hz). (Reference Example 17) 4-({ 6-[4-fluoro-5-(methylsulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1 -T-butyl carboxylic acid using 4-[(6-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylic acid tert-butyl ester hydrazine (1 93 mg, 0·6 14 mmol) instead of 4-[ (6-chlorosulfonate 4-yl)(methyl)amino] piperidine-1-carboxylic acid tert-butyl ester was carried out in the same manner as in Example 5 described later to obtain a labeled compound (276 mg, yield: 91%). ). 1H-NMR (400MHz, CDCl3) 5ppm: 8.51 (1H, s), 8.34 (1H, d, J = 9Hz), 7.82-7.76 (1H, m), 5.98 (1H, s), 5.3 5-5.29 ( 1 H, m), 4.12 (2H, t, J = 9Hz), 3.84-3.7 5 (2H, m), 3.32 (2H, t, J = 9Hz), 3.32-3.24 (2H, m), 3.20 (3H , s), 2.03 -1.96 (2H, m), 1.77-1.68 (2H, m), 1.48 (9H, s). -34- 201039827 (Reference 18) 2-{4-[(6-chloropyrimidine- 4-(5-isopropyl-2-pyrimidinyl)-4-piperidinol (W02008/0 1 2277 ' 481 mg, 2.18) M.substituent ^ (5·ethyl-2-pyranyl)_4·piperrol was carried out in the same manner as in Reference Example 16 to give the title compound (381 mg, yield: 53%). 'H-NMR (400MHz, CDCh) 6ppm: 8.57 (1H, s), 8.22 (2H, s), 6.76 (1H, s), 5 46_5 3 6 ( 1 H, 〇m), 4.32-4.19 (2H, m), 3.64-3.51 (2H, m), 2.85-2.71 (1H, m), 2.14-2.01 (2H, m), 1.8 8- 1.73 (2H, m), 1.24 (6H, d, J = 7Hz) (Reference Example 19) (±)-Benzyl (3R,4S)_4-[(6-chloropyrimidin-4-yl)oxy]-3-fluoropiperidine-1-carboxylate (±)- Substrate (3 R,4S)-3 -Fluor_4·Phase-based steep 1 ·Residue ester (W02006/1 1 3471 '724pg, 2.86mmol) instead of b...ethyl-2-pyrimidinyl)-4- Piperidinol was carried out in the same manner as in Reference Example 16 to give the title compound (941 mg, yield: 90%). q !H-NMR (500MHz, DMSO-d6) 6ppxn: 8.70 (1H, s), 7.39-7.31 (5H, m), 5.45-5.37 (1H, m), 5.10 (2H, s), 5.03 (1H, Br), 4.27-4.21 (1H, m), 4.05.3.99 (1H, m), 3.45-3.05 (2H, m), 1.96-1.94 (1H, m), 1-88-1.8〇 (1H, m) (Reference Example 20) (±) -nodal (3R,4S)-3 -fluoro- 4__({6_[4 fluoro_5_(methylindenyl)-2,3-dihydro-1H-indole -1-yl]pyrimidin-4-ylmethoxyoxy)piperidine-bucarboxylate The compound obtained in Reference Example 19 (499 mg, i.wmmoi) was used instead of 4-[(6-chloropyrimidin-4-yl). The (meth)amino]piperidine-1-carboxylic acid tert-butyl ester was carried out in the same manner as in Example 5, which was described later, from -35-201039827 to give the title compound (531 mg, yield: 72%). *H-NMR (500MHz, DMS Ο - d6) δρριη : 8.58 (1Η,d,J=lHz), 8.35 (1Η,d,J = 9Hz), 7.69 (1Η,t, J = 8Hz), 7.40-7.31 (5H,m), 6.37 (1H,s),5.45-5.3 6 ( 1 H,m), 5.10 (2H, s), 5.04 (1H, br), 4.30-4.24 (1H, m), 4.18 (2H , t, J = 9 Hz), 4.05 (1H, br), 3.44-3.05 (7H, m), 1.97- 1.80 (2H, m). (Reference Example 21) 1-(5-Bromopyrimidin-4-yl) Benzyl carbazide Q benzylpiperidin-4-ylcarbamate dihydrochloride (6.86 mg, 2.23 mmol), N,N-diisopropylethylamine (1.94 mL, ll.lmmol And a solution of 5-bromo-2-chloropyrimidine (647 mg, 3.34 mmol) in ethanol (13.7 mL) was stirred at 80 ° C for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. Ethyl acetate was added to the obtained residue, and the resulting precipitate was collected by filtration and dried to give the title compound (820 mg, yield: 94%). W-NMR (500 MHz, CDCl3) Sppm: 〇 8.27 (2Η, s), 7.3 7-7.3 0 (5Η, m), 5.10 (2H, s), 4.66 (1H, br), 4.60-4.5 5 (2H , m), 3.79 (1H, br), 3.09-3.04 (2H, m), 2.03 (2H, br), 1.40- 1.3 3 (2H, m). (Ref. 22) [1-(5-Isopropene) Benzylpyrimidin-2-yl)piperidin-4-yl]carbamic acid benzyl ester The compound obtained in Reference Example 21 (820 mg, 2.10 mmol) was used instead of 1-(5-bromopyridin-2-yl)piperidine- The 4-alcohol was replaced with the vinyl boronic acid pinacol ester with the isopropenylboronic acid pinacol ester (7 8 8 μί, 4.19 mm 〇l), and the same procedure as in Reference Example 12 was carried out to obtain a labeled compound (5 3 Omg, produced). Rate: 72%). -36- 201039827 h-NMR (500 MHz, CDCl3) Sppm: 8.42 (2H, s), 7.37-7.31 (5H, m), 5.24 (1H, s), 5.11 (2H, s), 4.96-4.95 (1H , m), 4.67-4.63 (3H, m), 3.81 (1H, br), 3.12-3.07 (2H, m), 2.08 (3H, s), 2.06-2.03 (2H, m), 1.42-1.34 (2H , m). (Reference Example 2 3 ) 6-Chloro-N-[1-(5-isopropylpyrimidin-2-yl)piperidin-4-yl]pyrimidine-4-amine obtained in Reference Example 22 Palladium-carbon (10% w/w, wet weight, 2.50 g), palladium hydroxide-mixed solution of a compound (5.00 g, 14.2 mm 〇l) of a Q-alcohol (150 mL) and THF (150 mL) Carbon (20% w/w, wet weight, 2.50 g) was stirred at room temperature for 6.5 hours under a hydrogen atmosphere. The reaction solution was filtered with Celite, and the solvent was evaporated under reduced pressure. A solution of the obtained residue, 4,6-dichloropyrimidine (2.54 g, 17.3 mmol) and diisopropylethylamine (4.95 mL, 28.4 mmol) in ethanol (50.8 mL) was stirred at 80 ° C for 7 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9:1 -1:1, v/v) to give the title compound (2.43 g, yield: 51%). iH-NMR (500MHz, DMSO-d6) 3ppm: 8.26 (2H, s), 7.69 (2H, 2), 6.45 (1H, s), 4.49 (2H, br), 4.11 (1H, br), 3.09-3.02 (3H, m), 2.75 (1H, sept, J = 7Hz), 1.90 (2H, br), 1.3 8- 1.28 (2H, s), 1.16 (6H, d, J = 7Hz). (Reference Example 2 4 6-Chloro-N-[l-(5-isopropylnorran-2-yl)indole-4-yl]-N-methylpyrimidin-4-amine The compound obtained in Reference Example 23 was used ( 1〇9mg, 0.327mmol) -37- 201039827 Instead of 4-((6-chloropyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester, the same procedure as in Reference Example 2 was carried out to obtain a labeled compound. (66 mg, yield: 58%). ^-NMR (500MHz, CDCl3) 5ppm: 8.39 (1H, s), 8.22 (2H, s), 6.42 (1H, s), 4.93-4.89 (3H, m), 3.02-2.96 (2H, m), 2.85 (3H, s), 2.79 (1H, sept, J = 7Hz), 1.76-1.69 (4H, m), 1.24 (6H, d, J = 7Hz). (Ref. 25) [1-(5-Isopropene) Tert-butylpyridin-2-yl)piperidin-4-yl]carbamic acid tert-butyl ester 0 The compound obtained in Reference Example 30 (475 mg, 1.33 mmol) was used instead of benzyl 1-(5-bromopyrimidine-4). The -amino)carbamate was carried out in the same manner as in Reference Example 22 to give the title compound (403 mg, yield: 95%). *H-NMR (400MHz, CDCl3) 6ppm: 8.30 (1H,d,J = 3Hz)} 7.61 (1H, dd, J = 9Hz, 3Hz), 6.63 (1H, d, J = 9Hz), 5.25 (1H, s), 4.95 (1H, s), 4.43 (1H, br), 4.26-4.17 (2H, m), 3.70 (1H, br), 3.04-2.93 (2H, m), 2.10 (3H, s), 2.07 -1.97 (2H, m), 1.48- 1.3 5 (2H, m), 1.45 (9H, s). 〇 (Ref. 26) [1-(5-isopropylpyridin-2-yl)piperidine-4 -Based] tert-butyl carbazate The compound obtained in Reference Example 25 (391 mg, 1.23 mmol) was used instead of 1-(5-vinylpyridin-2-yl)piperidin-4-ol, which was the same as Reference Example 13. This was carried out to obtain a labeled compound (322 mg, yield: 82%). ^-NMR (400MHz, CDCl3) 6ppm: 8.05 (1H, d, J = 2Hz), 7.36 (1Η, dd, J = 9Hz, 2Hz), 6.63 (1H, d, J = 9Hz), 4.49 (1H, br ), 4.18-4.10 (2H, m), 3.68 (1H, br), 2.99-2.89 (2H, m), 2.81 (1H, sept, J = 7Hz), 2.07-1.97 -38- 201039827 (2H, m) , 1.50- 1.3 8 (2H, m), 1.45 (9H, s), 1.21 (6H, d, J = 7Hz). (Ref. 27) 1-(5-isopropylpyridin-2-yl)piperidine 4-Amine hydrochloride was added to a solution of the compound ( 312 mg, 0.975 mmol) of ethyl acetate (2. Stir for 30 minutes. The solvent was distilled off under reduced pressure to give the title compound. ^-NMR (400MHz, CD3〇D) 8ppm: 0 8.08 (1H, d, J = 9Hz), 7.78 (1H, s), 7.43 (1H, d, J = 9Hz), 4.33-4.24 (2H, m) , 3.59-3.47 ( 1 H, m), 3.41-3.27 (2H, m), 2.96 (1H, sept, J = 7Hz), 2.27-2.18 (2H, m), 1.76 (2H, dq, J = 4Hz, 13 Hz), 1.27 (6H, d, J = 7 Hz). (Reference Example 28) 6-Chloro-N-[l-(5-isopropylpyridin-2-yl)piperidin-4-yl] 4-Amine The compound obtained in Reference Example 27 (theoretical amount: 0.975 mmol) was used instead of the tert-butyl 4-aminopiperidine-1-carboxylate, and the same procedure as in Reference Example 1 was carried out to obtain a labeled compound (98 mg, yield). 25%). • H-NMR (500MHz, CDCl3) 6ppm: 8.36 (1H, s), 8.08 (1H, d, J = 2Hz), 7.39 (1H, dd, J = 9Hz, 2Hz), 6.66 (1H, d, J = 9Hz), 6.35 (1H, s), 4.87 (1H, br), 4.24-4.17 (2H, m), 3.90 (1H, br), 3.08-3.00 (2H, m), 2.83 (1H, sept, J = 7Hz), 2.15-2.08 (2H, m), 1.62- 1.50 (2H, m), 1.23 (6H, d, J = 7Hz). (Reference Example 29) 6-Chloro-N-[l-(5- Propylpyridin-2-yl)piperidin-4-yl]-N-methylpyrimidin-4-amine-39-201039827 The compound obtained in Reference Example 28 (90 mg, 〇.272 mmol) was used instead of 4-[(6) -Chloropyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester was carried out in the same manner as in Reference Example 2 to give the title compound (59 mg, yield: 62%). !H-NMR (400MHz, CDCl3) 6ppm: 8.39 (1H, s), 8.08 (1H, d, J = 2Hz), 7.39 (1H, dd, J = 9Hz, 2Hz), 6.67 (1H, d, J = 9Hz), 6.42 (1H, s), 4.85 (1H, br), 4-44-4.35 (2H, m), 2.99-2.90 (2H, m), 2.87 (3H, s), 2.83 (1H, sept, J = 7 Hz), 1.88-1.71 (4H, m), 1.23 (6H, d, J = 7 Hz). O (Reference Example 30) [1-(5-bromopyridin-2-yl)piperidin-4-yl The third butyl carbamic acid ester was used in the same manner as in Reference Example 11 to obtain the labeled compound (1.32) using the second butyl piperidin-4-yl-carbamic acid (1.50 g, 7.79 mmol) instead of 4-hydroxypiperidine. g, yield: 66%). • H-NMR (400MHz, CDCl3) 6ppm: 8.17 (1H, d, J = 3Hz), 7.51 (1H, dd, J = 9Hz, 3Hz), 6.56 OH, d, J = 9Hz), 4.49 (1H, br ), 4.19-4.11 (2H, m), 3.70 (1H, o W bO, 3.01-2.92 (2H, m), 2.06- 1.98 (2H, m), 1.49- 1.34 (2H, m), 1 -45 ( 9H, s). ' (Reference Example 31) [1-(5-vinylpyridin-2-yl)piperidin-4-yl]carbamic acid tert-butyl ester The compound obtained in Reference Example 30 (852 mg, 2.39 mmol) was substituted for 1-(5-bromopyridin-2-yl)piperidin-4-ol' in the same manner as in Reference Example 12 to give the title compound (628 mg, yield: 86%). 'H-NMR (400 MHz) , CDCl3) 5ppm: 8.15 (1H, d, J = 2Hz), 7.59 (1H, dd, J = 9Hz, 2Hz), 6.64 -40- 201039827 (1H,d,J = 9Hz), 6.59 (1H, dd, J=18Hz, 1 1 Hz), 5.55 (1H, d, J=18Hz), 5.10 (1H, d, J=llHz), 4.48 (1H, br), 4.27-4.17 (2H, m), 3.71 (1H , br), 3.05-2.94 (2H, m), 2.06- 1.98 (2H, m), 1.48- 1.35 (2H, m), 1.45 (9H, s). (Reference Example 3 2 ) [ 1 - (5 - Triethyl butyl 2-pyridin-2-yl)piperidin-4-ylcarbamate The compound obtained in Reference Example 31 (620 mg, 2.04 mmol) was used instead of 1-(5-vinylpyridin-2-yl). Pyridin-4-ol, in the same manner as in Reference Example 13, to give the title compound (572 mg, yield: 92%). NMR (400 MHz, CDCl3) 6 ppm: 8.03 (1H, d, J = 2 Hz), 7.33 (1H, dd, J = 8Hz, 2Hz), 6.63 (1H, d, J = 8Hz), 4.44 (1H, br), 4.18-4.08 (2H, m), 3.70 (1H, br), 3.00-2.8 8 (2H, m), 2.51 (2H, q, J = 7Hz), 2.08- 1.98 (2H, m), 1.45 (9H, s), 1.51-1.37 (2H, m), 1.18 (3H, t, J = 7 Hz). (Reference Example 33) 1-(5-ethylpyridin-2-yl)piperidin-4-amine hydrochloride The compound obtained in Reference Example 32 (565 mg, 1.85 mmol). (5-isopropylpyridin-2-yl)piperidin-4-yl]carbamic acid tert-butyl ester was obtained in the same manner as in Reference Example 27 to give the title compound (5 93 mg). ^-NMR (400MHz, CD3〇D) 6ppm: 8.03 (1H, dd, J = 9Hz, 2Hz), 7.79 (1H, d, J = 2Hz), 7.42 (1H, d, J = 9Hz), 4.31-4.24 (2H, m), 3.5 8-3.47 ( 1 H, m), 3.40-3.31 (2H, m), 2.65 (2H, q, J = 7Hz), 2.26-2.18 (2H, m), 1.75 (dq, 2H, J = 4 Hz, 13 Hz), 1.25 (3 H, t, J = 7 Hz). (Reference Example 34) 6-Chloro-N-[l-(5-ethylpyridin-2-yl)piperidine-4 -yl]pyrimidin-4-amine-41-201039827 The compound obtained in Reference Example 33 (5 93 mg, 1.85 mmol) was used instead of the tert-butyl 4-aminopiperidine-1-carboxylate, and Reference Example 1 The same procedure was carried out to obtain a labeled compound (339 mg, yield: 58%). ^-NMR (400MHz, CDCl3) 6ppm: 8.36 (1H, s), 8.05 (1H, d, J = 2Hz), 7.36 (1H, dd, J = 9Hz, 2Hz), 6.66 (1H, d, J = 9Hz ), 6.35 (1H, s), 5.00 (1H, br), 4.26-4.16 (2H, m), 4.00 (1H, br), 3.09-2.98 (2H, m), 2.53 (2H, q, J = 8Hz ), 2.16-2.07 (2H, m), 1.62- 1.49 (2H, m), 1.20 Q (3H, t, J = 8Hz). (Reference Example 35) 6-Chloro-N-[l-(5-B Pyridyl-2-yl)piperidin-4-yl]-N-methylpyrimidin-4-amine The compound obtained in Reference Example 34 (3 30 mg, 1·04ηηη〇1) was used instead of 4-[(6-chloro Pyridyl-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester was obtained in the same manner as in Reference Example 2 to give the title compound (3 3 9 mg, yield: 98%). !H-NMR (400MHz, CDCl3) 8ppm: 8.38 (1H, s), 8.05 (1H, d, J = 2Hz), 7.36 (1H, dd, J = 9Hz, 〇2Hz), 6.66 (1H, d, J = 9Hz), 6.42 (1H, s), 4.81 (1H, br), 4.48-4.31 (2H, m), 3.00-2.89 (2H, m), 2.86 (3H, s), 2.53 (2H, q, J -7Hz), 1.90-1.71 (4H, m), 1.20 (3H, t, J = 7Hz). (Ref. 36) 4-({6-[5-Methoxycarbonyl-2,3-dihydro- 1H-Indol-1-yl]pyrimidin-4-yl}oxy)piperidine-l-carboxylic acid tert-butyl ester using 5-methoxycarbonyl-2,3-dihydro-1H-carboline ( 2.24 g, 7.13 mmol), instead of 5-(methylsulfonyl)porphyrin, was carried out in the same manner as in Example 3 to be described later to obtain a labeled compound (2.24 g, yield: 83%). 'H-NMR (4〇〇MHz, CDCl3) 5ppm: -42- 201039827 8.49 (1H, s), 8.40 (1H, d, J = 9Hz), 7.92 (1H, d, J = 9Hz), 7.84 (1H , S), 5.96 (1H, s), 5.3 5-5.26 ( 1 H, m), 4.01 (2H, t, J-9Hz), 3.89 (3H, s), 3.87-3.71 (2H, m), 3.33 -3.22 (4H, m), 2.05-1.92 (2H, m), 1.82- 1.65 (2H, m), 1.43 (9H, s). (Reference Example 37) l-(6-{[l-(5 - Ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)porphyrin·5-carboxylic acid methyl ester The compound obtained in Reference Example 36 (289 mg, 0.635 mmol) was used. 4-({4·[5-(methylsulfonyl)-2,3-dihydro-iH_吲哚-yl]pyridinium-2-yl}oxy)piperidine-1-carboxylic acid Butyl ester was subjected to the same procedure as in Example 1 1 described later to obtain a labeled compound (207 mg, yield: 71%). ^-NMR (400MHz, CDCl3) 8ppm: 8.52-8.50 ( 1 H, m), 8.41 (1H, d, J = 8Hz), 8.18 (2H, s), 7.95-7.90 ( 1 H, m), 7.87- 7.84 ( 1 H, m), 5.99-5.97 (1 H, m), 5.44-5.3 7 ( 1 H, m), 4.3 3 -4.25 (2H, m), 4.02 (2H, t, J = 9Hz), 3.89 (3H, s), 3.61-3.53 (2H, m), 3.25 (2H, t, J = 9Hz), 2.47 (2H, q, J = 8Hz), 2.13-2.06 (2H, m), 1.84- 1.75 (2H, m), 1.20 〇(3H, t, J = 8Hz). (Reference 38) l-(6-{[l-(5-ethyl-anthran-2-yl)indole-4-yl a solution of the compound (94 mg, 0.203 mmol) in methanol (100 mL), m.p. The mixture was stirred under heating and reflux for 2.5 hours. Further, a 5N aqueous sodium hydroxide solution (2.00 mL) was added, and the mixture was stirred under reflux for 1 hour. After cooling the reaction mixture, the solvent was evaporated under reduced pressure, and then, 6N sodium hydroxide aqueous solution (2.20 mL) was added, and the resulting precipitate was collected by filtration. The precipitate was washed with water and ethyl acetate to give the title compound (55 mg, yield: 61 - 43 - 201039827 %). *H-NMR (400MHz, DMSO-d6) 5ppm: 12.56 (1H, s), 8.53 (1H, s), 8.44 (1H, d, J = 9Hz), 8.26 (2H, s), 7.84-7.78 (1 H, m), 7.78-7.75 ( 1 H, m), 6.21-6.18 (1H, m), 5.39-5.31 (1H, m), 4.32-4.22 (2H, m), 4.05 (2H, t, J = 9Hz), 3.49-3.40 (2H, m), 3.23 (2H, t, J = 9Hz), 2.44 (2H, q, J = 7Hz), 2.10-2.00 (2H, m), 1.68- 1.57 (2H, m ), 1.14 (3H, t, J = 7Hz). Q (Example 1) 4-[6-(5-(S-Methylsulfonylamino)-2,3-dihydroinden-1-yl Ointment-4-yloxy]piperidine-1-decanoic acid isopropyl vinegar

4-[6-(5-(Methanesulfinylidene)-2,3-dihydroindol-1-yl)pyrimidin-4-yloxy]piperidine-1-carboxylic acid isopropyl ester (W02009) To a methylene chloride solution (2.00 mL) of /5 1 1 19, 100 mg, 〇.22 5 mmol) was added hydrazine-sulfonyl hydrazine hydroxyamine (150 mg, 0.697 mmol). A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was evaporated to ethyl ether. The residue was purified by silica gel column chromatography (dichloromethane:methanol = EtOAc: EtOAc (EtOAc) W-NMRHOOMHz JDChMppm: 8.55 (1H, d, J = 9Hz), 8.51 (1H, s), 7.86 (1H, dd, J = 9Hz, 2Hz), 7.80 (1H, br), 5.98 (1H, s), 5.3 6-5.3 0 (1 H, m), 4.94 (1H, sept, J = 6Hz), 4.07 (2H, t, J = 9Hz)s 3.8 8-3.78 (2H, m), -44- 201039827 3.32 (2H , t, J = 9Hz), 3.3 7-3.27 (2H, m), 3.10 (3H, s), 2.06-1.96 (2H, m), 1.79- 1.69 (2H, m), 1.26 (6H, d, J = 6 Hz). (Example 2) 4-[6-(5-(S-Methylsulfonylamino)-2,3-dihydroinden-1-yl)pyrimidin-4-yloxy]piperidin Pyridine-1-carboxylic acid 2,2,2-trifluoroethyl ester

4-[6-(5-(Methanesulfinylidene)-2,3-dihydroindol-1-yl)pyrimidine Q-4-yloxy]piperidine-1-carboxylic acid 2,2, 2-Trifluoroethyl ester (promoting 2009/51119, 237 mg, 0.491 mmol) instead of 4-[6-(5-(methanesulfinylidene)-2,3-dihydroinden-1-yl)pyrimidine Isopropyl -4-yloxy]piperidine-1-carboxylate was carried out in the same manner as in Example 1 to give the title compound (3 5 mg, yield: 16%). !H-NMR (400MHz, CDCl3) 6ppm: 8.55 (1H, d, J = 9Hz), 8.51 (1H, s), 7.86 (1H, dd, J = 9Hz, 2Hz), 7.80 (1H, d, J = 2Hz), 5.98 (1H, s), 5.41-5.33 (1H, m), 4.55-4.46 (2H, m), 4.07 (2H, t, J = 9Hz), 3.87-3.78 (2H, m), Q 3.49 -3.40 (2H, m), 3.3 1 (2H, t, J = 9Hz), 3.11 (3H, s), 2.09-1.99 (2H, m), 1.87- 1.74 (2H, m). (Example 3) 4-(methyl{6-[5-(methylsulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}amino)piperidine-1-carboxylate Tert-butyl acid

5-(methylsulfonic acid) π porphyrin (736 mg, 3.73 mmol), the compound obtained in Reference Example 2 (1.22 g, 3.73 mmol), potassium carbonate (10.3 g, -45-201039827 74.7 mmol), 2-(Dicyclohexylphosphino)-2'-(N,N-dimethylamino)biphenyl (300 mg, 0-747 mmol), and 1,4-palladium acetate (85 mg, 〇.3 73 mmol) The suspension of dioxane (3 6.8 mL) was stirred at 105 ° C for 2 hours. The reaction solution was filtered, and aq. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified to silica gel column chromatography (hexane: ethyl acetate=9:1 - 3:7, v/v) to give the title compound (1.67 g, yield: 92%). • H-NMR (500MHz, DMSO-d6) 5ppm: 〇8.54 (1Η, d, J = 8Hz), 8.32 (1H, s), 7.69 (1H, s), 7.68 (1H, d, J = 8Hz), 5.82 (1H, s), 4.13-4.02 (5H, m), 3.26 (2H, t, J = 9Hz), 3.13 (3H, s), 2.91-2.81 (5H, m), 1.66-1.54 (4H, m ), 1.42 (9H, s). (Example 4) 4-(methyl{6-[5-(methylsulfonyl)-2,3-dihydro-;^-indol-1-yl] Pyrimidin-4-yl}amino)piperidine-1-carboxylic acid isopropyl ester

To a solution of the compound (46 mg, 0.943 mmol) obtained from EtOAc (EtOAc m. After distilling off the solvent from the reaction mixture, a 1N aqueous solution of sodium hydroxide (20.0 mL) was added, and the resulting precipitate was filtered, and dried under reduced pressure to give a portion (23 mg) of the residue (23 mg) and N, N- To a solution of isopropylethylamine (31 μί, 0.178 mmol) in dichloromethane (1.15 mL), isopropyl chloroformate (14eL, 0.119 mmol) was added and stirred at room temperature for 2 hours. After adding a saturated aqueous solution of ammonium chloride, the mixture was extracted three times with ethyl acetate-46 - 201039827. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. (expansion) purification to give the title compound (25 mg, yield: 62%). <H-NMR (500 MHz, DMSO-d6) 5 ppm: 8.54 (1 Η, d, J = 8 Hz), 8.32 (1 Η, s), 7.69 ( 1Η, s), 7.68 (1Η d, J = 8Hz), 5.82 (1H, s), 4.81-4.74 (1H, m), 4 ΐ4·4 〇6 (5h m), 3.26 (2H, t, J = 9Hz ), 3.13 (3H, s), 2·89 (2H br, o ... , ^.87 (3H, s), 1.68- 1.56 (4H, m), 1.20 (6H, d, J = 6HZ). Ο ( Example 5) 4-[{6-[4·Fluoro-5-(methylsulfonylfluoren-1-yl)pyrimidin-4-yl}(methyl)amino]piperidine-1-carboxylic acid First

3_Dihydro-1H-tributyl ester 〇 The compound obtained in Reference Example 6 (500 rn 6 2.20 generation 5-(methylsulfonyl) porphyrin was used, and the compound (822 mg, produced in the same manner as in Example 3) was used. Rate: 88%) h-NMR (400MHz, CDCl3) Sppm: 8.39 (1H, s), 8.30 (1H, d, J = 9Hz), 7 79 7 5.58 (1H, s), 4.99-4.84 (1 H , m), 4.36-4.16 (2li t, J = 9Hz), 3.28 (2H, t, J = 9Hz), 3.19 (3H, s) 2 m), 2.86 (3H, s), 1.71-1.62 (4H, m), 1.48 (9r Sister) for the ••72 (1H, ^), 4 •94ο (2Η 80 (2Η s) Hydrogen-1Η-propyl ester (Example 6) 4-[{6-[4 -fluoro-5-(methylsulfonyl '^, 吲哚-1-yl]pyrimidin-4-yl}(methyl)amino]piperidine-1-residual acid stomach-47- 201039827

Substituting the compound obtained in Example 5 (571 mg, 1.1 3 mm 〇l) for 4-(methyl{6-[5-(methylsulfonyl)-2,3-dihydro-1H-indole-1 Tributyl butyl-pyrimidin-4-yl}amino)piperidine-1-carboxylate was carried out in the same manner as in Example 4 to give the title compound (461 mg, yield: 86%). h-NMR (400MHz, CDCl3) Sppm: Ο 8.39 (1H, s), 8.30 (1H, d, J = 9Hz), 7.79-7.73 ( 1 H, m), 5.58 (1H, s), 4.99-4.87 ( 1H, m), 4.94 (1H, sept, J = 6Hz), 4.39-4.21 (2H, m), 4.15 (2H, t, J = 9Hz), 3.29 (2H, t, J = 9Hz), 3.19 (3H , s), 2.96-2.82 (2H, m), 2.86 (3H, s), 1.73-1.62 (4H, m), 1.27 (6H, d, J-6Hz). (Example 7) 4-(methyl {6-[5-(Methylsulfinyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}amino)piperidine-1-carboxylic acid tert-butyl ester

Substituting 2,3-dihydro-5-(methylsulfinyl)-(1Η)-fluorene (189 mg, 1.05 mmol) for 5-(methylsulfonyl)porphyrin, the same as in Example 3. The title compound (436 mg, yield: 88%) was obtained. ^-NMR (400MHz, CDCl3) 5ppm: 8.50 (1H, d, J = 9Hz), 8.39 (1H, s), 7.55 (1H, s), 7.40 (1H, dd, J = 9Hz, 2Hz), 5.56 ( 1H, s), 4.96-4.86 ( 1 H, m), 4.31-4.17 (2H, m), 4.07 (2H, t, J = 9Hz), 3.28 (2H, t, J = 9Hz), 2.92-2.80 - 48- 201039827 (2H, m), 2.86 (3H, s), 2.71 (3H, m), 1.69- 1.62 (4H, m), 1.49 (9H, s); MS (ESI) m/z: 472 [M + H] + . (Example 8) 4-(methyl{6-[5-(methylsulfinyl)-2,3-dihydro-1H-indol-1-yl]pyrimidine-4- Isopropyl)piperidine-1-carboxylic acid isopropyl ester

J

The compound obtained in Example 7 (216 m g, 0, 4 5 8 mmol) was used instead of 4-(methyl{6-[5-(methylsulfonyl)-2,3-dihydro-1 fluorene-fluorene. The tert-butyl ester of -1-yl]pyrimidin-4-yl}amino)piperidine-1-carboxylate was obtained in the same manner as in Example 4 to give the title compound (125 mg, yield: 60%). *H-NMR (5 00MHz, CDCl3) 6ppm: 8_50 (1H, d, J = 9Hz), 8.39 (1H, s), 7.55 (1H, s), 7.40 (1H, dd, J = 8Hz, 2Hz), 5.56 (1H, s), 4.98-4.90 ( 1 H, m), 4.94 (1H, sept, J = 6Hz), 4.3 8-4.22 (2H, m), 4.07 (2H, t, J = 9Hz), 3.28 (2H, t, J = 9Hz), 2.96-2.83 (2H, m), 2.85 (3H, s), 2.71 (3H, s), 1.69- 1.66 (4H, m), 1.27 (6H, d, J = MS (ESI) m/z: 458 [M + H] + . (Example 9) 4-({4-[5-(methylsulfonyl)-2,3-dihydro-1H-吲哚-1-yl]pyridin-2-yl}oxy)piperidine-1-carboxylic acid tert-butyl ester

Using the compound obtained in Reference Example 7 (200 mg, 0.63 9 mmol) for the third-butyl 4-[(6-chloropyrimidin-4-yl)(methyl)amino]piperidine-1-carboxylic acid of 201039827, Example 3 was carried out in the same manner to obtain a labeled compound (3 〇 3 mg, yield: 1%). ^-NMR (400MHz, DMSO-d6) 5ppm: 8.04 (1H, d, J = 6Hz), 7.71 (1H, d, J = 2Hz), 7.67 (1H, dd, J = 9Hz, 2Hz), 7.43 (1H , d, J = 9Hz), 6.98 (1H, dd, J = 6Hz, 2Hz), 6.49 (1H, d, J = 2Hz), 5.22-5.17 (1H, m), 4.09 (2H, t, J = 9Hz ), 3.71 (2H, dt, J=14Hz, 5Hz), 3.22-3.15 (4H, m), 3.14 (3H, s), 0 1.99-1.92 (2H, m), 1.5 8- 1.5 0 (2H, m ), 1.41 (9H, s). (Example l) l-(2-{[l-(5-fluoropyrimidin-2-yl)piperidin-4-yl]oxy}pyridin-4-yl) -5-(methylsulfonyl) porphyrin

To the compound (1.85 g, 3.91 mmol) obtained in Example 9, 4N hydrochloric acid-ethyl acetate solution (18.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected from the reaction suspension, washed with hexane and then dried. One part of the obtained compound (1.70 g) (450 mg), N,N-diisopropylethylamine (956 pL, 5.49 mmol), and 2-chloro-5-fluoropyrimidine (280 pL, 2-20 mmol) of ethanol (1) 1. 3 mL) The solution was stirred at 80 ° C for 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The obtained organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography (hexane: ethyl acetate = 9:1 - 1:1, v/v) to give the title compound (3 39 mg, yield 66%). H-NMR (500MHz, CDCl3) 5ppm: -50- 201039827 8.20 (2H, s), 8.07 (1H, d, J = 6Hz), 7.74-7.71 (2H, m), 7.34 (1H, d, J = 8Hz ), 6.80 (1H, dd, J = 6Hz, 2Hz), 6.45 (1H, d, J-2Hz), 5.3 7-5.3 3 ( 1 H, m), 4.27-4.22 (2H, m), 4.09 (2H , t, J = 8Hz), 3.59 (2H, ddd, J=1 3Hz, 9Hz, 3 H z), 3 · 2 3 (2 H,t, J = 8Hz), 3.04 (3H, s), 2.12- 2.07 (2H, m), 1.83 - 1.70 (2H, m). (Example 11) l-(2-{[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy }pyridin-4-yl)-5-(methylsulfonyl)porphyrin

2-Chloro-5-ethylpyrimidine (275 pL, 2, 20 mmol) was used instead of 2-chloro-5-fluoropyrimidine, and the same procedure as in Example 1 was carried out to obtain a labeled compound (25 mg, yield: 48%). ^-NMR (5 00MHz, CDCl3) 6ppm: 8.18 (2H, s), 8.07 (1H, d, J = 6Hz), 7.73-7.71 (2H, m), 7.34 (1H, d, J = 9Hz), 6.80 (1H, dd, J = 8Hz, 2Hz), 6.45 (1H, d, ◎ J = 2Hz), 5.3 7-5.3 2 ( 1 H, m), 4.32-4.27 (2H, m), 4.09 (2H, t , J = 9Hz), 3.57 (2H, ddd, J=1 3Hz, 9Hz, 3Hz), 3.22 (2H, t, J = 8Hz), 3.04 (3H, s), 2.47 (2H, q, J = 7Hz) , 2.12-2.07 (2H, m), 1.83 - 1.76 (2H, m), 1.19 (3H, t, J = 7Hz). (Example 12) l-(2-{[l-(5-ethylpyridine) -2-yl)piperidin-4-yl]oxy}pyridin-4-yl)-5-(methylsulfonyl)porphyrin

-51 - 201039827 In a mixed solution of the compound (40 mg, 83·8 μηιο1) of ethanol (2.00 mL) and THF (2.00 mL) obtained in Reference Example 9, a palladium hydroxide-carbon (20% w/w, Wet weight, 40 mg), stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered with Celite, and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc *H-NMR (500MHz, CDCl3) 6ppm:

8.06 (1H, d, J = 6Hz), 8.05 (1H, d, J = 2Hz), 7.73 -7.70 (2H, m), 7.3 6-7.22 (2H, m), 6.80 (1H, dd, J = 6Hz , 2Hz), 6.67 (1H, d, J = 9Hz), 6.44 (1H, d, J = 2Hz), 5.3 3 -5.28 ( 1 H, m), 4.09 (2H, t, J = 9Hz), 4.00- 3.95 (2H, m), 3.37-3.3 2 (2H, m), 3.22 (2H, t, J = 9Hz), 3.04 (3H, s), 2.52 (2H, q, J = 7Hz), 2.16-2.11 ( 2H, m), 1.88-1.81 (2H, m), 1.19 (3H, t, J = 7Hz). (Example 13) 4-{3-[5-(methylsulfonyl)-2,3- Dihydro-1H-indol-1-yl]phenoxy}piperidine-1-carboxylic acid tert-butyl ester

于 In a solution of the compound (630 mg, 1.66 mmol) obtained in Reference Example 10 in methanol (30.0 mL), THF (20% w/w, wet weight, OOmg) was added under a hydrogen atmosphere. Stir for 4 hours. The reaction mixture was filtered with celite and washed with ethyl acetate. The solvent was evaporated, and the solvent was evaporated to give the residue, and the residue, and the residue of 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3 34 mg, 1.66 mmol). To the solution of toluene (30.0 mL) was added nitrilemethylenetris-n-butylphosphine (66 8 μί, 2.4 6 mmol), and the mixture was stirred under reflux for 5 hours. Water was added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=7:3, v/v) to give the title compound (557 mg, yield: 71%). ^-NMR (400MHz, CDCl3) 6ppm: 7.67-7.62 (2H, m), 7.29 (1H, t, J = 8Hz), 7.07 (1H, d,

J = 9Hz), 6.90-6.83 (1 H, m), 6.82-6.78 ( 1 H, m), 6.68-6.62 (1 H, m), 4.53-4.44 (1H, m), 4.07 (2H, t, J = 9Hz), 3.76-3.65 (2H, m), 3.41-3.31 (2H,.m), 3.19 (2H, t, J = 9Hz), 3.03 (3H, s), 1.99-1.89 (2H, m) , 1.82-1.71 (2H, m), 1.47 (9H, s). (Example 14) l-(3-{[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy Phenyl)-5-(methylsulfonyl)porphyrin

A solution of the compound (128 mg, 0.271 mmol), m. The solvent was distilled off under reduced pressure from the reaction mixture, and the obtained residue was dissolved in dimethyl carbamide ( 5.00 mL), and 2-chloro-5-ethylpyrimidine (66pL, 〇.543mmol) '1,8-diazepine was added. Heterobicyclo[5 _ 4.0 ] - 7 -undecene (1 6 2 μL, l. 〇 3 mmol ) ' was stirred at 80 ° C for 2.5 hours. A saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was applied to ethyl acetate. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4:1 - 3: 2, v/v) to afford the title compound (83 mg, yield: 64%). -53- 201039827 】Η-ΝΜΙΙ (400MHz, CDCl3) 3ppm: 8.19 (2H, s), 7.66-7.62 (2H, m), 7.30 (1H, t, J = 8Hz), 7.10 (1H, d, J = 9Hz), 6.89-6.85 (1H, m), 6.84-6.80 ( 1 H, m), 6.71-6.67 (1H, m), 4.60-4.53 (1 H, m), 4.22-4.14 (2H, m), 4.08 (2H, t, J = 9Hz), 3.70-3.61 (2H, m), 3.19 (2H, t, J = 9Hz), 3.02 (3H, s), 2.47 (2H, q, J = 7Hz), 2.08 -1.99 (2H, m), 1.89- 1.78 (2H, m), 1.20 (3H, t, J = 7Hz); MS (ESI) m/z: 479 [M + H] + . 0 (Example 15) 5-(methylsulfonyl)-1-{6-[(1-phenylpiperidin-4-yl)oxy]pyrimidin-4-yl}porphyrin

4-{6-[5-(methyl-bulk)-2,3-diazo-B-indol-1-yl]-m-throm-4-yloxy}piperidine (W02009/51119, 166 mg, 〇 _444 mmol), iodine iodide (99 pL, 0.888 mmol), palladium acetate (10 mg, 44.5 μιηο1), 2-bicyclo Q hexylphosphino-2^(N,N-dimethylamino)biphenyl (35 mg) A solution of 1,4-dioxane (5.00 mL) of 88.7 μιηο1) and sodium tributoxide (85 mg, 0.88 mmol) was stirred under reflux for 6 hours. A saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was evaporated to ethyl ether. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=7: 3-&gt;1:1, v/v) to give the title compound (74 mg, yield: 37%) 〇^-NMR (400 MHz , CDCl3) 5ppm: 8.59 (1H, d, J = 9Hz), 8.53 (1H, s), 7.79 (1H, dd, J = 9Hz, -54- 201039827 2Hz), 7.72 (1H, s), 7.32-7.25 (2H, m), 7.01-6.96 (2H, m), 6.90-6.84 ( 1 H, m), 6.01-5.98 (1H, m), 5.3 7-5.28 ( 1 H, m), 4.07 (2H, t , J = 9Hz), 3.60-3.51 (2H, m), 3.31 (2H, t, J = 9Hz), 3.17-3.07 (2H, m), 3.04 (3H, s), 2.23-2.13 (2H, m) , 2.01-1.89 (2H, m); MS (ESI) m/z: 451 [M + H] + (Example 16) 5-(methylsulfonylpyridinyl)piperidin-4-yl)oxy Pyrimidine-4-yl}porphyrin

❹ Under cold ice, 1-(2-pyridyl)-4-hydroxypiperidine (115 mg, 〇.646 mmol), 1-(6-chloropyrimidin-4-yl)-5-(methylsulfonyl) Hydroxide (63%, 26 mg, 0.655 mmol) was added to a solution of porphyrin (W Ο 2 0 0 9 / 5 1 1 1 9 , 200 mg, 0.646 mmol) in THF ( 4.00 mL). 〇 Minutes, • Heat back to 3 small E temples. After returning to room temperature, add dichloromethyl; hospital, water for liquid separation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by chromatography (hexane: ethyl acetate = 9 : 1 -&gt; 1 ·1, v / v ) to give the title compound (16 6m, yield :57% )° 'H-NMR (400MH z, CDCl3) 5ppm : 8.55 (1H, d, J = 8Hz), 8.51 (1H, s), 8.18-8.10 (1H, m), 7. 77 -7.74 ( 2H, m), 7.55-7 .40 (1H, m), 6.75-6.60 (2H, m), 6. 00 (1H, s), 5.45 -5.3 5 (1H, m), 4.15-3.95 ( 4H, m), 3. 43 -3.30 (4H, m), 3.03 (3H, s), 2 .20-2.10 (2H, m), -55- 201039827 1.95-1.80 (2H, m); MS (ESI m/z: 452 [M + H] + . (Example 17) l-(6-{[l-(5-ethylpyridin-2-yl)piperidin-4-yl]oxy}pyrimidine- 4-yl)-5-(methylsulfonyl) D porphyrin

The compound obtained in Reference Example 13 (100 mg, 0.484 mmol) was used instead of 1-(2-pyridyl)-4-hydroxypiperidine, and was carried out in the same manner as in Example 16 to give the title compound (10 mg, yield: 68%) ). *H-NMR (400MHzs CDCl3) 6ppm: 8.58 (1H, d, J = 9Hz), 8.53 (1H, s), 8.05 (1H, d, J = 2Hz), 7.79 (1H, dd, J = 9Hz, 2Hz ), 7.71 (1H, br), 7.35 (1H, dd, J = 9Hz, 2Hz), 6.67 (1H, d, J = 9Hz), 5.98 (1H, s), 5.42-5.34 (1H, m)5 4.06 (2H, t, J = 9Hz), 4.01-3.92 (2H, m), 3.40-3.29 (2H, m)s 3.31 (2H, t, J = 9Hz), 3.04 (3H, s), 2.53 (2H, q, J = 8 Hz), 2.18-2.08 (2H, m), 1.91-1.80 (2H, m), 1.20 (3H, t, J = 8 Hz). (Example 18) Methylpyridine-2-phenyl) Pyridin-4_yl]oxy}pyrimidin-4-yl)-5-(methylsulfonyl)porphyrin

Substituting 1-(2-pyridyl)-4 hydroxypiperidine' was carried out in the same manner as in Example 16 to give the title compound (1 〇 m g, yield: 5%). ^-NMR (400MHz, CDCl3) 6ppm: 8.58 (1H, d, J = 9Hz), 8.53 (1H, s), 8.03 (1H, d, J = 2Hz), 7.79 (1H, dd, J = 9Hz, 2Hz ), 7.72 (1H, br), 7.33 (1H, dd, J = 9Hz, 2Hz), 6.65 (1H, d, J = 9Hz), 5.99 (1H, s), 5.42-5.33 (1H, m), 4.06 (2H, t, J = 9Hz), 4.00-3.91 (2H, m), 3.38-3.30 (2H, m), 3.31 (2H, t, J = 9Hz), 3.04 (3H, s), 2.20 (3H, s), 2.17-2.08 (2H, m), 1.91-1.80 (2H, m).

(Example 19) l-(6-{[l-(5-isopropylpyridin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-5-(methylsulfonate) Porphyrin

The compound (130 mg, 0.590 mmol) obtained in Reference Example 15 was used instead of 1-(2-pyridyl)-4-hydroxypiperidine, and the title compound was obtained in the same manner as in Example 16 (141 mg yield: 72% h). *H-NMR (400MHz, CDCl3) 6ppm: 8.58 (1H, d, J = 9Hz), 8.53 (1H, s), 8.08 (1H, d, J = 2Hz), 7.79 (1H, dd, J = 9Hz, 2Hz), 7.72 (1H, d, J = 2Hz), 7.38 (1H, d, J = 9Hz, 2Hz), 6.68 (1H, d, J = 9Hz), 5.98 (1H, s), 5.42-5.34 (1H , m), 4.06 (2H, t, J-9Hz), 4.01-3.94 (2H, m), 3.39-3.29 (2H, m), 3.31 (2H, t, J = 9Hz), 3.04 (3H, s) , 2.83 (1H, sept, J = 7Hz), 2.18-2.09 (2H, m), 1.91-1.80 (2H, m), 1.23 (6H, d, J = 7Hz). -57- 201039827 (Embodiment 20) 1-(6-{[1-(5-fluoropyridin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-5-(methylsulfonyl)porphyrin

5-(Methylsulfonyl)-1-[6.(piperidin-4-yloxy)pyrimidin-4-yl]porphyrin hydrochloride (W02009/51119, 80 mg, 0.195 mmol), 2 A solution of 5-fluoropyroline (69 mg, 0-390 mmol) and potassium carbonate (135 mg, 0.975 mmol) in N-methylpyrrolidone (2.00 mL) was stirred at 140 ° C for 22 hours under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate=2:1 - 2:3, v/v), and the obtained crude product was washed with acetonitrile to give the title compound (15 mg, yield: 16%) ). ^-NMR (400MHz, CDCl3) 6ppm: 8.58 (1H, d, J = 9Hz), 8.53 (1H, s), 8.07 (1H, d, J = 3Hz), 7.79 (1H, dd, J = 9Hz, 2Hz ), 7.72 (1H, br), 7.30-7.23 (1 H, m), 6.67 (1H, dd, J = 9Hz, 3Hz), 5.99 (1H, s), 5.43 -5.34 (1 H, m), 4.06 (2H, t, J = 9Hz), 3.97-3.87 (2H, m), 3.40-3.32 (2H, m), 3.31 (2H, t, J = 9Hz), 3.04 (3H, s), 2.17-2.09 ( 2H, m), 1.92-1.81 (2H, m). (Example 21) 1-(6-{[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]oxy} Pyrimidin-4-yl)-5-(methylsulfonyl)porphyrin-58- 201039827

4-[6-(5·(Methylsulfonyl)-2,3-dihydroindol-1-yl)-pyrimidin-4-yloxy]-piperidine-1-carboxylate (W02009) Trifluoroacetic acid (1.0 mL) was added to a solution of methylene chloride (4.00 mL). The solvent was distilled off from the reaction mixture under reduced pressure. Toluene (1O.OmL) was added N,N-diisopropylethylamine ( 877 μί, 5.16 mmol), 2-chloro-5-fluoromethane. (76 μί, 0.620 mmol), stirred under reflux with heating under reflux for 9.5 hours. The solvent was evaporated under reduced pressure and the residue was purified (jjjjjjjjjjjjjjjjjjj %). *H-NMR (400MHz, CDCl3) 6ppm: 8.59 (1H, d, J = 9Hz), 8.53 (1H, s), 8.21 (2H, s), 7.79 (1H, dd, J = 9Hz, 2Hz), 7.73 -7.71 (1 H, m), 5.99 (1 H, s), 5.47-5.38 (1H, m), 4.29-4.19 (2H, m), 4.07 (2H, t, J = 9Hz), 3.64-3.55 ( 2H, m), 3.31 (2H, t, J = 9Hz), 3.04 (3H, s), 2.14-2.04 (2H, m), 1.86- 1.75 (2H, m); MS (ESI) m/z: 471 [M + H] + . (Example 22) 5-(methylsulfonyl)-1-(6·{[1-(5-propylsulfonium-2-yl)piperidin-4-yl]oxy Pyrimidine-4-yl)porphyrin

2-Chloro-5-propylpyrimidine (123 mg, 0.785 mmol) was used instead of 2-chloro-59-201039827-5-fluoropyrimidine, and the title compound (217 mg, yield: 84%) was obtained. • H-NMR (400MHz, CDCl3) 6ppm: 8·58 (1H, d, J = 9Hz), 8.54-8.53 ( 1 H, m), 8·17 (2H, s), 7.81-7.76 (1H, m ), 7.73-7.70 ( 1 H, m), 5.99 (1H, s), 5.46-5.38 (1H, m), 4.34 - 4.25 (2H, m), 4.07 (2H, t, J = 9Hz), 3.62- 3.53 (2H, m), 3.31 (2H, t, J = 9Hz), 3.04 (3H, s), 2.41 (2H, t, J = 8Hz), 2.15-2.06 (2H, m), 1.86- 1.75 (2H , m) q 1.63-1.52 (2H, m), 0.94 (3H, t, J = 7Hz); MS (ESI) m/z: 495 [M + H] + . (Example 23) l-(6- {[l-(5-ethylpyrimidin-2-yl)piperazin-4 alkyl]oxy}pyrimidin-4-yl)-5-(methylsulfonyl)porphyrin

2-chloro-5-ethylanthracene (66 mg, 0.463 mmol) was used instead of 2-chlorofluoropyrimidine, and was carried out in the same manner as in Example 21 to obtain the labeled compound f 1 λ U v 1 20 mg (yield: 81%). *H-NMR (400MHz, CDCl3) 6ppm: 8.58 (1H, d, J = 9Hz), 8.54-8.5 3 ( 1 H, m), 8 i9 UH&gt; s), 7.79 (1H, dd, J = 9Hz, 2Hz), 7.73 -7.70 ( 1 H,m),6 〇〇" ·98 (1H, m), 5.45-5.3 8 ( 1 H,m), 4.3 3 -4.25 (2H, m), 4 〇6 ( 2H,t, J = 9Hz), 3.62-3.53 (2H,m), 3.31 (2H,t,J = 9Hz), 3 〇4 .(3H,s), 2.47 (2H, q, J = 8Hz), 2.15-2.05 (2H, m), 1.86-1 7c ,, m), 1.20 (3H, t, J = 8Hz); -60- 201039827 MS (ESI) m/z: 481 [Μ + Η] + . Example 24) l-(6-{[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4yl)-5-(methylsulfinyl) Porphyrin

❹ Ο The compound obtained in Reference Example 16 (56 mg, 0.310 mmol), 2,3-dihydro-5-(methylsulfinyl)-(111)-fluorene (9911^, 0.31〇111111〇1) ), palladium acetate (7 mg '0.03 10 mmol), 2-dicyclohexylphosphino-2(.(Ν,Ν-dimethylamino)biphenyl (24 mg, 0_0620 mmol) and potassium carbonate (856 mg, 6.20 mmol) A solution of 1,4-dioxane (10 mL) was stirred for 2 hours under reflux. A saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was applied to ethyl acetate. The obtained residue was purified to silica gel column chromatography (ethyl acetate) toield (yield: 43%). ^-NMR (400MHz, CDCl3) 8ppm: 8.54 (1H, d, J = 9Hz), 8.52-8.51 (1H, m), 8.19 (2H, s), 7.59-7.5 6 ( 1 H, m), 7.45- 7.41 (1 H, m), 5 · 9 6 (1 H, s), 5.45-5.3 7 ( 1 H, m), 4.3 4-4.25 (2H, m), 4.04 (2H, t, J = 9Hz) , 3.62-3.5 3 (2H, m), 3.30 (2H, t, J = 9Hz), 2.71 (3H, s), 2.48 (2H, q, J = 8Hz), 2.14-2.05 (2H, m), 1.85 - 1.7 5 (2H, m), 1.20 (3H, t, J = 8Hz); MS (ESI) m/z: 465 [M + H] + . (Example 25) N-[l-(5-B Pyrimidin-2-yl)piperidin-4-yl]-N-methyl-6-[5-(methylsulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidine- 4-amine-61 - 201039827

Trifluoroacetic acid (10 mL) was added to a solution of the compound (2.94 g, 6.04 mmol. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was obtained from chloroformamide (20.0 mL), 2-chloro-5-ethylpyrimidine (1. 〇9 mL, 1.91 mmol), 1,8- Azabicyclo[5.4.0]-7-undecene (2.72 mL, 1.91 mmol) was stirred at 100 ° C for 7.5 hours. A saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was applied to ethyl acetate. The obtained residue was purified by silica gel column chromatography ((i)hexane: ethyl acetate = 3: 2 - 7: 3, (ii) methanol: dichloromethane = 1: 99 - 1: 49, v/v), The labeled compound (2.06 g - yield: 69%) was obtained. ^-NMR (400MHz, CDCl3) 6ppm: 8.54 (1H, d, J = 9Hz), 8.44-8.41 (1H, m), 8.19 (2H, s), 7.76 (1H, dd, J = 9Hz, 2Hz), 7.70-7.67 (1H, m), 5.60 (1H, s), 5.10-4.96 (1H, m), 4.94-4.85 (2H, m), 4.10 (2H, t, J = 9Hz), 3.28 (2H, t , J = 9Hz), 3.07-2.97 (5H, m), 2.85 (3H, s), 2.48 (2H, q, J = 8Hz), 1.81-1.67 (4H, m), 1.20 (3H, t, J = MS (ESI) m/z: 494 [M + H] + . (Example 26) 1-(6-{[1-(3-fluoropyridin-2-yl)piperidin-4-yl] Oxy}pyrimidin-4-yl)-5-(methylsulfonyl)porphyrin-62- 201039827

5 5-Methylsulfonyl-1-[6-(piperidin-4-yloxy)-pyrimidin-4-yl]-2,3-dihydro-1Η-indole hydrochloride (W02009/ A solution of 51119, 201 mg, 0.488 mmol), 2-chloro-3-fluoro-stadium (321 mg, 2.44 mmol) and a carbonated ( 674 mg of &lt;RTI ID=0.0&gt;&gt; Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue obtained was purified by silica gel column chromatography ((i) dichloromethane: ethyl acetate = 5:1 - 1:1, v/v, (ii)hexane: ethyl acetate = 1: 1 - 1 : 2 , v/v), the title compound (31 mg, yield: 14%) was obtained. !H-NMR (400MHz, CDCl3) 5ppm: 8.58 (1H, d, J = 9Hz), 8.53 (1H, s), 8.03 -8.00 ( 1 H, m), 7.79 (1H, d, J = 9Hz), 7.72 (1H, s), 7.27-7.19 (1H, m), 6.79-6.73 (1 H, m), 6.00 (1H, s), 5.42-5.34 (1 H, m), 4.07 (2H, t, J = 9Hz), 3.91-3.82 (2H, m), 3.39-3.3 0 (2H, m), 3.31 (2H, t, J = 9Hz), 3.04 (3H, s), 2.21-2.12 (2H, m), 1.98-1.86 (2H, m). (Example 27) l-(6-{[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl) -4-fluoro-5-(methylsulfonyl) porphyrin

To a solution of the compound (263 mg, 0.534 mmol) obtained from the title compound (m.p. After a minute, the solvent was distilled off under reduced pressure to give a crude product. To the solution of the crude product in DMF (3.000 mL) was added 1,8-azabicyclo[5.4.0]-7-~f carbon (240 μΙν, 1.60 mmol) and 2-chloro-5-ethylpyrimidine. (84 μί, 0.694 mmol), stirred at 100 ° C for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography ((i)hexane: ethyl acetate==3:1, v/v, (ii) ethyl acetate: methylene chloride = 1: 2, v/v). The compound 0 (185 mg, yield: 70%) was labeled. 'H-NMR (400MHz, CDCl3) 6ppm: 8.54 (1H, s), 8.35 (1H, d, J = 9Hz), 8.19 (2H, s), 7.82-7.76 ( 1 H, m), 5.99 (1H, s), 5.46-5.3 8 (1 H, m), 4.33 -4.24 (2H, m), 4.12 (2H, t, J = 9Hz), 3.62-3.5 3 (2H, m), 3.31 (2H, t, J = 9Hz), 3.20 (3H, s), 2.48 (2H, q, J = 8Hz), 2.14-2.05 (2H, m), 1.8 5 - 1.75 (2H, m), 1.20 (3H, t, J = 8 Hz). (Example 28) l-(6-{[l-(5-isopropylpyrimidin-2-yl)piperidin-4-yl] Q oxy}pyrimidin-4-yl)-5-( Methylsulfonyl)porphyrin

The compound obtained in Reference Example 18 (59 mg, 0.298 mmol) was used instead of 2-{4-[(6-ironopyridin-4-yl)oxy]piperazin-1-yl}-5-ethyl spray. Steep, using 5-(methylsulfonic acid) hydrazine porphyrin (l〇9mg, 0.327mmol) instead of 2,3-diamino-5-(methylsulfinyl)-(1Η)-吲哚, The title compound (137 mg, yield: 93%) was obtained in the same manner as Example !H-NMR (400MHz, CDCl3) 6ppm: 8.58 (1H,d,J = 9Hz), 8.54 - 8.52 ( 1 H,m), 8.22 (2H, s), 7.79 (1H, dd, J = 9Hz, 2Hz ), 7.73 -7.70 ( 1 H, m), 6.01-5.98 (1H, m), 5.46-5.38 (1H, m), 4.34-4.25 (2H, m), 4.07 (2H, t, J = 9Hz), 3.62-3.5 3 (2H, m), 3.31 (2H, t, J = 9Hz), 3.04 (3H, s), 2.83 -2.73 ( 1 H, m), 2.14-2.05 (2H, m), 1.86- 1.75 (2H, m), 1.24 (6H, d, J = 7Hz); MS (ESI) m/z: 495 [M + H] + . (Example 29) (±)-l-(6-{[( 3R,4S)-l-(5-ethylpyrimidin-2-yl)-3-fluoropiperidin-4yl]oxy}pyrimidin-4-yl)-4-fluoro-5 ·(methylsulfonate) Porphyrin

The compound obtained in Reference Example 20 (528 mg, 0.970 mmol)

(10% w/w, wet weight, 528 mg), stirred at room temperature for 5.5 hours under a hydrogen atmosphere. The reaction solution was filtered with Celite, and the solvent was evaporated under reduced pressure. One part (98 mg) of the obtained residue (389 mg), hydrazine, hydrazine-diisopropylethylamine (208 pL, 1, 19 mmol) and 2-chloro-5-ethylpyrimidine (90 pL, 0.716 mmol) of ethanol (3.00 mL) The solution was stirred at 80 ° C for 1 5.5 hours. The solvent was evaporated under reduced pressure, and DMF ( 3.00 mL) and 1,8-diazabicyclo[5.4.0]-7-undecene (350 μί, 2.39 mmol) were added to the residue, and stirred at 80 ° C. 13 hours. Reaction -65-201039827 A saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified to silica gel column chromatography (hexane: ethyl acetate=9:1 -1 :1, v/v) to give the title compound (41 mg, yield: 33%). *H-NMR (500MHz, DMSO-d6) 5ppm: 8.59 (1H, s), 8.36 (1H, d, J = 9Hz), 8.26 (2H, s), 7.69 (1H, t, J = 8Hz), 6.37 (1H, s), 5.54-5.45 ( 1 H, m), 5.07 (1H, d, J = 50Hz), 4.87-4.81 (1H, m), 4.56 (1H, br), 4.18 (2H, t, 〇 J = 9Hz), 3.47 (1H, dd, J = 34Hz, J=14Hz), 3.29 (2H, t, J = 9Hz), 3.26 (3H, s), 2.44 (2H, q, J = 8Hz), 2.02 -1.97 (lH,.m), 1.94-1.87 (1 H, m), 1.66-1.51 (1H, m), 1.14 (3H, t, J = 7Hz). (Example 30) N-[l-( 5-isopropylpyrimidin-2-yl)piperidin-4-yl]-N-methyl-6_[5-(methylsulfonyl)-2,3-dihydro-111-fluoren-1-yl Pyrimidine-4-amine

The compound obtained in Reference Example 24 (63 mg, 0 - 1 82 mmol) was used instead of the tert-butyl 4-[(6-chloropyrimidin-4-yl)(methyl)amino]piperidine-1-carboxylate' Example 3 was carried out in the same manner to obtain a labeled compound (7 8 mg 'yield: 85 %). • H-NMR (500MHz, DMSO-d6) 6ppm: 8.54 (1H, d, J=10Hz), 8.33 (1H, s), 8.29 (2H, s), 7.69-7.68 (2H, m), 5.84 (1H , s), 4.91 (1H, br), 4.79 (2H, br), 4.12 (2H, t, J = 9Hz), 3.26 (2H, t, J = 9Hz), 3.13 (3H, s), -66- 201039827 2.98-2.92 (2H, m), 2.85 (3H, s), 2.80-2.75 (1 H, m), 1.72-1.61 (4H, m), 1.20 (6H, d, J = 7Hz). (Example 31) N-[l-(5-isopropylpyridin-2-yl)piperidin-4-yl]-N-methyl-6-[5-(methylsulfonyl)-2,3-di Hydrogen-1H-indol-1-ylpyrimidine-4-amine

The compound (52 mg, 0.149 mmol) obtained in Reference Example 29 was used instead of the tert-butyl 4-[(6-chloropyrimidin-4-yl)(methyl)amino]piperidine-1-carboxylate, and was carried out. Example 3 was carried out in the same manner to give the title compound (42 mg, yield: 56%). !H-NMR (400MHz, CDCl3) 6ppm: 8.54 (1H, d, J = 9Hz), 8.4 1 (1H, s), 8.08 (1H, d, J = 2Hz), 7.76 (1H, dd, J = 9Hz , 2Hz), 7.69 (1H, d, J = 2Hz), 7.39 (1H, dd, J = 9Hz, 2Hz), 6.68 (1H,d, J = 9Hz), 5.60 (1H, s), 4.91 (1H, Br), 4.44-4.36 (2H, m), 4.10 (2H, t, J = 9Hz), 3.28 (2H, t, J = 9Hz), 3.03 (3H, s), 3.04-2.93 (2H, m), 2.87 (3H, s), 2.83 (1H, sept, J = 7Hz), 1.89-1.74 (4H, m), 1.23 (6H, d, J = 7Hz). (Example 32) N-[l-(5 -ethylpyridin-2-yl)piperidin-4-yl]-6-[4-fluoro-5-(methylsulfonyl)-2,3-dihydro-1H-inden-1-yl ]-N-methylpyrimidine- 4-amine

-67-201039827 The compound obtained in Reference Example 35 (155 mg, 0.468 mmol) was used instead of the tert-butyl 4-[(6-chloropyrimidin-4-yl)(methyl)amino]piperidine-1-carboxylic acid. The ester was used in the same manner as in Example 5 except that the compound (147 mg, 0.586 mmol) obtained in Reference Example 6 was used instead of 5-(methylsulfonyl) porphyrin to obtain a labeled compound (181 mg yield: 73%). h-NMR (400MHz, CDCl3) Sppm: 8.41 (1H, s), 8.31 (1H, d, J = 9Hz), 8.06 (1H, d, J = 2Hz), 7.79-7.73 (1 H, m), 7.36 (1H, dd, J = 9Hz, 2Hz), 6.67 (1H, d, J = 9Hz), 5.60 (1H, s), 4.96 (1H, br), 4.44-4.34 (2H, m), 4.15 (2H, t, J = 9Hz), 3.29 (2H, t, J = 9Hz), 3.03 - 2.93 (2H, m), 2.86 (3H, s), 2.54 (2H, q5 J = 7Hz), 1.90- 1.72 (4H, m), 1.20 (3H, t, J = 7 Hz). (Example 33) l-(6-{[l-(5-trifluoromethylpyridin-2-yl)piperidin-4-yl]oxy }pyrimidin-4-yl)-5-(methylsulfonyl)porphyrin

5-(Methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]porphyrin hydrochloride (W02009/51119, 300 mg, 0.730 mmol), 2 a solution of bromo-5-trifluoromethylpyridine (265 mg, 1.46 mmol) and N,N-diisopropylethylamine (63 6 h, 3.65 mmol) in ethanol (9.00 mL) at 70T: stirring 1 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1 - 3: -68 - 201039827, v/v) to give the title compound (100 mg, yield: 26%). ^-NMR (400MHz, CDCl3) 6ppm: 8.59 (1H, d, J = 9Hz), 8.53 (1H, s), 8.41 (1H, s), 7.79 (1H, dd, J = 9Hz, 2Hz), 7.72 ( 1H, s), 7.63 (1H, dd, J = 9Hz, 2Hz), 6.70 (1H, d, J = 9Hz), 5.99 (1H, s), 5.46-5.42 ( 1 H, m), 4.09-4.04 ( 4H, m), 3.57-3.52 (2H, m), 3.31 (2H, t, J = 9Hz), 3.04 (3H, s), 2.15-2.10 (2H, m), 1.8 8- 1.82 (2H, m) (Example 34) l-(6-{[l-(5-Cyanopyridin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-5-(methylsulfonate) Porphyrin

5-(Methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]porphyrin hydrochloride (W0200 9/5 1119, 19 0 mg, 0.511 mmol) To a solution of 2-bromo-5-cyanopyridine (93 mg, 0.511 mmol) in DMF (5.70 mL) was added 1,8-diazabicyclo[5,4,0]-7-undecene (153 μί 〇1.60 mmol), stirred at 100 ° C for 3.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography (hexane: ethyl acetate = 4:1 - 2: 3, v/v) to afford the title compound (155 mg, yield: 76%). ^-NMR (400MHz, CDCl3) 6ppm: 8.58 (1H, d, J = 9Hz), 8.53 (1H, s), 8.42 (1H, d, J = 2Hz), 7.80 (1H, dd, J = 9Hz, 2Hz ), 7.73 (1H, d, J = 2Hz), 7.62 (1H, dd, -69- 201039827 J = 9Hz, 2Hz), 6.66 (1H, d, J = 9Hz), 6.00 (1H, s), 5.48- 5.43 (1H, m), 4.09-4.03 (4H, m), 3.64-3.5 8 (2H, m), 3.32 (2H, ts J = 9Hz), 3.04 (3H, s), 2.15-2.08 (2H, m ), 1.90-1.82 (2H, m). (Example 35) l-(6-{[l-(5-Methoxypyridin-2-yl)piperidin-4-yl]

5-(Methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]porphyrin hydrochloride (W02009/5 1 1 19, 1 70 mg) , (0.456 mmol), 2-bromo 5-methoxyindole ratio (72 mg, 0.610 mmol), ginseng (diphenylidene acetonide) two (6 mg, hydrazine, hydrazine 6 mmol), (-)-(R) -N,N-dimethyl-l-[(S)-2-(diphenylphosphino)ferrocenyl]-ethylamine (9 mg, 0.021 mmol) and sodium butoxide (219 mg, A solution of 2.28 mmol) in toluene (8.50 mL) was stirred for 4 hours under heat. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography (ethyl acetate, 1 EtOAc) toield (yield: 3%). • H-NMR (400MHz, CDCl3) 6ppm: 8.58 (1H, d, J=8Hz), 8.53 (1H, s), 7.95 (1H, d, J = 3Hz), 7.79 (1H, dd, J = 8Hz, 2Hz), 7.72 (1H, s), 7.16 (1H, dd, J = 8Hz, 2Hz), 6.70 (1H, d, J = 9Hz), 5.99 (1H, s), 5.3 9-5.3 3 ( 1 H, m), 4.06 (2H, t, J = 9Hz), 3.91-3.86 (2H, m), 3.80 (3H, s), 3.32-3.28 (4H, m), 3.04 (3H, s), 2.16-2.11 ( 2H, m), 1.91-1.84 -70-201039827 (2H, m). (Example 36) 1-(6-{[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl] Oxy}pyrimidin-4-yl)-5-(morpholine-4-ylcarbonyl)porphyrin

To a solution of the compound (23 mg, 0.0507 mmol) obtained in Reference Example 38, dimethylformamide (2.00 mL) was added 4-{4,6-dimethoxy[1,3,5] 〇trim- 2-Base}-4-methylmorpholine-4-key (21 mg, 0.0761 mmol) and stirred for 20 minutes. Further, morphine (9 pL, 0.10 lmmol) was added to the reaction mixture and stirred for 1 hour. Further, water was added to the reaction mixture, and the mixture was extracted with EtOAc. The obtained residue was purified to silica gel column chromatography (hexane: ethyl acetate=4: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> *H-NMR (400MHz, CDCl3) 6ppm: 8.50-8.48 ( 1 H, m), 8.39 (1H, d, J = 8Hz), 8.19 (2H, s), O 7.34-7.31 (1H, m), 7.28 -7.24 (1H, m), 5.96-5.94 (1 H, m), 5.44-5.3 6 ( 1 H, m), 4.3 3 -4.25 (2H, m), 4.00 (2H, t, J = 9Hz), 3.76-3.53 ( 1 0H, m), 3.25 (2H, t, J = 9Hz), 2.47 (2H, q, J = 7Hz), 2.14-2.05 (2H, m), 1.85- 1.74 (2H, m), 1-20 (3H, t, J = 7 Hz); MS (ESI) m/z: 5 1 6 [M + H] + (Example 37) l-(6-{[l-(5-ethyl) Pyrimidine_2_yl) piperazine_4-yl]oxy}pyrimidin-4-yl)-N-(2-methoxyethyl)porphyrin_5_formamide-71- 201039827

2-Methoxyethylamine (17b [, 0.196111111〇1) was used instead of the phenanthroline. The title compound (41 mg, yield: 85%) was obtained. *H-NMR (400MHz, CDCl3) 6ppm: 8.52-8.49 ( 1 H, m), 8.40 (1H, d, J = 8Hz), 8.19 (2H, s), O 7.70-7.66 (1H, m), 7.65 -7.60 (1H, m), 6.54-6.47 ( 1 H, m), 5.96 (1H, s), 5.44-5.3 6 ( 1 H, m), 4.34-4.25 (2H, m), 4.01 (2H, t , J = 9Hz), 3.6 8 -3.49 (6H, m), 3.40 (3H, s), 3.25 (2H, t, J = 9Hz), 2.47 (2H, q, J = 7Hz), 2.15-2.05 (2H , m), 1.86-1.74 (2H, m), 1.20 (3H, t, J = 7Hz); MS (ESI) m/z: 504 [M + H] + . (Example 38) l-(6- {[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N-(2-hydroxyethyl)porphyrin-5-carboxamide

The title compound (29 mg, yield: 53%) was obtained by the same procedure as in Example 36, using ethanolamine (20 μM, 0.336 mmol) instead of chloroform. !H-NMR (400MHz, CDCl3) 5ppm: 8.49-8.48 ( 1 H, m), 8.36 (1H, d, J = 9Hz), 8.19 (2H, s), 7.66-7.62 (1 H, m), 7.62 -7.57 (1H, m), 6.79-6.72 (1H, m), -72- 201039827 5.92 (1H, s), 5.43-5.34 (1H, m), 4.33-4.24 (2H, m), 3.96 (2H, t, J = 9Hz), 3.83 (2H, t, J = 5Hz), 3.65 -3.52 (4H, m), 3.20 (2H, t, J = 9Hz), 2.47 (2H, q, J = 7Hz), 2.13 -2.04 (2H, m), 1.85-1.74 (2H, m), 1.19 (3H, t, J = 7 Hz); MS (ESI) m/z: 490 [M + H] + . (Example 39) l -(6-{[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N,N-bis(2-methoxyethyl) Porphyrin-5-carboxamide

Using bis(2-methoxyethyl)amine (87 pL, 0.589 mmol) in place of the phenanthroline, the title compound (55 mg, yield: 66%) was obtained in the same manner as in Example 36. !H-NMR (400MHz, CDCl3) 5ppm: 8.50-8.48 (1 H, m), 8.36 (1H, d, J = 9Hz), 8.19 (2H, s), 7.32-7.27 (2H, m), 5.95 ( 1H, s), 5.44-5.3 5 ( 1 H, m), 4.34-4.24 (2H, m), 3.99 (2H, t, J = 9Hz), 3.81-3.16 (18H, m), 2.47 (2H, q , J = 7Hz), 2.14-2.05 (2H, m), 1.86- 1.74 (2H, m), 1.20 (3H, t, J = 7Hz); MS (ESI) m/z: 5 62 [M + H] (Example 40) l-(6-{[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N-(2-A Oxyethyl)-N-methyl porphyrin-5-formamide-73- 201039827

XT was replaced with N-(2-methoxyethyl)methylamine (53 μί, 0.500 mmol) to give the title compound (47 mg, yield: 73%). *H-NMR (400MHz, CDCl3) 5ppm: 8.5 0-8.48 ( 1 H, m), 8.36 (1H, d, J = 9Hz), 8.19 (2H, s),

Cl U 7·34-7.25 (2H, m), 5.95 (1H, s), 5.44-5.3 6 ( 1 H, m), 4·33-4.24 (2H, m), 3.99 (2H, t, J = 8Hz), 3.76-3.45 (6H, m), 3·36 (3H, br), 3.24 (2H, t, J = 9Hz), 3.10 (3H, s), 2.47 (2H, q, J^7Hz), 2.14-2.04 (2H, m), 1.8 6- 1.75 (2H, m), 1.20 (3H, t, J = 7Hz); MS (ESI) m/z: 518 [M + H] + . (Example 41 L-(6-{[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N-[(2S)-2-hydroxypropyl Porphyrin-5-carboxamide

(S)-(+)-l-Amino-2-propanol (50 μί, 0.63 3 mmol) was used in the same manner as in Example 36 to give the title compound (72 mg, yield: 91%). iH-NMR (500MHz, CDCl3) 5ppm: 8.51-8.49 (1H, m), 8.41 (1H, d, J = 8Hz), 8.19 (2H, s), -74- 201039827 7.70-7.66 (1 H, m) , 7.63 - 7.5 9 ( 1 H, m), 6.5 6-6.50 (1H, m), 5.96 (1H, s), 5.43 -5.3 6 ( 1 H, m), 4.32-4.25 (2H, m), 4.09 -3.98 (3H, m), 3.68-3.62 (1H, m), 3.62-3.53 (2H, m), 3.36-3.29 (1 H, m), 3.25 (2H, t, J = 9Hz), 2.75-2.71 (1H, m), 2.47 (2H, q, J = 7Hz), 2.13-2.05 (2H, m), 1.84- 1.75 (2H, m), 1.26 (3H, d, J = 6Hz), 1.20 (3H, t, J = 7 Hz); MS (ESI) m/z: 504 [M + H] + (Example 42) l-(6-{[l-(5-ethylpyrimidin-2-yl)piperidine 4-yl]oxoyl}pyrimidin-4-yl)-N-[(lR)-2-hydroxy-1-methylethyl]porphyrin_5-carboxylic acid hydrazine

(R)-(-)-2-Amino-1-propanol (55 μί, 0.700 mmol) was used instead of the phenanthroline to carry out the same procedure as in Example 36 to give the title compound (6 8 mg, yield 7. 7 7 % ).

*H-NMR (400MHz, CDCl3) 6ppm: 8.52-8.48 ( 1 H, m), 8.40 (1H, d, J = 9Hz), 8.19 (2H, s), 7.68-7.63 ( 1 H, m), 7.62 -7.56 (1 H, m), 6.30-6.21 (1H, m), 5.95 (1H, s), 5.45-5.3 5 ( 1 H, m), 4.35-4.22 (3H, m), 4.01 (2H, t , J-9Hz), 3.83 -3.75 (1 H, m), 3.70-3.62 ( 1 H, m), 3.62-3.52 (2H, m), 3.25 (2H, t, J = 9Hz), 3.11-3.03 ( 1H, m), 2.47 (2H, q, J = 7Hz), 2.14-2.03 (2H, m), 1.86- 1.74 (2H, m), 1.30 (3H, d, J = 7Hz), 1.20 (3H, t , J = 7 Hz); -75- 201039827 MS (ESI) m/z: 504 [M + H] + . (Example 43) l-(6-{[l-(5-ethylpyrimidin-2-yl) Piperidin-4-yl]oxy}pyrimidin-4-yl)-N-(3-hydroxypropyl)porphyrin-5-carboxamide

XT was treated with 3-amino-1-propanol (51 μί, 0.676 mmol) in the same manner as in Example 36 to give the title compound (54 mg, yield: 63%). • H-NMR (400MHz, CDCl3) 6ppm: 8.51-8.49 (1H, m), 8.41 (1H, d, J = 9Hz), 8.19 (2H, s), 7-70-7.67 (1 H, m), 7.61-7.56 (1H, m), 6.57-6.51 (1H, m), 5·97-5.95 ( 1 H, m), 5.44-5.3 6 ( 1 H, m), 4.33-4.24 (2H, m), 4·〇1 (2H, t, J = 9Hz), 3.71 (2H, t, J = 5Hz)s 3.67-3.52 (4H, m), 3·26 (2H, t, J = 9Hz), 2.48 (2H , q, J = 7Hz), 2.14-2.05 (2H, m), 1.86-1.74 (4H, m), 1.20 (3H, t, J = 7Hz); 〇MS (ESI) m/z: 5 04 [M + H] + . (Example 44) l-(6-{[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N-[ (2R)-2-hydroxypropyl]porphyrin-5-carboxamide

(R)-(-)-l-Amino-2-propanol (52pL, 0.659mmol) was used in the same manner as in Example 36 to obtain the labeled compound (51 mg, yield -76-.201039827 rate: 61%). iH-NMR (400MHz, CDCl3) Sppm:

8.52-8.5 0 ( 1 H, m), 8.41 (1H, d, J = 8Hz), 8.19 (2H, s), 7.70-7.67 ( 1 H, m), 7.63 -7.59 (2H, m), 6.5 6 -6.50 ( 1 H, m), 5.96 (1H, s), 5.44-5.3 6 ( 1 H, m), 4.3 3 -4.24 (2H, m), 4.08-3.97 (3H, m), 3.69-3.62 ( 1 H, m), 3.62-3.5 3 (2H, m), 3.3 7-3.28 ( 1 H, m), 3.26 (2H, t, J = 9Hz), 2.78-2.72 (1 H, m), 2.47 ( 2H, q, J = 7Hz), 2.14-2.05 (2H, m), 1.85- 1.74 (2H, m), 1.26 (3H, d, J = 6Hz), 1.20 (3 H,t,J = 7 Hz) MS (ESI) m/z: 504 [M + H] + . (Example 45) l-(6-{[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy 5-pyrimidin-4-yl)-N-(2-hydroxyethyl)-N-methylporphyrin-5-carboxamide

N-methylethanolamine (56 pL, 0.692 mmol) was used instead of the morpholine' oxime to give the title compound (69 mg, yield: 79%). 'H-NMR (400MHz, CDCl3) 6ppm: 8.52-8.49 ( 1 H, m), 8.39 (1H, d, J = 9Hz), 8.19 (2H, s), 7.37 (1H, s), 7.33 (1H, d, J = 8Hz), 5.96 (1H, s), 5.44-5.3 6 ( 1 H, m), 4.34-4.24 (2H, m), 4.01 (2H, t, J = 9Hz), 3.96-3.82 (2H , m), 3.77-3.62 (2H, m), 3.62-3.5 3 (2H, m), 3.25 (2H, t, J = 9Hz), 3.11 (3H, s), 2.47 (2H, q, J = 7Hz ), 2.15-2.05 (2H, m), -77- 201039827 1.86- 1.75 (2H, m), 1.20 (3H, t, J = 7Hz); MS (ESI) m/z: 504 [M + H] + (Example 46) l-(6-{[l-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N-[(lS)- 2-hydroxy-1-methylethyl]porphyrin-5-formamide

( Using (S)-(+)-2-amino-1-propanol (54 kL, 0.68 8 mmol) in place of the phenanthroline, the title compound (65 mg, yield: 75%) was obtained in the same manner as in Example 36. !H-NMR (400MHz, CDCl3) 5ppm: 8.52-8.49 (1 H, m), 8.40 (1H, d, J = 9Hz), 8.19 (2H, s), 7.6 8-7.65 ( 1 H, m), 7.63 -7.5 7 ( 1 H, m), 6.25 -6.20 ( 1 H, m), 5.96 (1H, s), 5.44-5.36 (1H, m), 4.33-4.24 (3H, m), 4.01 (2H, t, J = 9Hz), 3.82-3.76 (1 H, m), 3.69-3.62 ( 1 H, m), 3.62-3.53 Ο (2H, m), 3.25 (2H, t, J = 9Hz), 3.05- 2.92 (1 H, m), 2.47 (2H, q, J = 7Hz), 2.14-2.05 (2H, m), 1.85- 1.74 (2H, m), 1.30 (3H, d, J = 7Hz), 1.20 ( 3H, t, J = 7 Hz); MS (ESI) m/z: 504 [M + H] + . (Examples 47 to 50) The following compounds can also be produced with reference to the above Reference Examples and Examples. [Table 1] -78-201039827 Example R1 R4 47 -C(0)NHCH2CH(0H)CH20H 5-ethylpyridin-2-yl 48-C(0)N(CH3)CH2CH(0H)CH20H 5-B Base eye steep-2-yl 49 -C(0)NHCH2CH(0H)CH20H 5-trifluoromethylpyridin-2-yl 50-C(0)N(CH3)CH2CH(0H)CH20H 5-trifluoromethyl Pyridin-2-yl

(Formulation Example) 5 g of the compound obtained in the examples, 90 g of lactose, 34 g of corn starch, 20 g of crystallization cellulose, and lg of magnesium stearate were mixed with a stirrer, and then tableted by a tableting machine to obtain a tablet. (Test Example 1) Mouse OGTT (Oral Glucose Tolerance Test) The test compound was weighed in an amount of 2.0 to 8 mg of the test compound, and then placed in an agate mortar, and the compound was pulverized while adding a 0.5% methylcellulose solution. A suspension of 1 mg/ml was prepared. Mouse C57/BL6J (male, 6-8 weeks old) was purchased from Charlesriver, Japan, and was bred in cages to 9 to 13 weeks of age. The food was fasted from 17 to 18 pm on the day before the test implementation day. Until the test. After the blood is collected from the tail vein on the day of the implementation, the suspension prepared in advance is orally administered. After administration for 30 minutes, blood was collected from the tail vein (at this time, plasma serum was used as pre値), and then 20 to 30% glucose solution was orally administered in an amount of 10 ml/kg to carry out glucose load. After the glucose load, blood was collected from the tail vein at 15, 30, 60, and 120 minutes. The blood taken is separated by centrifugation to separate the plasma. Pre-値, blood glucose levels at 15, 30, 60, and 120 minutes after glucose load were measured by Glucoroder GXT (Shino-Test Co., Ltd.), and the AUC reduction rate (%) of blood glucose was calculated relative to the vehicle administration group. -79- 201039827 Further, a 0.5% methylcellulose solution was added to replace the suspension of the compound with respect to the vehicle administration group. [Table 2] Compound AUC reduction rate (%) Compound AUC reduction rate (%) Example 2 6 Example 25 12 Example 4 16 Example 27 20 Example 6 26 Example 2_8 10 Example 8 23 Example 38 16 Example 16 8 Example 41 11 Example 19 10 Example 42 20 Example 21 17 Example 43 22 Example 22 21 Example 45 18 Example 23 31 Example 46 9 Example 24 18 (Test Example 2) Large The concentration of the compound in the blood of the rat was measured by weighing 20 to 50 mg of the test compound, and then the mixture was placed in an agate mortar, and the compound was pulverized, and a 0.5% methylcellulose solution was added thereto to prepare a suspension of 2.5 mg/ml. F3 44 rats (male, 5 to 7 weeks old) were purchased from Charlesriver, Japan, and Q was fasted from 17 to 18 o'clock on the day before the test implementation day, and continued to fast until the test. After measuring the body weight of the rats on the day of the test, the test compound was orally administered at a dose of 1 Omg/kg, and administered after 5, 1, 2, 4, 6 and 24 hours, blood was collected from the tail vein. The blood taken is separated by centrifugation to separate the plasma. The plasma was subjected to deproteinization treatment, and then supplied to a liquid chromatography/mass analyzer to calculate the concentration of the compound in the plasma. (Test Example 3) Rat 〇GTT (oral glucose tolerance test) The test compound was weighed in an amount of 200 mg, and then placed in an agate mortar, and the compound was pulverized while adding a 0.5% methylcellulose solution to prepare 7.5 mg/ml. Suspension. In the case of preparing other suspensions, the suspension prepared in advance in -80-201039827 is diluted with a 0.5% methylcellulose solution to prepare a suspension. Zucker fatty rats and Zucker Diabetic Fatty rats (male, 8-12 weeks old) were purchased from Charlesriver, Japan, and the groups were adjusted in the same manner as the basic blood glucose level and body weight of the group were administered before the test. The food was started between 15 and 18 o'clock before the implementation date and the food was continued until the test. After the blood was collected from the tail vein on the day of the test, the previously prepared suspension was orally administered. After administration for 30 minutes, blood was collected from the tail vein (at this time, plasma blood was removed as pre値), and a 50% grape 0 sugar solution was orally administered at a dose of 4 ml/kg to carry out a glucose load. After the glucose load, blood was collected from the tail vein at 30 minutes, 1, 2, and 4 hours. The blood taken is separated by centrifugation to separate the plasma. Pre-値, plasma glucose, 30 minutes, 1, 2, and 4 hours after glucose load was measured by Glucoroder GXT (Shino-Test Co., Ltd.), and the AUC reduction rate (%) of blood glucose was calculated relative to the vehicle administration group. . Further, a 0.5% methylcellulose solution was added to replace the suspension of the compound with respect to the vehicle administration group. INDUSTRIAL APPLICABILITY The compound of the present invention or a pharmaceutically acceptable salt thereof is useful for treating and/or preventing type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other causes, and tolerance to glucose insufficiency An effective component of a pharmaceutical composition for use in diabetes, related diseases, and diabetes complications. [Simple description of the diagram] 4nr no 0 [Description of main component symbols]

/flTT no 0

Claims (1)

201039827 VII. Patent application scope: 1. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof Wherein R1 is -S(0)-Rn, -SiOh-R11, -S(NH)(0)-R&quot; or -C(0)-NR12R13; R&quot; is C1-C6 alkyl; R12 or Each of R13 is independently a hydrogen atom or a C1 to C6 alkyl group which may have 1 to 3 substituents selected from the substituent group α, or Ri2 and r&quot; together with the nitrogen atom to which they are combined form a kofolinyl group. The substituent group α is a group consisting of a halogen atom, a hydroxyl group, and a C1 to C6 alkoxy group; m is an integer of 0 to 5; R2 is the same or a different halogen atom; η is an integer of 0 to 4; R3 is The same or different halogen atoms; R4 is -C(0)-0-R41, a phenyl group which may have 1 to 3 substituents selected from the substituent group ρ, may have 1 to 3 substituent groups selected a shame-steep group of a substituent of β, or a pyrimidyl group which may have 1 to 3 substituents selected from the substituent group β; R41 is a C1-C6 alkyl group which may be substituted by a halogen atom; and a substituent group β is a halogen group a group of an atom, a Cl~c6-82-201039827 alkyl group which may be substituted by a halogen atom, a Cl~C6 alkoxy group which may be substituted by a halogen atom, and a cyano group; X is CH or N; Y is CH or N; Is Ο or NR5; R5 is a hydrogen atom or C1- C6 alkyl; if 'X and Y are both N, Z is 0, and R4 is -C(0)-〇-R41, R1 is -S(NH)(0)-Rn or -C(〇) -NR12R13]. q 2· As claimed in the first item of the patent scope, R1 is - SCOhR11. 3. For the compound of claim 1, the R1 is - SCOh-R1, 4. The compound of claim 2 or 3, and the R11 is the Cl~C3 compound. 5. If the compound of claim 1 is claimed, R1 is -C(0)-NR12R13. 6. The compound of claim 5, wherein each of Rl2 or R!3 is independently a hydrogen atom or a C1 to C3 alkyl group which may have 1 to 3 substituents selected from the substituent group α. 7. A compound of claim 5, wherein R12 and R13 together with the nitrogen atom to which they are combined form a morpholinyl group. 8. The compound of any one of claims 1 to 7 wherein m is 〇 or 1. 9. The compound of any one of claims 1 to 8, wherein n is 〇 or 1 〇1 〇. As the compound of any one of claims 1 to 9, R4 has 1 selection. The phenyl group which is a substituent of the substituent group β may have a pyridyl group which is a substituent selected from the substituent group β, or a pyrimidyl group which may have one substituent selected from the substituent group Ρ. -83-201039827 1 1. The compound of any one of claims 1 to 1 wherein χ is N and Y is N. 12. The compound of any one of claims 1 to 11, wherein z is hydrazine. A compound selected from the group consisting of a pharmaceutically acceptable salt thereof, which is: 1-(2 - {[1-(5-ethylpyridin-2-yl)piperidin-4-yl ]oxy}pyridin-4-yl)-5-(methylsulfonyl)porphyrin; 1-(6-{[1-(5-ethylpyridin-2-yl)piperidin-4-yl Oxy}pyrimidin-4-yl)-5-(methylsulfonyl)porphyrin; 1-(6-{[1-(5-isopropylpyridin-2-yl)piperidine-4 -yl]oxy}pyrimidin-4-yl)-5-(methylsulfonyl)porphyrin; 1-(6-{[1_(5-ethylpyrimidin-2-yl)piperidin-4-yl Oxy}pyrimidin-4-yl)-5-(methylsulfinyl)porphyrin; 1-(6-{ [1-(5-isopropylpyrimidin-2-yl)piperidine-4 -yl]oxy}pyrimidin-4-yl)-5-(methylsulfonyl)porphyrin; 1-(6-{[1-(5-trifluoromethylpyridin-2-yl)piperidine 4-yl]oxy}pyrimidineQ-4-yl)-5-(methylsulfonyl)porphyrin; [1-(5-methoxypyridin-2-yl)piperidin-4-yl Oxy}pyrimidin-4-yl)-5-(methylsulfonyl)porphyrin; 1-(6-{[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl) Oxy}pyrimidin-4-yl)-N-(2-methoxyethyl)porphyrin-5-formamide; 1-(6-{[1-(5-ethylpyrimidin-2-) Piperidin-4- Alkyloxypyrimidin-4-yl)-N-(2-hydroxyethyl)porphyrin-5-carboxamide; 1-(6-{[1-(5-ethylpyrimidin-2-yl) Piperidin-4-yl]oxy}pyrimidin-4-yl)-N-[(2S)-2-hydroxypropyl]porphyrin-5-carboxamide; -84- 201039827 1-(6- {[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N-[(2R)-2-hydroxypropyl]porphyrin-5 -Procarbamide; and 1-(6-{[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]oxy}pyrimidin-4-yl)-N-(2-hydroxyethyl Base) -N-methyl porphyrin-5-formamide. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient. 15. A pharmaceutical composition according to claim 14 for use in the treatment and/or prevention of type 1 diabetes, type 2 diabetes, diabetes related diseases or obesity. The use of a compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition. 17. A method of treating and/or preventing a disease comprising administering a pharmaceutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof to a mammal . 18. The method of claim 17, wherein the mammal is a human. -85- 201039827 IV. Designation of Representative Representatives (1) The representative representative of the case is: None. (2) A brief description of the component symbols of this representative figure: None. 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: (f) z /, 3 \(R3) (I)