WO2010119881A1

WO2010119881A1 - Indoline compound

Info

Publication number: WO2010119881A1
Application number: PCT/JP2010/056646
Authority: WO
Inventors: 雄本田; 克治影近; 俊雄金子; 瑞香横山; 貴之馬場; 健志田; 康嗣松本; 隆太郎中島
Original assignee: 第一三共株式会社
Priority date: 2009-04-15
Filing date: 2010-04-14
Publication date: 2010-10-21
Also published as: TW201039827A

Abstract

Disclosed is a compound having a novel structure and an excellent hypoglycemic action, or a pharmaceutically acceptable salt of the compound. Specifically disclosed is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

Description

Indoline compounds

The present invention relates to a novel indoline compound having a hypoglycemic action or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these compounds or a pharmaceutically acceptable salt thereof as active ingredients.

Diabetes is a metabolic disease mainly characterized by chronic hyperglycemia due to insufficient insulin action. For the treatment of diabetes, drug therapy is generally administered together with diet therapy and exercise therapy. Oral hypoglycemic agents that are a type of anti-diabetic agent include biguanides or thiazolidinediones that improve insulin resistance, sulfonylureas or glinides that promote insulin secretion from pancreatic β cells, and α that inhibit sugar absorption -Glucosidase inhibitors are used.

However, biguanides have side effects such as lactic acidosis, thiazolidinedione has weight gain and edema, sulfonylureas and glinides have secondary effects due to hypoglycemia and long-term use, and α-glucosidase inhibitors have diarrhea and other side effects. It has been reported. Therefore, development of an oral hypoglycemic agent that solves such problems is desired.

In recent years, pyrimidine compounds, piperidine-1-carboxylate compounds, and the like have been developed as oral hypoglycemic agents having a new structure (see, for example, Patent Documents 1 to 5).

International Publication No. 05/7647 Pamphlet International Publication No. 05/121121 Pamphlet International Publication No. 06/83491 Pamphlet International Publication No. 07/3962 Pamphlet WO09 / 51119 pamphlet

However, the compounds described in Patent Documents 1 to 4 have a problem that it is difficult to obtain a sufficient hypoglycemic effect. On the other hand, the patent document 5 discloses an indoline compound, but it is a patent document filed before the priority date of the present application and published after the priority date. Therefore, the present invention provides a compound having a novel structure that is not described or suggested in Patent Documents 1 to 4 and having an excellent hypoglycemic action, or a pharmaceutically acceptable salt thereof, and a sugar It is an object of the present invention to provide a pharmaceutical composition having an excellent therapeutic effect and / or preventive effect on type 1 diabetes, type 2 diabetes and the like, which cause an increase in blood sugar due to metabolic abnormality.

The present invention
(1) General formula (I):

[Where,
R ¹ is -S (O) -R ¹¹ , -S (O) ₂ -R ¹¹ , -S (NH) (O) -R ¹¹ or -C (O) -NR ¹² R ¹³ ;
R ¹¹ is a C1-C6 alkyl group,
R ^{12 and} R ¹³ are each independently a hydrogen atom or a C1-C6 alkyl group optionally having 1 to 3 substituents selected from the substituent group α, or R 12 ¹² and R ¹³ together with the nitrogen atom to which they are attached form a morpholino group,
Substituent group α is a group consisting of a halogen atom, a hydroxyl group and a C1-C6 alkoxy group,
m is an integer from 0 to 5,
R ² is the same or different and is a halogen atom;
n is an integer from 0 to 4,
R ³ is the same or different and is a halogen atom;
R ⁴ represents —C (O) —OR ⁴¹ , a phenyl group optionally having 1 to 3 substituents selected from the substituent group β, and 1 to 3 substituents selected from the substituent group β. A pyridinyl group which may have 3 or a pyrimidinyl group which may have 1 to 3 substituents selected from the substituent group β,
R ⁴¹ is a C1-C6 alkyl group optionally substituted with a halogen atom,
Substituent group β is a group consisting of a halogen atom, a C1-C6 alkyl group optionally substituted with a halogen atom, a C1-C6 alkoxy group optionally substituted with a halogen atom, and a cyano group,
X is CH or N;
Y is CH or N;
Z is O or NR ⁵
R ⁵ is a hydrogen atom or a C1-C6 alkyl group,
Provided that when X and Y are both N, Z is O and R ⁴ is —C (O) —OR ⁴¹ , R ¹ is —S (NH) (O) —R ¹¹ or — C (O) -NR ¹² R ¹³ )
Or a pharmaceutically acceptable salt thereof,
(2) The compound according to (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ is —S (O) —R ¹¹ ;
(3) The compound or a pharmaceutically acceptable salt thereof according to (1), wherein R ¹ is —S (O) ₂ —R ¹¹ ,
(4) The compound or a pharmaceutically acceptable salt thereof according to the above (2) or (3), wherein R ¹¹ is a C1-C3 alkyl group,
(5) The compound according to (2) or (3) above, wherein R ¹¹ is a methyl group, or a pharmaceutically acceptable salt thereof,
(6) The compound or a pharmaceutically acceptable salt thereof according to (1), wherein R ¹ is —C (O) —NR ¹² R ¹³ ;
(7) each of R ^{12 and} R ¹³ independently represents a hydrogen atom or a C1-C3 alkyl group optionally having 1 to 3 substituents selected from the substituent group α, (6) or a pharmaceutically acceptable salt thereof,
(8) R ¹² or R ¹³ is each independently a hydrogen atom, a C1-C3 alkyl group, a C1-C3 alkoxy C1-C3 alkyl group, a hydroxy C1-C3 alkyl group or a dihydroxy C1-C3 alkyl group. The compound according to (6) or a pharmaceutically acceptable salt thereof,
(9) R ¹² or R ¹³ each independently represents a hydrogen atom, a methyl group, — (CH ₂ ) ₂ OCH ₃ , — (CH ₂ ) ₂ OH, — (CH ₂ ) ₃ OH, —CH ₂ CH (CH ₃ ) OH, —CH (CH ₃ ) CH ₂ OH or —CH ₂ CH (OH) CH ₂ OH, the compound according to (6) above or a pharmaceutically acceptable salt thereof,
(10) The compound according to (6) or a pharmaceutically acceptable salt thereof, wherein R ¹² and R ¹³ together with the nitrogen atom to which they are bonded form a morpholino group,
(11) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (10), wherein m is 0 or 1.
(12) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (10), wherein m is 0,
(13) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (10), wherein m is 1 and R ² is a fluorine atom,
(14) The compound according to any one of the above (1) to (13) or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
(15) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (13), wherein n is 0,
(16) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (13), wherein n is 1 and R ³ is a fluorine atom,
(17) R ⁴ is a phenyl group which may have one substituent selected from substituent group β, and a pyridyl group which may have one substituent selected from substituent group β Or a compound according to any one of (1) to (16) above or a pharmaceutically acceptable salt thereof, which is a pyrimidinyl group optionally having one substituent selected from substituent group β. Obtain salt,
(18) R ⁴ is a pyridyl group which may have one substituent, and the substituent is substituted with a halogen atom, a C1-C3 alkyl group which may be substituted with a halogen atom, or a halogen atom. The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (16), selected from the group consisting of C1-C3 alkoxy groups which may optionally be:
(19) R ⁴ is an optionally substituted pyridyl group, and the substituent is selected from a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a trifluoromethyl group, and a methoxy group. The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (16), selected from the group consisting of:
(20) R ⁴ is a pyrimidinyl group which may have one substituent, and the substituent is substituted with a halogen atom, a C1-C3 alkyl group which may be substituted with a halogen atom, or a halogen atom. The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (16), selected from the group consisting of C1-C3 alkoxy groups which may optionally be:
(21) R ⁴ is a pyrimidinyl group optionally having one substituent, and the substituent is selected from a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a trifluoromethyl group, and a methoxy group. The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (16), selected from the group consisting of:
(22) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (16), wherein R ⁴ is —C (O) —OR ⁴¹ ,
(23) The compound or a pharmaceutically acceptable salt thereof according to the above (22), wherein R ⁴¹ is a C1-C3 alkyl group optionally substituted with a halogen atom,
(24) The compound or a pharmaceutically acceptable salt thereof according to (22), wherein R ⁴¹ is an ethyl group optionally substituted with a fluorine atom or an isopropyl group optionally substituted with a fluorine atom. ,
(25) The compound according to any one of (1) to (24), wherein X is N and Y is N,
(26) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (25), wherein Z is O,
(27) A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof:
1- (2-{[1- (5-Ethylpyridin-2-yl) piperidin-4-yl] oxy} pyridin-4-yl) -5- (methylsulfonyl) indoline; 1- (6-{[1 -(5-Ethylpyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline; 1- (6-{[1- (5-isopropylpyridin-2) -Yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline; 1- (6-{[1- (5-ethylpyrimidin-2-yl) piperidin-4-yl ] Oxy} pyrimidin-4-yl) -5- (methylsulfinyl) indoline; 1- (6-{[1- (5-isopropylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl ) -5- (methylsulfonyl) indoline; 1- (6-{[1- (5-trifluoromethylpyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methyl Sulfonyl) indoline; 1- (6-{[1- (5-methoxypyridin-2-yl) piperidi N-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline; 1- (6-{[1- (5-ethylpyrimidin-2-yl) piperidin-4-yl] oxy} Pyrimidin-4-yl) -N- (2-methoxyethyl) indoline-5-carboxamide; 1- (6-{[1- (5-ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidine- 4-yl) -N- (2-hydroxyethyl) indoline-5-carboxamide; 1- (6-{[1- (5-ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidine-4- Yl) -N-[(2S) -2-hydroxypropyl] indoline-5-carboxamide; 1- (6-{[1- (5-ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidine- 4-yl) -N-[(2R) -2-hydroxypropyl] indoline-5-carboxamide; and 1- (6-{[1- (5-ethylpyrimidin-2-yl) piperidin-4-yl] oxy } Pyrimidin-4-yl) -N- (2-hydroxyethyl) -N-methylindoline-5- Carboxamide,
(28) A pharmaceutical composition comprising as an active ingredient the compound according to any one of (1) to (27) or a pharmaceutically acceptable salt thereof,
(29) The pharmaceutical composition according to the above (28), for treating and / or preventing type 1 diabetes, type 2 diabetes, diabetes-related disease or obesity,
(30) Use of the compound according to any one of (1) to (27) or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition,
(31) Treating a disease and / or comprising administering to a mammal a pharmacologically effective amount of the compound according to any one of (1) to (27) or a pharmaceutically acceptable salt thereof How to prevent, and
(32) The method according to (31) above, wherein the mammal is human.
I will provide a.

INDUSTRIAL APPLICABILITY According to the present invention, an indoline compound having an excellent hypoglycemic action or a pharmaceutically acceptable salt thereof, and an excellent therapeutic effect and / or preventive effect for type 1 diabetes, type 2 diabetes, etc. A pharmaceutical composition can be provided.

In the present specification, the “C1-C6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group, isohexyl group and the like.

In this specification, “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, the “C1-C6 alkoxy group” refers to a group in which the “C1-C6 alkyl group” is bonded to an oxygen atom. Specific examples include methoxy group, ethoxy group, propoxy group, butoxy group, pentyloxy group, hexyloxy group and the like.

In the present specification, the “pharmaceutically acceptable salt” refers to a salt formed by reacting the compound of the present invention with an acid.

Examples of the salt include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; hydrochloride, nitrate, perchlorate, sulfate, phosphate, etc. Inorganic acid salts; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; acetate and malic acid Examples thereof include organic acid salts such as salts, fumarate, succinate, citrate, ascorbate, tartrate, oxalate and maleate.

The compound of the present invention represented by the general formula (I), for example, when left in the atmosphere, absorbs moisture and attaches adsorbed water, and may form a hydrate. Japanese salts are also included in the salts of the present invention.

Since the compound of the present invention represented by the general formula (I) may have an asymmetric carbon atom in the molecule, optical isomers exist. These isomers and mixtures of these isomers are all represented by a single formula, i.e. general formula (I). Therefore, the compound of the present invention represented by the general formula (I) includes all optical isomers and mixtures of optical isomers in an arbitrary ratio.

The present invention can also include compounds in which one or more of the atoms that constitute a compound of the present invention is replaced by an isotope of that atom. There are two types of isotopes: radioisotopes and stable isotopes. Examples of isotopes include hydrogen isotopes ( ² H and ³ H), carbon isotopes ( ¹¹ C, ¹³ C and ¹⁴ C), nitrogen isotopes ( ¹³ N and ¹⁵ N), oxygen isotopes ( ¹⁵ O, ¹⁷ O and ¹⁸ O), fluorine isotopes ( ¹⁸ F) and the like. A composition containing a compound labeled with an isotope is useful, for example, as a therapeutic agent, prophylactic agent, research reagent, assay reagent, diagnostic agent, in vivo diagnostic imaging agent, and the like. Isotopically labeled compounds are also encompassed by the compounds of the invention, and any mixture of isotope-labeled compounds in any proportion is also encompassed by the compounds of the invention. The isotope-labeled compound of the present invention can be produced by a method known in the art, for example, by using an isotope-labeled raw material instead of the raw material in the production method of the present invention described later. .

R ¹ is preferably —S (O) —R ¹¹ , —S (O) ₂ —R ¹¹ or —C (O) —NR ¹² R ¹³ . R ¹¹ is preferably a C1-C3 alkyl group, and more preferably a methyl group. R ¹² is preferably a hydrogen atom or a C1 to C3 alkyl group optionally having 1 to 3 substituents selected from the substituent group α, more preferably a hydrogen atom, C1 to A C3 alkyl group, a hydroxy C1-C3 alkyl group, or a C1-C3 alkoxy group, a C1-C3 alkyl group, and still more preferably a hydrogen atom, a methyl group, a 2-hydroxyethyl group, or a 2-hydroxypropyl group. R ¹³ is preferably a hydrogen atom or a C1 to C3 alkyl group optionally having 1 to 3 substituents selected from the substituent group α, more preferably a hydrogen atom, C1 to A C3 alkyl group, a hydroxy C1-C3 alkyl group, or a C1-C3 alkoxy group, a C1-C3 alkyl group, and still more preferably a hydrogen atom, a methyl group, a 2-hydroxyethyl group, or a 2-hydroxypropyl group. It is also preferred that R ¹² and R ¹³ together with the nitrogen atom to which they are bonded form a morpholino group.

M is preferably 0 or 1.

R ² is preferably a fluorine atom.

N is preferably 0 or 1.

R ³ is preferably a fluorine atom.

R ⁴ is preferably a phenyl group which may have one substituent selected from the substituent group β, and a pyridyl group which may have one substituent selected from the substituent group β. Or a pyrimidinyl group which may have one substituent selected from substituent group β, more preferably a halogen atom, a C1-C3 alkyl group optionally substituted with a halogen atom, and a halogen A pyridyl group optionally having one substituent selected from the group consisting of C1-C3 alkoxy groups optionally substituted with atoms, or a halogen atom, C1-optionally substituted with halogen atoms A pyrimidinyl group optionally having one substituent selected from the group consisting of a C3 alkyl group and a C1 to C3 alkoxy group optionally substituted with a halogen atom, still more preferably a fluorine atom, methyl Group A pyridyl group, a fluorine atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group, which may have one substituent selected from the group consisting of an alkyl group, a propyl group, an isopropyl group, a trifluoromethyl group, and a methoxy group A pyrimidinyl group optionally having one substituent selected from the group consisting of a group, a trifluoromethyl group and a methoxy group.

R ⁴¹ is preferably a C1-C3 alkyl group which may be substituted with a halogen atom, more preferably an ethyl group which may be substituted with a fluorine atom, or isopropyl which may be substituted with a fluorine atom. It is a group.

X is preferably N. Y is preferably N. More preferably, X is N and Y is N. Z is preferably O. Provided that when Z is O and R ⁴ is -C (O) -OR ⁴¹ , R ¹ is -S (NH) (O) -R ¹¹ or -C (O) -NR ¹² R ¹³ It is.

R ⁵ is preferably a hydrogen atom or a C1-C3 alkyl group, and more preferably a methyl group.

Among the compounds of the present invention represented by the general formula (I), a preferable combination of substituents is that R ¹ is -S (O) -R ¹¹ , -S (O) ₂ -R ¹¹ or -C (O)- NR ¹² R ¹³ , m is 0, n is 0, and R ⁴ may have one substituent selected from substituent group β, or substituent group β A pyrimidinyl group optionally having one substituent selected from X, CH is N or Y, Y is N, and Z is O.

A more preferable combination of substituents is that R ¹ is —S (O) ₂ —R ¹¹ , m is 0, n is 0, and R ⁴ is a substituent selected from substituent group β. A combination of R ¹ is —S (O) ₂ —R ¹¹ , and m is a pyridyl group that may be present, X is CH, Y is N, and Z is O. 0, n is 0, R ⁴ is a pyridyl group optionally having one substituent selected from the substituent group β, X is N, Y is N, and A combination in which Z is O, R ¹ is —S (O) ₂ —R ¹¹ , m is 0, n is 0, and R ⁴ is a substituent selected from the substituent group β A combination of the following: a pyrimidinyl group that may be present, X is N, Y is N, and Z is O; and R ¹ is —S (O) —R ¹¹ , m Is 0, n is 0, and R ⁴ is a pyrimidinyl group optionally having one substituent selected from substituent group β, and X Is a combination wherein R is N, Y is N and Z is O, R ¹ is —C (O) —NR ¹² R ¹³ , m is 0, n is 0, and R ⁴ Is a pyrimidinyl group optionally having one substituent selected from the substituent group β, a combination in which X is N, Y is N, and Z is O.

An even more preferred combination of substituents is R ¹ is a methylsulfonyl group, m is 0, n is 0, and R ⁴ is a pyridyl group having one C1-C6 alkyl group as a substituent, A combination in which X is CH, Y is N, and Z is O, R ¹ is a methylsulfonyl group, m is 0, n is 0, and R ⁴ is substituted with a halogen atom A pyridyl group having one optionally substituted C1-C6 alkyl group or one optionally substituted C1-C6 alkoxy group substituted with a halogen atom, X is N, Y is N, and A combination in which Z is O, R ¹ is a methylsulfinyl group, m is 0, n is 0, R ⁴ is a pyrimidinyl group having one C1-C6 alkyl group as a substituent, and X is Combinations of N, Y is N, and Z is O, R ¹ is —C (O) —NH— (CH ₂ ) ₂ —OCH ₃ , —C (O) —NH— (CH ₂ ) ₂ -O H, -C (O) -NH-CH ₂ CH ₂ (CH ₃ ) -OH, m is 0, n is 0, and R ⁴ is a substituent selected from substituent group β. A combination that may have one pyrimidinyl group, X is N, Y is N, and Z is O

The compound of the present invention can be produced, for example, by the following methods A to F. The indoline-based intermediate, benzene-based intermediate, pyridine-based intermediate, pyrimidine-based intermediate, and piperidine-based intermediate in the following production methods are, for example, J. Med. Chem, 41, 1998, 1598-1612, Bioorg Med. Chem. Lett., 2002, 12, 3105-3110, Chem. Pharm. Bull., 1993, 41, 529-538, J. Org. Chem., 53, (1988), 2047-2052, WO2003 / 47586, WO2006 / 76243, WO2009 / 51119 and the like. In addition, commercially available indoline derivatives, benzene derivatives, pyridine derivatives, pyrimidine derivatives, and piperidine derivatives may be used as the above intermediates.

When post-processing is required in each construction method, for example, post-processing may be performed according to the following procedure. Water is added to the reaction solution, and the product is extracted with an organic solvent such as ethyl acetate. The obtained organic layer is washed with water and saturated brine, and dried with a drying agent such as anhydrous magnesium sulfate and sodium sulfate. Subsequently, 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 Method A, in general formula (I), X and Y are both N, Z is O, and R ¹ is -S (O) -R ¹¹ or -S (O) ₂ -R ¹¹ One compound of the present invention, or in the general formula (I), one of X and Y is N, the other is CH, Z is O, and R ¹ is -S (O) Compounds of the invention that are —R ¹¹ or —S (O) ₂ —R ¹¹ can be prepared.

In Method B, in general formula (I), X and Y are both N, Z is NR ⁵ , and R ¹ is -S (O) -R ¹¹ or -S (O) ₂ -R ¹¹ Or in the general formula (I), one of X and Y is N, the other is CH, Z is NR ⁵ , and R ¹ is -S ( Compounds of the invention that are O) -R ¹¹ or -S (O) ₂ -R ¹¹ can be prepared.

In Method C, in general formula (I), X and Y are both CH, Z is O, and R ¹ is -S (O) -R ¹¹ or -S (O) ₂ -R ¹¹ Certain compounds of the invention can be prepared.

In Method D, in general formula (I), X and Y are both CH, Z is NR ⁵ , and R ¹ is -S (O) -R ¹¹ or -S (O) ₂ -R ¹¹ Can be produced.

In Method E, a compound of the present invention in which R ¹ is —S (O) (NH) —R ¹¹ in the general formula (I) can be produced.

In Method F, a compound of the present invention in which R ¹ is —C (O) —NR ¹² R ¹³ in general formula (I) can be produced.

The explanation of each process in the A to F method is described below.

(In the formula, X ^a and Y ^a are both N, or one of them is N and the other is CH, and R ^1a is —S (O) —R ¹¹ or —S ( O) ₂ -R ¹¹ and m, n, R ¹¹ , R ² , R ³ and R ⁴ are as described above.)

Step A-I is a step for producing compound (3) by reacting compound (1) with compound (2) in the presence of a base.

Examples of the solvent used include tetrahydrofuran (THF), 1,4-dioxane, cyclopentylmethyl ether, dimethylformamide (DMF), dimethylacetamide, and the like, preferably THF or DMF.

Examples of the base used include tert-butoxy potassium, tert-butoxy sodium, cesium carbonate, potassium carbonate, sodium hydride, N, N-diisopropylethylamine, and preferably tert-butoxy potassium, sodium hydride. Or N, N-diisopropylethylamine.

The reaction temperature is 0 to 150 ° C, preferably 20 to 130 ° C. The reaction time is 30 minutes to 24 hours, preferably 30 minutes to 6 hours.

Step A-II is a step for producing compound (Ia) of the present invention by reacting compound (3) obtained in step A-I with compound (4) by Buchwald-Hartwig reaction using a palladium catalyst.

The palladium catalyst, ligand, base and reaction conditions to be used are not particularly limited as long as they are reagents and conditions usually used for the Buchwald-Hartwig reaction.For example, A. R. Muci, S. L. Buchwald, Top. Curr. Chem. 2002, 219, 巻 p.131.

A preferred palladium catalyst is palladium (II) acetate or palladium (0) dibenzylideneacetone, more preferably palladium (II) acetate.

Preferred ligands are tricyclohexylphosphine, 1,3-bis (phenylphosphono) propane, 2,2'-bis (diphenylphosphanyl) -1,1'-binaphthyl, 2- (dicyclohexylphosphono) biphenyl or 2- Dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl is preferred, and 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl is more preferred.

Preferred bases are sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium or tert-butoxy potassium, more preferably potassium carbonate.

A preferred solvent is toluene or 1,4-dioxane, more preferably 1,4-dioxane.

The reaction temperature is preferably 20 to 150 ° C. The reaction time is preferably 30 minutes to 12 hours.

(In the formula, Q is a halogen atom, and m, n, R ^1a , R ² , R ³ , R ⁴ , R ⁵ , X ^a and Y ^a are as described above.)

Step B-I is a step of producing compound (6) by reacting compound (1) with compound (5) in the presence of a base.

The solvent used, the base used, the reaction temperature and the reaction time are the same as in the A-I step.

Step B-II is a step of producing compound (8) by reacting compound (6) obtained in step B-I with halogenated alkyl (7) in the presence of a base.

Examples of the solvent used include THF, 1,4-dioxane, cyclopentyl methyl ether, DMF, dimethylacetamide, and the like, and preferably DMF.

Examples of the base used include tert-butoxypotassium, cesium carbonate, potassium carbonate, sodium hydride, N, N-diisopropylethylamine, and preferably sodium hydride.

Examples of the halogenated C1-C6 alkyl used include methyl bromide, methyl iodide, ethyl bromide, methyl iodide, and the like, preferably methyl iodide.

The reaction temperature is 0 to 150 ° C, preferably 20 to 60 ° C. The reaction time is 30 minutes to 24 hours, preferably 30 minutes to 6 hours.

Step B-III is a step of producing Compound (Ib) of the present invention by reacting Compound (8) obtained in Step B-II with Compound (4) by Buchwald-Hartwig reaction using a palladium catalyst. It is.

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

(In the formula, m, n, Q, R ^1a , R ² , R ³ and R ⁴ are as described above.)

In the CI step, compound (9) is reacted with compound (2) by the method described in TetsuoetsuTsunoda, Fumie Ozaki, and Sho Ito, Tetrahedron Lett., 1994, 35, p.5081 and the like. 10).

Examples of the solvent to be used include benzene, toluene, xylene and the like, and preferably toluene.

Examples of the reagent to be used include cyanomethylenetri n-butylphosphine.

The reaction temperature is 30 to 150 ° C, preferably 100 to 130 ° C. The reaction time is 30 minutes to 12 hours, preferably 1 to 6 hours.

Step C-II is a step for producing compound (Ic) of the present invention by reacting compound (10) obtained in CI step with compound (4) by Buchwald-Hartwig reaction using a palladium catalyst. .

(Wherein m, n, Q, R ^1a , R ² , R ³ , R ⁴ and R ⁵ are as described above.)

Step D-I is a step of producing compound (13) by reacting compound (11) with compound (12) in the presence of a reducing agent.

Examples of the solvent used include methylene chloride, THF, acetonitrile (containing acetic acid), and the like, and preferably THF.

Examples of the reducing agent to be used include sodium triacetoxyborohydride and sodium cyanoborohydride, and sodium triacetoxyborohydride is preferable.

The reaction temperature is 0 to 50 ° C, preferably 20 to 30 ° C. The reaction time is 30 minutes to 12 hours, preferably 1 to 6 hours.

Step D-II is a step of producing compound (14) by reacting compound (13) obtained in step D-I with halogenated C1-C6 alkyl (7) in the presence of a base.

The solvent, base, halogenated C1-C6 alkyl, reaction temperature, and reaction time are the same as in Step B-II.

Step D-III is a step of producing compound (Id) of the present invention by reacting compound (14) obtained in step D-II with compound (4) by Buchwald-Hartwig reaction using a palladium catalyst. It is.

(In the formula, m, n, R ¹¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y and Z are as described above.)

Method E is obtained from compound (20) in which R ¹ in the general formula (I) is -S (O) -R ¹¹ , Carl R. Johnson, Robert A. Kirchhoff, H. Glenn Corkins, J. Org. Chem. , 1974, p. 2458, etc., to produce the compound (Ie) of the present invention.

Examples of the solvent used include methylene chloride and dichloroethane, and methylene chloride is preferred.

Examples of the reagent to be used include O-mesitylenesulfonylhydroxylamine.

The reaction temperature is 0 to 40 ° C, preferably 10 to 30 ° C. The reaction time is 30 minutes to 36 hours, preferably 2 to 24 hours.

(In the formula, m, n, Q, R ¹² , R ¹³ , R ² , R ³ , R ⁴ , X, Y and Z are as described above.)

The FI step is a step of producing the compound (24) by reacting the compound (22) with the compound (23) by the Buchwald-Hartwig reaction using a palladium catalyst.

The F-II step is a step of producing the compound (25) by hydrolyzing the compound (24) obtained in the F-I step.

Examples of the solvent used include THF, ethanol, methanol, isopropyl alcohol, and the like, and preferably methanol.

Examples of the reagent used include an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, and an aqueous lithium hydroxide solution, and an aqueous sodium hydroxide solution is preferable.

The reaction temperature is 0 to 130 ° C, preferably 50 to 70 ° C. The reaction time is 30 minutes to 12 hours, preferably 30 minutes to 4 hours.

When post-processing is necessary in this step, post-processing may be performed according to the following procedure. After neutralizing the solution with 1N hydrochloric acid, the compound (25) is extracted with an organic solvent, and the obtained organic layer is dried with a desiccant such as sodium sulfate or anhydrous magnesium sulfate. Next, the solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel chromatography, or the solvent is distilled off under reduced pressure, and then an aqueous sodium hydroxide solution is added, and the resulting precipitate is collected by filtration. And wash with water, ethyl acetate, etc.

The F-III step is a step of producing the compound (If) of the present invention by reacting the compound (25) obtained in F-II with the compound (26) in the presence of a condensing agent.

Examples of the solvent used include alcohols, THF, 1,4-dioxane, DMF, dimethylacetamide and the like, preferably alcohols or DMF, more preferably DMF.

The condensing agent to be used is not particularly limited as long as it is used in the amidation reaction.For example, R. C. Larock, Comprehensive Organic Transformations. Second Edition, 1999, John Wiley & Sons, Inc. And the like. Specific examples include phosphate esters such as diethyl phosphoryl cyanide; carbodiimides such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC). Imidazoles such as 1,1'-carbonyldiimidazole (CDI); 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT- MM); O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-1-yl-N, N , N ', N'-tetramethyluronium, phosphates such as hexafluorophosphate (HBTU), and the like, preferably DMT-MM.

The reaction temperature is 0 to 100 ° C., preferably 0 to 50 ° C. The reaction time is 30 minutes to 96 hours, preferably 1 to 12 hours.

Since the compound of the present invention represented by the general formula (I) obtained by the above method or a pharmaceutically acceptable salt thereof has an excellent hypoglycemic action, it has type 1 diabetes, type 2 diabetes, gestational diabetes, and others. Hyperglycemia, impaired glucose tolerance (IGT), diabetes related diseases (eg obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema) , Heart failure, angina pectoris, myocardial infarction, arteriosclerosis, hyperuricemia, gout, etc.) or diabetic complications (eg retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) It can be used as an active ingredient of a pharmaceutical composition that can be used for treatment and / or prevention.

The pharmaceutical composition containing the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof is administered to a mammal (eg, human, horse, cow, pig, etc., preferably human). If so, it can be administered systemically or locally, orally or parenterally.

The pharmaceutical composition of the present invention can be prepared by selecting an appropriate form according to the administration method and preparing various preparations usually used.

Examples of the form of an oral pharmaceutical composition include tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, syrups, elixirs and the like. The preparation of such a pharmaceutical composition includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, anti-fouling agents, ordinarily used as additives. An oxidizing agent, a coloring agent, a solubilizing agent, a suspending agent, an emulsifying agent, a sweetening agent, a preservative, a buffering agent, a diluent, a wetting agent and the like are appropriately selected as necessary, and can be produced according to a conventional method.

The forms of parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. Agents and the like. Preparation of the pharmaceutical composition in such a form involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, and dissolution agents that are commonly used as additives. Adjuvants, buffering agents, isotonic agents, surfactants, colorants, buffering agents, thickeners, wetting agents, fillers, absorption enhancers, suspending agents, binders, etc. are selected as necessary. However, it can be produced according to a conventional method.

The dose of the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof varies depending on symptoms, age, body weight, etc., but in the case of oral administration, 1 to several times a day 1 to 2000mg, preferably 1 to 400mg per compound per adult, and 0.01 to 500mg per compound per adult once or several times a day for parenteral administration The amount is preferably 0.1 to 300 mg.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, Formulation Examples and Test Examples, but the scope of the present invention is not limited thereto.

Reference Example 1 tert-butyl 4-[(6-chloropyrimidin-4-yl) amino] piperidine-1-carboxylate 4,6-dichloropyrimidine (1.55 g, 10.4 mmol), tert-butyl 4-aminopiperidine To a solution of -1-carboxylate (2.50 g, 12.5 mmol) in DMF (25.0 mL), N, N-diisopropylethylamine (2.70 mL, 15.6 mmol) was added 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 the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 1, v / v) to obtain the title compound (3.24 g, yield: 97%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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), 1.55- 1.33 (2H, m), 1.47 (9H, s).

Reference Example 2 tert-butyl 4-[(6-chloropyrimidin-4-yl) (methyl) amino] piperidine-1-carboxylate DMF (10.0 of the compound (887 mg, 2.84 mmol) obtained in Reference Example 1 To the solution, add sodium hydride (63% mineral oil dispersion, hereinafter sometimes referred to simply as sodium hydride (63%)) (162 mg, 4.25 mmol), and stir at room temperature for 10 minutes, followed by iodination Methyl (283 μL, 4.25 mmol) was added and stirred at room temperature for 20 minutes. A saturated aqueous ammonium chloride solution 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 the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 2: 1, v / v) to obtain the title compound (867 mg, yield: 94%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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), 1.48 (9H, s).

Reference Example 3 4-Fluoro-5-isothiocyanatoindoline To a solution of 4-fluoroindoline (1.12 g, 8.17 mmol) and potassium thiocyanate (2.24 g, 24.4 mmol) in methanol (24.5 mL) under ice-water cooling A saturated sodium bromide-methanol (5.50 mL) solution of bromine (437 μL, 17.1 mmol) was added and stirred for 1.5 hours. Water was added to the reaction mixture under cooling with ice water, neutralized with sodium carbonate, and extracted three times with ethanol. The organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 4: 1, v / v) to obtain the title compound (828 mg, yield: 52%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
7.25-7.20 (1H, m), 6.37 (1H, d, J = 8Hz), 4.15 (1H, br), 3.72 (2H, t, J = 9Hz), 3.12 (2H, t, J = 9Hz).

Reference Example 4 4-Fluoro-5- (methylthio) indoline Sodium sulfide nonahydrate (1.02 g, 4.26 mmol) in water (1.60 mL) was added to the compound (816 mg, 4.20 mmol) obtained in Reference Example 3. ) In ethanol (7.50 mL) was added, and the mixture was stirred at 50 ° C. for 2 hours. A solution of iodomethane (670 μL, 5.78 mmol) in ethanol (1.50 mL) was added to the reaction mixture, and the mixture was stirred at 50 ° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted 3 times with ether. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 11: 9, v / v) to obtain the title compound (703 mg, yield: 91%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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).

Reference Example 5 tert-Butyl 4-fluoro-5- (methylthio) indoline-1-carboxylate To a solution of the compound obtained in Reference Example 4 (350 mg, 1.91 mmol) in dichloromethane (5.00 mL) was added dicarbonate (tert -Butyl) (790 μL, 3.44 mmol) and triethylamine (620 μL, 4.44 mmol) were added and stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 4: 1, v / v) to obtain the title compound (743 mg, yield: 100%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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) indoline hydrochloride To a solution of the compound (2.08 g, 7.34 mmol) obtained in Reference Example 5 in dichloromethane (20.0 mL), m-chloroperbenzoic acid (ca .65%, 3.38 g, 12.8 mmol) was added under ice-water cooling, and the mixture was stirred for 1 hour. A 10% aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Left. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 2, v / v). This compound was suspended in ethyl acetate (10.0 mL), 4N hydrochloric acid-ethyl acetate solution (10.0 mL) was added, and the mixture was stirred at room temperature for 1.5 hours and allowed to stand for 14 hours. The reaction solution was filtered, and the resulting crude product was washed with a mixed solvent of ethyl acetate and diisopropyl ether to obtain the title compound (1.42 g, yield: 61%).
¹ H-NMR (400MHz, CD ₃ OD) δppm:
7.59-7.53 (1H, m), 6.58 (1H, d, J = 8Hz), 3.78 (2H, t, J = 9Hz), 3.17 (2H, t, J = 9Hz), 3.16 (3H, s).

Reference Example 7 tert-butyl 4-[(4-chloropyridin-2-yl) oxy] piperidine-1-carboxylate tert-butyl 4-hydroxypiperidine-1-carboxylate (3.40 g, 16.9 mmol) in THF To the (50.0 mL) solution, tert-butoxypotassium (2.84 g, 25.3 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was added dropwise to a solution of 2,4-dichloropyridine (1.82 mL, 16.9 mmol) in THF (50.0 mL) at 70 ° C. and stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 7: 3, v / v) to obtain the title compound (3.29 g, yield: 62%).
¹ H-NMR (500MHz, DMSO-d ₆ ) δppm:
8.16 (1H, d, J = 5Hz), 7.10 (1H, dd, J = 5Hz, 2Hz), 6.96 (1H, d, J = 2Hz), 5.20-5.15 (1H, m), 3.68 (2H, dt, J = 14Hz, 5Hz), 3.16 (2H, br), 1.96-1.91 (2H, m), 1.57-1.50 (2H, m), 1.40 (9H, s).

Reference Example 8 2- [4-({4- [5- (Methylsulfonyl) -2,3-dihydro-1H-indol-1-yl] pyridin-2-yl} oxy) piperidin-1-yl] Pyridine-5-carbaldehyde To a solution of the compound obtained in Example 9 (230 mg, 0.486 mmol) described later in dichloromethane (2.30 mL) was added 4N hydrochloric acid-ethyl acetate solution (2.30 mL) at room temperature, and 1.5 mL at room temperature. Stir for hours. The solvent was distilled off under reduced pressure, and a part (178 mg) of the obtained compound (181 mg), N, N-diisopropylethylamine (378 μL, 2.17 mmol), and 6-chloro-nicotinaldehyde (61 mg, 0.434 mmol) Of ethanol (5.34 mL) was stirred at 80 ° C. for 21 hours. Saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 0: 1, v / v) to obtain the title compound (140 mg, yield: 67%).
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
9.78 (1H, s), 8.56 (1H, 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), 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), 5.42-5.38 (1H, m), 4.15-4.08 (4H, m), 3.70-3.65 (2H, m), 3.23 (2H, t, J = 8Hz), 3.04 (3H, s) , 2.16-2.10 (2H, m), 1,91-1.85 (2H, m).

Reference Example 9 5- (methylsulfonyl) -1- (2-{[1- (5-vinylpyridin-2-yl) piperidin-4-yl] oxy} pyridin-4-yl) indoline methyl iodide To a solution of phenylphosphonium (118 mg, 0.293 mmol) in THF (1.18 mL) was added a 38% THF solution (154 μL) of hexamethyldisilazane sodium salt at room temperature, and the mixture was stirred at room temperature for 30 minutes. A solution of the compound obtained in Reference Example 8 (140 mg, 0.293 mmol) in THF (1.18 mL) was added to the reaction solution while cooling in an ice bath, and the mixture was stirred at room temperature for 30 minutes. Saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 3: 7, v / v) to obtain the title compound (44 mg, yield: 32%).
¹ H-NMR (500MHz, CD ₃ OD) δppm:
7.17 (1H, d, J = 2Hz), 7.14 (1H, d, J = 6Hz), 6.86-6.84 (1H, m), 6.78-6.74 (1H, m), 6.69-6.74 (2H, m), 6.69 -6.65 (1H, 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 (1H, m), 4.23 (1H, d, J = 11Hz), 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 1- [3- (benzyloxy) phenyl] -5- (methylsulfonyl) indoline 5- (methylsulfonyl) indoline (197 mg, 1.00 mmol), 3-benzyloxybromobenzene (263 mg, 1.00 mmol) , Palladium acetate (22 mg, 0.100 mmol), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (95 mg, 0.200 mmol) and sodium tert-butoxy (241 mg, 2.50 mmol) The dioxane (20.0 mL) solution was stirred with heating under reflux for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 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 by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 2, v / v) to obtain the title compound (307 mg, yield: 81%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
7.66-7.60 (1H, m), 7.60-7.56 (1H, m), 7.47-7.25 (6H, m), 6.93 (1H, d, J = 9Hz), 6.88-6.82 (2H, m), 6.77-6.70 (1H, 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, 7.79 mmol), 4-hydroxypiperidine (1.50 g, 11.7 mmol) and A solution of potassium carbonate (3.23 g, 23.4 mmol) in DMF (20.0 mL) was stirred at 100 ° C. for 17 hours under a 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 the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1, v / v) to obtain the title compound (1.32 g, yield: 66%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.18 (1H, d, J = 2Hz), 7.51 (1H, dd, J = 9Hz, 2Hz), 6.58 (1H, d, J = 9Hz), 4.04-3.88 (3H, m), 3.20-3.11 (2H, m), 2.01-1.91 (2H, m), 1.62-1.51 (2H, m), 1.46 (1H, d, J = 4Hz).

Reference Example 12 1- (5-Vinylpyridin-2-yl) piperidin-4-ol The compound obtained in Reference Example 11 (1.54 g, 5.99 mmol), vinylboronic acid pinacol ester (2.00 mL, 12.0 mmol), Palladium acetate (130 mg, 0.599 mmol), 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl (470 mg, 1.20 mmol) and potassium carbonate (2.48 g, 18.0 mmol) in 1,4-dioxane A suspension of (80.0 mL) and water (20.0 mL) was heated to reflux under a nitrogen atmosphere for 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 saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 2: 3, v / v) to give a crude product (1.30 g) of the title compound.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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 = 11Hz), 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, m), 1.46 (1H, d, J = 4Hz).

Reference Example 13 1- (5-Ethylpyridin-2-yl) piperidin-4-ol To a solution of the crude product (1.30 g) obtained in Reference Example 12 in ethanol (25.0 mL) was added palladium-carbon (10% w / w, wet, 200 mg) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 2: 3, v / v) to obtain the title compound (925 mg, yield: 75% for 2 steps in total).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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 (1H, 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 (158 mg, 0.194 mmol) and potassium carbonate (804 mg, 5.82 mmol) in a mixed solution of 1,4-dioxane (6.00 mL) and water (600 μL) were added trimethylboroxine (271 μL, 1.94 mmol), nitrogen The mixture was heated to reflux for 2.5 hours under an 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 the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography ((i) hexane: ethyl acetate = 3: 1 → 1: 3, v / v, (ii) dichloromethane: ethyl acetate = 2: 1 → 2: 3, v / v) To obtain the title compound (141 mg, yield: 38%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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, 2.44 mmol), 2-chloro-5- (1-methylethyl) pyridine (Journal of Medicinal Chemistry., 1980, 23, p.93, 80 mg, 2.44 mmol), palladium acetate (55 mg, 0.244 mmol), 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl (192 mg, 0.488) mmol) and potassium carbonate (6.75 g, 48.8 mmol) in 1,4-dioxane (12.0 mL) were heated to reflux for 9 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 1: 1, v / v), and the resulting crude product was subjected to basic silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 2: 1, v / v) to obtain the title compound (140 mg, yield: 26%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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] piperidin-1-yl} -5-ethylpyrimidine 1- (5-ethyl-2-pyrimidinyl) -4-piperidinol ( To a solution of WO2008 / 008895 (368 mg, 1.78 mmol) in THF (20.0 mL) was added tert-butoxypotassium (299 mg, 2.67 mmol), and the mixture was stirred for 20 minutes. Furthermore, 4,6-dichloropyrimidine (318 mg, 2.13 mmol) was added to the reaction solution under ice water cooling, and the mixture was stirred for 30 minutes while warming to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 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 by silica gel column chromatography (hexane: ethyl acetate = 19: 1 → 4: 1, v / v) to obtain the title compound (313 mg, yield: 55%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.57 (1H, s), 8.19 (2H, s), 6.77 (1H, s), 5.45-5.37 (1H, 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), 1.86-1.72 (2H, m), 1.20 (3H, t, J = 7Hz).

Reference Example 17 tert-butyl 4-({6- [4-fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indol-1-yl] pyrimidin-4-yl} oxy) piperidine- 1-carboxylate tert-butyl 4-[(6-chloropyrimidin-4-yl) (methyl) amino] piperidine-1-carboxylate instead of tert-butyl 4-[(6-chloropyrimidin-4-yl) The title compound (276 mg, yield: 91%) was obtained in the same manner as in Example 5 using oxy] piperidine-1-carboxylate (193 mg, 0.614 mmol).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.51 (1H, s), 8.34 (1H, d, J = 9Hz), 7.82-7.76 (1H, m), 5.98 (1H, s), 5.35-5.29 (1H, m), 4.12 (2H, t, J = 9Hz), 3.84-3.75 (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).

Reference Example 18 2- {4-[(6-chloropyrimidin-4-yl) oxy] piperidin-1-yl} -5-isopropylpyrimidine 1- (5-ethyl-2-pyrimidinyl) -4-piperidinol Instead of 1- (5-isopropyl-2-pyrimidinyl) -4-piperidinol (WO2008 / 012277, 481 mg, 2.18 mmol), the title compound (381 mg, yield: 53%) was obtained in the same manner as in Reference Example 16. Obtained.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.57 (1H, s), 8.22 (2H, s), 6.76 (1H, s), 5.46-5.36 (1H, 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), 1.88-1.73 (2H, m), 1.24 (6H, d, J = 7Hz).

Reference Example 19 (±) -Benzyl (3R, 4S) -4-[(6-chloropyrimidin-4-yl) oxy] -3-fluoropiperidine-1-carboxylate 1- (5-ethyl-2- (±) -benzyl (3R, 4S) -3-fluoro-4-hydroxypiperidine-1-carboxylate (WO2006 / 113471, 724 μg, 2.86 mmol) was used instead of pyrimidinyl) -4-piperidinol, and Reference Example 16 and Similarly, the title compound (941 mg, yield: 90%) was obtained.
¹ H-NMR (500MHz, DMSO-d ₆ ) δppm:
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), 4.06- 3.99 (1H, m), 3.45-3.05 (2H, m), 1.96-1.94 (1H, m), 1.88-1.80 (1H, m).

Reference Example 20 (±) -Benzyl (3R, 4S) -3-fluoro-4-({6- [4-fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1- Yl] pyrimidin-4-yl} oxy) piperidine-1-carboxylate tert-butyl In Reference Example 19 instead of 4-[(6-chloropyrimidin-4-yl) (methyl) amino] piperidine-1-carboxylate Using the obtained compound (499 mg, 1.36 mmol), the title compound (531 mg, yield: 72%) was obtained in the same manner as in Example 5 described later.
¹ H-NMR (500MHz, DMSO-d ₆ ) δppm:
8.58 (1H, d, J = 1Hz), 8.35 (1H, d, J = 9Hz), 7.69 (1H, t, J = 8Hz), 7.40-7.31 (5H, m), 6.37 (1H, s), 5.45 -5.36 (1H, m), 5.10 (2H, s), 5.04 (1H, br), 4.30-4.24 (1H, m), 4.18 (2H, t, J = 9Hz), 4.05 (1H, br), 3.44 -3.05 (7H, m), 1.97-1.80 (2H, m).

Reference Example 21 Benzyl 1- (5-bromopyrimidin-4-yl) carbamate Benzyl piperidin-4-ylcarbamate dihydrochloride (6.86 mg, 2.23 mmol), N, N-diisopropylethylamine (1.94 mL, 11.1 mmol) 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 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resulting residue, and the resulting precipitate was collected by filtration and air-dried to obtain the title compound (820 mg, yield: 94%).
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
8.27 (2H, s), 7.37-7.30 (5H, m), 5.10 (2H, s), 4.66 (1H, br), 4.60-4.55 (2H, m), 3.79 (1H, br), 3.09-3.04 ( 2H, m), 2.03 (2H, br), 1.40-1.33 (2H, m).

Reference Example 22 benzyl [1- (5-isopropenylpyrimidin-2-yl) piperidin-4-yl] carbamate Reference Example 21 instead of 1- (5-bromopyridin-2-yl) piperidin-4-ol In the same manner as in Reference Example 12 using the compound (820 mg, 2.10 mmol) obtained in 1) and isopropenylboronic acid pinacol ester (788 μL, 4.19 mmol) instead of vinylboronic acid pinacol ester, the title compound (530 mg, yield: 72%).
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
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 23 6-Chloro-N- [1- (5-isopropylpyrimidin-2-yl) piperidin-4-yl] pyrimidin-4-amine Compound obtained in Reference Example 22 (5.00 g, 14.2 mmol) In a mixed solution of ethanol (150 mL) and THF (150 mL), palladium-carbon (10% w / w, wet, 2.50 g), palladium hydroxide-carbon (20% w / w, wet, 2.50 g) And stirred at room temperature for 6.5 hours under hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off 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 ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1, v / v) to obtain the title compound (2.43 g, yield: 51%).
¹ H-NMR (500MHz, DMSO-d ₆ ) δppm:
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), 1.38-1.28 (2H, s), 1.16 (6H, d, J = 7Hz).

Reference Example 24 6-Chloro-N- [1- (5-isopropylpyrimidin-2-yl) piperidin-4-yl] -N-methylpyrimidin-4-amine tert-butyl 4-[(6-chloropyrimidine -4-yl) amino] piperidine-1-carboxylate The title compound (66 mg, yield: 58) was obtained in the same manner as in Reference Example 2 using the compound (109 mg, 0.327 mmol) obtained in Reference Example 23. %).
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
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).

Reference Example 25 tert-butyl [1- (5-isopropenylpyridin-2-yl) piperidin-4-yl] carbamate Instead of benzyl 1- (5-bromopyrimidin-4-yl) carbamate, the following reference The title compound (403 mg, yield: 95%) was obtained in the same manner as in Reference Example 22 using the compound (475 mg, 1.33 mmol) obtained in Example 30.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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), 1.48-1.35 (2H, m), 1.45 (9H, s).

Reference Example 26 tert-butyl [1- (5-isopropylpyridin-2-yl) piperidin-4-yl] carbamate Reference instead of 1- (5-vinylpyridin-2-yl) piperidin-4-ol The title compound (322 mg, yield: 82%) was obtained in the same manner as in Reference Example 13 using the compound (391 mg, 1.23 mmol) obtained in Example 25.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.05 (1H, d, J = 2Hz), 7.36 (1H, 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 (2H, m), 1.50-1.38 (2H, m), 1.45 (9H, s), 1.21 (6H, d, J = 7Hz).

Reference Example 27 1- (5-Isopropylpyridin-2-yl) piperidin-4-amine hydrochloride To a solution of the compound obtained in Reference Example 26 (312 mg, 0.975 mmol) in ethyl acetate (2.00 mL) was added 4N hydrochloric acid. -Ethyl acetate (5.00 mL) was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain the title compound.
¹ H-NMR (400MHz, CD ₃ OD) δppm:
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 (1H, 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, 13Hz), 1.27 (6H, d, J = 7Hz).

Reference Example 28 instead of 6-chloro-N- [1- (5-isopropylpyridin-2-yl) piperidin-4-yl] pyrimidin-4-amine tert-butyl 4-aminopiperidine-1-carboxylate The title compound (98 mg, 25% yield) was obtained in the same manner as in Reference Example 1 using the compound obtained in Reference Example 27 (theoretical amount: 0.975 mmol).
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
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- [1- (5-isopropylpyridin-2-yl) piperidin-4-yl] -N-methylpyrimidin-4-amine tert-butyl 4-[(6-chloropyrimidine -4-yl) amino] piperidine-1-carboxylate In the same manner as in Reference Example 2 using the compound obtained in Reference Example 28 (90 mg, 0.272 mmol), the title compound (59 mg, yield: 62 %).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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 = 7Hz), 1.88-1.71 (4H, m) , 1.23 (6H, d, J = 7Hz).

Reference Example 30 tert-butyl [1- (5-bromopyridin-2-yl) piperidin-4-yl] carbamate tert-butyl piperidin-4-yl-carbamate (1.50 g, 7.79 instead of 4-hydroxypiperidine) In the same manner as in Reference Example 11, the title compound (1.32 g, yield: 66%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.17 (1H, d, J = 3Hz), 7.51 (1H, dd, J = 9Hz, 3Hz), 6.56 (1H, d, J = 9Hz), 4.49 (1H, br), 4.19-4.11 (2H, m) , 3.70 (1H, br), 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) tert-butyl [1- (5-vinylpyridin-2-yl) piperidin-4-yl] carbamate Reference example instead of 1- (5-bromopyridin-2-yl) piperidin-4-ol The title compound (628 mg, yield: 86%) was obtained in the same manner as in Reference Example 12 using the compound obtained in 30 (852 mg, 2.39 mmol).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.15 (1H, d, J = 2Hz), 7.59 (1H, dd, J = 9Hz, 2Hz), 6.64 (1H, d, J = 9Hz), 6.59 (1H, dd, J = 18Hz, 11Hz), 5.55 ( 1H, d, J = 18Hz), 5.10 (1H, d, J = 11Hz), 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 32 Reference example instead of tert-butyl [1- (5-ethylpyridin-2-yl) piperidin-4-yl] carbamate 1- (5-vinylpyridin-2-yl) piperidin-4-ol The title compound (572 mg, yield: 92%) was obtained in the same manner as in Reference Example 13 using the compound obtained in 31 (620 mg, 2.04 mmol).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.03 (1H, d, J = 2Hz), 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), 3.00-2.88 (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 = 7Hz).

Reference Example 33 1- (5-Ethylpyridin-2-yl) piperidin-4-amine hydrochloride instead of tert-butyl [1- (5-isopropylpyridin-2-yl) piperidin-4-yl] carbamate The title compound (593 mg) was obtained in the same manner as in Reference Example 27 using the compound (565 mg, 1.85 mmol) obtained in Reference Example 32.
¹ H-NMR (400MHz, CD ₃ OD) δppm:
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), 3.58-3.47 (1H, m), 3.40-3.31 (2H, m), 2.65 (2H, q, J = 7Hz), 2.26-2.18 (2H, m), 1.75 (dq, 2H, J = 4Hz, 13Hz), 1.25 (3H, t , J = 7Hz).

Reference Example 34 instead of 6-chloro-N- [1- (5-ethylpyridin-2-yl) piperidin-4-yl] pyrimidin-4-amine tert-butyl 4-aminopiperidine-1-carboxylate The title compound (339 mg, yield: 58%) was obtained in the same manner as in Reference Example 1 using the compound (593 mg, 1.85 mmol) obtained in Reference Example 33.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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 (3H, t, J = 8Hz).

Reference Example 35 6-Chloro-N- [1- (5-ethylpyridin-2-yl) piperidin-4-yl] -N-methylpyrimidin-4-amine tert-butyl 4-[(6-chloropyrimidine -4-yl) amino] piperidine-1-carboxylate In the same manner as in Reference Example 2 using the compound obtained in Reference Example 34 (330 mg, 1.04 mmol), the title compound (339 mg, yield: 98 %).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.38 (1H, s), 8.05 (1H, d, J = 2Hz), 7.36 (1H, dd, J = 9Hz, 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).

Reference Example 36 tert-butyl 4-({6- [5-methoxycarbonyl-2,3-dihydro-1H-indol-1-yl] pyrimidin-4-yl} oxy) piperidine-1-carboxylate 5- In the same manner as in Example 3 below using 5-methoxycarbonyl-2,3-dihydro-1H-indoline (2.24 g, 7.13 mmol) instead of (methylsulfonyl) indoline, the title compound (2.24 g, yield) : 83%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.49 (1H, s), 8.40 (1H, d, J = 9Hz), 7.92 (1H, d, J = 9Hz), 7.84 (1H, s), 5.96 (1H, s), 5.35-5.26 (1H, 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), 1.48 (9H, s).

Reference Example 37 Methyl 1- (6-{[1- (5-ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) indoline-5-carboxylate tert-butyl 4- Obtained in Reference Example 36 instead of ({4- [5- (methylsulfonyl) -2,3-dihydro-1H-indol-1-yl] pyridin-2-yl} oxy) piperidine-1-carboxylate Using the compound (289 mg, 0.635 mmol), the title compound (207 mg, yield: 71%) was obtained in the same manner as in Example 11 described later.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.52-8.50 (1H, m), 8.41 (1H, d, J = 8Hz), 8.18 (2H, s), 7.95-7.90 (1H, m), 7.87-7.84 (1H, m), 5.99-5.97 (1H , m), 5.44-5.37 (1H, m), 4.33-4.25 (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 (3H, t, J = 8Hz).

Reference Example 38 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) indoline-5-carboxylic acid obtained in Reference Example 37 To a solution of the compound (94 mg, 0.203 mmol) in methanol (100 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred with heating under reflux for 2.5 hours. Further, 5N aqueous sodium hydroxide solution (2.00 mL) was added, and the mixture was stirred for 1 hour with heating under reflux. After cooling the reaction solution, the solvent was distilled off under reduced pressure, 6N aqueous sodium hydroxide solution (2.20 mL) was added, and the resulting precipitate was collected by filtration. The precipitate was washed with water and ethyl acetate to obtain the title compound (55 mg, yield: 61%).
¹ H-NMR (400MHz, DMSO-d ₆ ) δppm:
12.56 (1H, s), 8.53 (1H, s), 8.44 (1H, d, J = 9Hz), 8.26 (2H, s), 7.84-7.78 (1H, m), 7.78-7.75 (1H, 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).

Example 1 Isopropyl 4- [6- (5- (S-methylsulfonimidoyl) -2,3-dihydroindol-1-yl) pyrimidin-4-yloxy] piperidine-1-carboxylate

Dichloromethane solution of isopropyl 4- [6- (5- (methanesulfinyl) -2,3-dihydroindol-1-yl) pyrimidin-4-yloxy] piperidine-1-carboxylate (WO2009 / 51119, 100 mg, 0.225 mmol) (2.00 mL) was added O-mesitylenesulfonylhydroxylamine (150 mg, 0.697 mmol), and the mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 1: 0 → 40: 1, v / v) to obtain the title compound (60 mg, yield: 58%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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), 5.36-5.30 (1H , m), 4.94 (1H, sept, J = 6Hz), 4.07 (2H, t, J = 9Hz), 3.88-3.78 (2H, m), 3.32 (2H, t, J = 9Hz), 3.37-3.27 ( 2H, m), 3.10 (3H, s), 2.06-1.96 (2H, m), 1.79-1.69 (2H, m), 1.26 (6H, d, J = 6Hz).

(Example 2) 2,2,2-trifluoroethyl 4- [6- (5- (S-methylsulfonimidoyl) -2,3-dihydroindol-1-yl) pyrimidin-4-yloxy] piperidine- 1-carboxylate

2,2,2-trifluoroethyl instead of isopropyl 4- [6- (5- (methanesulfinyl) -2,3-dihydroindol-1-yl) pyrimidin-4-yloxy] piperidine-1-carboxylate With 4- [6- (5- (methanesulfinyl) -2,3-dihydroindol-1-yl) pyrimidin-4-yloxy] piperidine-1-carboxylate (WO2009 / 51119, 237 mg, 0.491 mmol), In the same manner as in Example 1, the title compound (35 mg, yield: 16%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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), 3.49-3.40 (2H, m), 3.31 (2H, t, J = 9Hz), 3.11 (3H, s), 2.09-1.99 (2H, m), 1.87-1.74 (2H, m).

(Example 3) tert-butyl 4- (methyl {6- [5- (methylsulfonyl) -2,3-dihydro-1H-indol-1-yl] pyrimidin-4-yl} amino) piperidine-1-carboxy rate

5- (Methylsulfonyl) indoline (736 mg, 3.73 mmol), the compound obtained in Reference Example 2 (1.22 g, 3.73 mmol), potassium carbonate (10.3 g, 74.7 mmol), 2- (dicyclohexylphosphino) -2 ′ A suspension of-(N, N-dimethylamino) biphenyl (300 mg, 0.747 mmol) and palladium acetate (85 mg, 0.373 mmol) in 1,4-dioxane (36.8 mL) was stirred at 105 ° C. for 2 hours. The reaction solution was filtered, saturated aqueous ammonium chloride solution was added to the obtained filtrate, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 3: 7, v / v) to obtain the title compound (1.67 g, yield: 92%).
¹ H-NMR (500MHz, DMSO-d ₆ ) δppm:
8.54 (1H, 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 Isopropyl 4- (methyl {6- [5- (methylsulfonyl) -2,3-dihydro-1H-indol-1-yl] pyrimidin-4-yl} amino) piperidine-1-carboxylate

To a solution of the compound obtained in Example 3 (46 mg, 0.943 mmol) in ethyl acetate (230 μL) was added 4N hydrochloric acid-ethyl acetate solution (690 μL) at room temperature, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off from the reaction solution under reduced pressure, 1N aqueous sodium hydroxide solution (20.0 mL) was added, and the resulting precipitate was collected by filtration and dried under reduced pressure. Isopropyl chloroformate (14 μL, 0.119 mmol) is added to a solution of a part (23 mg) of the obtained residue (26 mg) and N, N-diisopropylethylamine (31 μL, 0.178 mmol) in dichloromethane (1.15 mL) at 0 ° C. The mixture was further stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate, developed once) to obtain the title compound (25 mg, yield: 62%).
¹ H-NMR (500MHz, DMSO-d ₆ ) δppm:
8.54 (1H, d, J = 8Hz), 8.32 (1H, s), 7.69 (1H, s), 7.68 (1H, d, J = 8Hz), 5.82 (1H, s), 4.81-4.74 (1H, m ), 4.14-4.06 (5H, m), 3.26 (2H, t, J = 9Hz), 3.13 (3H, s), 2.89 (2H, br), 2.87 (3H, s), 1.68-1.56 (4H, m ), 1.20 (6H, d, J = 6Hz).

(Example 5) tert-butyl 4-[{6- [4-fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indol-1-yl] pyrimidin-4-yl} (methyl) amino ] Piperidine-1-carboxylate

The title compound (822 mg, yield: 88%) was obtained in the same manner as in Example 3 using the compound (500 mg, 2.20 mmol) obtained in Reference Example 6 instead of 5- (methylsulfonyl) indoline. .
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.39 (1H, s), 8.30 (1H, d, J = 9Hz), 7.79-7.72 (1H, m), 5.58 (1H, s), 4.99-4.84 (1H, m), 4.36-4.16 (2H, m ), 4.15 (2H, t, J = 9Hz), 3.28 (2H, t, J = 9Hz), 3.19 (3H, s), 2.94-2.80 (2H, m), 2.86 (3H, s), 1.71-1.62 (4H, m), 1.48 (9H, s).

(Example 6) Isopropyl 4-[{6- [4-fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indol-1-yl] pyrimidin-4-yl} (methyl) amino] piperidine -1-carboxylate

Instead of tert-butyl 4- (methyl {6- [5- (methylsulfonyl) -2,3-dihydro-1H-indol-1-yl] pyrimidin-4-yl} amino) piperidine-1-carboxylate Using the compound (571 mg, 1.13 mmol) obtained in Example 5, the title compound (461 mg, yield: 86%) was obtained in the same manner as in Example 4.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.39 (1H, s), 8.30 (1H, d, J = 9Hz), 7.79-7.73 (1H, 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) tert-butyl 4- (methyl {6- [5- (methylsulfinyl) -2,3-dihydro-1H-indol-1-yl] pyrimidin-4-yl} amino) piperidine-1-carboxy rate

In the same manner as in Example 3 except that 2,3-dihydro-5- (methylsulfinyl)-(1H) -indole (189 mg, 1.05 mmol) was used instead of 5- (methylsulfonyl) indoline, the title compound (436 mg Yield: 88%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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 (1H , m), 4.31-4.17 (2H, m), 4.07 (2H, t, J = 9Hz), 3.28 (2H, t, J = 9Hz), 2.92-2.80 (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 Isopropyl 4- (methyl {6- [5- (methylsulfinyl) -2,3-dihydro-1H-indol-1-yl] pyrimidin-4-yl} amino) piperidine-1-carboxylate

Instead of tert-butyl 4- (methyl {6- [5- (methylsulfonyl) -2,3-dihydro-1H-indol-1-yl] pyrimidin-4-yl} amino) piperidine-1-carboxylate The title compound (125 mg, yield: 60%) was obtained in the same manner as in Example 4 using the compound (216 mg, 0.458 mmol) obtained in Example 7.
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
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 (1H , m), 4.94 (1H, sept, J = 6Hz), 4.38-4.22 (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 = 6Hz);
MS (ESI) m / z: 458 [M + H] ⁺ .

(Example 9) tert-butyl 4-({4- [5- (methylsulfonyl) -2,3-dihydro-1H-indol-1-yl] pyridin-2-yl} oxy) piperidine-1-carboxylate

Example using the compound (200 mg, 0.639 mmol) obtained in Reference Example 7 instead of tert-butyl 4-[(6-chloropyrimidin-4-yl) (methyl) amino] piperidine-1-carboxylate In the same manner as in Example 3, the title compound (303 mg, yield: 100%) was obtained.
¹ H-NMR (400MHz, DMSO-d ₆ ) δppm:
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), 1.99-1.92 (2H, m), 1.58-1.50 (2H, m), 1.41 (9H, s).

Example 10 1- (2-{[1- (5-Fluoropyrimidin-2-yl) piperidin-4-yl] oxy} pyridin-4-yl) -5- (methylsulfonyl) indoline

To the compound obtained in Example 9 (1.85 g, 3.91 mmol) was added 4N hydrochloric acid-ethyl acetate solution (18.5 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected from the reaction suspension by filtration, washed with hexane, and then air-dried. A part (450 mg) of the obtained compound (1.70 g), N, N-diisopropylethylamine (956 μL, 5.49 mmol) and 2-chloro-5-fluoropyrimidine (280 μL, 2.20 mmol) in ethanol (11.3 mL) The mixture 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 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1, v / v) to obtain the title compound (339 mg, yield: 66%).
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
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), 5.37-5.33 (1H, m), 4.27-4.22 (2H, m), 4.09 (2H, t, J = 8Hz), 3.59 (2H, ddd, J = 13Hz , 9Hz, 3Hz), 3.23 (2H, t, J = 8Hz), 3.04 (3H, s), 2.12-2.07 (2H, m), 1.83-1.70 (2H, m).

Example 11 1- (2-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyridin-4-yl) -5- (methylsulfonyl) indoline

The title compound (250 mg, yield: 48%) was obtained in the same manner as in Example 10 except that 2-chloro-5-ethylpyrimidine (275 μL, 2.20 mmol) was used instead of 2-chloro-5-fluoropyrimidine. .
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
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), 5.37-5.32 (1H, m), 4.32-4.27 (2H, m), 4.09 (2H, t, J = 9Hz), 3.57 (2H, ddd, J = 13Hz , 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 1- (2-{[1- (5-Ethylpyridin-2-yl) piperidin-4-yl] oxy} pyridin-4-yl) -5- (methylsulfonyl) indoline

To a mixed solution of the compound obtained in Reference Example 9 (40 mg, 83.8 μmol) in ethanol (2.00 mL) and THF (2.00 mL), palladium hydroxide-carbon (20% w / w, wet, 40 mg) was added. In addition, the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 0: 1, v / v) to obtain the title compound (13 mg, yield: 33%).
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
8.06 (1H, d, J = 6Hz), 8.05 (1H, d, J = 2Hz), 7.73-7.70 (2H, m), 7.36-7.22 (2H, m), 6.80 (1H, dd, J = 6Hz, 2Hz), 6.67 (1H, d, J = 9Hz), 6.44 (1H, d, J = 2Hz), 5.33-5.28 (1H, m), 4.09 (2H, t, J = 9Hz), 4.00-3.95 (2H , m), 3.37-3.32 (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) tert-butyl 4- {3- [5- (methylsulfonyl) -2,3-dihydro-1H-indol-1-yl] phenoxy} piperidine-1-carboxylate

Palladium hydroxide-carbon (20% w / w, wet, 300 mg) was added to a solution of the compound obtained in Reference Example 10 (630 mg, 1.66 mmol) in methanol (30.0 mL), and the resulting mixture was kept under a hydrogen atmosphere at room temperature for 4 hours. Stir. The reaction solution was filtered through celite and washed with ethyl acetate, and the resulting solution was evaporated under reduced pressure to remove the solvent and tert-butyl 4-hydroxypiperidine-1-carboxylate (334 mg). , 1.66 mmol) in toluene (30.0 mL) was added cyanomethylenetri n-butylphosphine (668 μL, 2.46 mmol), and the mixture was stirred with heating under reflux for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3, v / v) to obtain the title compound (557 mg, yield: 71%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
7.67-7.62 (2H, m), 7.29 (1H, t, J = 8Hz), 7.07 (1H, d, J = 9Hz), 6.90-6.83 (1H, m), 6.82-6.78 (1H, m), 6.68 -6.62 (1H, 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 1- (3-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} phenyl) -5- (methylsulfonyl) indoline

Trifluoroacetic acid (2.00 mL) was added to a solution of the compound obtained in Example 13 (128 mg, 0.271 mmol) in dichloromethane (8.00 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue was dissolved in dimethylformamide (5.00 mL), and 2-chloro-5-ethylpyrimidine (66 μL, 0.543 mmol), 1,8-diazabicyclo [5.4 .0] -7-undecene (162 μL, 1.03 mmol) was added and stirred at 80 ° C. for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 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 by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 2, v / v) to obtain the title compound (83 mg, yield: 64%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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 (1H, m), 6.71-6.67 (1H, m), 4.60-4.53 (1H, 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] ⁺ .

Example 15 5- (Methylsulfonyl) -1- {6-[(1-phenylpiperidin-4-yl) oxy] pyrimidin-4-yl} indoline

4- {6- [5- (methylsulfonyl) -2,3-dihydroindol-1-yl] -pyrimidin-4-yloxy} piperidine (WO2009 / 51119, 166 mg, 0.444 mmol), iodobenzene (99 μL, 0.888 mmol) ), Palladium acetate (10 mg, 44.5 μmol), 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl (35 mg, 88.7 μmol) and 1,4 of sodium tert-butoxy (85 mg, 0.888 mmol) -The dioxane (5.00 mL) solution was stirred for 6 hours under heating to reflux. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 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 by silica gel column chromatography (hexane: ethyl acetate = 7: 3 → 1: 1, v / v) to obtain the title compound (74 mg, yield: 37%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.59 (1H, d, J = 9Hz), 8.53 (1H, s), 7.79 (1H, dd, J = 9Hz, 2Hz), 7.72 (1H, s), 7.32-7.25 (2H, m), 7.01-6.96 (2H, m), 6.90-6.84 (1H, m), 6.01-5.98 (1H, m), 5.37-5.28 (1H, 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- (Methylsulfonyl) -1- {6-[(1- (2-pyridinyl) piperidin-4-yl) oxy] pyrimidin-4-yl} indoline

Under ice-water cooling, 1- (2-pyridinyl) -4-hydroxypiperidine (115 mg, 0.646 mmol), 1- (6-chloropyrimidin-4-yl) -5- (methylsulfonyl) indoline (WO2009 / 51119, 200 mg, 0.646 mmol) in THF (4.00 mL) was added sodium hydride (63%, 26 mg, 0.655 mmol), stirred at room temperature for 30 minutes, and heated to reflux for 3 hours. After returning to room temperature, dichloromethane and water were added for liquid separation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1, v / v) to give the title compound (166 mg, yield: 57%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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), 5.45-5.35 (1H, m), 4.15-3.95 (4H, m), 3.43-3.30 (4H, m), 3.03 (3H, s), 2.20-2.10 (2H , m), 1.95-1.80 (2H, m);
MS (ESI) m / z: 452 [M + H] ⁺ .

Example 17 1- (6-{[1- (5-Ethylpyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline

The title compound (109 mg, yield: 68) was obtained in the same manner as in Example 16 except that the compound (100 mg, 0.484 mmol) obtained in Reference Example 13 was used instead of 1- (2-pyridinyl) -4-hydroxypiperidine. %).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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), 4.06 (2H, t, J = 9Hz), 4.01-3.92 (2H, m), 3.40-3.29 (2H, m), 3.31 (2H, t, J = 9Hz), 3.04 (3H, s), 2.53 (2H, q, J = 8Hz), 2.18-2.08 (2H, m), 1.91-1.80 (2H, m), 1.20 (3H, t, J = 8Hz).

Example 18 1- (6-{[1- (5-Methylpyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline

Instead of 1- (2-pyridinyl) -4-hydroxypiperidine, the compound obtained in Reference Example 14 (130 mg, 0.676 mmol) was used and the title compound (10 mg, yield: 5) was obtained in the same manner as in Example 16. %).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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 1- (6-{[1- (5-Isopropylpyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline

The title compound (141 mg, yield: 72) was obtained in the same manner as in Example 16 except that the compound (130 mg, 0.590 mmol) obtained in Reference Example 15 was used instead of 1- (2-pyridinyl) -4-hydroxypiperidine. %).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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).

Example 20 1- (6-{[1- (5-Fluoropyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline

5- (methylsulfonyl) -1- [6- (piperidin-4-yloxy) pyrimidin-4-yl] indoline hydrochloride (WO2009 / 51119, 80 mg, 0.195 mmol), 2-bromo-5-fluoropyridine (69 mg, 0.390 mmol) and potassium carbonate (135 mg, 0.975 mmol) in N-methylpyrrolidone (2.00 mL) were 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 the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 2: 3, v / v), and the resulting crude product was washed with acetonitrile to give the title compound (15 mg, yield). : 16%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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 (1H, m), 6.67 (1H, dd, J = 9Hz, 3Hz), 5.99 (1H, s), 5.43-5.34 (1H, 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) indoline

4- [6- (5- (Methylsulfonyl) -2,3-dihydroindol-1-yl) -pyrimidin-4-yloxy] -piperidine-1-carboxylate (WO2009 / 51119, 245 mg, 0.516 mmol) in dichloromethane (4.00 mL) To the solution was added trifluoroacetic acid (1.00 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction mixture under reduced pressure, and a solution of the obtained residue in ethanol (10.0 mL) was added to N, N-diisopropylethylamine (877 μL, 5.16 mmol), 2-chloro-5-fluoropyrimidine (76 μL, 0.620 mmol) was added and the mixture was stirred with heating under reflux for 9.5 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1, v / v) to give the title compound (223 mg, Yield: 92%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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 (1H, m), 5.99 (1H , 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-propylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) indoline

The title compound (217 mg, yield: 84%) was obtained in the same manner as in Example 21 using 2-chloro-5-propylpyrimidine (123 mg, 0.785 mmol) instead of 2-chloro-5-fluoropyrimidine.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.58 (1H, d, J = 9Hz), 8.54-8.53 (1H, m), 8.17 (2H, s), 7.81-7.76 (1H, m), 7.73-7.70 (1H, 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), 1.63-1.52 (2H, m), 0.94 (3H, t, J = 7Hz);
MS (ESI) m / z: 495 [M + H] ⁺ .

Example 23 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline

The title compound (120 mg, yield: 81%) was obtained in the same manner as in Example 21 using 2-chloro-5-ethylpyrimidine (66 mg, 0.463 mmol) instead of 2-chloro-5-fluoropyrimidine.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.58 (1H, d, J = 9Hz), 8.54-8.53 (1H, m), 8.19 (2H, s), 7.79 (1H, dd, J = 9Hz, 2Hz), 7.73-7.70 (1H, m), 6.00 -5.98 (1H, m), 5.45-5.38 (1H, m), 4.33-4.25 (2H, m), 4.06 (2H, t, J = 9Hz), 3.62-3.53 (2H, m), 3.31 (2H, t, J = 9Hz), 3.04 (3H, s), 2.47 (2H, q, J = 8Hz), 2.15-2.05 (2H, m), 1.86-1.75 (2H, m), 1.20 (3H, t, J = 8Hz);
MS (ESI) m / z: 481 [M + H] ⁺ .

Example 24 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfinyl) indoline

Compound obtained in Reference Example 16 (56 mg, 0.310 mmol), 2,3-dihydro-5- (methylsulfinyl)-(1H) -indole (99 mg, 0.310 mmol), palladium acetate (7 mg, 0.0310 mmol), 2 -Dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl (24 mg, 0.0620 mmol) and potassium carbonate (856 mg, 6.20 mmol) in 1,4-dioxane (10.0 mL) were heated under reflux for 2 hours. Stir. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 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 by silica gel column chromatography (ethyl acetate) to obtain the title compound (62 mg, yield: 43%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.54 (1H, d, J = 9Hz), 8.52-8.51 (1H, m), 8.19 (2H, s), 7.59-7.56 (1H, m), 7.45-7.41 (1H, m), 5.96 (1H, s ), 5.45-5.37 (1H, m), 4.34-4.25 (2H, m), 4.04 (2H, t, J = 9Hz), 3.62-3.53 (2H, m), 3.30 (2H, t, J = 9Hz) , 2.71 (3H, s), 2.48 (2H, q, J = 8Hz), 2.14-2.05 (2H, m), 1.85-1.75 (2H, m), 1.20 (3H, t, J = 8Hz);
MS (ESI) m / z: 465 [M + H] ⁺ .

Example 25 N- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -N-methyl-6- [5- (methylsulfonyl) -2,3-dihydro-1H-indole -1-yl] pyrimidin-4-amine

To a solution of the compound (2.94 g, 6.04 mmol) obtained in Example 3 in dichloromethane (40.0 mL) was added trifluoroacetic acid (10.0 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and 2-chloro-5-ethylpyrimidine (1.09 mL, 1.91 mmol), 1,8-diazabicyclo [5.4] was added to a solution of the resulting residue in dimethylformamide (20.0 mL). .0] -7-undecene (2.72 mL, 1.91 mmol) was added and stirred at 100 ° C. for 7.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction three times with ethyl acetate and twice with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 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 title compound (2.06 g, yield: 69%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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 = 8Hz);
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) indoline

5-methylsulfonyl-1- [6- (piperidin-4-yloxy) -pyrimidin-4-yl] -2,3-dihydro-1H-indole hydrochloride (WO2009 / 51119, 201 mg, 0.488 mmol), 2-chloro A solution of -3-fluoropyridine (321 mg, 2.44 mmol) and potassium carbonate (674 mg, 4.88 mmol) in DMF (3.00 mL) was stirred at 100 ° C. for 27 hours. 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 the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography ((i) dichloromethane: ethyl acetate = 5: 1 → 1: 1, v / v, (ii) hexane: ethyl acetate = 1: 1 → 1: 2, v / v) To give the title compound (31 mg, yield: 14%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.58 (1H, d, J = 9Hz), 8.53 (1H, s), 8.03-8.00 (1H, m), 7.79 (1H, d, J = 9Hz), 7.72 (1H, s), 7.27-7.19 (1H , m), 6.79-6.73 (1H, m), 6.00 (1H, s), 5.42-5.34 (1H, m), 4.07 (2H, t, J = 9Hz), 3.91-3.82 (2H, m), 3.39 -3.30 (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 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -4-fluoro-5- (methylsulfonyl) indoline

To a solution of the compound obtained in Reference Example 17 (263 mg, 0.534 mmol) in dichloromethane (1.00 mL) was added 4N hydrochloric acid-ethyl acetate solution (3.00 mL), and the mixture was stirred at room temperature for 25 minutes, and then the solvent was removed under reduced pressure. Distilled to obtain the crude product. To a solution of this crude product in DMF (3.00 mL) was added 1,8-diazabicyclo [5.4.0] -7-undecene (240 μL, 1.60 mmol) and 2-chloro-5-ethylpyrimidine (84 μL, 0.694 mmol), Stir 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 saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography ((i) hexane: ethyl acetate = 3: 1, v / v, (ii) ethyl acetate: dichloromethane = 1: 2, v / v) to give the title compound ( 185 mg, yield: 70%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.54 (1H, s), 8.35 (1H, d, J = 9Hz), 8.19 (2H, s), 7.82-7.76 (1H, m), 5.99 (1H, s), 5.46-5.38 (1H, m), 4.33-4.24 (2H, m), 4.12 (2H, t, J = 9Hz), 3.62-3.53 (2H, m), 3.31 (2H, t, J = 9Hz), 3.20 (3H, s), 2.48 (2H , q, J = 8Hz), 2.14-2.05 (2H, m), 1.85-1.75 (2H, m), 1.20 (3H, t, J = 8Hz).

Example 28 1- (6-{[1- (5-Isopropylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline

In place of 2- {4-[(6-chloropyrimidin-4-yl) oxy] piperidin-1-yl} -5-ethylpyrimidine, the compound obtained in Reference Example 18 (59 mg, 0.298 mmol), 2, The title compound (137 mg, yield) was obtained in the same manner as in Example 24 using 5- (methylsulfonyl) indoline (109 mg, 0.327 mmol) instead of 3-dihydro-5- (methylsulfinyl)-(1H) -indole. : 93%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.58 (1H, d, J = 9Hz), 8.54-8.52 (1H, m), 8.22 (2H, s), 7.79 (1H, dd, J = 9Hz, 2Hz), 7.73-7.70 (1H, 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), 3.62-3.53 (2H, m), 3.31 (2H, t, J = 9Hz), 3.04 (3H, s), 2.83-2.73 (1H, 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 (±) -1- (6-{[(3R, 4S) -1- (5-ethylpyrimidin-2-yl) -3-fluoropiperidin-4-yl] oxy} pyrimidine-4- Yl) -4-fluoro-5- (methylsulfonyl) indoline

To a mixed solution of the compound obtained in Reference Example 20 (528 mg, 0.970 mmol) in THF (21.2 mL) and methanol (5.28 mL), palladium-carbon (10% w / w, wet, 528 mg) was added, The mixture was stirred at room temperature for 5.5 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. A portion (98 mg) of the obtained residue (389 mg), N, N-diisopropylethylamine (208 μL, 1.19 mmol) and 2-chloro-5-ethylpyrimidine (90 μL, 0.716 mmol) in ethanol (3.00 mL) were added to a solution of 80 The mixture was stirred at ° C for 15.5 hours. The solvent was distilled off under reduced pressure, and DMF (3.00 mL) and 1,8-diazabicyclo [5.4.0] -7-undecene (350 μL, 2.39 mmol) were added to the resulting residue. Stir for hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1, v / v) to obtain the title compound (41 mg, yield: 33%).
¹ H-NMR (500MHz, DMSO-d ₆ ) δppm:
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 (1H, m ), 5.07 (1H, d, J = 50Hz), 4.87-4.81 (1H, m), 4.56 (1H, br), 4.18 (2H, t, 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 (1H, m), 1.94-1.87 (1H, m ), 1.66-1.51 (1H, m), 1.14 (3H, t, J = 7Hz).

Example 30 N- [1- (5-Isopropylpyrimidin-2-yl) piperidin-4-yl] -N-methyl-6- [5- (methylsulfonyl) -2,3-dihydro-1H-indole -1-yl] pyrimidin-4-amine

Example using the compound (63 mg, 0.182 mmol) obtained in Reference Example 24 instead of tert-butyl 4-[(6-chloropyrimidin-4-yl) (methyl) amino] piperidine-1-carboxylate In the same manner as in Example 3, the title compound (78 mg, yield: 85%) was obtained.
¹ H-NMR (500MHz, DMSO-d ₆ ) δppm:
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), 2.98-2.92 (2H, m), 2.85 (3H, s), 2.80-2.75 (1H, m), 1.72-1.61 (4H, m), 1.20 (6H, d, J = 7Hz).

Example 31 N- [1- (5-Isopropylpyridin-2-yl) piperidin-4-yl] -N-methyl-6- [5- (methylsulfonyl) -2,3-dihydro-1H-indole -1-yl] pyrimidin-4-amine

Example using the compound (52 mg, 0.149 mmol) obtained in Reference Example 29 instead of tert-butyl 4-[(6-chloropyrimidin-4-yl) (methyl) amino] piperidine-1-carboxylate In the same manner as in Example 3, the title compound (42 mg, yield 56%) was obtained.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.54 (1H, d, J = 9Hz), 8.41 (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- [1- (5-Ethylpyridin-2-yl) piperidin-4-yl] -6- [4-fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole -1-yl] -N-methylpyrimidin-4-amine

In place of tert-butyl 4-[(6-chloropyrimidin-4-yl) (methyl) amino] piperidine-1-carboxylate, the compound (155 mg, 0.468 mmol) obtained in Reference Example 35, 5- (methyl The title compound (181 mg, yield: 73%) was obtained in the same manner as in Example 5 using the compound (147 mg, 0.586 mmol) obtained in Reference Example 6 instead of (sulfonyl) indoline.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.41 (1H, s), 8.31 (1H, d, J = 9Hz), 8.06 (1H, d, J = 2Hz), 7.79-7.73 (1H, 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, q, J = 7Hz), 1.90-1.72 (4H, m), 1.20 (3H, t, J = 7Hz).

Example 33 1- (6-{[1- (5-Trifluoromethylpyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline

5- (methylsulfonyl) -1- [6- (piperidin-4-yloxy) pyrimidin-4-yl] indoline hydrochloride (WO2009 / 51119, 300 mg, 0.730 mmol), 2-bromo-5-trifluoromethylpyridine ( A solution of 265 mg, 1.46 mmol) and N, N-diisopropylethylamine (636 μL, 3.65 mmol) in ethanol (9.00 mL) was stirred at 70 ° C. for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 3: 7, v / v) to obtain the title compound (100 mg, yield: 26%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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 (1H, 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), 1.88-1.82 (2H, m).

Example 34 1- (6-{[1- (5-Cyanopyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline

5- (Methylsulfonyl) -1- [6- (piperidin-4-yloxy) pyrimidin-4-yl] indoline hydrochloride (WO2009 / 51119, 190 mg, 0.511 mmol), 2-bromo-5-cyanopyridine (93 mg, To a solution of 0.511 mmol) in DMF (5.70 mL) was added 1,8-diazabicyclo [5,4,0] -7-undecene (153 μL, 1.60 mmol), and the mixture was stirred at 100 ° C. for 3.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 3, v / v) to obtain the title compound (155 mg, yield: 76%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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, 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 ), 3.64-3.58 (2H, m), 3.32 (2H, t, J = 9Hz), 3.04 (3H, s), 2.15-2.08 (2H, m), 1.90-1.82 (2H, m).

Example 35 1- (6-{[1- (5-Methoxypyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline

5- (methylsulfonyl) -1- [6- (piperidin-4-yloxy) pyrimidin-4-yl] indoline hydrochloride (WO2009 / 51119, 170 mg, 0.456 mmol), 2-bromo5-methoxypyridine (72 mg, 0.610 mmol), tris (dibenzylideneacetone) dipalladium (6 mg, 0.006 mmol), (-)-(R) -N, N-dimethyl-1-[(S) -2- (diphenylphosphino) ferrocenyl] -ethylamine A solution of (9 mg, 0.021 mmol) and sodium tert-butoxy (219 mg, 2.28 mmol) in toluene (8.50 mL) was stirred with heating under reflux for 4 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 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 by silica gel thin layer chromatography (ethyl acetate, developed once) to obtain the title compound (7 mg, yield: 3%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
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), 5.39-5.33 (1H, 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 (2H, m).

Example 36 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (morpholin-4-ylcarbonyl) indoline

To a solution of the compound obtained in Reference Example 38 (23 mg, 0.0507 mmol) in dimethylformamide (2.00 mL), 4- {4,6-dimethoxy [1,3,5] triazin-2-yl} -4-methylmorpholine was added. -4-ium (21 mg, 0.0761 mmol) was added and stirred for 20 minutes. Further, morpholine (9 μL, 0.101 mmol) was added to the reaction solution and stirred for 1 hour. Water was further added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 1, v / v) to obtain the title compound (22 mg, yield: 83%).
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.50-8.48 (1H, m), 8.39 (1H, d, J = 8Hz), 8.19 (2H, s), 7.34-7.31 (1H, m), 7.28-7.24 (1H, m), 5.96-5.94 (1H , m), 5.44-5.36 (1H, m), 4.33-4.25 (2H, m), 4.00 (2H, t, J = 9Hz), 3.76-3.53 (10H, 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 = 7Hz);
MS (ESI) m / z: 516 [M + H] ⁺ .

Example 37 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N- (2-methoxyethyl) indoline-5 -Carboxamide

The title compound (41 mg, yield: 85%) was obtained in the same manner as in Example 36 using 2-methoxyethylamine (17 μL, 0.196 mmol) instead of morpholine.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.52-8.49 (1H, m), 8.40 (1H, d, J = 8Hz), 8.19 (2H, s), 7.70-7.66 (1H, m), 7.65-7.60 (1H, m), 6.54-6.47 (1H , m), 5.96 (1H, s), 5.44-5.36 (1H, m), 4.34-4.25 (2H, m), 4.01 (2H, t, J = 9Hz), 3.68-3.49 (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 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N- (2-hydroxyethyl) indoline-5 -Carboxamide

The title compound (29 mg, yield: 53%) was obtained in the same manner as in Example 36 using ethanolamine (20 μL, 0.336 mmol) instead of morpholine.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.49-8.48 (1H, m), 8.36 (1H, d, J = 9Hz), 8.19 (2H, s), 7.66-7.62 (1H, m), 7.62-7.57 (1H, m), 6.79-6.72 (1H , m), 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 = 7Hz);
MS (ESI) m / z: 490 [M + H] ⁺ .

Example 39 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N, N-bis (2-methoxyethyl) Indoline-5-carboxamide

The title compound (55 mg, yield: 66%) was obtained in the same manner as in Example 36 using bis (2-methoxyethyl) amine (87 μL, 0.589 mmol) instead of morpholine.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.50-8.48 (1H, m), 8.36 (1H, d, J = 9Hz), 8.19 (2H, s), 7.32-7.27 (2H, m), 5.95 (1H, s), 5.44-5.35 (1H, 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: 562 [M + H] ⁺ .

Example 40 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N- (2-methoxyethyl) -N- Methylindoline-5-carboxamide

The title compound (47 mg, yield: 73%) was obtained in the same manner as in Example 36 using N- (2-methoxyethyl) methylamine (53 μL, 0.500 mmol) instead of morpholine.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.50-8.48 (1H, m), 8.36 (1H, d, J = 9Hz), 8.19 (2H, s), 7.34-7.25 (2H, m), 5.95 (1H, s), 5.44-5.36 (1H, 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), 1.86-1.75 (2H, m), 1.20 (3H, t, J = 7Hz);
MS (ESI) m / z: 518 [M + H] ⁺ .

Example 41 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N-[(2S) -2-hydroxypropyl ] Indoline-5-carboxamide

The title compound (72 mg, yield: 91%) was obtained in the same manner as in Example 36 using (S)-(+)-1-amino-2-propanol (50 μL, 0.633 mmol) instead of morpholine. .
¹ H-NMR (500MHz, CDCl ₃ ) δppm:
8.51-8.49 (1H, m), 8.41 (1H, d, J = 8Hz), 8.19 (2H, s), 7.70-7.66 (1H, m), 7.63-7.59 (1H, m), 6.56-6.50 (1H , m), 5.96 (1H, s), 5.43-5.36 (1H, 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 (1H, 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 = 7Hz);
MS (ESI) m / z: 504 [M + H] ⁺ .

Example 42 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N-[(1R) -2-hydroxy- 1-methylethyl] indoline-5-carboxamide

The title compound (68 mg, yield: 77%) was obtained in the same manner as in Example 36 using (R)-(−)-2-amino-1-propanol (55 μL, 0.700 mmol) instead of morpholine. .
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.52-8.48 (1H, m), 8.40 (1H, d, J = 9Hz), 8.19 (2H, s), 7.68-7.63 (1H, m), 7.62-7.56 (1H, m), 6.30-6.21 (1H , m), 5.95 (1H, s), 5.45-5.35 (1H, m), 4.35-4.22 (3H, m), 4.01 (2H, t, J = 9Hz), 3.83-3.75 (1H, m), 3.70 -3.62 (1H, 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 = 7Hz);
MS (ESI) m / z: 504 [M + H] ⁺ .

Example 43 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N- (3-hydroxypropyl) indoline-5 -Carboxamide

The title compound (54 mg, yield: 63%) was obtained in the same manner as in Example 36 using 3-amino-1-propanol (51 μL, 0.676 mmol) instead of morpholine.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.51-8.49 (1H, m), 8.41 (1H, d, J = 9Hz), 8.19 (2H, s), 7.70-7.67 (1H, m), 7.61-7.56 (1H, m), 6.57-6.51 (1H , m), 5.97-5.95 (1H, m), 5.44-5.36 (1H, m), 4.33-4.24 (2H, m), 4.01 (2H, t, J = 9Hz), 3.71 (2H, t, J = 5Hz), 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);
MS (ESI) m / z: 504 [M + H] ⁺ .

Example 44 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N-[(2R) -2-hydroxypropyl ] Indoline-5-carboxamide

The title compound (51 mg, yield: 61%) was obtained in the same manner as in Example 36 using (R)-(−)-1-amino-2-propanol (52 μL, 0.659 mmol) instead of morpholine. .
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.52-8.50 (1H, m), 8.41 (1H, d, J = 8Hz), 8.19 (2H, s), 7.70-7.67 (1H, m), 7.63-7.59 (2H, m), 6.56-6.50 (1H , m), 5.96 (1H, s), 5.44-5.36 (1H, m), 4.33-4.24 (2H, m), 4.08-3.97 (3H, m), 3.69-3.62 (1H, m), 3.62-3.53 (2H, m), 3.37-3.28 (1H, m), 3.26 (2H, t, J = 9Hz), 2.78-2.72 (1H, 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 (3H, t, J = 7Hz);
MS (ESI) m / z: 504 [M + H] ⁺ .

Example 45 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N- (2-hydroxyethyl) -N- Methylindoline-5-carboxamide

The title compound (69 mg, yield: 79%) was obtained in the same manner as in Example 36 using N-methylethanolamine (56 μL, 0.692 mmol) instead of morpholine.
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.52-8.49 (1H, 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 ), 5.44-5.36 (1H, 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 -3.53 (2H, m), 3.25 (2H, t, J = 9Hz), 3.11 (3H, s), 2.47 (2H, q, J = 7Hz), 2.15-2.05 (2H, m), 1.86-1.75 ( 2H, m), 1.20 (3H, t, J = 7Hz);
MS (ESI) m / z: 504 [M + H] ⁺ .

Example 46 1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N-[(1S) -2-hydroxy- 1-methylethyl] indoline-5-carboxamide

The title compound (65 mg, yield: 75%) was obtained in the same manner as in Example 36 using (S)-(+)-2-amino-1-propanol (54 μL, 0.688 mmol) instead of morpholine. .
¹ H-NMR (400MHz, CDCl ₃ ) δppm:
8.52-8.49 (1H, m), 8.40 (1H, d, J = 9Hz), 8.19 (2H, s), 7.68-7.65 (1H, m), 7.63-7.57 (1H, m), 6.25-6.20 (1H , 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 (1H, m), 3.69 -3.62 (1H, m), 3.62-3.53 (2H, m), 3.25 (2H, t, J = 9Hz), 3.05-2.92 (1H, 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 = 7Hz);
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.

(Formulation example)
A compound is obtained by mixing 5 g of the compound obtained in Examples, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate with a blender, and then tableting with a tableting machine.

(Test Example 1) Mouse oGTT (oral glucose tolerance test) test 2.0-8.0 mg of the test compound was weighed and placed in an agate mortar. While pulverizing the compound, 0.5% methylcellulose solution was added, and 1 mg / ml suspension was added. A suspension was prepared. Mouse C57 / BL6J (male, 6-8 weeks old) was purchased from Japan Charles River, raised until 9-13 weeks of age with a gauge, and started fasting from 17:00 to 18:00 the day before the test was conducted. We continued to fast until the test. On the day of the test day, blood was collected from the tail vein, and the previously prepared suspension was orally administered. 30 minutes after administration, blood was further collected from the tail vein (the plasma serum level at this time was pre-valued), and then a 20-30% glucose solution was orally administered at a dose of 10 ml / kg to perform glucose loading. After glucose loading, blood was collected from the tail vein at 15, 30, 60 and 120 minutes. The collected blood was centrifuged to separate the plasma. The plasma blood glucose level at 15, 30, 60 and 120 minutes after glucose loading was measured with Glucoloader GXT (Sinotest Co., Ltd.), and the AUC reduction rate (%) of the blood glucose level for the vehicle administration group was calculated. For the vehicle administration group, 0.5% methylcellulose solution was administered instead of the compound suspension.

(Test Example 2) Rat blood compound concentration measurement test 20 to 50 mg of the test compound was weighed and placed in an agate mortar. While pulverizing the compound, a 0.5% methylcellulose solution was added and a 2.5 mg / ml suspension was obtained. To prepare. F344 rats (male, 5-7 weeks old) are purchased from Japan Charles River and fasted from 17:00 to 18:00 on the day before the test. After measuring the body weight of the rat on the day of the test, the test compound is orally administered at a dose of 10 mg / kg, and blood is collected from the tail vein 0.5, 1, 2, 4, 6 and 24 hours after administration. The collected blood is centrifuged to separate the plasma. After deproteinizing the plasma, it is used in a liquid chromatography / mass spectrometer to calculate the compound concentration in the plasma.

(Test Example 3) Rat oGTT (oral glucose tolerance test) test 200 mg of the test compound was weighed and placed in an agate mortar, and 0.5% methylcellulose solution was added while pulverizing the compound, and a 7.5 mg / ml suspension was prepared. Prepare. When preparing another dose of the suspension, the suspension prepared above is sequentially diluted with a 0.5% methylcellulose solution to prepare the desired suspension. Zucker fatty rats and Zucker Diabetic Fatty rats (male, 8-12 weeks old) are purchased from Japan Charles River, and the groups are adjusted so that the basal blood glucose level and body weight between the administered groups are the same level before the test. Start fasting from 15:00 to 18:00 the day before the test, and continue to fast until the test. After the blood is collected from the tail vein on the day of the test, the previously prepared suspension is orally administered. 30 minutes after administration, blood was further collected from the tail vein (the plasma serum level at this time was pre-valued), and a 50% glucose solution was orally administered at a dose of 4 ml / kg to perform glucose loading. Blood is collected from the tail vein at 30 minutes, 1, 2 and 4 hours after glucose loading. The collected blood is centrifuged to separate the plasma. The plasma blood glucose level at 30 minutes, 1, 2, and 4 hours after glucose loading is measured with Glucoloader GXT (Sinotest Co., Ltd.), and the AUC reduction rate (%) of blood glucose level for the vehicle administration group is calculated. For the vehicle administration group, 0.5% methylcellulose solution is administered instead of the compound suspension.

The compound of the present invention or a pharmaceutically acceptable salt thereof treats and / or treats type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, glucose intolerance, diabetes related diseases, diabetic complications and the like. Or it is useful as an active ingredient of the pharmaceutical composition for prevention.

Claims

Formula (I):

[Where,
R 1 is -S (O) -R 11 , -S (O) 2 -R 11 , -S (NH) (O) -R 11 or -C (O) -NR 12 R 13 ;
R 11 is a C1-C6 alkyl group,
R 12 and R 13 are each independently a hydrogen atom or a C1-C6 alkyl group optionally having 1 to 3 substituents selected from the substituent group α, or R 12 12 and R 13 together with the nitrogen atom to which they are attached form a morpholino group,
Substituent group α is a group consisting of a halogen atom, a hydroxyl group and a C1-C6 alkoxy group,
m is an integer from 0 to 5,
R 2 is the same or different and is a halogen atom;
n is an integer from 0 to 4,
R 3 is the same or different and is a halogen atom;
R 4 represents —C (O) —OR 41 , a phenyl group optionally having 1 to 3 substituents selected from the substituent group β, and 1 to 3 substituents selected from the substituent group β. A pyridinyl group which may have 3 or a pyrimidinyl group which may have 1 to 3 substituents selected from the substituent group β,
R 41 is a C1-C6 alkyl group optionally substituted with a halogen atom,
Substituent group β is a group consisting of a halogen atom, a C1-C6 alkyl group optionally substituted with a halogen atom, a C1-C6 alkoxy group optionally substituted with a halogen atom, and a cyano group,
X is CH or N;
Y is CH or N;
Z is O or NR 5
R 5 is a hydrogen atom or a C1-C6 alkyl group,
Provided that when X and Y are both N, Z is O and R 4 is —C (O) —OR 41 , R 1 is —S (NH) (O) —R 11 or — C (O) -NR 12 R 13 )
Or a pharmaceutically acceptable salt thereof.
The compound of claim 1, wherein R 1 is —S (O) —R 11 .
The compound of claim 1, wherein R 1 is —S (O) 2 —R 11 .
The compound according to claim 2 or 3, wherein R 11 is a C1-C3 alkyl group.
The compound of claim 1, wherein R 1 is —C (O) —NR 12 R 13 .
6. Each of R 12 and R 13 is independently a hydrogen atom or a C1-C3 alkyl group optionally having 1 to 3 substituents selected from substituent group α. The described compound.
R 12 and R 13 are, they form a morpholino group together with the nitrogen atom bonded compound according to claim 5.
The compound according to any one of claims 1 to 7, wherein m is 0 or 1.
The compound according to any one of claims 1 to 8, wherein n is 0 or 1.
R 4 is a phenyl group that may have one substituent selected from substituent group β, a pyridyl group that may have one substituent selected from substituent group β, or The compound according to any one of claims 1 to 9, which is a pyrimidinyl group which may have one substituent selected from substituent group β.
The compound according to any one of claims 1 to 10, wherein X is N and Y is N.
The compound according to any one of claims 1 to 11, wherein Z is O.
Or a pharmaceutically acceptable salt thereof selected from the group consisting of:
1- (2-{[1- (5-ethylpyridin-2-yl) piperidin-4-yl] oxy} pyridin-4-yl) -5- (methylsulfonyl) indoline;
1- (6-{[1- (5-ethylpyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline;
1- (6-{[1- (5-isopropylpyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline;
1- (6-{[1- (5-ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfinyl) indoline;
1- (6-{[1- (5-isopropylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline;
1- (6-{[1- (5-trifluoromethylpyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline;
1- (6-{[1- (5-methoxypyridin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -5- (methylsulfonyl) indoline;
1- (6-{[1- (5-ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N- (2-methoxyethyl) indoline-5-carboxamide;
1- (6-{[1- (5-ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N- (2-hydroxyethyl) indoline-5-carboxamide;
1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N-[(2S) -2-hydroxypropyl] indoline-5- Carboxamide;
1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N-[(2R) -2-hydroxypropyl] indoline-5- Carboxamide; and
1- (6-{[1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] oxy} pyrimidin-4-yl) -N- (2-hydroxyethyl) -N-methylindoline-5- Carboxamide.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient.
The pharmaceutical composition according to claim 14, for treating and / or preventing type 1 diabetes, type 2 diabetes, diabetes-related diseases or obesity.
Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition.
A method for treating and / or preventing a disease, comprising administering to a mammal a pharmacologically effective amount of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.
The method according to claim 17, wherein the mammal is a human.