Nitrogen-containing heterocyclic compounds or their salts, uses thereof, and intermediates thereof

Abstract

The present invention addresses the problem of providing: a compound useful as an antitumor agent; an intermediate thereof; and a pharmaceutical composition, an antitumor agent, and a dihydroorotic acid dehydrogenase inhibitor containing the compound. According to the present invention, a compound represented by general formula (1) or a salt thereof is provided. In the formula, Z1, Z2, and Z3 are identical or different, and each represent a nitrogen atom or CH; Z4 represents a nitrogen atom or general formula CR6; Z5 represents a nitrogen atom or general formula CR7; at least one among Z1, Z2, Z3, Z4, and Z5 represents a nitrogen atom; R1 represents general formula CONHR8 or the like; R2 represents a C3-8 cycloalkyl group or the like which may be substituted; R3, R5, R6, and R7 are identical or different, and each represent a hydrogen atom or a halogen atom, etc.; R4 represents an aryl group which may be substituted or a heterocyclic group which may be substituted; R8 represents general formula SO2R9 or the like; and R9 represents an amino group or the like which may be protected.

Description

[Technical field]

[0001] The present invention relates to a nitrogen-containing heterocyclic compound or a salt thereof, and an intermediate thereof, which are useful as an antitumor agent, etc. The present invention further relates to a pharmaceutical composition, an antitumor agent, and a dihydroorotate dehydrogenase inhibitor, each of which contains the nitrogen-containing heterocyclic compound or a salt thereof. [Background technology]

[0002] Cancer is a major health problem in modern medicine and one of the leading causes of death in developed countries. Major cancers include blood cancers and solid cancers.

[0003] Blood contains blood cells such as red blood cells, white blood cells, and platelets, which are produced in the bone marrow inside the bones by proliferation and differentiation (immature cells becoming mature cells) of hematopoietic stem cells, the source of blood cells. Blood cancer develops when some genetic abnormality occurs in myeloblasts, which are immature blood cells during the blood production process, causing cancerous cells (leukemia cells) to proliferate indefinitely.

[0004] On the other hand, Patent Document 1 discloses a pyrazine derivative that has an excellent inhibitory effect on keratinocyte proliferation and is useful for the prevention or treatment of diseases associated with the excessive proliferation of keratinocytes.

[0005] Moreover, Patent Document 2 discloses a pyridine derivative useful for treating blood cancer. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2014 / 069510 [Patent Document 2] International Publication No. 2019 / 235571 Summary of the Invention [Problem to be solved by the invention]

[0007] There are various treatments for blood cancer, including chemotherapy, radiation therapy, molecular targeted therapy, and high-dose chemotherapy combined with hematopoietic stem cell transplantation. However, the number of deaths from blood cancer is increasing, and there are issues such as resistance to treatment drugs, and no completely curative treatment has been established.

[0008] In addition, many solid cancers have poor prognoses, and no effective treatment has yet been established. In addition, these cancer cells grow autonomously and uncontrolled, which poses the problem of rapid proliferation, and there is a demand for effective treatment methods for solid cancers.

[0009] Various methods for preventing or treating cancer are known, but the effects are not satisfactory, and more effective antitumor agents are desired. An object of the present invention is to provide a nitrogen-containing heterocyclic compound or a salt thereof, and an intermediate thereof, which are useful as an antitumor agent, etc. Another object of the present invention is to provide a pharmaceutical composition, an antitumor agent, and a dihydroorotate dehydrogenase inhibitor, each of which contains the nitrogen-containing heterocyclic compound or a salt thereof. [Means for solving the problem]

[0010] Under such circumstances, the present inventors have conducted intensive research and found that the compound represented by formula (1) or a salt thereof has excellent dihydroorotate dehydrogenase (hereinafter also referred to as DHODH) inhibitory activity and is useful as a DHODH inhibitor. The present inventors have also found that the compound represented by formula (1) or a salt thereof has excellent antitumor activity and is useful as an antitumor agent, and have completed the present invention.

[0011] The present invention provides the following: [1] A compound represented by general formula (1) or a salt thereof: [ka] During the ceremony, Z1 , Z 2 and Z 3 are the same or different and represent a nitrogen atom or CH; Z 4 is a nitrogen atom or a group of the general formula CR 6 indicates; Z 5 is a nitrogen atom or a group of the general formula CR 7 indicates; However, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 at least one of represents a nitrogen atom; R 1 is the general formula CONHR 8 , general formula CH2NHR 8 , CH2OH, CH(OH)CH3, C(O)CH3, CHO or formula (1-1) to (1-3) [ka] indicates; R 2 is optionally substituted C 1-6 Alkyl group or optionally substituted C 3-8 represents a cycloalkyl group; R 3 , R 5 , R 6 and R 7 are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkoxy group, optionally substituted C 1-6 alkylamino group, optionally substituted di(C 1-6 (alkyl)amino group or optionally substituted C1-6 Alkoxy C 1-6 represents an alkyl group; R 4 represents an optionally substituted aryl group or an optionally substituted heterocyclic group; R 8 represents a hydrogen atom, an optionally protected hydroxyl group, an optionally protected amino group, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkoxy group, optionally substituted C 1-6 alkylamino group, optionally substituted di(C 1-6 alkyl)amino group or general formula SO2R 9 indicates; R 9 represents an optionally protected hydroxyl group, an optionally protected amino group, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkoxy group, optionally substituted C 1-6 Alkylamino group or optionally substituted di(C 1-6 (alkyl)amino group. [2] Z 1 is a nitrogen atom, and Z 2 is CH and Z 3 is a nitrogen atom or CH, and Z 4 But the general formula is CR 6 and Z 5 But the general formula is CR 7 The compound or salt thereof according to [1], [3] R 2 But, C 1-6 Alkyl group or C 3-8 The compound or salt thereof according to [1] or [2], wherein the compound is a cycloalkyl group. [4] R 1 The general formula is CONHR 8 Or formulas (1-1) to (1-3) [ka] The compound or salt thereof according to any one of [1] to [3], [5] R 3 , R 5 , R 6 and R 7 are the same or different, and may be substituted with one or more substituents selected from a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, and a substituent group A. 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 2-6 an alkenyl group, C optionally substituted with one or more substituents selected from the substituent group A; 2-6 an alkynyl group, C optionally substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkyl group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 an alkylamino group, a di(C 1-6 C which may be substituted with one or more substituents selected from the group A of alkylamino groups or the group B of substituents 1-6 Alkoxy C 1-6 The compound or salt thereof according to any one of [1] to [4], wherein the compound is an alkyl group. Substituent group A: Halogen atom; Cyano group; Optionally protected hydroxyl group; Optionally protected amino group; C 1-6 Alkyl group; C 2-6 Alkenyl group; C 2-6 Alkynyl group; C 3-8 Cycloalkyl group; C1-6 Alkoxy group; C 3-8 Cycloalkoxy group; C 1-6 Alkylamino group; Di(C 1-6 an alkyl)amino group; an aryl group which may be substituted with one or more substituents selected from substituent group B; a heterocyclic group which may be substituted with one or more substituents selected from substituent group B Substituent group B: Halogen atom; optionally protected hydroxyl group; optionally protected amino group; C 1-6 Alkyl group; C 2-6 Alkenyl group; C 2-6 Alkynyl group; C 3-8 Cycloalkyl group; C 1-6 Alkoxy group; C 3-8 Cycloalkoxy group; C 1-6 Alkylamino group; Di(C 1-6 (alkyl)amino group; C 1-6 Alkoxy C 1-6 Alkyl group. [6] R 3 C which may be substituted with one or more substituents selected from a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, and a substituent group A 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 2-6 an alkenyl group, C optionally substituted with one or more substituents selected from the substituent group A; 2-6 an alkynyl group, C optionally substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkyl group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 an alkylamino group, a di(C 1-6 C which may be substituted with one or more substituents selected from the group A of alkylamino groups or the group B of substituents 1-6Alkoxy C 1-6 The compound or salt thereof according to any one of [1] to [5], wherein the compound is an alkyl group. [7] R 5 , R 6 and R 7 may be substituted with one or more substituents selected from a hydrogen atom, a halogen atom, and a substituent group A, which may be the same or different, 1-6 C which may be substituted with an alkyl group or one or more substituents selected from the substituent group A 1-6 The compound or salt thereof according to any one of [1] to [6], wherein R is an alkoxy group. [8] R 4 is an aryl group optionally substituted with one or more substituents selected from substituent group A, a monocyclic nitrogen-containing heterocyclic group optionally substituted with one or more substituents selected from substituent group A, a monocyclic oxygen-containing heterocyclic group optionally substituted with one or more substituents selected from substituent group A, a bicyclic nitrogen-containing heterocyclic group optionally substituted with one or more substituents selected from substituent group A, or a bicyclic oxygen-containing heterocyclic group optionally substituted with one or more substituents selected from substituent group A. The compound or a salt thereof according to any one of [1] to [7]. [9] R 4 is a phenyl group optionally substituted with one or more substituents selected from substituent group A, a pyridyl group optionally substituted with one or more substituents selected from substituent group A, a tetrahydropyranyl group optionally substituted with one or more substituents selected from substituent group A, or a dihydropyranyl group optionally substituted with one or more substituents selected from substituent group A. The compound or a salt thereof according to [8].

[10] R 8 C which may be substituted with one or more substituents selected from a hydrogen atom, an optionally protected hydroxyl group, an optionally protected amino group, and substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 an alkylamino group, a di(C 1-6 alkyl)amino group or general formula SO2R 9 The compound or salt thereof according to any one of [1] to [9],

[11] R 9 an optionally protected amino group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 3-8 Cycloalkyl group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 An alkylamino group or a di(C 1-6 The compound or salt thereof according to any one of [1] to

[10] , wherein R is an alkyl)amino group.

[12] A pharmaceutical composition comprising the compound or a salt thereof according to any one of [1] to

[11] .

[13] An antitumor agent comprising the compound or a salt thereof according to any one of [1] to

[11] .

[14] A dihydroorotate dehydrogenase inhibitor comprising the compound according to any one of [1] to

[11] or a salt thereof.

[15] An intermediate for producing the compound or a salt thereof according to [1], which is a compound or a salt thereof selected from compound group X: Compound group X: 6-cyclopropyl-3-((3-(2,6-dimethylpyridin-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylic acid, 3-((4'-cyano-2'-methyl-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid, (S)-5-cyclopropyl-2-((2-(3,6-dihydro-2H-pyran-4-yl)-3-((1,1,1-trifluoropropane -2-yl)oxy)pyridin-4-yl)amino)benzoic acid, 5-cyclopropyl-2-((5-(3,6-dihydro-2H-pyran-4-yl)-4-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)benzoic acid, 5-cyclopropyl-2-((3-(tetrahydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinic acid, 5-cyclopropyl-2-((2-(difluoromethoxy)-5-fluoro-3-(tetrahydro-2H -pyran-4-yl)phenyl)amino)nicotinic acid, 3-((4'-cyano-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid, 5-cyclopropyl-2-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinic acid, (S)-5-cyclopropyl-2-((5-(3,6-dihydro-2H-pyran-4-yl)-4-((1,1 ,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)amino)benzoic acid, 2-((4'-cyano-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinic acid, 3-((3'-cyano-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid, 5-cyclopropyl-2-((2-ethyl-3-(tetrahydro-2H-pyran-4-yl)phenyl)amino)nicotinic acid, 3-((4'-cyano-2-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid, 3-((4'-cyano-2-(difluoromethoxy)-5-fluoro-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid, 6-cyclopropyl-3-((4'-fluoro-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)pyrazine nicotinic acid, 5-cyclopropyl-2-((3-(3,6-dihydro-2H-pyran-4-yl)-2-ethoxy-6-fluorophenyl)amino)nicotinic acid, 5-cyclopropyl-2-((3-(3,6-dihydro-2H-pyran-4-yl)-2-ethoxy-4-fluorophenyl)amino)nicotinic acid, 2-cyclopropyl-5-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)isonicotinic acid, (S)-6-cyclopropyl-3-((3-(tetrahydro-2H-pyran-4-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)phenyl)amino)pyrazine-4-carboxylic acid.

[0012] [A] A method for treating a tumor, comprising administering to a subject the compound or a salt thereof according to any one of [1] to

[11] . [B] A method for inhibiting dihydroorotate dehydrogenase, comprising administering to a subject the compound according to any one of [1] to

[11] or a salt thereof. [C] The compound or salt thereof according to any one of [1] to

[11] for use in treating a tumor. [D] The compound or salt thereof according to any one of [1] to

[11] for use in treatment for inhibiting dihydroorotate dehydrogenase. [E] Use of the compound or salt thereof according to any one of [1] to

[11] for the manufacture of a pharmaceutical composition. [F] Use of the compound or salt thereof according to any one of [1] to

[11] for the manufacture of an antitumor agent. [G] Use of the compound or a salt thereof according to any one of [1] to

[11] for the manufacture of a dihydroorotate dehydrogenase inhibitor. Effect of the Invention

[0013] The compound of the present invention or a salt thereof has excellent DHODH inhibitory activity and is useful as a DHODH inhibitor. In addition, the compound of the present invention or a salt thereof has excellent antitumor activity and is useful as a pharmaceutical composition for an antitumor agent, etc. The compound of the present invention or a salt thereof is useful for treatment such as prevention or treatment of blood cancer, for example. Furthermore, the compound selected from compound group X or a salt thereof is useful as an intermediate for producing the compound of the present invention or a salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present invention will be described in detail below. The "%" used in the present invention means mass percentage unless otherwise specified. In the present invention, a numerical range indicated using "to" indicates a range including the numerical values ​​before and after "to" as the minimum and maximum values, respectively. Furthermore, in the present invention, when a composition contains a plurality of substances corresponding to each component, the amount of each component in the composition means the total amount of the plurality of substances present in the composition, unless otherwise specified.

[0015] In the present invention, unless otherwise specified, each term has the following meaning. A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0016] C 1-6Alkyl groups are straight or branched C groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 2-pentyl, 3-pentyl and hexyl groups. 1-6 It means an alkyl group.

[0017] C 1-6 Alkylsulfonyl groups are C arylsulfonyl groups such as methylsulfonyl, ethylsulfonyl and propylsulfonyl groups. 1-6 This means an alkylsulfonyl group.

[0018] C 1-6 Alkylsulfonyloxy groups are C groups such as methylsulfonyloxy and ethylsulfonyloxy groups. 1-6 This means an alkylsulfonyloxy group.

[0019] C 2-6 Alkenyl groups are straight-chain or branched C alkyl groups such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups. 2-6 It means an alkenyl group.

[0020] C 2-6 Alkynyl groups are straight-chain or branched C alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl and hexynyl groups. 2-6 It means an alkynyl group.

[0021] C 3-8 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups. 3-8 It means a cycloalkyl group.

[0022] C 1-6 The alkylamino group refers to a straight-chain or branched C arylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino, and hexylamino groups. 1-6It means an alkylamino group.

[0023] Ji (C 1-6 The term "alkyl)amino group" refers to a linear or branched di(C)amino group, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di(tert-butyl)amino, dipentylamino, dihexylamino, (ethyl)(methyl)amino and (methyl)(propyl)amino groups. 1-6 (alkyl)amino group.

[0024] C 1-6 Alkoxy groups are straight-chain or branched C alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups. 1-6 It means an alkyloxy group.

[0025] C 1-6 Alkoxy C 1-6 Alkyl groups are C aryl groups such as methoxymethyl and 1-ethoxyethyl groups. 1-6 Alkyloxy C 1-6 It means an alkyl group.

[0026] C 1-6 The alkoxycarbonyl group is a straight-chain or branched C alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups. 1-6 It means an alkyloxycarbonyl group.

[0027] C 3-8 Cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy groups. 3-8 It means a cycloalkyloxy group.

[0028] Aryl groups include phenyl and naphthyl groups. An aryloxy group means a phenoxy, naphthalene-1-yloxy or naphthalene-2-yloxy group, or the like. The arylsulfonyl group means a benzenesulfonyl group, a p-toluenesulfonyl group, a naphthalenesulfonyl group, or the like. The arylsulfonyloxy group means a benzenesulfonyloxy or p-toluenesulfonyloxy group, or the like. Aryl C 1-6 The alkyl group is an aryl C group such as benzyl, diphenylmethyl, trityl, phenethyl, 2-phenylpropyl, 3-phenylpropyl, and naphthylmethyl groups. 1-6 It means an alkyl group. Aryl C 1-6 The alkoxy group is an aryl C group such as benzyloxy, diphenylmethoxy, trityloxy, phenethyloxy, 2-phenylpropoxy, 3-phenylpropoxy, and naphthylmethoxy groups. 1-6 It means an alkyloxy group. Aryl C 1-6 Alkoxy C 1-6 The alkyl group is an aryl group such as benzyloxymethyl and phenethyloxymethyl groups. 1-6 Alkyloxy C 1-6 It means an alkyl group. Aryl C 1-6 The alkoxycarbonyl group is an aryl C group such as benzyloxycarbonyl and phenethyloxycarbonyl groups. 1-6 It means an alkyloxycarbonyl group. The aryloxycarbonyl group means a phenoxycarbonyl, naphthalene-1-yloxycarbonyl or naphthalene-2-yloxycarbonyl group, or the like.

[0029] A heterocyclic group means a monocyclic heterocyclic group, a bicyclic heterocyclic group, a spiro heterocyclic group or a bridged heterocyclic group.

[0030] The monocyclic heterocyclic group means a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur-containing heterocyclic group, a monocyclic nitrogen-oxygen heterocyclic group or a monocyclic nitrogen-sulfur heterocyclic group.

[0031] The monocyclic nitrogen-containing heterocyclic group means a monocyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a heteroatom forming the ring, such as aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidyl, tetrahydropyridyl, dihydropyridyl, pyridyl, homopiperidinyl, octahydroazocinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, homopiperazinyl, triazolyl, and tetrazolyl groups.

[0032] The monocyclic oxygen-containing heterocyclic group means a monocyclic oxygen-containing heterocyclic group containing only oxygen atoms as heteroatoms forming the ring, such as oxetanyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, dihydropyranyl, pyranyl, 1,3-dioxanyl and 1,4-dioxanyl groups.

[0033] The monocyclic sulfur-containing heterocyclic group means a thienyl group.

[0034] The monocyclic nitrogen-containing oxygen heterocyclic group means a monocyclic nitrogen-containing oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as heteroatoms forming the above ring, such as oxazolyl, isoxazolyl, oxadiazolyl, morpholinyl and oxazepanyl groups.

[0035] The monocyclic nitrogen-containing sulfur heterocyclic group means a monocyclic nitrogen-containing sulfur heterocyclic group containing only nitrogen atoms and sulfur atoms as hetero atoms forming the above ring, such as thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxidethiomorpholinyl and 1,1-dioxidethiomorpholinyl groups.

[0036] A bicyclic heterocyclic group means a bicyclic nitrogen-containing heterocyclic group, a bicyclic oxygen-containing heterocyclic group, a bicyclic sulfur-containing heterocyclic group, a bicyclic nitrogen-oxygen heterocyclic group or a bicyclic nitrogen-sulfur heterocyclic group.

[0037] The bicyclic nitrogen-containing heterocyclic group means a bicyclic nitrogen-containing heterocyclic group containing only nitrogen atoms as heteroatoms forming the ring, such as indolinyl, indolyl, isoindolinyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrazolopyridinyl, quinolyl, tetrahydroquinolinyl, quinolyl, tetrahydroisoquinolinyl, isoquinolinyl, quinolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pteridinyl and quinuclidinyl groups.

[0038] The bicyclic oxygen-containing heterocyclic group means a bicyclic oxygen-containing heterocyclic group containing only oxygen atoms as heteroatoms forming the ring, such as 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodioxanyl and 1,4-benzodioxanyl groups.

[0039] The bicyclic sulfur-containing heterocyclic group means a bicyclic sulfur-containing heterocyclic group containing only sulfur atoms as heteroatoms forming the ring, such as 2,3-dihydrobenzothienyl and benzothienyl groups.

[0040] The bicyclic nitrogen-containing oxygen heterocyclic group means a bicyclic nitrogen-containing oxygen heterocyclic group containing only nitrogen atoms and oxygen atoms as heteroatoms forming the above ring, such as benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzomorpholinyl, dihydropyranopyridyl, dioxolopyridyl, furopyridinyl, dihydrodioxinopyridyl and dihydropyridoxazinyl groups.

[0041] The bicyclic nitrogen-containing sulfur heterocyclic group means a bicyclic nitrogen-containing sulfur heterocyclic group containing a nitrogen atom and a sulfur atom as hetero atoms forming the above ring, such as benzothiazolyl, benzoisothiazolyl and benzothiadiazolyl groups.

[0042] The spiro heterocyclic group means a spiro heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom as a heteroatom forming the above ring, such as 2-oxa-6-azaspiro[3.3]heptyl, 1,4-dioxaspiro[4.5]decyl, 1-oxa-8-azaspiro[4.5]decyl and 1-thia-8-azaspiro[4.5]decyl.

[0043] The bridged heterocyclic group refers to a bridged heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom forming the above, such as 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl and quinuclidinyl groups.

[0044] The acyl group is a formyl group, a succinyl group, a glutaryl group, a maleoyl group, a phthaloyl group, a C 2-6 Alkanoyl group, C 3-8 It means a cycloalkylcarbonyl group, an aroyl group or a heterocyclic carbonyl group.

[0045] C 2-6 Alkanoyl groups are straight-chain or branched C alkoxy groups such as acetyl, propionyl, valeryl, isovaleryl, and pivaloyl groups. 2-6 It means an alkanoyl group.

[0046] C 3-8 The cycloalkylcarbonyl group is a C aryl group such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, and cycloheptylcarbonyl. 3-8 It means a cycloalkylcarbonyl group.

[0047] The aroyl group means a benzoyl or naphthoyl group, or the like.

[0048] The heterocyclic carbonyl group means a heterocyclic carbonyl group such as a pyrrolylcarbonyl, pyridylcarbonyl, furanylcarbonyl or thienylcarbonyl group.

[0049] A silyl group means a trimethylsilyl, triethylsilyl, tributylsilyl or tert-butyldimethylsilyl group.

[0050] Leaving groups are halogen atoms, C 1-6 It means an alkylsulfonyloxy group, an aryloxy group, or an arylsulfonyloxy group. 1-6 The alkylsulfonyloxy group, the aryloxy group and the arylsulfonyloxy group are not limited to halogen atoms, nitro groups, C 1-6 Alkyl groups and C 1-6 It may be substituted with one or more substituents selected from alkoxy groups.

[0051] The hydroxyl protecting group includes all groups that can be used as a protecting group for a normal hydroxyl group, and examples thereof include those described in TW Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 16-299, 2007, John Wiley & Sons, Inc. Specifically, for example, 1-6 Alkyl group, C 2-6 Alkenyl group, aryl C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, aryl group C 1-6 Alkoxy C 1-6 Alkyl group, acyl group, C 1-6 Alkoxycarbonyl group, aryl C 1-6 Alkoxycarbonyl group, C 1-6 Examples of the group include an alkylsulfonyl group, an arylsulfonyl group, a silyl group, a tetrahydrofuranyl group, and a tetrahydropyranyl group.

[0052] The amino-protecting group includes all groups that can be used as a protecting group for a normal amino group, and examples thereof include those described in W. Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 696-926, 2007, John Wiley & Sons, INC. Specifically, aryl C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, acyl group, C 1-6 Alkoxycarbonyl group, aryl C 1-6 Alkoxycarbonyl group, aryloxycarbonyl group, C 1-6 Examples of the sulfonyl group include an alkylsulfonyl group, an arylsulfonyl group, and a silyl group.

[0053] By aliphatic hydrocarbons is meant pentane, hexane, heptane, cyclohexane, methylcyclohexane or ethylcyclohexane. By halogenated hydrocarbons is meant dichloromethane, chloroform or dichloroethane. The alcohols include methanol, ethanol, propanol, 2-propanol, butanol, and 2-methyl-2-propanol. The glycols include ethylene glycol, propylene glycol, and diethylene glycol. Ethers means diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether. Ketones means acetone, 2-butanone, 4-methyl-2-pentanone or methyl isobutyl ketone. By esters is meant methyl acetate, ethyl acetate, propyl acetate or butyl acetate. Amides means N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone. Nitriles means acetonitrile or propionitrile. Sulfoxides means dimethyl sulfoxide or sulfolane. By aromatic hydrocarbons is meant benzene, toluene or xylene.

[0054] By inorganic base is meant sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium bicarbonate, sodium carbonate, potassium carbonate, tripotassium phosphate, potassium acetate, cesium fluoride, cesium carbonate or tert-butylmagnesium chloride. By organic base is meant triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine, N-methylmorpholine or imidazole.

[0055] Each of the substituent groups has the following meaning. <Substituent group A> Halogen atom; Cyano group; Optionally protected hydroxyl group; Optionally protected amino group; C 1-6 Alkyl group; C 2-6 Alkenyl group; C 2-6 Alkynyl group; C 3-8 Cycloalkyl group; C 1-6 Alkoxy group; C 3-8 Cycloalkoxy group; C 1-6 Alkylamino group; Di(C 1-6 an aryl group which may be substituted with one or more substituents selected from substituent group B; a heterocyclic group which may be substituted with one or more substituents selected from substituent group B.

[0056] <Substituent group B> Halogen atom; optionally protected hydroxyl group; optionally protected amino group; C1-6 Alkyl group; C 2-6 Alkenyl group; C 2-6 Alkynyl group; C 3-8 Cycloalkyl group; C 1-6 Alkoxy group; C 3-8 Cycloalkoxy group; C 1-6 Alkylamino group; Di(C 1-6 (alkyl)amino group; C 1-6 Alkoxy C 1-6 Alkyl group.

[0057] Examples of salts of the compound represented by the general formula (1) of the present invention include commonly known salts of basic groups such as amino groups, and acidic groups such as hydroxyl groups and carboxyl groups.

[0058] Salts of basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.

[0059] Salts of acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine.

[0060] Among the above salts, preferred salts include pharmacologically acceptable salts.

[0061] The compound represented by general formula (1) includes, for example, compounds represented by general formula (1a), general formula (1b) or general formula (1c). [ka] (In the formula, R 10 represents a substituent group A; m represents an integer of 0 to 6; the dashed line represents a single bond or a double bond; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , R 1 , R 2 , R 3 and R 5 has the same meaning as above.)

[0062] Among the compounds represented by general formula (1a), general formula (1b) or general formula (1c), the compounds represented by general formula (1a) or general formula (1b) are preferred, and the compounds represented by general formula (1a) are more preferred.

[0063] Z 1 Z 1 is a nitrogen atom or CH.

[0064] Z 1 As the group, a nitrogen atom is preferable.

[0065] Z 2 Z 2 is a nitrogen atom or CH.

[0066] Z 2 As the alkyl group, CH is preferable.

[0067] Z 3 Z 3 is a nitrogen atom or CH.

[0068] Z 3is preferably a nitrogen atom or CH, and more preferably a nitrogen atom.

[0069] Z 4 Z 4 is a nitrogen atom or a group of the general formula CR 6 It is.

[0070] Z 4 As the general formula, CR 6 is preferred.

[0071] Z 5 Z 5 is a nitrogen atom or a group of the general formula CR 7 It is.

[0072] Z 5 As the general formula, CR 7 is preferred.

[0073] Z 1 is a nitrogen atom, and Z 2 is CH and Z 3 is a nitrogen atom or CH, and Z 4 But the general formula is CR 6 and Z 5 But the general formula is CR 7 Preferred are compounds in which:

[0074] Z 1 is a nitrogen atom, and Z 2 is CH and Z 3 is a nitrogen atom, and Z 4 But the general formula is CR 6 and Z 5 But the general formula is CR 7 More preferred is a compound in which:

[0075] R 1 R 1 is the general formula CONHR 8 , general formula CH2NHR 8, CH2OH, CH(OH)CH3, C(O)CH3, CHO or formulas (1-1) to (1-3).

[0076] R 1 The general formula is CONHR 8 or formula (1-1) to (1-3) is preferred, and the general formula CONHR 8 is more preferred.

[0077] R 2 R 2 is optionally substituted C 1-6 Alkyl group or optionally substituted C 3-8 It is a cycloalkyl group.

[0078] R 2 C which may be substituted with one or more substituents selected from the substituent group A 1-6 C which may be substituted with an alkyl group or one or more substituents selected from the substituent group A 3-8 Cycloalkyl groups are preferred.

[0079] R 2 As for C 1-6 Alkyl group or C 3-8 Cycloalkyl groups are more preferred, C 3-8 Cycloalkyl groups are more preferred, and cyclopropyl groups are most preferred.

[0080] R 3 R 3 represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8Cycloalkoxy group, optionally substituted C 1-6 alkylamino group, optionally substituted di(C 1-6 (alkyl)amino group or optionally substituted C 1-6 Alkoxy C 1-6 It is an alkyl group.

[0081] R 3 Examples of the substituents include a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, and C which may be substituted with one or more substituents selected from the substituent group A. 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 2-6 an alkenyl group, C optionally substituted with one or more substituents selected from the substituent group A; 2-6 an alkynyl group, C optionally substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkyl group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 an alkylamino group, a di(C 1-6 C which may be substituted with one or more substituents selected from the group A of alkylamino groups or the group B of substituents 1-6 Alkoxy C 1-6 Alkyl groups are preferred.

[0082] R 3 Examples of the substituents include a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, and C optionally substituted with one or more substituents selected from the substituent group A. 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 2-6 an alkenyl group, C optionally substituted with one or more substituents selected from the substituent group A; 2-6an alkynyl group, C optionally substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkyl group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 an alkylamino group, a di(C 1-6 C which may be substituted with one or more substituents selected from the group A of alkylamino groups or the group B of substituents 1-6 Alkoxy C 1-6 Alkyl groups are more preferred.

[0083] R 3 C which may be substituted with one or more substituents selected from the substituent group A 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 3-8 Cycloalkyl group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 C which may be substituted with one or more substituents selected from a cycloalkoxy group or the substituent group A 1-6 Alkoxy C 1-6 Alkyl groups are more preferred.

[0084] R 3 C which may be substituted with one or more substituents selected from the substituent group A 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 1-6 Alkoxy groups are even more preferred.

[0085] R 4 R 4is an optionally substituted aryl group or an optionally substituted heterocyclic group.

[0086] R 4 is preferably an aryl group which may be substituted with one or more substituents selected from Substituent group A, or a heterocyclic group which may be substituted with one or more substituents selected from Substituent group A.

[0087] R 4 As the heterocyclic group, an aryl group which may be substituted with one or more substituents selected from the substituent group A, a monocyclic nitrogen-containing heterocyclic group which may be substituted with one or more substituents selected from the substituent group A, a monocyclic oxygen-containing heterocyclic group which may be substituted with one or more substituents selected from the substituent group A, a bicyclic nitrogen-containing heterocyclic group which may be substituted with one or more substituents selected from the substituent group A, or a bicyclic oxygen-containing heterocyclic group which may be substituted with one or more substituents selected from the substituent group A is more preferable.

[0088] R 4 As the heterocyclic group, an aryl group which may be substituted with one or more substituents selected from the substituent group A, a monocyclic nitrogen-containing heterocyclic group which may be substituted with one or more substituents selected from the substituent group A, or a monocyclic oxygen-containing heterocyclic group which may be substituted with one or more substituents selected from the substituent group A is more preferable.

[0089] R 4 As the alkyl group, a phenyl group which may be substituted with one or more substituents selected from the substituent group A, a pyridyl group which may be substituted with one or more substituents selected from the substituent group A, a tetrahydropyranyl group which may be substituted with one or more substituents selected from the substituent group A, and a dihydropyranyl group which may be substituted with one or more substituents selected from the substituent group A are even more preferable.

[0090] R 5 R 5represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkoxy group, optionally substituted C 1-6 alkylamino group, optionally substituted di(C 1-6 (alkyl)amino group or optionally substituted C 1-6 Alkoxy C 1-6 It is an alkyl group.

[0091] R 5 Examples of the substituents include a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, and C which may be substituted with one or more substituents selected from the substituent group A. 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 2-6 an alkenyl group, C optionally substituted with one or more substituents selected from the substituent group A; 2-6 an alkynyl group, C optionally substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkyl group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 an alkylamino group, a di(C 1-6 C which may be substituted with one or more substituents selected from the group A of alkylamino groups or the group B of substituents 1-6 Alkoxy C 1-6 Alkyl groups are preferred.

[0092] R5 C which may be substituted with one or more substituents selected from a hydrogen atom, a halogen atom, or a substituent group A 1-6 C which may be substituted with an alkyl group or one or more substituents selected from the substituent group A 1-6 An alkoxy group is more preferred.

[0093] R 5 The substituents are hydrogen atoms, halogen atoms, or C 1-6 An alkoxy group is more preferred.

[0094] R 6 R 6 represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkoxy group, optionally substituted C 1-6 alkylamino group, optionally substituted di(C 1-6 (alkyl)amino group or optionally substituted C 1-6 Alkoxy C 1-6 It is an alkyl group.

[0095] R 6 Examples of the substituents include a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, and C which may be substituted with one or more substituents selected from the substituent group A. 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 2-6 an alkenyl group, C optionally substituted with one or more substituents selected from the substituent group A; 2-6 an alkynyl group, C optionally substituted with one or more substituents selected from the substituent group A; 3-8Cycloalkyl group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 an alkylamino group, a di(C 1-6 C which may be substituted with one or more substituents selected from the group A of alkylamino groups or the group B of substituents 1-6 Alkoxy C 1-6 Alkyl groups are preferred.

[0096] R 6 C which may be substituted with one or more substituents selected from a hydrogen atom, a halogen atom, or a substituent group A 1-6 C which may be substituted with an alkyl group or one or more substituents selected from the substituent group A 1-6 An alkoxy group is more preferred.

[0097] R 6 The substituents are hydrogen atoms, halogen atoms, or C 1-6 An alkoxy group is more preferred.

[0098] R 7 R 7 represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkoxy group, optionally substituted C 1-6 alkylamino group, optionally substituted di(C 1-6 (alkyl)amino group or optionally substituted C 1-6Alkoxy C 1-6 It is an alkyl group.

[0099] R 7 Examples of the substituents include a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected amino group, and C which may be substituted with one or more substituents selected from the substituent group A. 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 2-6 an alkenyl group, C optionally substituted with one or more substituents selected from the substituent group A; 2-6 an alkynyl group, C optionally substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkyl group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 an alkylamino group, a di(C 1-6 C which may be substituted with one or more substituents selected from the group A of alkylamino groups or the group B of substituents 1-6 Alkoxy C 1-6 Alkyl groups are preferred.

[0100] R 7 C which may be substituted with one or more substituents selected from a hydrogen atom, a halogen atom, or a substituent group A 1-6 C which may be substituted with an alkyl group or one or more substituents selected from the substituent group A 1-6 An alkoxy group is more preferred.

[0101] R 7 The substituents are hydrogen atoms, halogen atoms, or C 1-6 An alkoxy group is more preferred.

[0102] R 8 R 8represents a hydrogen atom, an optionally protected hydroxyl group, an optionally protected amino group, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkoxy group, optionally substituted C 1-6 alkylamino group, optionally substituted di(C 1-6 alkyl)amino group or general formula SO2R 9 It is.

[0103] R 8 Examples of the substituents include a hydrogen atom, an optionally protected hydroxyl group, an optionally protected amino group, and C which may be substituted with one or more substituents selected from the substituent group A. 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 3-8 Cycloalkyl group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 an alkylamino group, a di(C 1-6 alkyl)amino group or general formula SO2R 9 is preferred.

[0104] R 8 Examples of the substituents include a hydrogen atom, an optionally protected hydroxyl group, an optionally protected amino group, and C which may be substituted with one or more substituents selected from the substituent group A. 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 an alkylamino group, a di(C1-6 alkyl)amino group or general formula SO2R 9 is more preferred.

[0105] R 9 R 9 represents an optionally protected hydroxyl group, an optionally protected amino group, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 Cycloalkyl groups, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-8 Cycloalkoxy group, optionally substituted C 1-6 Alkylamino group or optionally substituted di(C 1-6 alkyl)amino group.

[0106] R 9 Examples of the substituents include an optionally protected hydroxyl group, an optionally protected amino group, and C which may be substituted with one or more substituents selected from the substituent group A. 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 3-8 Cycloalkyl group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 An alkylamino group or a di(C 1-6 Alkyl)amino groups are preferred.

[0107] R 9 Examples of the substituents include an optionally protected amino group, C which may be substituted with one or more substituents selected from the substituent group A. 1-6 C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A 3-8Cycloalkyl group, C optionally substituted with one or more substituents selected from the substituent group A 1-6 an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; 3-8 Cycloalkoxy group, C optionally substituted with one or more substituents selected from Substituent group A 1-6 An alkylamino group or a di(C 1-6 An alkyl)amino group is more preferred.

[0108] m m is an integer from 0 to 6.

[0109] As m, an integer of 0 to 4 is preferable, and an integer of 0 to 2 is more preferable.

[0110] Dashed line The dashed lines represent single or double bonds.

[0111] As the broken line, both a single bond and a double bond are preferred.

[0112] R 2 , R 3 , R 4 , R 5 , R 6 and R 7 In the above, the substituent group A is preferably a halogen atom, a cyano group, or 1-6 Alkyl group; C 2-6 Alkenyl group; C 2-6 Alkynyl group; C 3-8 Cycloalkyl group; C 1-6 Alkoxy group; C 3-8 A cycloalkoxy group; an aryl group which may be substituted with one or more substituents selected from Substituent group B; and a heterocyclic group which may be substituted with one or more substituents selected from Substituent group B are preferred.

[0113] Substituent group A includes halogen atoms, cyano groups, C 1-6 Alkyl group; C 1-6 An alkoxy group is more preferred.

[0114] R 2 , R 3 , R 4 , R 5 , R 6 and R 7 In the above, the substituent group B is a halogen atom; 1-6 Alkyl group; C 2-6 Alkenyl group; C 2-6 Alkynyl group; C 3-8 Cycloalkyl group; C 1-6 Alkoxy group; C 3-8 Cycloalkoxy group; C 1-6 Alkoxy C 1-6 Alkyl groups are preferred.

[0115] The substituent group B includes halogen atoms; 1-6 Alkyl group; C 1-6 Alkoxy group; C 1-6 Alkoxy C 1-6 Alkyl groups are more preferred.

[0116] In the case where isomers (e.g., optical isomers, geometric isomers, tautomers, etc.) exist in the compound represented by general formula (1), general formula (1a), general formula (1b), or general formula (1c), these isomers can also be used. In addition, in the case where solvates, hydrates, and various forms of crystals exist, these solvates, hydrates, and various forms of crystals can also be used.

[0117] Next, the method for producing the compound of the present invention will be described. The compound of the present invention can be produced by combining methods known per se, for example, according to the following production method.

[0118] [Manufacturing method 1] [ka] (In the formula, Z 1 , Z 2 , Z 3 , Z 4, Z 5 , R 2 , R 3 , R 4 and R 5 has the same meaning as above.)

[0119] The compound represented by the general formula (2) can be produced by subjecting a compound represented by the general formula (6) described below to a reaction known per se, such as hydrolysis.

[0120] The compound represented by the general formula (2) is useful as an intermediate for producing the compound represented by the general formula (1).

[0121] The compound represented by general formula (2) is preferably a compound selected from compound group X. According to the present invention, there is provided a compound or a salt thereof selected from compound group X, which is an intermediate for producing a compound represented by general formula (1) or a salt thereof.

[0122] <Compound group X> 6-cyclopropyl-3-((3-(2,6-dimethylpyridin-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylic acid (Example 1-4), 3-((4'-cyano-2'-methyl-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid (Example 1-5), (S)-5-cyclopropyl-2-((2-(3,6-dihydro-2H-pyran-4-yl)-3-((1,1,1-trifluoropropan-2-yl) oxy)pyridin-4-yl)amino)benzoic acid (Example 1-18), 5-cyclopropyl-2-((5-(3,6-dihydro-2H-pyran-4-yl)-4-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)benzoic acid (Example 2-1), 5-cyclopropyl-2-((3-(tetrahydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinic acid (Example 2-2), 5-cyclopropyl-2-((2-(difluoromethoxy)-5-fluoro-3-(tetrahydro-2H-pyra (S)-5-cyclopropyl-2-((5-(3,6-dihydro-2H-pyran-4-yl)-4-((1,1, 1-trifluoropropan-2-yl)oxy)pyridin-3-yl)amino)benzoic acid (Example 2-6), 2-((4'-cyano-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)-5-cyclopropylnicotinic acid (Example 2-7), 5-cyclopropyl-2-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinic acid (Example 2-8), 3-((3'-cyano-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid (Example 2-9), 5-cyclopropyl-2-((2-ethyl-3-(tetrahydro-2H-pyran-4-yl)phenyl)amino)nicotinic acid (Example 2-10), 3-((4'-cyano-2-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid (Example 2-11), 3-((4'-cyano-2-(difluoromethoxy)-5-fluoro-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid (Example 2-12), 6-cyclopropyl-3-((4'-fluoro-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)pyrazine-2- Carboxylic acid (Example 2-13), 5-cyclopropyl-2-((3-(3,6-dihydro-2H-pyran-4-yl)-2-ethoxy-6-fluorophenyl)amino)nicotinic acid (Example 2-14), 5-cyclopropyl-2-((3-(3,6-dihydro-2H-pyran-4-yl)-2-ethoxy-4-fluorophenyl)amino)nicotinic acid (Example 2-15), 2-cyclopropyl- 5-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)isonicotinic acid (Example 2-16), (S)-6-cyclopropyl-3-((3-(tetrahydro-2H-pyran-4-yl)-2-((1,1,1-trifluoropropan-2-yl)oxy)phenyl)amino)pyrazine-4-carboxylic acid (Example 2-17).

[0123] The compound represented by general formula (1d) can be produced by reacting the compound represented by general formula (2) with ammonia or an ammonium salt in the presence of a condensing agent and in the presence or absence of a base.

[0124] The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferred solvents include ethers and amides. The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w) the amount of the compound represented by general formula (2), more preferably 1 to 10 times (v / w), and even more preferably 1 to 5 times (v / w).

[0125] Condensing agents used in this reaction include, for example, carbodiimides such as N,N'-dicyclohexylcarbodiimide and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; carbonyls such as 1,1'-carbonyldiimidazole; acid azides such as diphenylphosphoryl azide; acid cyanides such as diethylphosphoryl cyanide; 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate; and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate.

[0126] The base optionally used in this reaction includes inorganic bases and organic bases.

[0127] The amount of the condensing agent and the base used is preferably 1 to 10 times by mol, more preferably 1 to 5 times by mol, based on the amount of the compound represented by the general formula (2).

[0128] Examples of ammonium salts include ammonium chloride, ammonium bromide, and ammonium acetate. The amount of ammonia or ammonium salt used may be 1 to 100 times by mol, preferably 1 to 10 times by mol, based on the compound represented by formula (2).

[0129] This reaction may be carried out in the presence of a reaction promoter. Examples of the reaction accelerator include 1-hydroxybenzotriazole and N-hydroxysuccinimide. The amount of the reaction promoter used is preferably 1 to 10 times by mol, more preferably 1 to 5 times by mol, based on the amount of the compound represented by formula (2). This reaction may be carried out at -20 to 150°C, preferably 0 to 100°C, for 1 minute to 24 hours.

[0130] [Manufacturing method 2] [ka] (In the formula, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , R 2 , R 3 , R 4 , R 5 and R 9 has the same meaning as above.)

[0131] As a compound represented by the general formula (3), for example, methanesulfonamide is known.

[0132] The compound represented by general formula (1e) can be produced by reacting a compound represented by general formula (2) with a compound represented by general formula (3) in the presence of a condensing agent and a base.

[0133] The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferred solvents include ethers and amides. The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w) the amount of the compound represented by general formula (2), more preferably 1 to 10 times (v / w), and even more preferably 1 to 5 times (v / w).

[0134] Condensing agents used in this reaction include, for example, carbodiimides such as N,N'-dicyclohexylcarbodiimide and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; carbonyls such as 1,1'-carbonyldiimidazole; acid azides such as diphenylphosphoryl azide; acid cyanides such as diethylphosphoryl cyanide; 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate; and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate.

[0135] The base used in this reaction includes inorganic bases and organic bases. Preferred bases include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate, and organic bases such as pyridine, 4-(dimethylamino)pyridine, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo(5,4,0)undec-7-ene.

[0136] The amount of the condensing agent and the base used is preferably 1 to 10 times by mol, more preferably 1 to 5 times by mol, based on the amount of the compound represented by the general formula (2).

[0137] This reaction may be carried out at -20 to 150°C, preferably 0 to 100°C, for 1 minute to 24 hours. [Manufacturing method 3] [ka] (In the formula, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , R 2 , R 3 , R 4 , R 5 and R 9 has the same meaning as above.)

[0138] The compound represented by general formula (1f) can be produced by reacting the compound represented by general formula (2) with an alkali metal borohydride in the presence of a condensing agent and in the presence or absence of a base.

[0139] The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons, which may be used in combination. Preferred solvents include ethers. The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w) the amount of the compound represented by general formula (2), more preferably 1 to 10 times (v / w), and even more preferably 1 to 5 times (v / w).

[0140] The condensing agent and base used in this reaction may be the same as those in Production Method 1.

[0141] The amount of the condensing agent and the base used is preferably 1 to 10 times by mol, more preferably 1 to 5 times by mol, based on the amount of the compound represented by the general formula (2).

[0142] The alkali metal borohydride used in this reaction includes, for example, sodium borohydride, lithium borohydride, potassium borohydride, etc., with sodium borohydride being preferred. The amount of the alkali metal borohydride used is preferably 1 to 10 times by mol, more preferably 1 to 2 times by mol, based on the amount of the compound represented by the general formula (2).

[0143] This reaction may be carried out at -20 to 150°C, preferably 0 to 100°C, for 1 minute to 24 hours. [Manufacturing method 4] [ka] (In the formula, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , R 2 , R 3 , R 4 and R 5 has the same meaning as above.)

[0144] The compound represented by the general formula (1g) can be produced, for example, by the method described in New Heterocyclic Compounds, Applied Science, pp. 98-100, Kodansha, 2004, or a method similar thereto. Specifically, the compound can be produced by reacting the compound represented by the general formula (4) with an azide in the presence or absence of a base.

[0145] The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, amides, sulfoxides, and aromatic hydrocarbons, and these may be used in combination. Preferred solvents include amides. The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w) the amount of the compound represented by general formula (2), more preferably 1 to 10 times (v / w), and even more preferably 1 to 5 times (v / w).

[0146] The base optionally used in this reaction includes inorganic bases and organic bases.

[0147] The azide used in this reaction includes, for example, sodium azide and trimethylsilyl azide. The amount of azide used may be 1 to 100 times by mol, preferably 1 to 10 times by mol, based on the amount of the compound represented by formula (4).

[0148] This reaction may be carried out at -20 to 150°C, preferably 0 to 100°C, for 1 minute to 24 hours. [Manufacturing method 5] [ka] (In the formula, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , R 2 , R 3 , R 4 and R 5 has the same meaning as above.)

[0149] The compound represented by the general formula (1h) can be produced by reacting the compound represented by the general formula (5) with a condensing agent in the presence or absence of a base.

[0150] The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons, which may be used in combination. Preferred solvents include ethers and amides. The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w) the amount of the compound represented by general formula (5), more preferably 1 to 10 times (v / w), and even more preferably 1 to 5 times (v / w).

[0151] The condensing agent and base used in this reaction may be the same as those in Production Method 1.

[0152] The amount of the condensing agent and the base used is preferably 1 to 10 times by mol, more preferably 1 to 5 times by mol, based on the amount of the compound represented by the general formula (5).

[0153] This reaction may be carried out at -20 to 150°C, preferably 0 to 100°C, for 1 minute to 24 hours. [Manufacturing method 6] [ka] (In the formula, R a represents a protecting group for the carboxyl group; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , R 2 , R 3 , R 4 and R 5 has the same meaning as above.)

[0154] (6-1) The compound represented by the general formula (1i) can be produced by reacting the compound represented by the general formula (6) with hydrazine.

[0155] The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferred solvents include alcohols. The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w) the amount of the compound represented by general formula (2), more preferably 1 to 10 times (v / w), and even more preferably 1 to 5 times (v / w).

[0156] The hydrazine used in this reaction may, for example, be hydrazine monohydrate. The amount of hydrazine used may be 1 to 100 times by mol, preferably 1 to 10 times by mol, based on the amount of the compound represented by the general formula (6).

[0157] This reaction may be carried out at -20 to 150°C, preferably 0 to 100°C, for 1 minute to 24 hours.

[0158] (6-2) The compound represented by general formula (1j) can be produced by reacting the compound represented by general formula (1i) with a condensing agent in the presence or absence of a base, according to Production Method 5.

[0159] [Manufacturing method A] [ka] (Wherein, L represents a leaving group; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , R 2 , R 3 , R 4 , R 5 and R a has the same meaning as above.)

[0160] Known examples of the compound represented by general formula (7) include methyl 3-bromo-6-cyclopropylpyrazine-2-carboxylate (US Patent Application Publication No. 2011 / 306589).

[0161] The compound represented by general formula (6) can be produced by reacting the compound represented by general formula (7) with the compound represented by general formula (8) in the presence or absence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand.

[0162] The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferred solvents include ethers, esters and aromatic hydrocarbons. The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w) the amount of the compound represented by general formula (7), more preferably 1 to 10 times (v / w), and even more preferably 1 to 5 times (v / w).

[0163] The base optionally used in this reaction includes inorganic bases and organic bases. Preferred bases include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate, and organic bases such as pyridine, 4-(dimethylamino)pyridine, triethylamine, and diisopropylethylamine. The amount of the base used is preferably 1 to 10 times the molar amount of the compound represented by formula (7), more preferably 1 to 5 times the molar amount, and even more preferably 1 to 2 times the molar amount.

[0164] Examples of the palladium catalyst used in this reaction include metallic palladium such as palladium on carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium(II) acetate; organic palladium complexes such as tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, tris(dibenzylideneacetone)dipalladium(0) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride; and polymer-immobilized organic palladium complexes such as polymer-supported bis(acetate)triphenylphosphinepalladium(II) and polymer-supported di(acetate)dicyclohexylphenylphosphinepalladium(II), which may be used in combination. The amount of the palladium catalyst used is preferably 0.00001 to 1 mole, and more preferably 0.001 to 0.2 moles, relative to the amount of the compound represented by formula (7).

[0165] Ligands optionally used in this reaction include, for example, trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphines such as triphenylphosphine and tritolylphosphine; trialkylphosphites such as trimethylphosphite, triethylphosphite and tributylphosphite; tricycloalkylphosphites such as tricyclohexylphosphite; triarylphosphites such as triphenylphosphite; imidazolium salts such as 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride; diketones such as acetylacetone and octafluoroacetylacetone; amines such as trimethylamine, triethylamine, tripropylamine, triisopropylamine and tributylamine; 1,1'-bis(diphenylphosphino)ferrocene; 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl; 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl; 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; and 2-(di-tert-butylphosphino)biphenyl, which may be used in combination. The amount of the ligand used is 0.00001 to 1 mole, preferably 0.02 to 0.5 moles, per mole of the compound represented by formula (7).

[0166] The amount of the compound represented by formula (8) used is preferably 1 to 50 times by mol, more preferably 1 to 2 times by mol, based on the amount of the compound represented by formula (7). This reaction may be carried out preferably in an inert gas (eg, nitrogen, argon) atmosphere at 40 to 170° C. for 1 minute to 24 hours. This reaction may be carried out under microwave irradiation.

[0167] [Manufacturing method B] [ka] (In the formula, R b and R c are the same or different and are a hydrogen atom or C 1-6 An alkyl group or R b and R c Together, they form one or more C 1-6 an ethylene group optionally substituted with an alkyl group; 4 , Z 5 , R 3 , R 5 , R 10 , m and L have the same meanings as above.

[0168] Known examples of the compound represented by the general formula (9) include 1-bromo-2-fluoro-3-nitrobenzene and 1-bromo-2,5-difluoro-3-nitrobenzene. As a compound represented by the general formula (10), for example, 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester is known. Moreover, the compound represented by the general formula (10) can be produced from the corresponding halogeno compound by a method known per se.

[0169] The compound represented by the general formula (11) can be produced by reacting the compound represented by the general formula (9) with the compound represented by the general formula (10) in the presence or absence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand, in accordance with the production method A.

[0170] [Manufacturing method C] [ka] (In the formula, Z 4 , Z 5 , R 3 , R 5 , R10 and m have the same meaning as above.

[0171] The compound represented by the general formula (8a) can be prepared by reducing the compound represented by the general formula (11). This reaction may be carried out according to the method described in Richard C. Larock et al., Comprehensive Organic Transformations, 2nd Edition, pp. 823-827, 1999, John Wiley & Sons, Inc., or a method analogous thereto. Specific examples include catalytic hydrogenation using a metal catalyst and reduction using a metal such as iron or zinc in the presence or absence of an acid and in the presence or absence of a salt.

[0172] <Catalytic hydrogenation reaction using metal catalyst> The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferred solvents include ethers, esters, alcohols, and amides. The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w) the amount of the compound represented by general formula (11), more preferably 1 to 10 times (v / w), and even more preferably 1 to 5 times (v / w).

[0173] Metal catalysts used in this reaction include, for example, palladium metal, such as palladium on carbon and palladium black; palladium salts, such as palladium oxide and palladium hydroxide; nickel metal, such as Raney nickel; and platinum salts, such as platinum oxide. The amount of the metal catalyst used is preferably 0.001 to 5 times (W / W), and more preferably 0.01 to 1 time (W / W), relative to the amount of the compound represented by general formula (11). Reducing agents include, for example, hydrogen; formic acid; formate salts such as sodium formate, ammonium formate, and triethylammonium formate; cyclohexene, and cyclohexadiene. The amount of the reducing agent used is preferably 2 to 100 times by mol, more preferably 2 to 10 times by mol, based on the amount of the compound represented by the general formula (11). This reaction may be carried out at 0 to 200° C., preferably 0 to 100° C., for 1 minute to 24 hours.

[0174] <Reduction reaction using metal> The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferred solvents include alcohols and water. The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w) the amount of the compound represented by general formula (11), more preferably 1 to 10 times (v / w), and even more preferably 1 to 5 times (v / w).

[0175] Metals used in this reaction include, for example, iron, zinc, tin and tin(II) chloride. The amount of the metal used is preferably 1 to 50 times by mol, more preferably 1 to 10 times by mol, based on the amount of the compound represented by the general formula (11).

[0176] The acid used in this reaction includes, for example, hydrogen chloride, hydrogen bromide, and acetic acid. The amount of the acid used is preferably 0.001 to 100 times (W / V), and more preferably 0.01 to 20 times (W / V), relative to the amount of the compound represented by formula (11).

[0177] The salt used in this reaction includes, for example, ammonium chloride. The amount of the salt used is preferably 0.01 to 10 times by mol, more preferably 0.1 to 5 times by mol, based on the amount of the compound represented by formula (11). This reaction may be carried out at 0 to 200° C., preferably 0 to 100° C., for 1 minute to 24 hours.

[0178] [Manufacturing method D] [ka] (In the formula, Z 4 , Z 5 , R 3 , R 5 , R 10 and m have the same meaning as above.

[0179] The compound represented by the general formula (8b) can be produced by reducing the compound represented by the general formula (8a) according to Production Method C.

[0180] [Manufacturing method E] [ka] (In the formula, Z 4 , Z 5 , R 3 , R 5 , R 10 , R b , R c , m and L have the same meanings as above.

[0181] Known examples of the compound represented by the general formula (12) include 3-bromo-2-methoxyaniline and 3-bromo-2-methylaniline. The compound represented by the general formula (8a) can be produced by reacting the compound represented by the general formula (12) with the compound represented by the general formula (10) in the presence or absence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand, in accordance with the production method B.

[0182] [Manufacturing method F] [ka] (In the formula, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , R 2 , R 3 , R 4 and R 5 has the same meaning as above.)

[0183] The compound represented by the general formula (4) can be prepared by reacting the compound represented by the general formula (1d) with a dehydrating agent in the presence or absence of a base.

[0184] The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferred solvents include halogenated hydrocarbons. The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w) the amount of the compound represented by general formula (2), more preferably 1 to 10 times (v / w), and even more preferably 1 to 5 times (v / w).

[0185] The base optionally used in this reaction includes inorganic bases and organic bases.

[0186] Examples of the dehydrating agent used in this reaction include acid anhydrides such as acetyl formyl oxide, acetic anhydride, trichloroacetic anhydride, and trifluoroacetic anhydride; mixed acid anhydrides of an organic carboxylic acid such as acetic acid and a carbonate monoalkyl ester such as ethyl chlorocarbonate and isobutyl chlorocarbonate; mixed acid anhydrides of an organic carboxylic acid such as acetic acid and an organic acid such as pivalic acid; acid chlorides such as acetyl chloride, trichloroacetyl chloride, and trifluoroacetyl chloride; and acid bromides such as acetyl bromide.

[0187] The amount of the base and the dehydrating agent used is preferably 1 to 10 times by mol, and more preferably 1 to 5 times by mol, relative to the compound of the general formula (1d). This reaction may be carried out at 0 to 200° C., preferably 0 to 100° C., for 1 minute to 24 hours.

[0188] [Manufacturing method G] [ka] (In the formula, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , R 2 , R 3 , R 4 and R 5 has the same meaning as above.)

[0189] The compound represented by the general formula (5) can be produced by reacting the compound represented by the general formula (4) with hydroxylamine in the presence or absence of a base.

[0190] The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these may be used in combination. Preferred solvents include amides. The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w) the amount of the compound represented by general formula (4), more preferably 1 to 10 times (v / w), and even more preferably 1 to 5 times (v / w).

[0191] The base optionally used in this reaction includes inorganic bases and organic bases. The amount of the base used is preferably 1 to 10 times by mol, more preferably 1 to 5 times by mol, based on the amount of the compound represented by formula (4).

[0192] The hydroxylamine used in this reaction includes, for example, hydroxylamine hydrochloride. The amount of hydroxylamine used may be 1 to 100 times by mol, preferably 1 to 10 times by mol, based on the amount of the compound represented by the general formula (4). This reaction may be carried out at 0 to 200° C., preferably 0 to 100° C., for 1 minute to 24 hours.

[0193] Among the compounds used in the above-mentioned production method, those that can take the form of a salt can also be used as a salt. Examples of such salts include the same salts as those of the compound represented by general formula (1).

[0194] In the compounds used in the above-mentioned production methods, when isomers (e.g., optical isomers, geometric isomers, tautomers, etc.) exist, these isomers can also be used. In addition, when solvates, hydrates, and various forms of crystals exist, these solvates, hydrates, and various forms of crystals can also be used.

[0195] The compound represented by the general formula (1) can be derived into another compound represented by the general formula (1) by subjecting it to a reaction known per se, such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or by an appropriate combination of these reactions.

[0196] In addition, among the compounds used in the above-mentioned production methods, those having a group that can be protected, such as an amino group, a hydroxyl group, or a carboxyl group, can be protected in advance with a conventional protecting group, and after the reaction, the protecting group can be removed by a method known per se.

[0197] When the compound of the present invention is used as a pharmaceutical composition, it may be appropriately mixed with formulation auxiliary agents such as excipients, carriers and diluents that are usually used in formulation. These can be administered orally or parenterally in the form of tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, liquids, powder preparations, suppositories, eye drops, nasal drops, ear drops, patches, ointments or injections according to conventional methods. The administration method, dosage and number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. Usually, for adults, 0.01 to 1000 mg / kg may be administered once or several times a day by oral or parenteral administration (for example, injection, drip and administration to the rectum).

[0198] The compound of the present invention or a salt thereof has excellent antitumor activity and can be used for treating tumors.

[0199] Treatment means prevention or therapy for various diseases. The therapeutic agent refers to a substance provided for the purpose of preventing or treating various diseases. Prevention means inhibiting the onset, reducing the risk of onset, or delaying the onset. Treatment refers to the improvement or inhibition of progression of a target disease or condition.

[0200] By tumor is meant a benign or malignant tumor. A benign tumor refers to a tumor in which the tumor cells and their sequences resemble those of the normal cells from which they originate, and which is not invasive or metastatic. A malignant tumor refers to a tumor in which the morphology and arrangement of tumor cells differ from those of the normal cells from which they originate, and which exhibits invasive or metastatic properties.

[0201] The antitumor agent of the present invention is preferably used as an anti-malignant tumor agent, and is preferably used as an agent for treating cancer (preferably, an agent for treating blood cancer).

[0202] Examples of blood cancers include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell leukemia (ALL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), lymphoblastic lymphoma (LBL), and adult T-cell leukemia / lymphoma (ATL).

[0203] The compound of the present invention or a salt thereof can also be used as a dihydroorotate dehydrogenase inhibitor. The compound of the present invention or a salt thereof can be used as a therapeutic agent for diseases associated with dihydroorotate dehydrogenase, such as tumors and rheumatism (for example, antitumor agents or antirheumatic agents). The dihydroorotate dehydrogenase inhibitor of the present invention can be used in the same manner as the pharmaceutical composition and antitumor agent of the present invention described above. EXAMPLES

[0204] The present invention will be described with reference to Reference Examples and Examples, but the present invention is not limited to these. Unless otherwise specified, purification by column chromatography was performed using an automatic purification apparatus ISOLERA (Biotage) or a medium pressure liquid chromatograph YFLC-Wprep2XY.N (Yamazen Corporation). Unless otherwise specified, the carriers used in silica gel column chromatography were SNAPKP-Sil Cartridge (Biotage), Hi-Flash Column W001, W002, W003, W004 or W005 (Yamazen Corporation), and CHROMATOREX Q-PACK Cartridge (Fuji Silysia Chemical Ltd.).

[0205] Preparative thin layer chromatography is performed using PLC glass plates and silica gel F 60 (Merck Ltd.) was used. The mixing ratio of the eluent is a volume ratio. For example, "hexane:ethyl acetate gradient elution = 50:50 to 0:100" means that the eluent of 50% hexane / 50% ethyl acetate was finally changed to the eluent of 0% hexane / 100% ethyl acetate.

[0206] The microwave reaction apparatus used was Initiator Sixty (manufactured by Biotage).

[0207] NMR spectra were measured using tetramethylsilane as an internal standard on a Bruker AV300 (Bruker, 300 MHz), a Bruker AV400 (Bruker, 400 MHz), and a Bruker Fourier-400 (Bruker, 400 MHz), and all δ values ​​are shown in ppm.

[0208] MS spectra were measured using an ACQUITY SQD LC / MS System (Waters, ionization method: ESI (ElectroSpray Ionization)), a Micromass ZQ2000 LCMS System (Waters, ionization method: ESI), an M-8000 model (Hitachi, ionization method: ESI) or an LCMS-2010EV (Shimadzu, ionization method: simultaneous ESI and APCI (Atmospheric Pressure Chemical Ionization)). Retention times (RT) were measured using SQD (Waters) and 2695 Separations Module (Waters), and are shown in minutes (min). The measurements were carried out under the following conditions. Method A Column: BEHC 18 1.7μm, 2.1x30 mm (Waters) Solvent: Solution A: 0.1% formic acid-water Solution B: 0.1% formic acid - acetonitrile Gradient cycle: 0.00 min (A / B = 95 / 5), 2.00 min (A / B = 5 / 95), 3.00 min (A / B = 5 / 95), 3.01 min (A / B = 100 / 0), 3.80 min (A / B = 100 / 0) Flow rate: 0.5 mL / min Column temperature: room temperature Detection wavelength: 254 nm Method B Column: XBridgeC18 5μm, 3.0x50 mm (Waters) Solvent: Solution A: 0.05% trifluoroacetic acid - water Solution B: 0.05% trifluoroacetic acid - acetonitrile Gradient cycle: 0.00 min (A / B = 90 / 10), 1.00 min (A / B = 90 / 10), 1.50 min (A / B = 70 / 30), 4.50 min (A / B = 30 / 70), 5.00 min (A / B = 10 / 90), 6.00 min (A / B = 10 / 90), 6.20 min (A / B = 90 / 10), 7.00 min (A / B = 90 / 10) Flow rate: 1.27 mL / min Column temperature: 30℃ Detection wavelength: 254 nm

[0209] In each example, the abbreviations have the following meanings. RT(min): Retention time (min)

[0210] [Reference example 1-1] [ka] Following the methods described in US Patent Application Publication No. 2011 / 306589, the following compounds were obtained. Methyl 3-amino-6-cyclopropylpyrazine-2-carboxylate LCMS (Method A) MS(ESI m / z): 194(M+H) RT(min):0.92

[0211] [Reference example 1-2] [ka] Following the methods described in US Patent Application Publication No. 2011 / 306589, the following compounds were obtained. Methyl 3-bromo-6-cyclopropylpyrazine-2-carboxylate LCMS (Method A) MS(ESI m / z):258(M+H) RT(min):1.31

[0212] [Reference example 1-3] [ka] A mixture of methyl 2-chloro-5-cyclopropylnicotinate (5.0 g), diethylene glycol ethyl methyl ether (15 mL), cesium carbonate (8.5 g), and 2,4-dimethoxybenzylamine (4.4 g) was stirred at 180° C. for 1 hour. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=100:0-80:20) to obtain methyl 5-cyclopropyl-2-((2,4-dimethoxybenzyl)amino)nicotinate (5.8 g) as a white solid. 1H-NMR (CDCl3) δ: 8.16 (d, 1H, J = 2.7 Hz), 8.10-8.03 (m, 1H), 7.79 (d, 1H, J = 2.7 Hz), 7.23 (d, 1H, J = 8.5 Hz), 6.47 (d, 1H, J = 2.2 Hz), 6.44-6.40 (m, 1H), 4.65 (d, 2H, J = 5.8 Hz), 3.85 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 1.83-1.74 (m, 1H), 0.92-0.85 (m, 2H), 0.64-0.56 (m, 2H).

[0213] [Reference example 1-4] [ka] A mixture of methyl 5-cyclopropyl-2-((2,4-dimethoxybenzyl)amino)nicotinate (5.8 g), dichloromethane (29 mL), and trifluoroacetic acid (29 mL) was stirred at room temperature for 2 hours. Ethyl acetate, water, aqueous sodium bicarbonate solution, and 5 mol / L aqueous sodium hydroxide solution were added to the reaction solution, and the solid matter was filtered. The organic layer of the filtrate was separated, washed with aqueous sodium chloride solution, and dried over magnesium sulfate. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=80:20-0:100). Hexane was added to the purified product, and the mixture was stirred and filtered to obtain methyl 2-amino-5-cyclopropylnicotinate (1.5 g) as a white solid. LCMS (Method A) MS(ESI m / z): 193(M+H) RT(min):0.69

[0214] [Reference example 1-5] [ka] A mixture of tert-butyl 2-amino-5-bromobenzoate (6.4 g), cyclopropylboronic acid monohydrate (2.7 g), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.83 g), potassium phosphate (11 g), 1,4-dioxane (24 mL), and water (8.0 mL) was stirred at 120° C. for 30 minutes. After cooling to room temperature, an aqueous sodium chloride solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. After drying with magnesium sulfate, the organic layer solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=20:1-2:1). Hexane was added to the purified product, and the mixture was stirred and filtered to obtain tert-butyl 2-amino-5-cyclopropylbenzoate (1.97 g) as a yellow solid. 1H-NMR (CDCl3) δ: 7.57 (d, 1H, J = 2.3 Hz), 7.00-6.95 (m, 1H), 6.57 (d, 1H, J = 8.5 Hz), 5.65-5.41 (m, 2H), 1.86-1.76 (m, 1H), 1.59 (s, 9H), 0.89-0.81 (m, 2H), 0.61-0.54 (m, 2H)

[0215] [Reference example 1-6] [ka] According to the method described in International Patent Application Publication No. 2019 / 043407, the following compounds were obtained. Methyl 3-bromo-6-methylpyrazine-2-carboxylate LCMS (Method A) MS(ESI m / z): 230(M+H) RT(min):0.96

[0216] [Reference example 1-7] [ka] According to the method described in International Patent Application Publication No. 2017 / 221008, the following compounds were obtained. Methyl 3-amino-6-ethylpyrazine-2-carboxylate LCMS (Method A) MS(ESI m / z): 182(M+H) RT(min):0.78

[0217] [Reference example 1-8] [ka] Bromotrimethylsilane (0.85mL) was added to a mixture of methyl 3-amino-6-ethylpyrazine-2-carboxylate (0.39g) and dibromomethane (3.9mL) under cooling with water. After stirring at room temperature, pentyl nitrite (0.64mL) was added and stirred at 10-20℃ for 1 hour. Aqueous sodium bicarbonate solution was added and the organic layer was separated. The aqueous layer was extracted with chloroform. The organic layers were combined and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=100:0-90:10) to obtain methyl 3-bromo-6-ethylpyrazine-2-carboxylate (0.42g) as a light brown oil. LCMS (Method A) MS(ESI m / z):246(M+H) RT(min):1.17

[0218] [Reference example 1-9] [ka] Following the methods described in US Patent Application Publication No. 2011 / 306589, the following compounds were obtained. Methyl 3-amino-6-isopropylpyrazine-2-carboxylate LCMS (Method A) MS(ESI m / z): 196(M+H) RT(min):0.98

[0219] [Reference example 1-10] [ka] Methyl 3-bromo-6-isopropylpyrazine-2-carboxylate was obtained in the same manner as in Reference Example 1-8. LCMS (Method A) MS(ESI m / z):259(M+H) RT(min):1.37

[0220] [Reference example 2-1] [ka] A mixture of 1-bromo-2-fluoro-3-nitrobenzene (1.0 g), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.1 g), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.16 g), potassium phosphate (1.9 g), 1,2-dimethoxyethane (10 mL), and water (2.0 mL) was irradiated with microwaves (microwave reactor, 110° C., 30 min, 2.45 GHz, 0-240 W). Aqueous sodium chloride solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The solvent in the organic layer was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 4-(2-fluoro-3-nitrophenyl)-3,6-dihydro-2H-pyran (0.95 g) as a brown solid. 1H-NMR (CDCl3) δ: 7.93-7.88 (m, 1H), 7.56-7.51 (m, 1H), 7.29-7.22 (m, 1H), 6.11-6.07 (m, 1H), 4.37-4.32 (m, 2H), 3.94 (t, 2H, J = 5.6 Hz), 2.56-2.48 (m, 2H).

[0221] [Reference example 2-2] [ka] 60% sodium hydride (22 mg) was added to a mixture of 4-(2-fluoro-3-nitrophenyl)-3,6-dihydro-2H-pyran (60 mg), 2,2,2-trifluoroethanol (34 μL), and N,N-dimethylformamide (0.50 mL) under ice cooling, and the mixture was stirred at room temperature for 5 minutes. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The solvent in the organic layer was distilled off under reduced pressure, and toluene was added to distill off the solvent under reduced pressure. Toluene was further added and the solvent was distilled off under reduced pressure, and 4-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)-3,6-dihydro-2H-pyran (80 mg) was obtained as a brown oil. 1H-NMR (CDCl3) δ: 7.76 (dd, 1H, J = 7.9, 2.0 Hz), 7.45 (dd, 1H, J = 7.6, 1.7 Hz), 7.29 (dd, 1H, J = 7.9, 7.6 Hz), 6.04-6.01 (m, 1H), 4.36 (q, 2H, J = 8.3 Hz), 4.34-4.30 (m, 2H), 3.93 (t, 2H, J = 5.3 Hz), 2.53-2.45 (m, 2H).

[0222] [Reference example 2-3] [ka] A mixture of 4-(3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)-3,6-dihydro-2H-pyran (80 mg), ammonium chloride (29 mg), isopropyl alcohol (1.0 mL), and water (0.50 mL) was stirred at 90° C., iron (150 mg) was added, and the mixture was stirred for 40 minutes. After cooling to room temperature, insoluble matter was removed, an aqueous sodium chloride solution was added, and the mixture was extracted twice with ethyl acetate. The solvent in the organic layer was distilled off under reduced pressure to obtain 3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)aniline (68 mg) as a brown oil. LCMS (Method A) MS(ESI m / z):274(M+H) RT(min):1.33

[0223] [Reference example 2-4] [ka] A mixture of 3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)aniline (34 mg), methyl 3-bromo-6-cyclopropylpyrazine-2-carboxylate (45 mg), tris(dibenzylideneacetone)dipalladium(0) (25 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (31 mg), cesium carbonate (88 mg), and toluene (2.0 mL) was irradiated with microwaves (microwave reactor, 140°C, 1.5 hours, 2.45 GHz, 0-240 W). Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The solvent in the organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=100:0-80:20) to obtain methyl 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylate (60 mg) as a yellow solid. LCMS (Method A) MS(ESI m / z): 450(M+H) RT(min):1.90

[0224] [Reference example 2-5] [ka] A mixture of methyl 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylate (60 mg), 5 mol / L aqueous sodium hydroxide solution (53 μL), tetrahydrofuran (0.50 mL), and ethanol (0.50 mL) was stirred at 50° C. for 1 hour. After cooling to room temperature, the pH was adjusted to 6 with 1 mol / L hydrochloric acid. Aqueous sodium chloride solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=100:0-70:30) to give 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylic acid (39 mg) as a yellow solid. 1H-NMR (DMSO-D6) δ: 13.41 (br s, 1H), 10.54 (br s, 1H), 8.43 (s, 1H), 8.34 (dd, 1H, J = 8.6, 1.3 Hz), 7.17 (dd, 1H, J = 7.9, 8.6 Hz), 6.90 (dd, 1H, J = 7.9, 1.3 Hz), 5.97 (s, 1H), 4.42 (q, 2H, J = 9.0 Hz), 4.24-4.17 (m, 2H), 3.82 (t, 2H, J = 5.3 Hz), 2.42 (br s, 2H), 2.21-2.11 (m, 1H), 1.01-0.91 (m, 4H). MS(ESI m / z):436(M+H) RT(min):1.74

[0225] [Reference example 2-6] [ka] A mixture of 2-chloro-6-nitrobenzaldehyde (1.0 g), potassium carbonate (1.5 g), ethyltriphenylphosphonium iodide (2.7 g), and tetrahydrofuran (10 mL) was stirred under heating and reflux for 4.5 hours. Isopropyl alcohol (10 mL) was added, and the mixture was stirred under heating and reflux for 5 hours. After cooling to room temperature, an aqueous solution of ammonium chloride was added to the reaction liquid, and the mixture was extracted with toluene. The organic layer was washed with a 10% aqueous solution of methanol, washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (gradient elution of hexane:ethyl acetate = 100:0-90:10) to obtain 1-chloro-3-nitro-2-(prop-1-en-1-yl)benzene (0.74 g) as a yellow oil. 1H-NMR (CDCl3) δ: 8.31-7.08 (m, 3H), 6.48-6.42 (m, 1H), 6.05-5.85 (m, 1H), 1.91-1.43 (m, 3H).

[0226] [Reference example 2-7] [ka] A mixture of 1-chloro-3-nitro-2-(prop-1-en-1-yl)benzene (0.74 g), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (0.99 g), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.27 g), potassium phosphate (2.0 g), 1,2-dimethoxyethane (11 mL), and water (3.7 mL) was irradiated with microwaves (microwave reactor, 100°C, 1 hour, 2.45 GHz, 0-240 W). Aqueous sodium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution = 100:0-80:20) to obtain a brown oil (0.61 g). A mixture of the obtained oil (0.30 g), 10% palladium carbon (0.30 g), ammonium formate (3.9 g), and methanol (24 mL) was stirred under heating and reflux for 2 hours. After cooling to room temperature, water and ethyl acetate were added to the reaction solution, and the solid matter was removed by celite filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution = 100:0-80:20) to obtain 2-propyl-3-(tetrahydro-2H-pyran-4-yl)aniline (0.24 g) as a white solid. LCMS (Method A) MS(ESI m / z): 220(M+H) RT(min):0.89

[0227] [Reference example 2-8] [ka] A mixture of 3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)aniline (50 mg), 10% palladium on carbon (29 mg), ammonium formate (0.46 g), and methanol (2.0 mL) was stirred for 1.5 hours under heating and reflux. 10% palladium on carbon (20 mg) and ammonium formate (0.23 g) were added and stirred for 1.5 hours. After cooling to room temperature, solids were removed by filtration through Celite. Water was added to the filtrate, and the mixture was extracted twice with ethyl acetate. The solvent in the organic layer was distilled off under reduced pressure to obtain 3-(tetrahydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)aniline (32 mg) as a yellow oil. LCMS (Method A) MS(ESI m / z):276(M+H) RT(min):1.33

[0228] [Reference example 2-9] [ka] A) A mixture of 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxamide (100 mg), methyl N-(triethylammoniosulfonyl)carbamate (137 mg), and dichloromethane (1.5 mL) was stirred at room temperature for 5 hours and 30 minutes. Methyl N-(triethylammoniosulfonyl)carbamate (55 mg) was added and stirred for 15 hours and 30 minutes. The mixture was passed through silica gel (5.0 g), eluted with dichloromethane, and the solvent was distilled off under reduced pressure. B) A mixture of 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxamide (200 mg), methyl N-(triethylammoniosulfonyl)carbamate (384 mg), and dichloromethane (3.0 mL) was stirred at room temperature for 22 hours. The mixture was passed through silica gel (5.0 g) and eluted with dichloromethane, and the solvent was distilled off under reduced pressure. The residues obtained in A and B were purified by NH silica gel column chromatography (hexane:ethyl acetate gradient elution=90:10-80:20) to obtain 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carbonitrile (259 mg) as a yellow solid. 1H-NMR (CDCl3) δ: 8.27 (s, 1H), 8.20 (dd, 1H, J = 8.2, 1.6 Hz), 7.63 (br s, 1H), 7.17 (t, 1H, J = 8.1 Hz), 6.92 (dd, 1H, J = 7.7, 1.6 Hz), 6.02 (s, 1H), 4.35-4.32 (m, 2H), 4.25 (q, 2H, J = 8.3 Hz), 3.94 (t, 2H, J = 5.4 Hz), 2.54-2.47 (m, 2H), 2.07-1.99 (m, 1H), 1.05-0.99 (m, 4H). LCMS (Method B) MS(ESI m / z): 417(M+H) RT(min):4.85

[0229] [Reference example 2-10] [ka] A mixture of 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carbonitrile (100 mg), N,N-dimethylformamide (4.0 mL), hydroxylamine hydrochloride (68 mg), and N,N-diisopropylethylamine (126 mg) was stirred at 70° C. for 2 hours and 30 minutes. The mixture was cooled to room temperature, and water was added. The precipitated solid was collected by filtration and dried to obtain 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)-N-hydroxypyrazine-2-carboximidamide (105 mg) as a white solid. 1H-NMR (CDCl3) δ: 10.59 (broad singlet, 1H), 8.48 (doublet of doublets, 1H, J = 8.2, 1.6 Hz), 8.12 (singlet, 1H), 7.14 (triplet, 1H, J = 7.9 Hz), 6.82 (doublet of doublets, 1H, J = 7.7, 1.6 Hz), 6.55 (singlet, 1H), 5.94 (broad singlet, 1H), 5.68 (broad singlet, 2H), 4.32 (doublet, 2H, J = 2.7 Hz), 4.22 (quartet, 2H, J = 8.6 Hz), 3.94 (triplet, 2H, J = 5.5 Hz), 2.55 - 2.49 (multiplet, 2H), 2.09 - 2.00 (multiplet, 1H), 1.01 - 0.94 (multiplet, 4H). LCMS(Method B) MS(ESI m / z): 450(M + H) RT(min): 4.72

[0230] [Reference Example 2 - 11] [Chemical Formula] To a mixture of 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylic acid (400 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (270 mg), 1-hydroxybenzotriazole hydrate (210 mg), and N,N-dimethylformamide (8.0 mL), N,O-dimethylhydroxylamine hydrochloride (180 mg) and N,N-diisopropylethylamine (475 mg) were added under ice cooling, and the mixture was stirred at room temperature for 18 hours. An aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, water, and an aqueous sodium chloride solution, and dried over sodium sulfate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=90:10-75:25) to give 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)-N-methoxy-N-methylpyrazine-2-carboxamide (450 mg) as a yellow oil. 1H-NMR (CDCl3) δ: 8.20-8.13 (m, 2H), 7.12 (t, 1H, J = 7.9 Hz), 6.84 (dd, 1H, J = 7.3, 1.7 Hz), 5.96 (br s, 1H), 4.31 (q, 2H, J = 2.7 Hz), 4.22 (q, 2H, J = 8.5 Hz), 3.92 (t, 2H, J = 5.4 Hz), 3.84 (s, 3H), 3.44 (br s, 3H), 2.54-2.46 (m, 2H), 2.07-1.99 (m, 1H), 1.01-0.91 (m, 4H). LCMS (Method B) MS(ESI m / z):479(M+H) RT(min):4.88

[0231] [Reference example 2-12] [ka] Diethyl (bromodifluoromethyl)phosphonate (2.7g) was added dropwise to a mixture of 2-bromo-6-nitrophenol (2.0g), acetonitrile (30mL), water (10mL), and 50% aqueous potassium hydroxide solution (10g), and the mixture was stirred at room temperature for 30 minutes. Diethyl (bromodifluoromethyl)phosphonate (0.49g) was added, and the mixture was stirred at room temperature for 10 minutes. Diethyl (bromodifluoromethyl)phosphonate (0.49g) was added, and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution, and the mixture was extracted twice with toluene. The solvent was distilled off under reduced pressure, and 1-bromo-2-(difluoromethoxy)-3-nitrobenzene (2.9g) was obtained as a brown oil. 1H-NMR (DMSO-D6) δ: 8.16 (dd, 1H, J = 8.0, 1.3 Hz), 8.11 (dd, 1H, J = 8.0, 1.3 Hz), 7.54 (t, 1H, J = 7.9 Hz), 7.26 (t, 1H, J = 71.6 Hz).

[0232] [Reference example 2-13] [ka] 1-Bromo-2-(difluoromethoxy)-5-fluoro-3-nitrobenzene was obtained in the same manner as in Reference Example 2-12. 1H-NMR (CDCl3) δ: 7.68-7.62 (m, 2H), 6.66 (t, 1H, J = 85.7 Hz).

[0233] [Reference example 2-14] [ka] 1,3-Dibromo-2-(difluoromethoxy)-5-fluorobenzene was obtained in the same manner as in Reference Example 2-12. 1H-NMR (CDCl3) δ: 7.36 (d, 2H, J = 7.3 Hz), 6.57 (t, 1H, J = 73.9 Hz).

[0234] [Reference example 2-15] [ka] 60% sodium hydride (0.12 g) was added to a mixture of 1-bromo-2,5-difluoro-3-nitrobenzene (0.60 g), 2,2,2-trifluoroethanol (0.24 mL), and N,N-dimethylformamide (6.0 mL) under ice cooling, and the mixture was stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain a residue. A mixture of the obtained residue (0.80 g), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (0.61 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.10 g), sodium carbonate (0.80 g), 1,2-dimethoxyethane (9.6 mL), and water (3.2 mL) was stirred under heating and reflux for 1 hour and 15 minutes. After cooling to room temperature, water was added to the reaction solution, and it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=90:10-80:20) to obtain 4-(5-fluoro-3-nitro-2-(2,2,2-trifluoroethoxy)phenyl)-3,6-dihydro-2H-pyran (0.35 g) as a light brown solid. 1H-NMR (CDCl3) δ: 7.50 (dd, 1H, J = 7.3, 3.3 Hz), 7.20 (dd, 1H, J = 7.9, 3.3 Hz), 6.10-6.06 (m, 1H), 4.37-4.29 (m, 4H), 3.93 (t, 2H, J = 5.3 Hz), 2.51-2.44 (m, 2H).

[0235] [Reference example 2-16] [ka] A mixture of 1-(2-amino-6-bromophenyl)ethan-1-one (0.15 g), hydrazine monohydrate (0.18 g), and diethylene glycol (3.0 mL) was stirred at 100°C for 2 hours. After cooling to room temperature, 50% aqueous potassium hydroxide solution (0.16 g) was added and stirred at 180°C for 3 hours. After cooling to room temperature, water was added to the reaction solution and extracted with toluene. The organic layer was washed twice with water, washed with an aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (gradient elution of hexane:ethyl acetate = 100:0-80:20) to obtain 3-bromo-2-ethylaniline (0.12 g) as a colorless oil. LCMS (Method A) MS(ESI m / z): 200(M+H) RT(min):1.39

[0236] [Reference example 2-17] [ka] A mixture of 3-fluoro-2-nitrophenol (1.0 g) and dichloromethane (10 mL) was cooled with ice, and N-bromosuccinimide (1.1 g) was added and stirred for 15 minutes. After stirring at room temperature for 20 minutes, acetic acid (10 mL) was added and stirred for 1 hour and 40 minutes. After stirring at 50°C for 1 hour and 40 minutes, N-bromosuccinimide (340 mg) was added and stirred for 10 minutes. After cooling to room temperature, an aqueous sodium sulfite solution was added and extracted twice with ethyl acetate. The solvent in the organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution = 100:0-40:60) to obtain 6-bromo-3-fluoro-2-nitrophenol (300 mg) as a brown solid. 1H-NMR (CDCl3) δ: 10.87-10.51 (m, 1H), 7.78 (dd, 1H, J = 8.6, 5.3 Hz), 6.77 (dd, 1H, J = 10.9, 8.9 Hz). LCMS (Method A) MS(ESI m / z):235(MH) RT(min):1.24

[0237] [Reference example 2-18] [ka] A mixture of 6-bromo-3-fluoro-2-nitrophenol (270 mg), iodoethane (270 μL), potassium carbonate (318 mg), and N,N-dimethylformamide (3.0 mL) was irradiated with microwaves (microwave reactor, 90° C., 30 min, 2.45 GHz, 0-240 W). Iodoethane (180 μL) was added to the reaction solution, and the mixture was irradiated with microwaves (microwave reactor, 100° C., 30 min, 2.45 GHz, 0-240 W). Water was added, and the mixture was extracted twice with ethyl acetate. The solvent in the organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 1-bromo-2-ethoxy-4-fluoro-3-nitrobenzene (0.13 g) as a yellow oil. 1H-NMR (CDCl3) δ: 7.66 (dd, 1H, J = 8.9, 5.9 Hz), 6.95 (t, 1H, J = 8.9 Hz), 4.28-4.19 (m, 2H), 1.46-1.40 (m, 3H).

[0238] [Reference example 2-19] [ka] 1-Chloro-2-ethoxy-3-nitrobenzene was obtained in the same manner as in Reference Example 2-18. 1H-NMR (DMSO-D6) δ: 7.92 (dd, 1H, J = 8.0, 1.6 Hz), 7.88 (dd, 1H, J = 8.0, 1.6 Hz), 7.38 (t, 1H, J = 8.0 Hz), 4.16 (q, 2H, J = 7.2 Hz), 1.35 (t, 3H, J = 7.2 Hz).

[0239] [Reference example 2-20] [ka] To a mixture of 2-chloro-1,3-difluoro-4-nitrobenzene (50 g) and ethanol (510 mL), 20% sodium ethoxide-ethanol solution (270 g) was added dropwise over 20 minutes under ice cooling. After stirring at 50°C for 20 minutes, the mixture was cooled on ice and water (2.5 L) was added. The precipitated solid was collected by filtration and dried to obtain 2-chloro-1,3-diethoxy-4-nitrobenzene (63 g) as a white solid. 1H-NMR (CDCl3) δ: 7.88 (d, 1H, J = 9.2 Hz), 6.74 (d, 1H, J = 9.2 Hz), 4.21 (q, 2H, J = 7.2 Hz), 4.20 (q, 2H, J = 6.8 Hz), 1.52 (t, 3H, J = 7.2 Hz), 1.49 (t, 3H, J = 6.8 Hz).

[0240] [Reference example 2-21] [ka] To a mixture of 2-chloro-1,3-difluoro-4-nitrobenzene (1.0 g) and ethanol (15 mL), 20% sodium ethoxide-ethanol solution (1.8 g) was added dropwise under ice cooling. After stirring at room temperature for 1 hour, water was added and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution and dried over sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution = 100:0-95:5) to obtain 2-chloro-3-ethoxy-1-fluoro-4-nitrobenzene (0.50 g) as a pale yellow oil. 1H-NMR (CDCl3) δ: 7.82 (dd, 1H, J = 9.2, 5.6 Hz), 7.05 (dd, 1H, J = 9.2, 7.2 Hz), 4.26 (q, 2H, J = 7.2 Hz), 1.49 (t, 3H, J = 7.2 Hz).

[0241] [Reference example 2-22] [ka] 3-Chloro-2-ethoxy-4-fluoroaniline was obtained in the same manner as in Reference Example 2-3. 1H-NMR (CDCl3) δ: 6.75 (t, 1H, J = 8.8 Hz), 6.58 (dd, 1H, J = 8.8, 5.4 Hz), 4.07 (q, 2H, J = 7.2 Hz), 3.74 (br s, 2H), 1.44 (t, 3H).

[0242] [Reference example 3] In the same manner as in Reference Example 2-2, Compound C was obtained from Compounds A and B. In Reference Examples 3-3 and 3-6, the reaction temperature was changed to 70° C. In Example 3-6, 1 equivalent of (S)-1,1,1-trifluoropropan-2-ol was used.

[0243] [Table 1]

[0244] [Reference example 4] [ka] In the same manner as in Reference Example 2-3, (S)-3-bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)aniline was obtained. LCMS (Method A) MS(ESI m / z):283(M+H) RT(min):1.61

[0245] [Reference example 5] Compound C was obtained from compounds A and B in the same manner as in Reference Example 2-1.

[0246] [Table 2-1]

[0247] [Table 2-2]

[0248] [Reference example 6] Compound B was obtained from compound A in the same manner as in Reference Example 2-3.

[0249] [Table 3-1]

[0250] [Table 3-2]

[0251] [Reference example 7] Compound B was obtained from compound A in the same manner as in Reference Example 2-8.

[0252] [Table 4]

[0253] [Reference example 8] Compound C was obtained from compounds A and B in the same manner as in Reference Example 2-4.

[0254] [Table 5-1]

[0255] [Table 5-2]

[0256] [Table 5-3]

[0257] [Reference example 9] By the method of Reference Example 2-1, the reaction solvent was changed from 1,2-dimethoxyethane to toluene and the reaction temperature was changed to 140° C., and Compounds C was obtained from Compounds A and B.

[0258] [Table 6]

[0259] [Reference example 10] Compound B was obtained from compound A in the same manner as in Reference Example 2-5.

[0260] [Table 7-1]

[0261] [Table 7-2]

[0262] [Example 1-1] [ka] 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylic acid (30 mg), A mixture of 1,1'-carbonyldiimidazole (15 mg) and tetrahydrofuran (0.80 mL) was stirred at room temperature for 30 minutes. 1,1'-carbonyldiimidazole (8.1 mg) was added and stirred for 15 minutes. 1,1'-carbonyldiimidazole (23 mg) was added and stirred for 10 minutes. 7 mol / L ammonia methanol solution (0.30 mL) was added and stirred for 30 minutes. Aqueous sodium chloride solution was added and extracted twice with ethyl acetate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution = 100:0-70:30) to obtain 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxamide (27 mg) as a yellow solid. 1H-NMR (DMSO-D6) δ: 11.30 (br s, 1H), 8.42-8.36 (m, 2H), 8.20 (br s, 1H), 7.94 (br s, 1H), 7.15 (t, 1H, J = 7.9 Hz), 6.86 (d, 1H, J = 7.9 Hz), 5.95 (br s, 1H), 4.40 (q, 2H, J = 9.0 Hz), 4.22-4.17 (m, 2H), 3.82 (t, 2H, J = 5.3 Hz), 2.44-2.37 (m, 2H), 2.20-2.07 (m, 1H), 1.08-0.87 (m, 4H). LCMS (Method A) MS(ESI m / z): 435(M+H) RT(min):1.74

[0263] [Example 1-2] [ka] 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylic acid (100 mg), A mixture of 1,1'-carbonyldiimidazole (150mg) and tetrahydrofuran (2.0mL) was stirred at room temperature for 1 hour. 1,1'-carbonyldiimidazole (37mg) was added and stirred for 30 minutes. Methanesulfonamide (87mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (140mg) were added and stirred for 30 minutes. The pH was adjusted to 5 with 1mol / L hydrochloric acid. Aqueous sodium chloride solution and ethyl acetate were added, and the solid matter was filtered off. The filtrate was extracted twice with ethyl acetate, and the solvent in the organic layer was distilled off under reduced pressure and combined with the solid matter. Methanol (3.0mL) was added to the obtained residue, and the mixture was suspended and stirred, and water (3.0mL) was added and stirred, and the solid matter was filtered off. The obtained solid was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=100:0-0:100-methanol:ethyl acetate gradient elution=20:80) to obtain 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)-N-(methylsulfonyl)pyrazine-2-carboxamide (72 mg) as a pale yellow solid. 1H-NMR (DMSO-D6) δ: 11.58 (br s, 1H), 10.53 (br s, 1H), 8.51 (s, 1H), 8.29 (d, 1H, J = 7.6 Hz), 7.18 (t, 1H, J = 7.6 Hz), 6.93 (d, 1H, J = 7.6 Hz), 5.99 (br s, 1H), 4.45 (q, 2H, J = 8.8 Hz), 4.25-4.18 (m, 2H), 3.83 (t, 2H, J = 5.3 Hz), 3.38 (s, 3H), 2.47-2.38 (m, 2H), 2.25-2.12 (m, 1H), 1.17-1.09 (m, 2H), 1.02-0.92 (m, 2H). LCMS (Method A) MS(ESI m / z):513(M+H) RT(min):1.74

[0264] [Examples 1-3] [ka] 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylic acid (30 mg), A mixture of 1,1'-carbonyldiimidazole (34 mg) and tetrahydrofuran (1.0 mL) was stirred at room temperature for 30 minutes. Sodium borohydride (16 mg) and 2-propanol (0.20 mL) were added and stirred for 1 hour. A mixture of sodium borohydride (16 mg) and methanol (0.30 mL) was added dropwise and stirred for 1 hour. An aqueous sodium chloride solution was added and extracted twice with ethyl acetate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution = 100:0-50:50) to obtain 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazin-2-yl)methanol (16 mg) as a yellow solid. 1H-NMR (DMSO-D6) δ: 8.86 (br s, 1H), 8.26 (d, 1H, J = 7.9 Hz), 8.07 (s, 1H), 7.12 (t, 1H, J = 7.9 Hz), 6.82 (d, 1H, J = 7.9 Hz), 6.10-5.91 (m, 2H), 4.65 (s, 2H), 4.38 (q, 2H, J = 9.0 Hz), 4.24-4.15 (m, 2H), 3.81 (t, 2H, J = 5.3 Hz), 2.45-2.36 (m, 2H), 2.13-2.00 (m, 1H), 1.00-0.77 (m, 4H). LCMS (Method A) MS(ESI m / z): 422(M+H) RT(min):1.71

[0265] [Examples 1-4] [ka] A mixture of methyl 3-((3-chloro-2-(2,2,2-trifluoroethoxy)phenyl)amino)-6-cyclopropylpyrazine-2-carboxylate (100 mg), 2,6-dimethylpyridine-3-boronic acid (42 mg), potassium phosphate (110 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (9.1 mg), 1,2-dimethoxyethane (3.0 mL), and water (1.0 mL) was irradiated with microwaves (microwave reaction apparatus, 135° C., 1 hour, 2.45 GHz, 0-240 W). Aqueous sodium chloride solution and 1 mol / L hydrochloric acid were added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6-cyclopropyl-3-((3-(2,6-dimethylpyridin-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylic acid (12 mg) as a yellow oil. 1H-NMR (CDCl3) δ: 10.43 (br s, 1H), 8.48-8.35 (m, 2H), 7.52 (d, 1H, J = 7.9 Hz), 7.31-7.19 (m, 1H), 7.10 (d, 1H, J = 7.9 Hz), 6.92 (d, 1H, J = 5.9 Hz), 3.97-3.66 (m, 2H), 2.62 (s, 3H), 2.46 (s, 3H), 2.17-2.01 (m, 1H), 1.26-0.86 (m, 4H). LCMS (Method A) MS(ESI m / z):459(M+H) RT(min):1.15

[0266] [Examples 1-5] [ka] The same procedure as in Example 1-4 was repeated, except that 2,6-dimethylpyridine-3-boronic acid was replaced with 4-cyano-2-methylphenylboronic acid, and 3-((4'-cyano-2'-methyl-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid was obtained as a yellow solid. 1H-NMR (DMSO-D6) δ: 13.72-13.09 (m, 1H), 10.73 (br s, 1H), 8.54 (d, 1H, J = 8.6 Hz), 8.45 (s, 1H), 7.83 (s, 1H), 7.75 (d, 1H, J = 9.2 Hz), 7.48 (d, 1H, J = 7.9 Hz), 7.30 (t, 1H, J = 7.9 Hz), 6.89 (d, 1H, J = 7.9 Hz), 4.32-3.84 (m, 2H), 2.24-2.11 (m, 4H), 1.03-0.85 (m, 4H). LCMS (Method A) MS(ESI m / z):469(M+H) RT(min):1.89

[0267] [Examples 1-6] [ka] A mixture of 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carbonitrile (100 mg), N,N-dimethylformamide (5.0 mL), ammonium chloride (17 mg), and sodium azide (21 mg) was stirred at 80° C. for 6 hours and 30 minutes. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated twice with an aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 50% aqueous methanol was added to the obtained residue, and the mixture was stirred. The solid was filtered off, and 5-cyclopropyl-N-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)-3-(1H-tetrazol-5-yl)pyrazin-2-amine (76 mg) was obtained as a yellow solid. 1H-NMR (DMSO-D6) δ: 10.36 (br s, 1H), 8.41 (s, 1H), 8.34 (dd, 1H, J = 8.3, 1.5 Hz), 7.20 (t, 1H, J = 7.9 Hz), 6.93 (dd, 1H, J = 7.7, 1.6 Hz), 6.00 (br s, 1H), 4.45 (q, 2H, J = 9.0 Hz), 4.25-4.19 (m, 2H), 3.84 (t, 2H, J = 5.4 Hz), 2.48-2.40 (m, 2H), 2.26-2.16 (m, 1H), 1.12-1.06 (m, 2H), 1.04-0.96 (m, 2H). LCMS (Method B) MS(ESI m / z): 460(M+H) RT(min):4.62

[0268] [Examples 1-7] [ka] A mixture of 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)-N-hydroxypyrazine-2-carboximidamide (99 mg), N,N-dimethylformamide (5.0 mL), and 1,1'-carbonyldiimidazole (36 mg) was stirred at 40°C for 2 hours. The mixture was stirred at 80°C for 7 hours. The mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=90:10-75:25) to give 3-(6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazin-2-yl)-1,2,4-oxadiazol-5(4H)-one (43 mg) as a yellow solid. 1H-NMR (DMSO-D6) δ: 13.06 (br s, 1H), 9.24 (s, 1H), 8.45 (s, 1H), 8.33 (dd, 1H, J = 7.9, 1.5 Hz), 7.19 (t, 1H, J = 7.9 Hz), 6.94 (dd, 1H, J = 7.6, 1.5 Hz), 5.98 (s, 1H), 4.42 (q, 2H, J = 9.0 Hz), 4.23-4.18 (m, 2H), 3.82 (t, 2H, J = 5.3 Hz), 2.45-2.38 (m, 2H), 2.23-2.14 (m, 1H), 1.13-1.07 (m, 2H), 0.99-0.93 (m, 2H). LCMS (Method B) MS(ESI m / z):476(M+H) RT(min):4.69

[0269] [Examples 1-8] [ka] A mixture of methyl 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylate (150 mg), ethanol (10 mL), and hydrazine monohydrate (84 mg) was stirred at room temperature for 2 hours. The mixture was stirred at 50° C. for 1 hour and then stirred under reflux for 15 hours. The mixture was stirred for 20 minutes under ice-cooling, and the precipitated solid was collected by filtration and dried to obtain 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carbohydrazide (123 mg) as a yellow solid. 1H-NMR (DMSO-D6) δ: 11.09 (s, 1H), 9.96 (br s, 1H), 8.38 (s, 1H), 8.32 (dd, 1H, J = 8.3, 1.5 Hz), 7.14 (t, 1H, J = 8.1 Hz), 6.86 (dd, 1H, J = 7.7, 1.6 Hz), 5.95 (br s, 1H), 4.63 (br s, 2H), 4.42 (q, 2H, J = 9.0 Hz), 4.23-4.18 (m, 2H), 3.82 (t, 2H, J = 5.4 Hz), 2.45-2.38 (m, 2H), 2.16-2.08 (m, 1H), 1.09-1.04 (m, 2H), 0.95-0.89 (m, 2H). LCMS (Method B) MS(ESI m / z): 450(M+H) RT(min):3.96

[0270] [Examples 1-9] [ka] To a mixture of 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carbohydrazide (120 mg), N,N-dimethylformamide (4.0 mL), and triethylamine (36 μL), 1,1'-carbonyldiimidazole (42 mg) was added under ice-cooling. The mixture was stirred at room temperature for 16 hours. The solvent was removed from the mixture under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=90:10-75:25) to give 5-(6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazin-2-yl)-1,3,4-oxadiazol-2(3H)-one (110 mg) as a yellow solid. 1H-NMR (DMSO-D6) δ: 13.04 (br s, 1H), 9.42 (s, 1H), 8.36 (s, 1H), 8.26 (dd, 1H, J = 8.3, 1.5 Hz), 7.19 (t, 1H, J = 7.9 Hz), 6.94 (dd, 1H, J = 7.6, 1.5 Hz), 5.98 (br s, 1H), 4.40 (q, 2H, J = 9.0 Hz), 4.23-4.18 (m, 2H), 3.83 (t, 2H, J = 5.3 Hz), 2.46-2.38 (m, 2H), 2.24-2.15 (m, 1H), 1.03-0.97 (m, 2H), 0.94-0.88 (m, 2H). LCMS (Method B) MS(ESI m / z):476(M+H) RT(min):4.59

[0271] [Examples 1-10] [ka] To a mixture of 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)-N-methoxy-N-methylpyrazine-2-carboxamide (440 mg) and tetrahydrofuran (9.0 mL), 3 mol / L methylmagnesium bromide diethyl ether solution (0.77 mL) was added under ice cooling, and the mixture was stirred for 1 hour and 30 minutes. An aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution and dried over sodium sulfate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=90:10-80:20) to give 1-(6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazin-2-yl)ethan-1-one (373 mg) as a yellow solid. 1H-NMR (CDCl3) δ: 10.90 (br s, 1H), 8.33-8.27 (m, 2H), 7.14 (t, 1H, J = 7.9 Hz), 6.89 (dd, 1H, J = 7.6, 1.5 Hz), 5.98 (br s, 1H), 4.32 (q, 2H, J = 2.7 Hz), 4.22 (q, 2H, J = 8.5 Hz), 3.93 (t, 2H, J = 5.4 Hz), 2.70 (s, 3H), 2.56-2.49 (m, 2H), 2.10-2.02 (m, 1H), 1.04-0.99 (m, 4H). LCMS (Method B) MS(ESI m / z):434(M+H) RT(min):5.50

[0272] [Examples 1-11] [ka] Lithium aluminum hydride (14 mg) was added to a mixture of 1-(6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazin-2-yl)ethan-1-one (80 mg) and tetrahydrofuran (4.0 mL), and the mixture was stirred at room temperature for 30 minutes. 1 mol / L aqueous sodium hydroxide solution and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution and dried over sodium sulfate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=90:10-80:20) to give 1-(6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazin-2-yl)ethan-1-ol (77 mg) as a yellow solid. 1H-NMR (DMSO-D6) δ: 9.25 (br s, 1H), 8.28 (dd, 1H, J = 8.3, 1.7 Hz), 8.04 (s, 1H), 7.11 (t, 1H, J = 7.9 Hz), 6.80 (dd, 1H, J = 7.7, 1.6 Hz), 6.25 (s, 1H), 5.94 (br s, 1H), 4.90-4.80 (m, 1H), 4.42-4.31 (m, 2H), 4.22-4.17 (m, 2H), 3.81 (t, 2H, J = 5.4 Hz), 2.44-2.37 (m, 2H), 2.10-2.01 (m, 1H), 1.42 (d, 3H, J = 6.6 Hz), 0.94-0.87 (m, 2H), 0.84-0.79 (m, 2H). LCMS (Method B) MS(ESI m / z):436(M+H) RT(min):4.80

[0273] [Examples 1-12] [ka] A mixture of methyl 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylate (100 mg), methanol (3 mL), and methylhydrazine (100 mg) was stirred in a sealed container at 80° C. for 18 hours. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=95:5-80:20). The purified product was added with 50% ethanol water and suspended and stirred, and the solid was collected by filtration and dried to obtain 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)-N'-methylpyrazine-2-carbohydrazide (65 mg) as a yellow solid. 1H-NMR (DMSO-D6) δ: 11.05 (s, 1H), 10.14 (br s, 1H), 8.38 (s, 1H), 8.30 (dd, 1H, J = 8.2, 1.6 Hz), 7.15 (t, 1H, J = 8.1 Hz), 6.87 (dd, 1H, J = 7.7, 1.6 Hz), 5.96 (br s, 1H), 5.20-5.08 (m, 1H), 4.41 (q, 2H, J = 9.0 Hz), 4.23-4.17 (m, 2H), 3.82 (t, 2H, J = 5.4 Hz), 2.57 (d, 3H, J = 4.4 Hz), 2.45-2.38 (m, 2H), 2.17-2.08 (m, 1H), 1.10-1.03 (m, 2H), 0.96-0.89 (m, 2H). LCMS (Method B) MS(ESI m / z):464(M+H) RT(min):3.99

[0274] [Examples 1-13] [ka] A mixture of methyl 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylate (100 mg), methanol (2.0 mL), and 1,1-dimethylhydrazine (340 μL) was irradiated with microwaves (microwave reactor, 120° C., 7 hours, 2.45 GHz, 0-240 W). 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (125 mg) was added and stirred at room temperature for 5 hours. The mixture was stirred at 40° C. for 3 hours. 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (125 mg) was added and stirred at 40° C. for 17 hours. The solvent was removed under reduced pressure, and the resulting residue was purified by reversed-phase silica gel column chromatography (KP-C18-HS, ​​gradient elution of 0.1% aqueous trifluoroacetic acid:methanol = 70:30-30:70). The fractions containing the target product were combined, the solvent was removed under reduced pressure, an aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution of hexane:ethyl acetate = 90:10-80:20). The product was purified by preparative thin-layer chromatography (hexane:ethyl acetate = 75:25) to obtain 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)-N',N'-dimethylpyrazine-2-carbohydrazide (21 mg) as a yellow solid. 1H-NMR (DMSO-D6) δ: 11.05 (s, 1H), 9.46 (s, 1H), 8.36 (s, 1H), 8.30 (dd, 1H, J = 7.9, 1.5 Hz), 7.14 (t, 1H, J = 7.9 Hz), 6.87 (dd, 1H, J = 7.6, 1.5 Hz), 5.96 (br s, 1H), 4.41 (q, 2H, J = 9.0 Hz), 4.23-4.18 (m, 2H), 3.82 (t, 2H, J = 5.3 Hz), 2.63 (s, 6H), 2.45-2.38 (m, 2H), 2.18-2.09 (m, 1H), 1.06-1.00 (m, 2H), 0.99-0.92 (m, 2H). LCMS (Method B) MS(ESI m / z):478(M+H) RT(min):4.31

[0275] [Examples 1-14] [ka] To a mixture of 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazin-2-yl)methanol (12 mg) and dichloromethane (1.0 mL) was added Dess-Martin reagent (12 mg) under ice cooling and stirred at room temperature for 1 hour. Dess-Martin reagent (6 mg) was added and stirred at room temperature for 30 minutes. Dess-Martin reagent (6 mg) was added and stirred at room temperature for 30 minutes. Dess-Martin reagent (6 mg) was added and stirred at room temperature for 30 minutes. An aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium sulfite were added, and the mixture was extracted twice with ethyl acetate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=100:0-80:20) to give 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carbaldehyde (9.2 mg) as a yellow solid. 1H-NMR (DMSO-D6) δ: 10.41 (br s, 1H), 9.95 (s, 1H), 8.53 (s, 1H), 8.36 (d, 1H, J = 7.9 Hz), 7.20 (t, 1H, J = 7.9 Hz), 6.96 (d, 1H, J = 7.9 Hz), 6.00 (br s, 1H), 4.45 (q, 2H, J = 9.0 Hz), 4.26-4.17 (m, 2H), 3.83 (t, 2H, J = 5.3 Hz), 2.47-2.38 (m, 2H), 2.32-2.18 (m, 1H), 1.06-0.93 (m, 4H). LCMS (Method A) MS(ESI m / z): 420(M+H) RT(min):1.96

[0276] [Examples 1-15] [ka] To a mixture of 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carbaldehyde (100 mg), methanesulfonamide (34 mg), dichloroethane (4.0 mL), and triethylamine (67 μL), sodium triacetoxyborohydride (130 mg) was added and stirred at room temperature for 23 hours. 1 mol / L hydrochloric acid was added, and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with an aqueous sodium hydrogen carbonate solution, and dried over sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution = 90:10-65:35). A mixture of heptane / ethyl acetate (10 / 1) was added to the purified product and the mixture was suspended and stirred. The solid matter was collected by filtration to obtain N-((6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazin-2-yl)methyl)methanesulfonamide (100 mg) as a white solid. 1H-NMR (DMSO-D6) δ: 8.02 (singlet, 1H), 7.72 (broad singlet, 1H), 7.63 (doublet of doublets, 1H, J = 8.1, 1.7 Hz), 7.47 (broad singlet, 1H), 7.13 (triplet, 1H, J = 7.9 Hz), 6.93 (doublet of doublets, 1H, J = 7.7, 1.6 Hz), 5.93 (broad singlet, 1H), 4.40 - 4.31 (multiplet, 4H), 4.22 - 4.18 (multiplet, 2H), 3.81 (triplet, 2H, J = 5.4 Hz), 2.96 (singlet, 3H), 2.44 - 2.37 (multiplet, 2H), 2.10 - 2.01 (multiplet, 1H), 0.94 - 0.86 (multiplet, 4H). LCMS(Method B) MS(ESI m / z): 499 (M + H) RT (min): 4.52

[0277] [Example 1 - 16] [Chemical Structure] A mixture of 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carbaldehyde (100 mg), cyanamide (20 mg), methanol (2.0 mL), dichloromethane (2.0 mL), and p-toluenesulfonic acid monohydrate (9.0 mg) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (38 mg) was added and stirred for 16 hours. The solvent was removed under reduced pressure, and an aqueous solution of sodium hydrogen carbonate was added, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride and dried over sodium sulfate. The solvent of the organic layer was removed under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (gradient elution of hexane:ethyl acetate=80:20-55:45). The product was purified by silica gel column chromatography (dichloromethane:ethyl acetate gradient elution=100:0-65:35). N-((6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazin-2-yl)methyl)cyanamide (11 mg) was obtained. LCMS (Method B) MS(ESI m / z):446(M+H) RT(min):2.87

[0278] [Example 1-17] [ka] A mixture of 6-cyclopropyl-3-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carbaldehyde (100 mg), ammonium acetate (190 mg), methanol (8.0 mL), and dichloromethane (8.0 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (41 mg) was added, and the mixture was stirred for 22 hours. The solvent was removed under reduced pressure, and 1 mol / L aqueous sodium hydroxide solution was added, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution and dried over sodium sulfate. The organic layer was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate gradient elution=90:10-60:40) to give 3-(aminomethyl)-5-cyclopropyl-N-(3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)pyrazin-2-amine (28 mg) as an orange oil. 1H-NMR (DMSO-D6) δ: 10.61 (br s, 1H), 8.25 (dd, 1H, J = 8.2, 1.6 Hz), 8.00 (s, 1H), 7.10 (t, 1H, J = 7.9 Hz), 6.78 (dd, 1H, J = 7.6, 1.7 Hz), 5.92 (br s, 1H), 4.39 (q, 2H, J = 9.0 Hz), 4.22-4.16 (m, 2H), 3.96 (s, 2H), 3.80 (t, 2H, J = 5.4 Hz), 2.44-2.36 (m, 2H), 2.08-2.00 (m, 1H), 0.92-0.77 (m, 4H). LCMS (Method B) MS(ESI m / z): 421(M+H) RT(min):3.30

[0279] [Example 1-18] [ka] A mixture of tert-butyl (S)-5-cyclopropyl-2-((2-(3,6-dihydro-2H-pyran-4-yl)-3-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)amino)benzoate (13 mg), dichloromethane (0.20 mL), and trifluoroacetic acid (70 μL) was stirred at room temperature for 1 hour. Water and ethyl acetate were added, and an aqueous solution of sodium bicarbonate was added to adjust the pH to 2.1. The organic layer was separated, washed with an aqueous solution of sodium chloride, and dried over sodium sulfate. The solvent in the organic layer was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (gradient elution of hexane:ethyl acetate = 90:10-0:100). Ethyl acetate and hexane were added to the obtained solid and stirred, and the solid was collected by filtration to obtain (S)-5-cyclopropyl-2-((2-(3,6-dihydro-2H-pyran-4-yl)-3-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)amino)benzoic acid (13 mg) as a white solid. 1H-NMR (CDCl3) δ: 9.72 (br s, 1H), 8.18 (d, 1H, J = 5.3 Hz), 7.83 (d, 1H, J = 2.0 Hz), 7.43 (d, 1H, J = 8.6 Hz), 7.28-7.19 (m, 2H), 6.36 (s, 1H), 4.61-4.46 (m, 1H), 4.33 (d, 2H, J = 2.6 Hz), 3.95 (t, 2H, J = 5.3 Hz), 2.79-2.49 (m, 2H), 1.99-1.84 (m, 1H), 1.39 (d, 3H, J = 6.6 Hz), 1.03-0.93 (m, 2H), 0.75-0.64 (m, 2H). LCMS (Method A) MS(ESI m / z):449(M+H) RT(min):1.13

[0280] [Example 2] Compound B was obtained from compound A in the same manner as in Reference Example 2-5.

[0281] [Table 8-1]

[0282] [Table 8-2]

[0283] [Example 3] Compound C was obtained from compounds A and B in the same manner as in Example 1-2.

[0284] [Table 9-1]

[0285] [Table 9-2]

[0286] [Table 9-3]

[0287] [Table 9-4]

[0288] [Table 9-5]

[0289] [Table 9-6] [Test example]

[0290] Test Example 1 Enzyme reaction inhibition test The DHODH enzyme assay was performed with reference to "Benjamin Bader, Wolfgang Knecht, Markus Fries, and Monika Loffler. Expression, Purification, and Characterization of Histidine-Tagged Rat and Human Flavoenzyme Dihydroorotate Dehydrogenase. Protein Expression and Purification, 1998, 13, 414-422." DHODH activity was assessed using an enzyme assay system coupled to a blue dye quenching assay, 2,6-dichlorophenolindophenol (DCIP, MP BIOMEDICALS, MP150118). Purified recombinant human DHODH (DHODH, 31-395aa, Human, His tag, E.coli, ATGP1615) was purchased from ATGen. The enzyme assay consisted of 100 mmol / L Hepes (Dojindo Laboratories, 342-01375), 400 mmol / L NaCl (Fujifilm Wako Pure Chemical Industries, 191-01665), 10% Glycerol (Fujifilm Wako Pure Chemical Industries, 075-00616), 0.05% TritonX-100 (Sigma-Aldrich, T8787-100ML), 0.2 mmol / L Ubiquinone-10 (Fujifilm Wako Pure Chemical Industries, 216-00761), 0.1 mmol / L DHO (L-Dihydroorotic acid) (Sigma-Aldrich, D7128), 0.5% DMSO (dimethyl sulfoxide) (Fujifilm Wako Pure Chemical Industries, 047-29353), 0.175 μg / mL DHODH, and 0.12 mmol / L DCIP at 5 mol / L. The reaction was carried out in a 384-well plate using a buffer adjusted to pH 8.0 by adding potassium hydroxide (FUJIFILM Wako Pure Chemical Industries, 168-21815). Test compounds were added at a given concentration using a BiomekNX (Beckman Coulter), and the enzyme reaction was initiated by the addition of substrate. Enzyme activity was assessed by measuring the decrease in DCIP absorbance (600 nm) for 50 min using an Envision plate-reading spectrophotometer (PerkinElmer).

[0291] The enzyme reaction inhibition rate at each test compound concentration was determined, and the 50% enzyme reaction inhibition concentration [IC50 (nmol / L)] was calculated using XLfit. Enzyme reaction inhibition rate (%) = (luminescence amount in wells to which test compound was added) ÷ (luminescence amount in wells to which DMSO was added) × 100

[0292] The results are shown in Table 10. The abbreviations in the table have the following meanings: A: IC50 value < 10 nmol / L B:10 nmol / L ≦ IC50 value <100 nmol / L C: 100 nmol / L ≦ IC50 value

[0293] As shown in Table 10, each test compound exhibited excellent enzyme reaction inhibitory activity.

[0294] Test Example 2 Cell proliferation test A cell proliferation test was performed using human myeloid leukemia cell line HL60 (ATCC, CRL-240). The culture medium for HL60 cells was RPMI1640 (Fujifilm Wako Pure Chemical Corporation, 189-02025) supplemented with 10% Fetal Bovine Serum (Thermo Fisher Scientific, 10437-028) and 1% Penicillin-Streptomycin (10,000U / mL, Thermo Fisher Scientific, 15140-122). HL60 cells were seeded at 1000 cells / 20 μL / well in a 384-well plate (Corning, 4588). After overnight incubation, 5 μL of a test compound at a given concentration was added, and 3 days later, 25 μL of Cell Titer-Glo® Luminescent Cell Viability Assay (Promega, G7573) was added, and the amount of luminescence was measured using an Envision plate reader (PerkinElmer). Since the amount of luminescence is proportional to the intracellular adenosine triphosphate (ATP) concentration, the amount of luminescence was used as an index of the number of live cells. The growth inhibition concentration at each test compound concentration was calculated using the following formula.

[0295] The growth inhibition rate at each test compound concentration was determined, and the 50% growth inhibition concentration [GI50 (nmol / L)] was calculated using XLfit. Growth inhibition rate (%) = (luminescence amount in wells to which test compound was added) ÷ (luminescence amount in wells to which DMSO was added) × 100

[0296] The results are shown in Table 10. The abbreviations in the table have the following meanings: A: GI50 value < 100 nmol / L B:100 nmol / L ≦ GI50 value < 1000 nmol / L C: 1000 nmol / L ≦ GI50 value

[0297] As shown in Table 10, each test compound exhibited an excellent cell proliferation inhibition rate.

[0298] [Table 10]

[0299] Test Example 3: In vivo efficacy test in tumor-bearing mice (Drug efficacy test in a mouse model bearing subcutaneously transplanted HL60 tumors) Human acute myeloid leukemia cell line HL60 (JCRB) was suspended in a mixture of RPMI-1640 medium and Matrigel (Corning) and then subcutaneously transplanted into 6-week-old female NOD / scid mice (CLEA Japan). The test compound was dispersed in a solvent (0.5% methylcellulose aqueous solution) and orally administered to the mice at 2.5-10 mg / kg once a day for 10-12 days from the time when tumor engraftment was confirmed with the naked eye. A solvent-administered group administered with 0.5% methylcellulose aqueous solution was set up as a negative control. The tumor diameter was measured daily and the tumor volume was calculated. The tumor volume was calculated by measuring the long and short diameters of the tumor and using the following formula.

[0300] Tumor volume (mm3) = [long diameter (mm) × short diameter (mm) × short diameter (mm)] / 2

[0301] The T / C (%) was calculated from the average tumor volume of each group using the following formula to evaluate the drug efficacy. T / C(%)=(average tumor volume of drug-administered group) / (average tumor volume of vehicle-administered group)×100%

[0302] As a result of evaluating the efficacy, each test compound (eg, the compounds described in Examples 1-2, 3-30, 3-41, 3-44 and 3-49) showed an excellent tumor growth inhibition rate. [Industrial Applicability]

[0303] The compound of the present invention or a salt thereof has excellent DHODH inhibitory activity and is useful as a DHODH inhibitor. In addition, the compound of the present invention or a salt thereof has excellent antitumor activity and is useful as a pharmaceutical composition for an antitumor agent, etc. The compound of the present invention or a salt thereof is useful for treatment such as prevention or treatment of blood cancer, for example. Furthermore, the compound selected from compound group X or a salt thereof is useful as an intermediate for producing the compound of the present invention or a salt thereof.

Claims

1. A compound represented by general formula (1) or a salt thereof: 【Chemistry 1】 During the ceremony, Z １ represents a nitrogen atom; Z ２ indicates CH; Z ３ represents a nitrogen atom or CH; Z ４ is represented by the general formula CR ６ indicates; Z ５ is represented by the general formula CR ７ indicates; R １ is represented by the general formula CONHR ８ , general formula CH ２ NHR ８ , C.H. ２ OH, CH(OH)CH ３ , C(O)CH ３ , CHO or formula (1-1) to (1-3) 【Chemistry 2】 indicates; R ２ is an optionally substituted C １－６ an alkyl group or an optionally substituted C ３－８ represents a cycloalkyl group; R ３ , R ５ , R ６ and R ７ are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally substituted C １－６ Alkyl group, optionally substituted C ２－６ Alkenyl group, optionally substituted C ２－６ Alkynyl group, optionally substituted C ３－８ Cycloalkyl group, optionally substituted C １－６ Alkoxy group, optionally substituted C ３－８ Cycloalkoxy group or optionally substituted C １－６ Alkoxy C １－６ represents an alkyl group; R ４ represents an optionally substituted aryl group or an optionally substituted heterocyclic group; R ８ represents a hydrogen atom, an optionally protected hydroxyl group, an optionally protected amino group, an optionally substituted C １－６ Alkyl group, optionally substituted C ３－８ Cycloalkyl group, optionally substituted C １－６ Alkoxy group, optionally substituted C ３－８ Cycloalkoxy group, optionally substituted C １－６ alkylamino group, optionally substituted di(C １－６ alkyl)amino group or a group of the general formula SO ２ R ９ indicates; R ９ represents an optionally protected hydroxyl group, an optionally protected amino group, an optionally substituted C １－６ Alkyl group, optionally substituted C ３－８ Cycloalkyl group, optionally substituted C １－６ Alkoxy group, optionally substituted C ３－８ Cycloalkoxy group, optionally substituted C １－６ Alkylamino group or optionally substituted di(C １－６ represents an alkyl)amino group.

2. R ２ But, C １－６ Alkyl group or C ３－８ 2. The compound of claim 1, or a salt thereof, which is a cycloalkyl group.

3. R １ is represented by the general formula CONHR ８ Or formula (1-1) to (1 to 3) 【Chemistry 3】 The compound according to any one of claims 1 to 2, or a salt thereof.

4. R ３ , R ５ , R ６ and R ７ are the same or different and may be substituted with one or more substituents selected from a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, and a substituent group A. １－６ C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A ２－６ an alkenyl group, C which may be substituted with one or more substituents selected from the substituent group A ２－６ an alkynyl group, C optionally substituted with one or more substituents selected from the substituent group A; ３－８ a cycloalkyl group, C which may be substituted with one or more substituents selected from the substituent group A; １－６ an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; ３－８ C which may be substituted with one or more substituents selected from a cycloalkoxy group or a substituent group A １－６ Alkoxy C １－６ The compound or salt thereof according to any one of claims 1 to 3, which is an alkyl group. Substituent group A: A halogen atom; a cyano group; an optionally protected hydroxyl group; an optionally protected amino group; C １－６ Alkyl group; C ２－６ Alkenyl group; C ２－６ Alkynyl group; C ３－８ Cycloalkyl group; C １－６ Alkoxy group; C ３－８ Cycloalkoxy group; C １－６ Alkylamino group; di(C １－６ an alkyl)amino group; an aryl group which may be substituted with one or more substituents selected from Substituent Group B; a heterocyclic group which may be substituted with one or more substituents selected from Substituent Group B Substituent group B: A halogen atom; an optionally protected hydroxyl group; an optionally protected amino group; C １－６ Alkyl group; C ２－６ Alkenyl group; C ２－６ Alkynyl group; C ３－８ Cycloalkyl group; C １－６ Alkoxy group; C ３－８ Cycloalkoxy group; C １－６ Alkylamino group; di(C １－６ (alkyl)amino group; １－６ Alkoxy C １－６ Alkyl group.

5. R ３ C which may be substituted with one or more substituents selected from a halogen atom, an optionally protected hydroxyl group, and substituent group A １－６ C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A ２－６ an alkenyl group, C which may be substituted with one or more substituents selected from the substituent group A ２－６ an alkynyl group, C optionally substituted with one or more substituents selected from the substituent group A; ３－８ a cycloalkyl group, C which may be substituted with one or more substituents selected from the substituent group A; １－６ an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; ３－８ C which may be substituted with one or more substituents selected from a cycloalkoxy group or a substituent group A １－６ Alkoxy C １－６ The compound or salt thereof according to any one of claims 1 to 4, which is an alkyl group.

6. R ５ , R ６ and R ７ C, which may be substituted with a hydrogen atom, a halogen atom, or one or more substituents selected from the group A of substituents, which may be the same or different. １－６ C which may be substituted with an alkyl group or one or more substituents selected from the substituent group A １－６ The compound or salt thereof according to any one of claims 1 to 5, which is an alkoxy group.

7. R ４ is an aryl group optionally substituted with one or more substituents selected from substituent group A, a monocyclic nitrogen-containing heterocyclic group optionally substituted with one or more substituents selected from substituent group A, a monocyclic oxygen-containing heterocyclic group optionally substituted with one or more substituents selected from substituent group A, a bicyclic nitrogen-containing heterocyclic group optionally substituted with one or more substituents selected from substituent group A, or a bicyclic oxygen-containing heterocyclic group optionally substituted with one or more substituents selected from substituent group A. The compound or a salt thereof according to any one of claims 1 to 6.

8. R ４ is a phenyl group optionally substituted with one or more substituents selected from substituent group A, a pyridyl group optionally substituted with one or more substituents selected from substituent group A, a tetrahydropyranyl group optionally substituted with one or more substituents selected from substituent group A, or a dihydropyranyl group optionally substituted with one or more substituents selected from substituent group A. The compound or a salt thereof according to claim 7,

9. R ８ C which may be substituted with one or more substituents selected from a hydrogen atom, an optionally protected hydroxyl group, an optionally protected amino group, and substituent group A １－６ an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; ３－８ a cycloalkoxy group, C optionally substituted with one or more substituents selected from the substituent group A １－６ an alkylamino group, a di-(C １－６ alkyl)amino group or a group of the general formula SO ２ R ９ The compound according to any one of claims 1 to 8, or a salt thereof.

10. R ９ an optionally protected amino group, C optionally substituted with one or more substituents selected from the substituent group A １－６ C which may be substituted with one or more substituents selected from the alkyl group and the substituent group A ３－８ a cycloalkyl group, C which may be substituted with one or more substituents selected from the substituent group A; １－６ an alkoxy group, C which may be substituted with one or more substituents selected from the substituent group A; ３－８ a cycloalkoxy group, C optionally substituted with one or more substituents selected from the substituent group A １－６ an alkylamino group or a di-(C １－６ The compound or salt thereof according to any one of claims 1 to 9, wherein the aryl group is an alkyl)amino group.

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a salt thereof.

12. An antitumor agent comprising the compound according to any one of claims 1 to 10 or a salt thereof.

13. A dihydroorotate dehydrogenase inhibitor comprising the compound according to any one of claims 1 to 10 or a salt thereof.

14. A compound selected from compound group X or a salt thereof: Compound group X: 6-cyclopropyl-3-((3-(2,6-dimethylpyridin-3-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)pyrazine-2-carboxylic acid, 3-((4'-cyano-2'-methyl-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid, 5-cyclopropyl-2-((3-(tetrahydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinic acid, 5-cyclopropyl-2-((3-(tetrahydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinic acid, -((2-(difluoromethoxy)-5-fluoro-3-(tetrahydro-2H-pyran-4-yl)phenyl)amino)nicotinic acid, 3-((4'-cyano-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid, 5-cyclopropyl-2-((3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinic acid, 2-((4'-cyano-2-(2,2,2-trifluoroethoxy)-[1 ,1'-biphenyl]-3-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)nicotinic acid, 3-((3'-cyano-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid, 5-cyclopropyl-2-((2-ethyl-3-(tetrahydro-2H-pyran-4-yl)phenyl)amino)nicotinic acid carboxylic acid, 3-((4'-cyano-2-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid, 3-((4'-cyano-2-(difluoromethoxy)-5-fluoro-[1,1'-biphenyl]-3-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid, 6-cyclopropyl-3-((4'-fluoro-2-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3-yl)amino)pyrazine-2-carboxylic acid, 5-cyclopropyl-2-((3-(3,6-dihydro-2H-pyran-4-yl)-2-ethoxy-6-fluorophenyl)amino)nicotinic acid, 5-cyclopropyl-2-((3-(3,6-dihydro-2H-pyran-4-yl)-2-ethoxy-4-fluorophenyl)amino)nicotinic acid.

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