Heterocyclic compounds

Abstract

Provided is a compound which has a glucosylceramide synthase-inhibiting activity and is expected to be useful as a prophylactic or therapeutic agent for a lysosomal storage disease (e.g., Gaucher disease, Fabry disease, GM1-gangliosidosis, GM2 activation factor deficiency disease, Tay–Sachs disease, Sandhoff disease), a neurodegenerative disease (e.g., Parkinson's disease, dementia with Lewy bodies, multiple system atrophy) and the like.　The present invention relates to a compound represented by formula (I) [wherein each symbol is as described in the description] or a salt thereof.

Description

[Technical field]

[0001] The present invention relates to a heterocyclic compound that has a glucosylceramide synthase inhibitory effect and is useful for the treatment of lysosomal diseases (e.g., Gaucher disease), neurodegenerative diseases (e.g., Parkinson's disease, dementia with Lewy bodies, multiple system atrophy), and the like, and a medicine containing the same.

[0002] BACKGROUND OF THEINVENTION Glycosphingolipids are formed by the stepwise addition of sugars such as glucose, galactose, N-acetylglucosamine, N-acetylgalactosamine, and sialic acid to ceramide by enzymes. Numerous glycolipid storage diseases, such as lysosomal diseases, have been reported, which develop as a result of accumulation of glycosphingolipids due to mutations in glycosphingolipid decomposition enzymes. Glycosphingolipids are also considered essential for the construction and functioning of nervous system tissues (Non-Patent Document 1), and quantitative and qualitative abnormalities in glycosphingolipids are known to be a cause of neurodegenerative diseases. For these reasons, inhibiting the accumulation of glycosphingolipids may lead to the treatment of these diseases. Glucosylceramide is present in all tissues and cells, and is an important sphingoglycolipid that is a common precursor glycolipid for more than 400 types of glycolipids. Glucosylceramide synthase is an enzyme that synthesizes glucosylceramide from uridine diphosphate glucose and ceramide, and its inhibitors have been proposed for the treatment of various diseases by suppressing the abnormal accumulation of sphingoglycolipids through the suppression of their production (Patent Document 1 and Patent Document 2). For example, it has been reported that sphingoglycolipids accumulate in the substantia nigra at the lesion site in patients with Parkinson's disease, a neurodegenerative disease (Non-Patent Document 2), and it has been proposed that glucosylceramide synthase inhibitors may be therapeutic agents for neurodegenerative diseases such as Parkinson's disease and dementia with Lewy bodies (Non-Patent Document 3). These findings suggest that glucosylceramide synthase inhibitors may be useful as preventive or therapeutic agents for lysosomal diseases (e.g., Gaucher disease, Fabry disease, GM1-gangliosidosis, GM2 activator deficiency, Tay-Sachs disease, Sandhoff disease) and neurodegenerative diseases (e.g., Parkinson's disease, dementia with Lewy bodies, multiple system atrophy).

[0003] As a glucosylceramide synthase inhibitor, Patent Document 1 discloses a compound represented by the following formula:

[0004] [ka]

[0005] (In the formula, each symbol is as defined in Patent Document 1.) In Patent Document 2, a compound represented by the following formula:

[0006] [ka]

[0007] (In the formula, each symbol is as defined in Patent Document 2.) A compound represented by the formula: Furthermore, Non-Patent Document 3 describes the compounds described in Patent Documents 1 and 2. Furthermore, as a compound having a glucosylceramide lowering effect, Patent Document 3 discloses a compound represented by the following formula:

[0008] [ka]

[0009] (In the formula, each symbol is as defined in Patent Document 3.) A compound represented by the formula: Furthermore, the following compounds are known as heterocyclic compounds. Patent Document 4 describes the following formula:

[0010] [ka]

[0011] (In the formula, each symbol is as defined in Patent Document 4.) It is disclosed that a compound represented by the formula: is useful for treating cancer. Patent Document 5 describes the following formula:

[0012] [ka]

[0013] [ka]

[0014] (In the formula, each symbol is as defined in Patent Document 5.) It is disclosed that a compound represented by the formula: is useful for treating cancer. Patent Document 6 describes the following formula:

[0015] [ka]

[0016] [ka]

[0017] (In the formula, each symbol is as defined in Patent Document 6.) It is disclosed that a compound represented by the formula: is useful for treating cancer. Patent Document 7 describes the following formula:

[0018] [ka]

[0019] [ka]

[0020] (In the formula, each symbol is as defined in Patent Document 7.) It is disclosed that a compound represented by the formula: is useful for treating cancer. [Prior art documents] [Patent documents]

[0021] [Patent Document 1] US2016 / 0361301 [Patent Document 2] US2015 / 0210681 [Patent Document 3] WO2019 / 151269 [Patent Document 4] US8445509 [Patent Document 5] US2005 / 0288290 [Patent Document 6] US7439246 [Patent Document 7] US2006 / 0004006 [Non-patent literature]

[0022] [Non-Patent Document 1] Brain Res Bull 24, 131-141 [Non-Patent Document 2] Ann Clin Transl Neurol. 2015 Apr; 2(4): 433-438 [Non-Patent Document 3] Proceedings of the National Academy of Sciences of the United States of America (2017), 114(10), 2699-2704 Summary of the Invention [Problem to be solved by the invention]

[0023] An object of the present invention is to provide a compound which has a glucosylceramide synthase inhibitory activity and is useful as an agent for the prevention or treatment of lysosomal diseases (e.g., Gaucher disease), neurodegenerative diseases (e.g., Parkinson's disease, dementia with Lewy bodies, multiple system atrophy), and the like. [Means for solving the problem]

[0024] As a result of intensive research aimed at solving the above-mentioned problems, the present inventors have found that a compound represented by the following formula (I) has a glucosylceramide synthase inhibitory effect and is therefore useful as an agent for the prevention or treatment of lysosomal diseases (e.g., Gaucher disease), neurodegenerative diseases (e.g., Parkinson's disease, dementia with Lewy bodies, multiple system atrophy), and the like, and have completed the present invention.

[0025] That is, the present invention is as follows. (1) Formula (I):

[0026] [ka]

[0027] [During the ceremony, X 1 indicates C or N, X 2 indicates C or N,

[0028] [ka]

[0029] represents a single or double bond, Ring A is an optionally further substituted 5- or 6-membered aromatic ring; R 1 is a C substituted with a chlorine atom, a bromine atom, an iodine atom, a cyano group, or one to five fluorine atoms. 1-6 represents an alkyl group, an optionally substituted hydroxy group, an optionally substituted amino group, or an optionally substituted cyclic group, Y 1 CR a (R a represents no group, a hydrogen atom or a substituent, or N; Y 2 CR b R c (R b is a hydrogen atom or a substituent, R c represents no group, a hydrogen atom, or a substituent) or NR d (R d represents no group or a hydrogen atom or a substituent; Y 3 CR e R f (R e is a hydrogen atom or a substituent, R f represents no group, a hydrogen atom, or a substituent) or NR g (R g represents no group or a hydrogen atom or a substituent; Ring B represents a 6-membered ring; R 2 teeth,

[0030] [ka]

[0031] indicates, Z 1 CR h (R h represents a hydrogen atom or a substituent) or N, Z 2 CR i (R i represents a hydrogen atom or a substituent) or N, Z 3 CR j (R j represents a hydrogen atom or a substituent) or N, Z 4 CR k (R k represents a hydrogen atom or a substituent) or N, Z 5indicates C or N, Z 6 CR l (R l represents a hydrogen atom or a substituent) or N, Z 7 CR m (R m represents a hydrogen atom or a substituent) or N, Z 8 CR n (R n represents a hydrogen atom or a substituent) or N, Z 9 indicates C or N, Z 10 indicates C or N, Z 11 CR o (R o represents a hydrogen atom or a substituent), NR p (R p represents no group or a hydrogen atom or a substituent, O or S; Z 12 indicates C or N, Z 13 CR q (R q represents a hydrogen atom or a substituent), NR r (R r represents no group or a hydrogen atom or a substituent, O or S; Z 14 CR s (R s represents a hydrogen atom or a substituent), NR t (R t represents no group or a hydrogen atom or a substituent, O or S; Z 15 indicates C or N, Z 16 CR u (R u represents a hydrogen atom or a substituent), NR v (R v represents no group or a hydrogen atom or a substituent, O or S; Z 17 indicates C or N, Z 18 CR w (R w represents a hydrogen atom or a substituent), NR x (R x represents no group or a hydrogen atom or a substituent, O or S; Z 19 indicates C or N, Ring C 1 and ring C 2 each independently represents a 6-membered aromatic ring, Ring C 3 represents an optionally substituted ring, R 3 represents a halogen atom, a cyano group, an optionally substituted C 1-6 Alkyl group, optionally substituted cyclic group, optionally substituted amino group, SO2R 7 OR 8 indicates, R 7 represents a substituent, R 8 is a hydrogen atom, optionally substituted C 1-6 represents an alkyl group, an optionally substituted saturated ring group, or an optionally substituted monocyclic unsaturated ring group, Ring D 1 and ring D 2 each independently represents a 5-membered aromatic ring, Ring D 3 represents an optionally substituted ring, R 4 represents a substituent; or a salt thereof;

[0032] (2)X 1 is C or N; X 2 But C; Ring A is R 1 and the formula:

[0033] [ka]

[0034] (wherein each symbol has the same meaning as in (1)).) In addition to the group represented by the formula: (1) halogen atoms, and (2) C 1-6 a 5- or 6-membered aromatic ring optionally further substituted with 1 to 3 substituents selected from an alkyl group; R 1 but, (1) a cyano group, (2) C substituted with 1 to 5 fluorine atoms 1-6 Alkyl groups, (3)(i) a halogen atom, (ii) a hydroxy group, and (iii) C 1-6 C optionally substituted with 1 to 5 substituents selected from an alkoxy group 1-6 an alkoxy group, or (4) a 3- to 8-membered monocyclic non-aromatic heterocyclic group; Y 1 is C or N; Y 2 But, CR b' (R b' is (1) a hydrogen atom, or (2) C 1-6 represents an alkyl group), or N; Y 3 But, CR e' (R e' is (1) a hydrogen atom, (2) a C 1-6 Alkyl group, (3) C 1-6 an alkyl-carbonyl group, or (4) C 1-6 alkoxy-carbonyl group), or NR g' (R g' is (1) absent or (2) C optionally substituted by 1 to 5 substituents selected from (i) a halogen atom, (ii) a hydroxy group, and (iii) a 3- to 8-membered monocyclic non-aromatic heterocyclic group. 1-6 Alkyl group, (3) C 3-6 (4) a 3- to 8-membered monocyclic non-aromatic heterocyclic group; and R 2 But the formula:

[0035] [ka]

[0036] [During the ceremony, Z 1' CR h' (R h' is a hydrogen atom, a halogen atom or C 1-6 represents an alkyl group) or N, Z 2' CR i' (R i' is a hydrogen atom, a halogen atom, a cyano group, C 1-6 Alkyl group or C 1-6 represents an alkoxy group) or N, Z 3' CR j' (R j' represents a hydrogen atom or a halogen atom) or N, Z 4' indicates CH or N, Z 5' indicates N, Z 6' indicates CH, Z 7' indicates CH, Z 8' indicates CH, Z 9' indicates C, Z 10' indicates C or N, Z 11' represents CH, N or S, Z 12' indicates C, Z 13' indicates CH or N, Z 14' CR s' (R s' is a hydrogen atom or optionally halogenated C 1-6 represents an alkyl group), N or O; Ring C 1' represents a six-membered aromatic ring, Ring C 2' represents a six-membered aromatic ring, Ring C 3' represents a five-membered ring, R 3' teeth, (1) a halogen atom, (2) a cyano group, (3) (i) a halogen atom, (ii) a cyano group, (iii) a hydroxy group, or (iv) C 3-6 (v) optionally halogenated cycloalkyl groups; 1-6 (vi) an alkoxy group, (vii) a 3- to 8-membered monocyclic non-aromatic heterocyclic group, and (vii) an oxo group, 1-6 Alkyl groups, (4) C 2-6 Alkenyl groups, (5) a cyclic group optionally substituted with 1 to 3 hydroxy groups, or (6) OR 8' (R 8' is (a) (i) a halogen atom, (ii) a hydroxy group, and (iii) C 3-6 C optionally substituted with 1 to 3 substituents selected from cycloalkyl groups 1-6 an alkyl group, or (b) C 6-10 aryl group), Ring D 1' represents a five-membered aromatic ring, and R 4' teeth, (1) (i) a halogen atom, (ii) a C optionally substituted by 1 to 3 halogen atoms 3-6 and (iii) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 halogen atoms. 1-6 Alkyl groups, (2) C 3-6 Cycloalkyl groups, (3) C optionally substituted by 1 to 3 halogen atoms 6-10 Aryl groups, (4) C 1-6 an alkoxy-carbonyl group, or (5) A 3- to 8-membered monocyclic non-aromatic heterocyclic group. The compound according to (1) or a salt thereof, wherein

[0037] (3) X 1 But C; X 2 But C; Ring A is R 1 and the formula:

[0038] [ka]

[0039] (wherein each symbol has the same meaning as in (1)).) is a benzene ring which may be further substituted with 1 to 3 halogen atoms in addition to the group represented by the formula: R 1 is substituted with 1 to 5 halogen atoms 1-6 is an alkoxy group; Y 1 is C or N; Y 2 is N; Y 3 But, CR e' (R e' is (1) a hydrogen atom, or (2) C 1-6 alkyl group), or NR g'' (R g'' (1) C optionally substituted with 1 to 5 substituents selected from (i) a halogen atom, and (ii) a hydroxy group 1-6 an alkyl group, or (2) C 3-6 is a cycloalkyl group; and R 2 But, the formula

[0040] [ka]

[0041] [During the ceremony, Z1' is CH or N, Z 2' is CH or CF, Z 3' is CH, Z 4' is CH, and R 3' C, which may be substituted with 1 to 5 substituents selected from a halogen atom and a hydroxy group; 1-6 is an alkyl group. The compound according to (1) or a salt thereof, wherein

[0042] (4) N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide or a salt thereof; (5) 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide or a salt thereof; (6) 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide or a salt thereof;

[0043] (7) A medicine comprising the compound according to (1) or a salt thereof; (8) The pharmaceutical agent according to (7), which is a glucosylceramide synthase inhibitor; (9) The pharmaceutical agent according to (7), which is an agent for preventing or treating a lysosomal disease or a neurodegenerative disease; (10) The pharmaceutical composition according to (9), wherein the lysosomal disease is Gaucher disease, Fabry disease, GM1-gangliosidosis, GM2 activator deficiency, Tay-Sachs disease, or Sandhoff disease; (11) The pharmaceutical composition according to (9), wherein the neurodegenerative disease is Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy;

[0044] (12) The compound or salt thereof according to (1) for use in the prevention or treatment of a lysosomal disease or a neurodegenerative disease; (13) The compound or salt according to (12), wherein the lysosomal disease is Gaucher disease, Fabry disease, GM1-gangliosidosis, GM2 activator deficiency, Tay-Sachs disease, or Sandhoff disease; (14) The compound or salt according to (12) above, wherein the neurodegenerative disease is Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy;

[0045] (15) A method for inhibiting glucosylceramide synthase in a mammal, comprising administering to the mammal an effective amount of the compound according to (1) or a salt thereof; (16) A method for preventing or treating a lysosomal disease or a neurodegenerative disease in a mammal, comprising administering to the mammal an effective amount of the compound according to (1) or a salt thereof; (17) The method according to (16), wherein the lysosomal disease is Gaucher disease, Fabry disease, GM1-gangliosidosis, GM2 activator deficiency, Tay-Sachs disease, or Sandhoff disease; (18) The method according to (16), wherein the neurodegenerative disease is Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy;

[0046] (19) Use of the compound or a salt thereof according to (1) for the manufacture of an agent for the prophylaxis or treatment of a lysosomal disease or a neurodegenerative disease; (20) The use according to (19), wherein the lysosomal disease is Gaucher disease, Fabry disease, GM1-gangliosidosis, GM2 activator deficiency, Tay-Sachs disease, or Sandhoff disease; and (21) The use according to (19), wherein the neurodegenerative disease is Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Effect of the Invention

[0047] According to the present invention, it is possible to provide a compound which has excellent glucosylceramide synthase inhibitory activity and is useful as an agent for preventing or treating lysosomal diseases (e.g., Gaucher disease), neurodegenerative diseases (e.g., Parkinson's disease, dementia with Lewy bodies, multiple system atrophy), etc.

[0048] Detailed Description of the Invention The present invention will be described in detail below.

[0049] The definition of each substituent used in the present specification is described in detail below. Unless otherwise specified, each substituent has the following definition. In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine. In this specification, "C 1-6 Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. In the present specification, "optionally halogenated C 1-6 The alkyl group may, for example, be a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of the alkyl group include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl. In this specification, "C 2-6Examples of the "alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl. In this specification, "C 2-6 Examples of the "alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl. In this specification, "C 3-10 Examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl. In the present specification, "optionally halogenated C 3-10 The "cycloalkyl group" is, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 3-10 Specific examples of the cycloalkyl group include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In this specification, "C 3-10 Examples of the "cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. In this specification, "C 6-14 The "aryl group" includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl. In this specification, "C 7-16The aralkyl group includes, for example, benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0050] In this specification, "C 1-6 Examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. In the present specification, "optionally halogenated C 1-6 The "alkoxy group" is, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of the alkoxy group include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy. In this specification, "C 3-10 Examples of the "cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy. In this specification, "C 1-6 Examples of the "alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio. In the present specification, "optionally halogenated C 1-6 The "alkylthio group" includes, for example, C alkylthio groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of the alkylthio group include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio. In this specification, "C 1-6Examples of the "alkyl-carbonyl group" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl. In the present specification, "optionally halogenated C 1-6 The "alkyl-carbonyl group" includes, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Examples of the alkyl-carbonyl group include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl. In this specification, "C 1-6 Examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl. In this specification, "C 6-14 The "aryl-carbonyl group" includes, for example, benzoyl, 1-naphthoyl, and 2-naphthoyl. In this specification, "C 7-16 The "aralkyl-carbonyl group" includes, for example, phenylacetyl and phenylpropionyl.

[0033] In the present specification, examples of the "5- to 14-membered aromatic heterocyclyl carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0043] In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0051] As used herein, "mono- or di-C 1-6 The "alkyl-carbamoyl group" includes, for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl. As used herein, "mono- or di-C 7-16 The "aralkyl-carbamoyl group" includes, for example, benzylcarbamoyl and phenethylcarbamoyl. In this specification, "C 1-6 Examples of the "alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl. In the present specification, "optionally halogenated C 1-6 The "alkylsulfonyl group" includes, for example, C alkylsulfonyl groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl. In this specification, "C 6-14 The "arylsulfonyl group" includes, for example, phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0052] In the present specification, examples of the "substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group, and an optionally substituted silyl group. In the present specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") include, for example, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Examples of such groups include aralkyl groups.

[0053] In the present specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group which may have a substituent selected from the following Substituent Group A. [Substituent group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) Optionally halogenated C 1-6 Alkoxy groups, (7) C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., morpholinyloxy, piperidinyloxy), (11) C 1-6 Alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy), (12) C 6-14 Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13) C 1-6 Alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) Mono- or di-C 1-6 Alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy); (15) C 6-14 Aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy); (16) 5- to 14-membered aromatic heterocyclylcarbonyloxy groups (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) Optionally halogenated C 1-6 Alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19)C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) Optionally halogenated C 1-6 Alkylthio groups, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) Optionally halogenated C 1-6 Alkyl-carbonyl groups, (26)C 6-14 Aryl-carbonyl groups, (27) a 5- to 14-membered aromatic heterocyclic carbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group, (29)C 1-6 Alkoxy-carbonyl groups, (30)C 6-14 Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl); (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) Mono- or di-C 1-6 Alkyl-carbamoyl groups, (35)C6-14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl), (36) 5- to 14-membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) Optionally halogenated C 1-6 Alkylsulfonyl groups, (39)C 6-14 Arylsulfonyl groups, (40) 5- to 14-membered aromatic heterocyclylsulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl), (41) Optionally halogenated C 1-6 an alkylsulfinyl group, (42)C 6-14 Arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) 5- to 14-membered aromatic heterocyclylsulfinyl groups (e.g., pyridylsulfinyl, thienylsulfinyl), (44) an amino group, (45) Mono- or di-C 1-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino); (46) Mono- or di-C 6-14 Arylamino groups (e.g., phenylamino), (47) 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), (48)C 7-16 aralkylamino groups (e.g., benzylamino), (49) a formylamino group, (50)C 1-6 Alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino), (51)(C 1-6 Alkyl)(C 1-6alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino); (52)C 6-14 Aryl-carbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino); (53)C 1-6 alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino); (54)C 7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55)C 1-6 Alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonylamino groups (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) Optionally halogenated C 1-6 Alkyl groups, (58)C 2-6 Alkenyl groups, (59)C 2-6 Alkynyl groups, (60)C 3-10 Cycloalkyl groups, (61)C 3-10 Cycloalkenyl groups, and (62)C 6-14 Aryl groups.

[0054] The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different. In the present specification, examples of the "heterocyclic group" (including the "heterocyclic group" in "optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered bridged heterocyclic group, each of which contains, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0055] In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0056] In the present specification, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl ... 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as isoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexyl Examples of such 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups include tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0057] In the present specification, preferable examples of the "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl. In the present specification, the term "nitrogen-containing heterocyclic group" includes "heterocyclic groups" which contain at least one nitrogen atom as a ring-constituting atom. In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group which may have a substituent selected from the above-mentioned Substituent group A. The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0058] As used herein, the term "acyl group" refers to, for example, a halogen atom, an optionally halogenated C 1-6 C optionally has 1 to 3 substituents selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group; 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Examples of the heterocyclic group include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, and a phosphono group, each of which optionally has "1 or 2 substituents selected from an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, and a 3- to 14-membered non-aromatic heterocyclic group." Further, the "acyl group" also includes a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group. Here, the term "hydrocarbon-sulfonyl group" refers to a sulfonyl group having a hydrocarbon group bonded thereto, the term "heterocycle-sulfonyl group" refers to a sulfonyl group having a heterocyclic group bonded thereto, the term "hydrocarbon-sulfinyl group" refers to a sulfinyl group having a hydrocarbon group bonded thereto, and the term "heterocycle-sulfinyl group" refers to a sulfinyl group having a heterocyclic group bonded thereto. Suitable examples of the "acyl group" include a formyl group, a carboxy group, and C 1-6 Alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl group (e.g., crotonoyl), C 3-10Cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (e.g., pyridylthiocarbamoyl), sulfino group, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1-6 Alkylsulfonyl group, C 6-14 Arylsulfonyl group, phosphono group, mono- or di-C 1-6 Examples of the alkylphosphono group include dimethylphosphono, diethylphosphono, diisopropylphosphono, and dibutylphosphono groups.

[0059] As used herein, the term "optionally substituted amino group" refers to, for example, "amino group optionally having 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and an arylsulfonyl group, optionally having 1 or 2 substituents selected from the group consisting of arylsulfonyl groups. Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C 1-6 alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6Alkenylamino groups (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino groups (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino groups (e.g., phenylamino), mono- or di-C 7-16 Aralkylamino groups (e.g., benzylamino, dibenzylamino), mono- or di-(optionally halogenated C 1-6 Alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonylamino group (e.g., benzoylamino), mono- or di-C 7-16 Aralkyl-carbonylamino group (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), carbamoylamino group, (mono- or di-C 1-6 Alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or di-C 7-16 aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C 1-6 Alkyl sulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 Arylsulfonylamino group (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 Alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), (C 1-6 Alkyl)(C 6-14 aryl-carbonyl)amino groups (e.g., N-benzoyl-N-methylamino).

[0060] As used herein, examples of the "optionally substituted carbamoyl group" include "carbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and aralkyl-carbamoyl groups, which may have 1 or 2 substituents selected from the group consisting of aryl, arylalkyl, and arylcarbamoyl. Suitable examples of the optionally substituted carbamoyl group include carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Examples of the aryl-carbonyl-carbamoyl group include aryl-carbonyl-carbamoyl groups (eg, benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

[0061] As used herein, examples of the "optionally substituted thiocarbamoyl group" include "thiocarbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and thiocarbamoyl groups which may have 1 or 2 substituents selected from aralkyl-carbamoyl groups. Suitable examples of the optionally substituted thiocarbamoyl group include thiocarbamoyl groups, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14Examples of such groups include aryl-carbonyl-thiocarbamoyl groups (eg, benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

[0062] As used herein, examples of the "optionally substituted sulfamoyl group" include "a sulfamoyl group which may optionally have 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and an aralkyl-carbamoyl group, which may have 1 or 2 substituents selected from the group consisting of aryl, arylalkyl, and arylcarbamoyl. Suitable examples of the optionally substituted sulfamoyl group include sulfamoyl groups, mono- or di-C 1-6 Alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), mono- or di-C 3-10 Cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl group (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C 1-6Alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-sulfamoyl groups (eg, benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridylsulfamoyl).

[0063] In the present specification, examples of the "optionally substituted hydroxy group" include "a hydroxy group which may have 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and arylsulfonyl groups, each of which may have a substituent selected from the group consisting of arylsulfonyl groups and arylsulfonyl groups. Preferable examples of the optionally substituted hydroxy group include a hydroxy group, C 1-6 Alkoxy group, C 2-6 Alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 Cycloalkyloxy group (e.g., cyclohexyloxy), C 6-14 Aryloxy groups (e.g., phenoxy, naphthyloxy), C 7-16 Aralkyloxy group (e.g., benzyloxy, phenethyloxy), C 1-6Alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 Aryl-carbonyloxy group (e.g., benzoyloxy), C 7-16 Aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), carbamoyloxy group, C 1-6 Alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), C 7-16 Aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), C 1-6 Alkyl sulfonyloxy group (e.g., methyl sulfonyloxy, ethyl sulfonyloxy), C 6-14 Arylsulfonyloxy groups (eg, phenylsulfonyloxy) are included.

[0064] As used herein, examples of the "optionally substituted sulfanyl group" include "a sulfanyl group which may have 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 and a halogenated sulfanyl group, which may have a substituent selected from an aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group. Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (-SH) group, 1-6 Alkylthio group, C 2-6 Alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10Cycloalkylthio groups (e.g., cyclohexylthio), C 6-14 Arylthio groups (e.g., phenylthio, naphthylthio), C 7-16 Aralkylthio groups (e.g., benzylthio, phenethylthio), C 1-6 Alkyl-carbonylthio groups (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 Examples of such groups include aryl-carbonylthio groups (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (eg, pyridylthio), and halogenated thio groups (eg, pentafluorothio).

[0065] In the present specification, examples of the "optionally substituted silyl group" include "a silyl group which optionally has 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl groups and C 7-16 and aralkyl groups. Suitable examples of the optionally substituted silyl group include tri-C 1-6 Examples of the silyl groups include alkylsilyl groups (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0066] In the present specification, examples of the "hydrocarbon ring" include C 6-14 Aromatic hydrocarbon ring, C 3-10 Cycloalkane, C 3-10 Cycloalkenes are mentioned. In this specification, "C 6-14 The aromatic hydrocarbon ring includes, for example, benzene and naphthalene. In this specification, "C 3-10 Examples of the "cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. In this specification, "C 3-10Examples of the "cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene. In the present specification, examples of the "heterocycle" include aromatic heterocycles and non-aromatic heterocycles each containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms.

[0067] In the present specification, examples of the "aromatic heterocycle" include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms. Preferable examples of the "aromatic heterocycle" include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine and 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocycles such as benzene, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0068] In the present specification, examples of the "non-aromatic heterocycle" include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, and oxepane; Examples of the heterocyclic ring include 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline. In the present specification, the "nitrogen-containing heterocycle" includes a "heterocycle" containing at least one nitrogen atom as a ring-constituting atom.

[0069] In the present specification, the "5- or 6-membered aromatic ring" includes a benzene ring and a "5- or 6-membered monocyclic aromatic heterocycle". In the present specification, the "5-membered aromatic ring" includes a 5-membered one among "5- or 6-membered monocyclic aromatic heterocycles". In the present specification, the term "six-membered aromatic ring" includes a benzene ring and a six-membered one of "five- or six-membered monocyclic aromatic heterocycles". In the present specification, the term "saturated ring group" refers to "C 3-10 Among "cycloalkyl groups" and "non-aromatic heterocyclic groups", saturated ones are included. In the present specification, the term "monocyclic unsaturated ring group" includes a phenyl group, 3-10 Examples of the unsaturated heterocyclic group include "a cycloalkenyl group," "a 5- or 6-membered monocyclic aromatic heterocyclic group," and "a 3- to 8-membered monocyclic non-aromatic heterocyclic group." In the present specification, the term "cyclic group" refers to a group including "C 3-10 Cycloalkyl group, C 3-10 Cycloalkenyl group, C 6-14 "aryl groups" and "heterocyclic groups." In the present specification, the "ring" includes a "hydrocarbon ring" and a "heterocycle".

[0070] The definition of each symbol in formula (I) is explained in detail below.

[0071] X 1 indicates C or N. Among them, X 1 As the group, C is preferable.

[0072] X 2 indicates C or N. Among them, X 2 As the group, C is preferable.

[0073] [ka]

[0074] represents a single bond or a double bond.

[0075] Ring A is an optionally further substituted 5- or 6-membered aromatic ring. The "5- or 6-membered aromatic ring" of the "optionally further substituted 5- or 6-membered aromatic ring" represented by ring A is R 1 and the formula:

[0076] [ka]

[0077] (wherein each symbol has the same meaning as defined above). In addition to the group represented by the formula (I), it may be further substituted, and examples of the substituent include those similar to those in the substituent group A, and it may have 1 to 4 substituents at substitutable positions. Among them, ring A is R 1 and the formula:

[0078] [ka]

[0079] (wherein each symbol has the same meaning as defined above). In addition to the group represented by (1) Halogen atoms (e.g., fluorine atoms), and (2) C 1-6 Alkyl group (e.g., methyl) and a 5- or 6-membered aromatic ring (eg, a pyrazole ring, a benzene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring) which may be further substituted by 1 to 3 substituents selected from the above. Ring A is, in particular, R 1 and the formula:

[0080] [ka]

[0081] (wherein each symbol has the same meaning as defined above). In addition to the group represented by the following formula, a benzene ring which may be further substituted with 1 to 3 halogen atoms (eg, fluorine atoms) is preferred.

[0082] R 1 is a C substituted with (1) a chlorine atom, (2) a bromine atom, (3) an iodine atom, (4) a cyano group, or (5) one to five fluorine atoms. 1-6 (6) an optionally substituted hydroxy group, (7) an optionally substituted amino group, or (8) an optionally substituted cyclic group. R 1 Examples of the substituent in the "optionally substituted cyclic group" represented by the following formula (1) include the same as those in the substituent group A, and the group may have 1 to 3 substituents at substitutable positions.

[0083] Among them, R 1 As for the following: (1) a cyano group, (2) C substituted with 1 to 5 fluorine atoms 1-6 Alkyl groups (e.g., 3,3,3-trifluoropropyl), (3)(i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, and (iii) C 1-6 Alkoxy groups (e.g., methoxy) C optionally substituted with 1 to 5 substituents selected from 1-6 an alkoxy group (e.g., methoxy, ethoxy, propoxy, isobutoxy), or (4) 3- to 8-membered monocyclic non-aromatic heterocyclic groups (e.g., morpholinyl, tetrahydropyranyl) is preferred. R 1 Examples of the halogen atom include, in particular, C substituted with 1 to 5 halogen atoms (e.g., fluorine atoms). 1-6 Alkoxy groups (eg, ethoxy) are preferred.

[0084] Y 1 CR a (R ais absent, represents a hydrogen atom or a substituent) or represents N. Among them, Y 1 As the substituent, C or N is preferable.

[0085] Y 2 CR b R c (R b is a hydrogen atom or a substituent, R c represents no group, a hydrogen atom, or a substituent) or NR d (R d represents either absent or a hydrogen atom or a substituent. Among them, Y 2 As for CR b' (R b' is (1) a hydrogen atom, or (2) C 1-6 An alkyl group (eg, methyl) or N is preferred. Y 2 As the group, N is particularly preferable.

[0086] Y 3 CR e R f (R e is a hydrogen atom or a substituent, R f represents no group, a hydrogen atom, or a substituent) or NR g (R g represents either absent or a hydrogen atom or a substituent. Among them, Y 3 As for CR e' (R e' is (1) a hydrogen atom, (2) a C 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), (3) C 1-6 Alkyl-carbonyl group (e.g., acetyl), or (4) C 1-6 alkoxy-carbonyl group (e.g., ethoxycarbonyl), or NR g' (R g'is (1) absent or (2) optionally substituted by 1 to 5 substituents selected from (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, and (iii) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl). 1-6 Alkyl groups (e.g., methyl, ethyl, isobutyl), (3) C 3-6 A cycloalkyl group (eg, cyclopropyl), or (4) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, oxetanyl, tetrahydrofuryl) is preferred. Y 3 In particular, CR e' (R e' is (1) a hydrogen atom, or (2) C 1-6 an alkyl group (e.g., methyl), or NR g'' (R g'' (1) C optionally substituted with 1 to 5 substituents selected from (i) a halogen atom (e.g., a fluorine atom), and (ii) a hydroxy group 1-6 (2) an alkyl group (e.g., methyl), or 3-6 Cycloalkyl groups (eg, cyclopropyl) are preferred.

[0087] Ring B represents a 6-membered ring.

[0088] [ka]

[0089] (wherein each symbol has the same meaning as defined above). Particularly, the partial structure represented by the formula:

[0090] [ka]

[0091] [During the ceremony, Y 1’ indicates C or N, Y 2’ CR b' (Rb' is (1) a hydrogen atom, or (2) C 1-6 Represents an alkyl group (e.g., methyl) or N, and Y 3’ CR e' (R e' is (1) a hydrogen atom, or (2) C 1-6 Indicates an alkyl group (e.g., methyl) or NR g' (R g' is (1) absent or (2) C optionally substituted with 1 to 5 substituents selected from (i) a halogen atom (e.g., a fluorine atom), and (ii) a hydroxy group. 1-6 (3) an alkyl group (e.g., methyl, isobutyl), or 3-6 It represents a cycloalkyl group (e.g., cyclopropyl). A partial structure represented by the following formula is preferred. As the partial structure, the following partial structure is particularly preferable.

[0092] [ka]

[0093] As the partial structure, the following partial structure is particularly preferable.

[0094] [ka]

[0095] R 2 teeth,

[0096] [ka]

[0097] indicates, Z 1 CR h (R h represents a hydrogen atom or a substituent) or N, Z 2 CRi (R i represents a hydrogen atom or a substituent) or N, Z 3 CR j (R j represents a hydrogen atom or a substituent) or N, Z 4 CR k (R k represents a hydrogen atom or a substituent) or N, Z 5 indicates C or N, Z 6 CR l (R l represents a hydrogen atom or a substituent) or N, Z 7 CR m (R m represents a hydrogen atom or a substituent) or N, Z 8 CR n (R n represents a hydrogen atom or a substituent) or N, Z 9 indicates C or N, Z 10 indicates C or N, Z 11 CR o (R o represents a hydrogen atom or a substituent), NR p (R p represents no group or a hydrogen atom or a substituent, O or S; Z 12 indicates C or N, Z 13 CR q (R q represents a hydrogen atom or a substituent), NR r (R r represents no group or a hydrogen atom or a substituent, O or S; Z 14 CR s (R s represents a hydrogen atom or a substituent), NR t (R trepresents no group or a hydrogen atom or a substituent, O or S; Z 15 indicates C or N, Z 16 CR u (R u represents a hydrogen atom or a substituent), NR v (R v represents no group or a hydrogen atom or a substituent, O or S; Z 17 indicates C or N, Z 18 CR w (R w represents a hydrogen atom or a substituent), NR x (R x represents no group or a hydrogen atom or a substituent, O or S; Z 19 indicates C or N, Ring C 1 and ring C 2 each independently represents a 6-membered aromatic ring, Ring C 3 represents an optionally substituted ring, R 3 represents a halogen atom, a cyano group, an optionally substituted C 1-6 Alkyl group, optionally substituted cyclic group, optionally substituted amino group, SO2R 7 OR 8 indicates, R 7 represents a substituent, R 8 is a hydrogen atom, optionally substituted C 1-6 represents an alkyl group, an optionally substituted saturated ring group, or an optionally substituted monocyclic unsaturated ring group, Ring D 1 and ring D 2 each independently represents a 5-membered aromatic ring, Ring D 3 represents an optionally substituted ring, R 4 indicates a substituent.

[0098] Ring C3 Examples of the substituent in the "optionally substituted ring" represented by the following formula (1) include the same as those in the substituent group A, and the ring may have 1 to 3 substituents at substitutable positions. R 3 "Optionally substituted C 1-6 The substituents in the "alkyl group" and the "optionally substituted cyclic group" include the same as those in the substituent group A, and the group may have 1 to 8 substituents at substitutable positions. R 8 "Optionally substituted C 1-6 The substituents in the "alkyl group," "optionally substituted saturated cyclic group," and "optionally substituted monocyclic unsaturated cyclic group" include the same as those in Substituent Group A, and the group may have 1 to 5 substituents at substitutable positions. Ring D 3 Examples of the substituent in the "optionally substituted ring" represented by the following formula (1) include the same as those in the substituent group A, and the ring may have 1 to 3 substituents at substitutable positions.

[0099] R 2 As for the following:

[0100] [ka]

[0101] (wherein each symbol has the same meaning as defined above). is preferred.

[0102] R 2 In particular,

[0103] [ka]

[0104] [During the ceremony, Z 1' CR h' (R h' is a hydrogen atom, a halogen atom (e.g., a fluorine atom) or C1-6 Represents an alkyl group (e.g., methyl) or N, Z 2' CR i' (R i' is a hydrogen atom, a halogen atom (e.g., a fluorine atom, a chlorine atom), a cyano group, C 1-6 Alkyl group (e.g., methyl) or C 1-6 represents an alkoxy group (e.g., methoxy) or N; Z 3' CR j' (R j' represents a hydrogen atom or a halogen atom (e.g., a fluorine atom) or N, Z 4' indicates CH or N, Z 5' indicates N, Z 6' indicates CH, Z 7' indicates CH, Z 8' indicates CH, Z 9' indicates C, Z 10' indicates C or N, Z 11' represents CH, N or S, Z 12' indicates C, Z 13' indicates CH or N, Z 14' CR s' (R s' is a hydrogen atom or optionally halogenated C 1-6 represents an alkyl group (e.g., trifluoromethyl), N or O; Ring C 1' represents a six-membered aromatic ring (e.g., a benzene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring), Ring C 2' represents a six-membered aromatic ring (e.g., a pyridine ring), Ring C 3' represents a five-membered ring (e.g., an imidazole ring), R 3' teeth, (1) Halogen atoms (e.g., fluorine atoms, chlorine atoms), (2) a cyano group, (3) (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, (iii) a hydroxy group, (iv) C 3-6 Cycloalkyl groups (e.g., cyclopropyl), (v) optionally halogenated C 1-6 C optionally substituted by 1 to 8 substituents selected from an alkoxy group (e.g., methoxy, ethoxy, 2,2,2-trifluoroethoxy), (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholinyl, piperidinyl), and (vii) an oxo group. 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl, isobutyl), (4) C 2-6 Alkenyl groups (e.g., propenyl), (5) A cyclic group (C 3-6 a cycloalkyl group (e.g., cyclopropyl, cyclobutyl), a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl, tetrahydrofuryl, morpholinyl), or (6) OR 8' (R 8' teeth, (a) (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, and (iii) C 3-6 C optionally substituted with 1 to 3 substituents selected from cycloalkyl groups (e.g., cyclopropyl) 1-6 an alkyl group (e.g., methyl, ethyl, propyl, isobutyl), or (b) C 6-10 Indicates an aryl group (e.g., phenyl) indicates, Ring D 1' represents a 5-membered aromatic ring (e.g., a pyrazole ring, an isoxazole ring, a thiophene ring), and R 4' teeth, (1) (i) a halogen atom (e.g., a fluorine atom), (ii) a C optionally substituted with 1 to 3 halogen atoms (e.g., a fluorine atom) 3-6C optionally substituted by 1 to 5 substituents selected from a cycloalkyl group (e.g., cyclopropyl), and (iii) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms). 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isobutyl, tert-butyl), (2) C 3-6 cycloalkyl groups (e.g., cyclopropyl); (3) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 6-10 Aryl groups (e.g., phenyl), (4) C 1-6 an alkoxy-carbonyl group (e.g., ethoxycarbonyl), or (5) 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl) Showing A group represented by the following formula is preferred.

[0105] R 2 In particular,

[0106] [ka]

[0107] [During the ceremony, Z 1' is CH or N, Z 2' is CH or CF, Z 3' is CH, Z 4' is CH, and R 3' may be substituted with 1 to 5 substituents selected from a halogen atom (e.g., a fluorine atom) and a hydroxy group; 1-6 an alkyl group (e.g., isopropyl) A group represented by the following formula is preferred.

[0108] As compound (I), the following compounds are preferred: [Compound (I-1)] X 1 is C or N; X 2 But C; Ring A is R 1 and the formula:

[0109] [ka]

[0110] (wherein each symbol has the same meaning as defined above). In addition to the group represented by (1) Halogen atoms (e.g., fluorine atoms), and (2) C 1-6 Alkyl group (e.g., methyl) a 5- or 6-membered aromatic ring (e.g., a pyrazole ring, a benzene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring) optionally further substituted by 1 to 3 substituents selected from R 1 but, (1) a cyano group, (2) C substituted with 1 to 5 fluorine atoms 1-6 Alkyl groups (e.g., 3,3,3-trifluoropropyl), (3)(i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, and (iii) C 1-6 Alkoxy groups (e.g., methoxy) C optionally substituted with 1 to 5 substituents selected from 1-6 an alkoxy group (e.g., methoxy, ethoxy, propoxy, isobutoxy), or (4) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholinyl, tetrahydropyranyl); Y 1 is C or N; Y 2 But, CR b' (R b' is (1) a hydrogen atom, or (2) C 1-6represents an alkyl group (e.g., methyl), or N; Y 3 But, CR e' (R e' is (1) a hydrogen atom, (2) a C 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), (3) C 1-6 Alkyl-carbonyl group (e.g., acetyl), or (4) C 1-6 alkoxy-carbonyl group (e.g., ethoxycarbonyl), or NR g' (R g' is (1) absent or (2) optionally substituted by 1 to 5 substituents selected from (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, and (iii) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl). 1-6 Alkyl groups (e.g., methyl, ethyl, isobutyl), (3) C 3-6 (4) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl, tetrahydrofuryl); and R 2 But the formula:

[0111] [ka]

[0112] [During the ceremony, Z 1' CR h' (R h' is a hydrogen atom, a halogen atom (e.g., a fluorine atom) or C 1-6 Represents an alkyl group (e.g., methyl) or N, Z 2' CR i' (R i' is a hydrogen atom, a halogen atom (e.g., a fluorine atom, a chlorine atom), a cyano group, C 1-6 Alkyl group (e.g., methyl) or C 1-6 represents an alkoxy group (e.g., methoxy) or N; Z 3'CR j' (R j' represents a hydrogen atom or a halogen atom (e.g., a fluorine atom) or N, Z 4' indicates CH or N, Z 5' indicates N, Z 6' indicates CH, Z 7' indicates CH, Z 8' indicates CH, Z 9' indicates C, Z 10' indicates C or N, Z 11' represents CH, N or S, Z 12' indicates C, Z 13' indicates CH or N, Z 14' CR s' (R s' is a hydrogen atom or optionally halogenated C 1-6 represents an alkyl group (e.g., trifluoromethyl), N or O; Ring C 1' represents a six-membered aromatic ring (e.g., a benzene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring), Ring C 2' represents a six-membered aromatic ring (e.g., a pyridine ring), Ring C 3' represents a five-membered ring (e.g., an imidazole ring), R 3' teeth, (1) Halogen atoms (e.g., fluorine atoms, chlorine atoms), (2) a cyano group, (3) (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, (iii) a hydroxy group, (iv) C 3-6 Cycloalkyl groups (e.g., cyclopropyl), (v) optionally halogenated C 1-6C optionally substituted by 1 to 8 substituents selected from an alkoxy group (e.g., methoxy, ethoxy, 2,2,2-trifluoroethoxy), (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholinyl, piperidinyl), and (vii) an oxo group. 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl, isobutyl), (4) C 2-6 Alkenyl groups (e.g., propenyl), (5) A cyclic group (C 3-6 a cycloalkyl group (e.g., cyclopropyl, cyclobutyl), a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl, tetrahydrofuryl, morpholinyl), or (6) OR 8' (R 8' is (a) (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, and (iii) C 3-6 C optionally substituted with 1 to 3 substituents selected from cycloalkyl groups (e.g., cyclopropyl) 1-6 an alkyl group (e.g., methyl, ethyl, propyl, isobutyl), or (b) C 6-10 Indicates an aryl group (e.g., phenyl) indicates, Ring D 1' represents a 5-membered aromatic ring (e.g., a pyrazole ring, an isoxazole ring, a thiophene ring), and R 4' teeth, (1) (i) a halogen atom (e.g., a fluorine atom), (ii) a C optionally substituted with 1 to 3 halogen atoms (e.g., a fluorine atom) 3-6 C optionally substituted by 1 to 5 substituents selected from a cycloalkyl group (e.g., cyclopropyl), and (iii) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms). 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isobutyl, tert-butyl), (2) C 3-6cycloalkyl groups (e.g., cyclopropyl); (3) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 6-10 Aryl groups (e.g., phenyl), (4) C 1-6 an alkoxy-carbonyl group (e.g., ethoxycarbonyl), or (5) 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl) Showing A compound represented by the formula:

[0113] [Compound (I-2)] Ring A is R 1 and the formula:

[0114] [ka]

[0115] (wherein each symbol has the same meaning as defined above). In addition to the group represented by (1) Halogen atoms (e.g., fluorine atoms), and (2) C 1-6 Alkyl group (e.g., methyl) a 5- or 6-membered aromatic ring (e.g., a pyrazole ring, a benzene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring) optionally further substituted by 1 to 3 substituents selected from R 1 but, (1) a cyano group, (2) C substituted with 1 to 5 fluorine atoms 1-6 Alkyl groups (e.g., 3,3,3-trifluoropropyl), (3)(i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, and (iii) C 1-6 Alkoxy groups (e.g., methoxy) C optionally substituted with 1 to 5 substituents selected from 1-6an alkoxy group (e.g., methoxy, ethoxy, propoxy, isobutoxy), or (4) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholinyl, tetrahydropyranyl); formula:

[0116] [ka]

[0117] [wherein each symbol has the same meaning as defined above],

[0118] [ka]

[0119] and R 2 But the formula:

[0120] [ka]

[0121] [During the ceremony, Z 1' CR h' (R h' is a hydrogen atom, a halogen atom (e.g., a fluorine atom) or C 1-6 Represents an alkyl group (e.g., methyl) or N, Z 2' CR i' (R i' is a hydrogen atom, a halogen atom (e.g., a fluorine atom, a chlorine atom), a cyano group, C 1-6 Alkyl group (e.g., methyl) or C 1-6 represents an alkoxy group (e.g., methoxy) or N; Z 3' CR j' (R j' represents a hydrogen atom or a halogen atom (e.g., a fluorine atom) or N, Z 4'indicates CH or N, Z 5' indicates N, Z 6' indicates CH, Z 7' indicates CH, Z 8' indicates CH, Z 9' indicates C, Z 10' indicates C or N, Z 11' indicates CH or N, Z 12' indicates C, Z 13' indicates CH or N, Z 14' CR s' (R s' is a hydrogen atom or optionally halogenated C 1-6 represents an alkyl group (e.g., trifluoromethyl), N or O; Ring C 1' represents a six-membered aromatic ring (e.g., a benzene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring), Ring C 2' represents a six-membered aromatic ring (e.g., a pyridine ring), Ring C 3' represents a five-membered ring (e.g., an imidazole ring), R 3' teeth, (1) Halogen atoms (e.g., fluorine atoms, chlorine atoms), (2) a cyano group, (3) (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, (iii) a hydroxy group, (iv) C 3-6 Cycloalkyl groups (e.g., cyclopropyl), (v) optionally halogenated C 1-6 C optionally substituted by 1 to 8 substituents selected from an alkoxy group (e.g., methoxy, 2,2,2-trifluoroethoxy), (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., morpholinyl, piperidinyl), and (vii) an oxo group. 1-6Alkyl groups (e.g., methyl, ethyl, isopropyl, isobutyl), (4) A cyclic group (C 3-6 a cycloalkyl group (e.g., cyclopropyl, cyclobutyl), a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl, tetrahydrofuryl, morpholinyl), or (5) OR 8' (R 8' teeth, (a) (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, and (iii) C 3-6 C optionally substituted with 1 to 3 substituents selected from cycloalkyl groups (e.g., cyclopropyl) 1-6 an alkyl group (e.g., methyl, ethyl, propyl, isobutyl), or (b) C 6-10 Indicates an aryl group (e.g., phenyl) indicates, Ring D 1' represents a 5-membered aromatic ring (e.g., a pyrazole ring, an isoxazole ring), and R 4' teeth, (1) (i) a halogen atom (e.g., a fluorine atom), (ii) a C optionally substituted with 1 to 3 halogen atoms (e.g., a fluorine atom) 3-6 C optionally substituted by 1 to 5 substituents selected from a cycloalkyl group (e.g., cyclopropyl), and (iii) a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., oxetanyl) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms). 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isobutyl, tert-butyl), (2) C 3-6 cycloalkyl groups (e.g., cyclopropyl); (3) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 6-10 an aryl group (e.g., phenyl), or (4) 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g., tetrahydropyranyl) Showing A compound represented by the formula:

[0122] [Compound (I-3)] X 1 But C; X 2 But C; Ring A is R 1 and the formula:

[0123] [ka]

[0124] (wherein each symbol has the same meaning as defined above). is a benzene ring which may be further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) in addition to the group represented by the formula: R 1 is substituted with 1 to 5 halogen atoms (e.g., fluorine atoms) 1-6 an alkoxy group (e.g., ethoxy); Y 1 is C or N; Y 2 is N; Y 3 But, CR e' (R e' is (1) a hydrogen atom, or (2) C 1-6 an alkyl group (e.g., methyl), or NR g'' (R g'' (1) C optionally substituted with 1 to 5 substituents selected from (i) a halogen atom (e.g., a fluorine atom), and (ii) a hydroxy group 1-6 (2) an alkyl group (e.g., methyl), or 3-6 is a cycloalkyl group (e.g., cyclopropyl); and R 2 But the formula:

[0125] [ka]

[0126] [During the ceremony, Z 1' is CH or N, Z 2' is CH or CF, Z 3' is CH, Z 4' is CH, and R 3' may be substituted with 1 to 5 substituents selected from a halogen atom (e.g., a fluorine atom) and a hydroxy group; 1-6 an alkyl group (e.g., isopropyl) A compound represented by the formula:

[0127] [Compound (I-4)] Ring A is R 1 and the formula:

[0128] [ka]

[0129] (wherein each symbol has the same meaning as defined above). is a benzene ring that is not substituted except for groups represented by the following formula: R 1 is substituted with 1 to 5 halogen atoms (e.g., fluorine atoms) 1-6 an alkoxy group (e.g., methoxy, ethoxy, propoxy, isobutoxy); formula:

[0130] [ka]

[0131] wherein each symbol is as defined above,

[0132] [ka]

[0133] and R 2 But the formula:

[0134] [ka]

[0135] [During the ceremony, Z 1' is CH or N, Z 2' is CH or CF, Z 3' is CH, Z 4' is CH, and R 3' may be substituted with 1 to 5 substituents selected from a halogen atom (e.g., a fluorine atom) and a hydroxy group; 1-6 an alkyl group (e.g., isopropyl) A compound represented by the formula:

[0136] Specific examples of compound (I) include the compounds of Examples 1 to 203. Among them, 2-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 95) or a salt thereof, 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide (Example 109) or a salt thereof, N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide (Example 127) or a salt thereof, 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 133) or a salt thereof, 2-[2-(2,2-difluoroethoxy)phenyl]-N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 135) or a salt thereof, 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 136) or a salt thereof, 2-[2-(2,2-difluoroethoxy)phenyl]-N-[2-fluoro-4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 146) or a salt thereof, N-[2-fluoro-4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide (Example 148) or a salt thereof, 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,3-dihydropyridazine-4-carboxamide (Example 152) or a salt thereof, 6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-methyl-5-oxo-2,5-dihydropyridazine-4-carboxamide (Example 158) or a salt thereof, 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide (Example 161) or a salt thereof, 3-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide (Example 162) or a salt thereof, 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,5-dihydropyridazine-4-carboxamide (Example 163) or a salt thereof, 2-Cyclopropyl-6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide (Example 169) or a salt thereof, or 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,5-dihydropyridazine-4-carboxamide (Example 177) or a salt thereof is preferred.

[0137] In particular, N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide (Example 127) or a salt thereof, 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 133) or a salt thereof, or 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 136) or a salt thereof is preferred.

[0138] When compound (I) is a salt, such salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Suitable examples of metal salts include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts and barium salts; and aluminum salts. Suitable examples of salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc. Suitable examples of salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Suitable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. Among these, pharma- ceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, examples of the salt include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.), and ammonium salts. When the compound has a basic functional group, examples of the salt include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. When compound (I) has isomers such as tautomers, optical isomers, stereoisomers, positional isomers, and rotational isomers, either one of the isomers and a mixture thereof are included in the compound of the present invention. Furthermore, when compound (I) has optical isomers, optical isomers resolved from the racemate are also included in compound (I). Compound (I) may be in the form of a crystal, and both a single crystal form and a mixture of crystal forms are included in Compound (I). Compound (I) may be a pharma- ceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt refers to a crystalline substance that is composed of two or more unique solids at room temperature, each of which has different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). A cocrystal or cocrystal salt can be prepared according to a cocrystallization method known per se. Compound (I) may be a solvate (for example, a hydrate) or a non-solvate, and both are encompassed in compound (I). Isotopes (e.g. 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 Compounds labeled or substituted with isotopes such as isotopes I are also encompassed in compound (I). Compounds labeled or substituted with isotopes can be used, for example, as tracers (PET tracers) used in positron emission tomography (PET), and are expected to be useful in fields such as medical diagnosis.

[0139] The process for producing the compound of the present invention is explained below.

[0140] The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt. Examples of such salts include the same salts as those of the compounds of the present invention described above.

[0141] When the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into a free form or another type of desired salt by a method known per se.

[0142] The compound obtained in each step can be used in the next reaction either as a reaction solution or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc. in accordance with a conventional method.

[0143] When the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0144] In the reaction of each step, the reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0145] In the reactions of each step, the reaction temperature may vary depending on the reagents and solvents used, but is usually from -78°C to 300°C, preferably from -78°C to 150°C, unless otherwise specified.

[0146] In the reaction of each step, the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0147] In the reactions of each step, a microwave synthesis device such as Biotage Initiator may be used. The reaction temperature may vary depending on the reagents and solvents used, but is usually room temperature to 300° C., preferably 50° C. to 250° C., unless otherwise specified. The reaction time may vary depending on the reagents and solvents used, but is usually 1 minute to 48 hours, preferably 1 minute to 8 hours, unless otherwise specified.

[0148] In the reaction of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When the reagent also serves as a reaction solvent, the reagent is used in an amount equivalent to the solvent.

[0149] Unless otherwise specified, the reactions in each step are carried out without a solvent or by dissolving or suspending the components in a suitable solvent. Specific examples of the solvent include those described in the Examples and the following. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water. The above solvents may be used as a mixture of two or more kinds in an appropriate ratio.

[0150] When a base is used in the reaction of each step, for example, the base shown below or the base described in the Examples can be used. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc.; Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; Organolithium compounds: n-butyllithium, etc.

[0151] When an acid or an acid catalyst is used in the reaction of each step, for example, the acids and acid catalysts shown below or the acids and acid catalysts described in the Examples can be used. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, etc.

[0152] Unless otherwise specified, the reactions in each step are carried out by a method known per se, for example, in Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (LF Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (by Jie Jack Li, published by OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. 1-14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers The method may be carried out in accordance with the method described in, for example, the 1989 issue of "The Method for Producing a Fluorescent Protein," published by the Japanese Patent Laid-Open Publication No. 2002-2003444, or the method described in the Examples.

[0153] In each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, a method described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004, or a method described in the Examples. Examples of the protecting group for the hydroxyl group of an alcohol or the like or a phenolic hydroxyl group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylate-type protecting groups such as acetate; sulfonate-type protecting groups such as methanesulfonate; and carbonate-type protecting groups such as tert-butyl carbonate. Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethylacetal; and cyclic acetal-type protecting groups such as 1,3-dioxane. Examples of protecting groups for the carbonyl group of a ketone include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone. Examples of the carboxy-protecting group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide. Examples of the thiol-protecting group include ether-type protecting groups such as benzylthioether; and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate. Examples of the protecting group for an amino group or an aromatic heterocycle such as imidazole, pyrrole, or indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide. The protecting group can be removed by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or a reduction method.

[0154] In each step, when a reduction reaction is carried out, examples of the reducing agent used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; etc. When a carbon-carbon double bond or triple bond is reduced, a catalyst such as palladium-carbon or Lindlar catalyst may be used.

[0155] In each step, when an oxidation reaction is carried out, examples of the oxidizing agent used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0156] In each step, when a radical cyclization reaction is carried out, examples of the radical initiator used include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Examples of the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0157] When a Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidene phosphoranes, etc. The alkylidene phosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0158] When the Horner-Emmons reaction is carried out in each step, examples of the reagent used include phosphonoacetates such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like; and bases such as alkali metal hydrides, organolithium compounds and the like.

[0159] In each step, when the Friedel-Crafts reaction is carried out, examples of the reagent used include a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, an organic acid or an inorganic acid can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acid chloride.

[0160] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, organic bases, etc.) are used as reagents.

[0161] In each step, when a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is performed, examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, and organic bases.

[0162] When a Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide, and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium in ether or tetrahydrofuran as a solvent.

[0163] In each step, when a Knoevenagel condensation reaction is carried out, an active methylene compound sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases) are used as reagents.

[0164] In each step, when the Vilsmeier-Haack reaction is carried out, phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) are used as reagents.

[0165] In each step, when an azidation reaction of alcohols, alkyl halides, or sulfonate esters is carried out, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, when azidating alcohols, there are a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and a method using trimethylsilyl azide and a Lewis acid.

[0166] In each step, when a reductive amination reaction is carried out, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amines used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0167] In each step, when Mitsunobu reaction is carried out, an azodicarboxylate (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0168] In each step, when an esterification reaction, an amidation reaction, or a urea reaction is performed, examples of the reagents used include acyl halides such as acid chlorides and acid bromides; activated carboxylic acids such as acid anhydrides, active esters, and sulfates. Examples of activators for carboxylic acids include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-Chloro-1-methyl-pyridinium iodide (Mukaiyama's Reagent); Thionyl chloride; Lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; or a combination thereof. When a carbodiimide-based condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or dimethylaminopyridine (DMAP) may be further added to the reaction.

[0169] In each step, when a coupling reaction is carried out, examples of the metal catalyst used include palladium compounds such as palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), dichlorobis(triphenylphosphine)palladium (II), dichlorobis(triethylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel (0); rhodium compounds such as tris(triphenylphosphine)rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide (I); and platinum compounds. A base may be added to the reaction, and examples of such bases include inorganic bases.

[0170] When a thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent. In addition to diphosphorus pentasulfide, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure, such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent), may also be used.

[0171] In each step, when a halogenation reaction is carried out, examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

[0172] In each step, when a halogenation reaction of a hydroxy group is carried out, examples of the halogenating agent used include hydrohalic acid and an acid halide of an inorganic acid, specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., and for bromination, 48% hydrobromic acid, etc. may be mentioned. In addition, a method of obtaining an alkyl halide from an alcohol by the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide, etc. may be used. Alternatively, a method of synthesizing an alkyl halide through a two-step reaction in which an alcohol is converted into a sulfonic acid ester and then reacted with lithium bromide, lithium chloride, or sodium iodide may be used.

[0173] When Arbuzov reaction is carried out in each step, examples of the reagent used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like.

[0174] When a sulfonyl esterification reaction is carried out in each step, examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0175] In each step, when a hydrolysis reaction is carried out, an acid or base, or a tin reagent such as bis(tributyltin)oxide is used as a reagent. When an acid hydrolysis reaction of a tert-butyl ester is carried out, formic acid or triethylsilane may be added to reductively trap the by-product tert-butyl cation.

[0176] When a dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

[0177] In each step, when an alkylation reaction is carried out, an electrophile (eg, alkyl halide, etc.) and a base (eg, organic bases, inorganic bases, metal alkoxides, metal amides, etc.) are used as reagents.

[0178] Compound (I) can be produced according to the following production methods A to H or methods similar thereto. The abbreviations in each general formula in the reaction scheme are the same as those defined above unless otherwise specified. HAL represents a halogen atom (e.g., a chlorine atom, a bromine atom, an iodine atom). R 9 is optionally substituted C 1-6 Alkyl group (e.g., methyl, ethyl) or C 7-16 R represents an aralkyl group (e.g., benzyl). 10 R represents a hydrogen atom or a substituent. 11 is optionally substituted C 1-6 R represents an alkyl group. g’’ represents a hydrogen atom or a substituent. Furthermore, if desired, compound (I) can be produced by carrying out a deprotection reaction, an amidation reaction, a urea reaction, an alkylation reaction, a Mitsunobu reaction, an oxidation reaction, a reduction reaction, a halogenation reaction, a coupling reaction, a nucleophilic addition reaction with a carbanion, a Grignard reaction, a dehydration reaction, or the like, either alone or in combination of two or more thereof.

[0179] Manufacturing method A Among the compounds (I), the compound (Ia) described below can be produced by the following method.

[0180] [ka]

[0181] (wherein the symbols are as defined above).) Compound (3) can be produced by subjecting compound (1) to an acylation reaction with compound (2). Compound (5) can be produced by an addition reaction of compound (3) to compound (4), followed by an intramolecular cyclization reaction. Compound (6) can be produced by hydrolysis of compound (5). Compound (Ia) can be produced by an amidation reaction between compound (6) and compound (7).

[0182] Manufacturing method B Of the compounds (I), the compound (Ib) described below can be produced by the following method.

[0183] [ka]

[0184] (wherein the symbols are as defined above).) Compound (9) can be produced by subjecting compound (1) to an addition reaction to compound (8), followed by an intramolecular cyclization reaction. Compound (10) can be produced by hydrolysis of compound (9). Compound (Ib) can be produced by an amidation reaction between compound (10) and compound (7).

[0185] The compound (9) used in Production Method B can also be produced by the following method.

[0186] [ka]

[0187] (wherein the symbols are as defined above).) Compound (9) can be prepared by an addition reaction of compound (1) to compound (11), followed by an intramolecular cyclization reaction.

[0188] The compound (9) used in Production Method B can also be produced by the following method.

[0189] [ka]

[0190] (wherein the symbols are as defined above).) Compound (9) can be produced by a coupling reaction between compound (12) and compound (13).

[0191] Manufacturing method C Among the compounds (I), the compound (Ic) described below can be produced by the following method.

[0192] [ka]

[0193] (wherein the symbols are as defined above).) Compound (15) can be produced by an addition reaction of compound (3) to compound (14), followed by an intramolecular cyclization reaction. Compound (16) can be produced by hydrolysis of compound (15). Compound (Ic) can be produced by an amidation reaction between compound (16) and compound (7).

[0194] Manufacturing method D Among the compounds (I), the compound (Id) described below can be produced by the following method.

[0195] [ka]

[0196] (wherein the symbols are as defined above).) Compound (17) can be produced by subjecting compound (1) to a thioisocyanation reaction. Examples of the reagent used include 1,1'-thiocarbonyldiimidazole. Compound (18) can be produced by subjecting compound (17) to an addition reaction of ammonia. Compound (20) can be prepared by addition reaction of compound (18) to compound (19), followed by intramolecular cyclization reaction. Compound (21) can be produced by subjecting compound (20) to a methylation reaction. Compound (22) can be produced by the reduction reaction of compound (21). Examples of the reagent used include a combination of a metal reagent and a reducing agent. Examples of the metal reagent include a combination of copper thiophene-2-carboxylate and tetrakis(triphenylphosphine)palladium. Examples of the reducing agent include the above reducing agents (triethylsilane, etc.). Compound (23) can be produced by hydrolysis of compound (22). Compound (24) can be produced by ester-amide exchange reaction between compound (21) and compound (7). Examples of the reagent used include trimethylaluminum. Compound (Id) can be produced by an amidation reaction between compound (23) and compound (7). Compound (Id) can also be produced by the reduction reaction of compound (24). Examples of the reagent used include a combination of a metal reagent and a reducing agent. Examples of the metal reagent include a combination of copper thiophene-2-carboxylate and tetrakis(triphenylphosphine)palladium. Examples of the reducing agent include the above reducing agents (triethylsilane, etc.).

[0197] Manufacturing method E Among the compounds (I), the compound (Ie) described below can be produced by the following method.

[0198] [ka]

[0199] (wherein the symbols are as defined above).) Compound (25) can be produced by diazotization of compound (1) and subsequent reduction. Compound (27) can be produced by condensation reaction of compound (25) with compound (26), followed by intramolecular cyclization reaction. Compound (28) can be produced by oxidation reaction of compound (27). Compound (29) can be produced by hydrolysis of compound (28). Compound (Ie) can be produced by an amidation reaction between compound (29) and compound (7).

[0200] Manufacturing method F Among the compounds (I), the compound (If) described below can be produced by the following method.

[0201] [ka]

[0202] (wherein the symbols are as defined above).) Compound (31) can be produced by a condensation reaction of compound (25) and compound (30). Compound (33) can be produced by a condensation reaction of compound (31) and compound (32). Compound (34) can be produced by intramolecular cyclization reaction of compound (33). Compound (If) can be produced by an amidation reaction between compound (34) and compound (7).

[0203] Manufacturing method G Among the compounds (I), the compound (Ig) described below can be produced by the following method.

[0204] [ka]

[0205] (wherein the symbols are as defined above).) Compound (35) can be produced from compound (1) according to the above-mentioned Production Method E and Production Method F. Compound (36) can be prepared by deprotecting compound (35). Compound (37) can be produced by alkylation reaction of compound (36). Compound (Ig) can be produced by the amidation reaction (R 10 is a hydrogen atom), or an amidation reaction of compound (37) with compound (7) (R 10 is a substituent).

[0206] Manufacturing method H Among the compounds (I), the compound (Ih) described below can be produced by the following method.

[0207] [ka]

[0208] (wherein the symbols are as defined above).) Compound (39) can be produced by a coupling reaction between compound (38) and propane-1-yne. The reagents used include a combination of a palladium catalyst, a copper compound, and a base. The palladium catalyst includes bis(triphenylphosphine)palladium(II) dichloride, etc. The copper compound includes copper(I) iodide, etc. The base includes triethylamine, etc. Compound (40) can be produced by oxidation reaction of compound (39). Reagents used include a combination of a metal reagent, an oxidizing agent, a base, and a dehydrating agent. Metal reagents include ruthenium chloride, etc. Oxidizing agents include sodium periodate, etc. Bases include sodium bicarbonate, etc. Dehydrating agents include magnesium sulfate, etc. Compound (42) can be produced by a condensation reaction of compound (40) and compound (41). Compound (44) can be produced by an addition reaction of compound (43) to compound (42), followed by an intramolecular cyclization reaction. Compound (45) can be produced by halogenation reaction of compound (44). Compound (46) can be produced by the alkylation reaction of compound (45) or the reaction of compound (45) with R g’’ Coupling reaction with the corresponding trialkyltin derivatives or boronic acid derivatives (R g’’ is a substituent). Compound (47) is R 9 can be produced by a coupling reaction of compound (45) with carbon monoxide in the presence of an alcohol corresponding to the formula: Compound (48) is R 9 The compound (45) is reacted with carbon monoxide in the presence of an alcohol corresponding to the formula (R g’’ is a hydrogen atom), or R 9 a coupling reaction of compound (46) with carbon monoxide in the presence of an alcohol corresponding to the formula: g’’ Coupling reaction with the corresponding trialkyltin derivatives or boronic acid derivatives (R g’’ is a substituent). Compound (49) can be produced by hydrolysis of compound (48). Compound (Ih) can be produced by an amidation reaction between compound (49) and compound (7).

[0209] Manufacturing method I Among the compounds (I), the compound (Ii) described below can be produced by the following method.

[0210] [ka]

[0211] (wherein the symbols are as defined above).) Compound (51) can be produced by a diazotization reaction of compound (1), a subsequent addition reaction to compound (50), and a hydrolysis reaction. Compound (53) can be produced by condensation reaction of compound (51) with compound (52), followed by intramolecular cyclization reaction. Compound (54) can be produced by subjecting compound (53) to hydrolysis or reduction. Compound (Ii) can be produced by an amidation reaction between compound (54) and compound (7).

[0212] Manufacturing method J Among the compounds (I), the compound (Ij) described below can be produced by the following method.

[0213] [ka]

[0214] (wherein the symbols are as defined above).) Compound (55) can be produced from compound (1) according to the above-mentioned Production Method I. Compound (Ij) can be produced by subjecting compound (55) to a reduction reaction.

[0215] Manufacturing method K Among the compounds (I), the compound (Ik) described below can be produced by the following method.

[0216] [ka]

[0217] (wherein the symbols are as defined above).) Compound (56) can be produced from compound (1) according to the above-mentioned Production Method I. Compound (57) can be produced by subjecting compound (56) to a reduction reaction. Compound (58) can be produced by subjecting compound (57) to a Grignard reaction. Compound (Ik) can be produced by subjecting compound (58) to an oxidation reaction.

[0218] Compounds (1), (2), (4), (7), (8), (11), (12), (13), (14), (19), (26), (30), (32), (38), (41), (43), (50), and (52) used as starting materials in each of the above-mentioned production methods are either commercially available products or can be produced according to methods known per se.

[0219] As for the configurational isomer (E,Z isomer) of compound (I), when isomerization occurs, it can be isolated and purified by ordinary separation means such as extraction, recrystallization, distillation, chromatography, etc., to produce a pure compound. In addition, according to the method described in New Experimental Chemistry Lectures 14 (edited by the Chemical Society of Japan), pages 251-253, and 4th Edition Experimental Chemistry Lectures 19 (edited by the Chemical Society of Japan), pages 273-274, or methods equivalent thereto, the isomerization of the double bond can be advanced by heating, an acid catalyst, a transition metal complex, a metal catalyst, a radical species catalyst, light irradiation, or a strong base catalyst, to obtain the corresponding pure isomer.

[0220] Compound (I) may have stereoisomers depending on the type of substituents, and both the isomers alone and mixtures thereof are included in the present invention. When the target compound is obtained in a free state by the above reaction, it may be converted into a salt according to a conventional method, and when it is obtained as a salt, it may be converted into a free form or another salt according to a conventional method. Compound (I) thus obtained can be isolated and purified from the reaction solution by known means, such as transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc. When compound (I) exists as configurational isomers, diastereomers, conformers, etc., they can be isolated by the above-mentioned separation and purification means, if desired. When compound (I) is a racemate, it can be separated into d- and l-forms, or S- and R-forms, by a conventional optical resolution means.

[0221] Compound (I) thus obtained, other reaction intermediates and starting compounds thereof can be isolated and purified from the reaction mixture by a method known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC), medium pressure preparative liquid chromatography (medium pressure preparative LC), or the like.

[0222] The salt of compound (I) can be produced by a method known per se, for example, by adding an inorganic acid or an organic acid when compound (I) is a basic compound, or by adding an organic base or an inorganic base when compound (I) is an acidic compound. When compound (I) may have optical isomers, all of these individual optical isomers and mixtures thereof are naturally included in the scope of the present invention, and if desired, these isomers can be optically resolved or individually produced according to known means.

[0223] The compound of the present invention can be used to inhibit, for example, the following in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.): (1) Mental disorders (e.g., depression, major depression, bipolar depression, dysthymic disorder, affective disorder (such as seasonal affective disorder), recurrent depression, postpartum depression, stress disorder, depressive symptoms, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, post-traumatic stress disorder, Tourette syndrome, autism, fragile X syndrome, Rett syndrome, adaptation disorders, bipolar disorder, neurosis, schizophrenia (e.g., positive symptoms, negative symptoms, cognitive impairment), chronic fatigue syndrome, anxiety neurosis, obsessive-compulsive disorder, panic disorder, epilepsy, anxiety disorder, anxiety symptoms, dysphoric mental state, dysthymia, cyclothymia, irritability, syncope, addiction, decreased libido, attention-deficit hyperactivity disorder (ADHD), major psychotic depression, treatment-resistant major depression, treatment-resistant depression, depressive disorder, catalepsy, schizophrenia of the hemorrhagic type, schizophrenia of the paranoid type], (2) Neurodegenerative diseases (e.g., Alzheimer's disease, Alzheimer's-type senile dementia, Parkinson's disease, Huntington's disease, multi-infarct dementia, frontotemporal dementia, Parkinson's-type dementia, progressive supranuclear palsy, Pick's syndrome, corticobasal degeneration, Down's syndrome, vascular dementia, postencephalitic Parkinson's disease, Lewy body dementia, multiple system atrophy, HIV-related dementia, amyotrophic lateral sclerosis (ALS), motor neurogenic disease (MND), Creutzfeldt-Jakob disease or prion disease, cerebral palsy, progressive supranuclear palsy, traumatic brain injury, glaucoma, multiple sclerosis, neuromyelitis optica (NMO), postoperative cognitive dysfunction (POCD), postoperative delirium (POD), delirium), (3) Age-related cognitive and memory disorders (e.g., age-related memory disorder, senile dementia), (4) Sleep disorders [e.g., endogenous sleep disorders (e.g., psychophysiological insomnia, etc.), exogenous sleep disorders, circadian rhythm disorders (e.g., time zone shift syndrome (jet lag), shift work sleep disorder, irregular sleep-wake patterns, delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wake, etc.), parasomnia, sleep disorders associated with medical or psychiatric disorders (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, vascular dementia, schizophrenia, depression, anxiety neurosis), stress insomnia, insomnia, insomnia neurosis, sleep apnea syndrome], (5) Respiratory depression caused by anesthetics, trauma, or neurodegenerative diseases, etc. (6) Traumatic brain injury, stroke, cerebral edema, cerebral ischemia, ischemia, anorexia nervosa, eating disorders, anorexia nervosa, bulimia, other eating disorders, alcoholism, alcohol abuse, alcoholic amnesia, alcohol delusion, alcohol preference, alcohol withdrawal, alcoholic psychosis, alcohol poisoning, alcoholic jealousy, alcoholic mania, alcohol-dependent mental disorder, alcoholic psychosis, drug preference, drug phobia, drug mania, drug withdrawal, migraine, stress headache, tension headache, diabetic neuropathy, rheumatoid arthropathy, obesity, diabetes, muscle spasms, Meniere's disease, autonomic imbalance, alopecia, glaucoma, high blood pressure, heart disease, tachycardia, congestive heart failure, hyperventilation, bronchial asthma, apnea, sudden infant death syndrome, inflammatory diseases, allergic diseases, impotence, menopausal disorders, infertility, tumors (e.g., cancer, liver cancer, colon cancer, breast cancer, prostate cancer, neuroblastoma, bone cancer, oral cancer, mast cell tumor, bile duct cancer, Lewis lung cancer), immunodeficiency syndrome due to HIV infection, immunodeficiency syndrome due to stress, cerebrospinal meningitis, acromegaly, incontinence, Metabolic syndrome, osteoporosis, peptic ulcer, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, stress-related gastrointestinal disorder, nervous vomiting, diarrhea, constipation, postoperative ileus, rheumatoid arthritis, osteoarthritis, functional dyspepsia, hyperalgesia, insulin resistance, boxer dementia, nausea, vomiting, tumor metastasis, brain injury, seizures, weight change, weight gain, weight loss, colitis, alcoholism, hypothermia, fatty liver, atherosclerosis, infection, muscle spasms, high blood pressure, stroke, early childhood malignant transitional partial seizures, diabetes mellitus, type 2 diabetes mellitus, dyslipidemia, visceral obesity, hypotony, anorexia, fibrosis, myocardial infarction, cachexia, induced psychotic disorder, ataxia, AIDS wasting syndrome, cirrhotic cardiomyopathy, uremic pruritus, neurobehavioral symptoms, tubulointerstitial nephritis and uveitis syndrome, interstitial cystitis, retinitis pigmentosa, complex regional pain syndrome, autoimmune diseases, coronary artery disease, aspirin asthma, platelet storage pool deficiency, diabetic embryo, Arthus type urticaria, asthma, toxic oil syndrome, otitis, etc. (7) Pain (e.g., inflammatory pain, cancer pain, neuropathic pain, acute pain, pain due to peripheral neuropathy, central pain, fibromyalgia, vasoocclusive painful crises in sickle cell disease, spasticity or pain mediated by multiple sclerosis, functional chest pain, complex regional pain syndrome, etc.) (8) Lysosomal storage diseases (e.g., Gaucher disease, Krabbe disease, Niemann-Pick syndrome), It is expected that this compound will be useful as a preventive or therapeutic agent for the following diseases:

[0224] Since the compound of the present invention has excellent glucosylceramide synthase inhibitory activity, it is expected to have excellent preventive and therapeutic effects against the above-mentioned diseases.

[0225] Since the compound of the present invention has an excellent glucosylceramide synthase inhibitory effect, it is expected to have excellent preventive and therapeutic effects against lysosomal diseases (e.g., Gaucher disease), neurodegenerative diseases (e.g., Parkinson's disease, dementia with Lewy bodies, multiple system atrophy), etc.

[0226] Compound (I) may be used as a prodrug.

[0227] A prodrug of compound (I) refers to a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted to compound (I) by hydrolysis due to gastric acid, etc.

[0228] Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated); compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, or pivaloylated). , succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); compounds in which the carboxy group of compound (I) is esterified or amidated (for example, compounds in which the carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compounds, etc.). These compounds can be produced from compound (I) by known methods. In addition, the prodrug of compound (I) may be one that changes to compound (I) under physiological conditions as described in "Drug Development" Vol. 7, Molecular Design, pp. 163 to 198, published by Hirokawa Shoten in 1990.

[0229] The compound of the present invention has excellent pharmacokinetics (e.g., blood drug half-life, brain transferability, metabolic stability) and low toxicity (e.g., superior as a medicine in terms of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interactions, carcinogenicity, etc.), and can be safely administered orally or parenterally to mammals (e.g., humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.) as a medicine as it is or as a pharmaceutical composition mixed with a pharmaceutically acceptable carrier, etc. "Parenteral" includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, rectal, vaginal, intraperitoneal, intratumor, proximal to a tumor, etc., and administration directly to a lesion.

[0230] The dosage of the compound of the present invention varies depending on the administration route, symptoms, etc., but for example, when orally administered to a patient with Parkinson's disease (adult, body weight 40 to 80 kg, e.g., 60 kg), the dosage is, for example, 0.001 to 1000 mg / kg body weight per day, preferably 0.01 to 100 mg / kg body weight per day, and more preferably 0.1 to 10 mg / kg body weight per day. This amount can be administered in one to three divided doses per day.

[0231] The pharmaceutical agent containing the compound of the present invention can be used alone or as a pharmaceutical composition in which the compound of the present invention is mixed with a pharma- ceutical carrier, according to a method known per se (e.g., a method described in the Japanese Pharmacopoeia, etc.) as a method for producing pharmaceutical preparations. Pharmaceutical agents containing the compound of the present invention can be used in the form of tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), troches, syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (e.g., orally disintegrating films ...

[0043] The composition can be safely administered orally or parenterally (e.g., intravenous, intramuscular, subcutaneous, intravisceral, intranasal, intradermal, eye drops, intracerebral, rectal, vaginal, intraperitoneal, etc.) in the form of an injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), infusion, transdermal preparation, ointment, lotion, patch, suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalation preparation), eye drops, etc.

[0232] As the "pharmaceutical acceptable carrier", various organic or inorganic carriers commonly used as starting materials for preparations are used. For example, excipients, lubricants, binders, disintegrants, etc. are used in solid preparations, while solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. are used in liquid preparations. Furthermore, preparation additives such as preservatives, antioxidants, colorants, sweeteners, etc. can also be used as necessary. Examples of excipients include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid. Examples of lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, and the like. Examples of binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, and sodium carboxymethyl cellulose. Examples of disintegrants include starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylstarch, and L-hydroxypropylcellulose. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like. Examples of solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate. Examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of isotonicity agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, and the like. Examples of the buffering agent include buffer solutions such as phosphate, acetate, carbonate, and citrate. An example of the soothing agent is benzyl alcohol. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, and sorbic acid. Antioxidants include, for example, sulfites, ascorbic acid, α-tocopherol, and the like.

[0233] Pharmaceutical compositions vary depending on the dosage form, administration method, carrier, etc., but can be produced according to conventional methods by adding the compound of the present invention in a proportion of usually 0.01 to 100% (w / w), preferably 0.1 to 95% (w / w), based on the total amount of the formulation.

[0234] The compound of the present invention may be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs).

[0235] Concomitant medications include, for example: Benzodiazepines (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel blockers (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, etc.) , paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), noradrenaline reuptake inhibitors (reboxetine mesylate, etc.), noradrenaline-dopamine reuptake inhibitors (bupropion hydrochloride, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT 1AAgonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT3 antagonists (cyamemazine, etc.), non-cardiac selective beta blockers (propranolol hydrochloride, oxyprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxyzine hydrochloride, etc.), schizophrenia medications (chlorpromazine, haloperidol, sulpride, clozapine, trifluoperazine hydrochloride, fluphenazine hydrochloride, olanzapine, quetiapine fumarate, risperidone, aripiprazole, etc.), CRF antagonists, other anxiolytics (meprobamate, etc.), tachykinin antagonists (MK-869, saredutant, etc.), drugs acting on metabotropic glutamate receptors agents, CCK antagonists, β3 adrenergic antagonists (amibegron hydrochloride, etc.), GAT-1 inhibitors (tiagabine hydrochloride, etc.), N-type calcium channel inhibitors, type 2 carbonic anhydrase inhibitors, NMDA glycine site agonists, NMDA antagonists (memantine, etc.), peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), 5-HT 2A Antagonist, 5-HT 2AInverse agonists, COMT inhibitors (entacapone, etc.), bipolar disorder medications (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate, etc.), cannabinoid CB1 antagonists (rimonabant, etc.), FAAH inhibitors, sodium channel blockers, anti-ADHD drugs (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), alcoholism medications, autism medications, chronic fatigue syndrome medications, convulsant medications, fibromyalgia medications, headache medications, insomnia medications (etizolam, zopiclone, triazolam, zolpidem, ramelteon, indiplon etc.), smoking cessation medication, myasthenia gravis medication, cerebral infarction medication, mania medication, hypersomnia medication, pain medication, mood disorders medication, autonomic nervous system disorders medication, male and female sexual dysfunction medication, migraine medication, pathological gambling medication, restless legs syndrome medication, substance addiction medication, alcohol-related disorders medication, irritable bowel syndrome medication, Alzheimer's disease medication (donepezil, galantamine, memantine, rivastigmine etc.), Parkinson's disease medication (levodopa, carbidopa, benserazide, selegiline, zonisamide, endacavone, amantadine, talipes Molecular targets such as rituximab, bramipexole, apomorphine, capergoline, bromocriptine, istradefylline, trihexyphenidyl, promethazine, pergolide, etc.), Huntington's disease drugs (chlorpromazine hydrochloride, haloperidol, reserpine, etc.), Gaucher disease drugs (imiglucerase, taliglucerase alfa, velaglucerase alfa, eliglustat, miglustat, etc.), ALS drugs (riluzole, etc., neurotrophic factors, etc.), multiple sclerosis drugs (fingolimod, interferon beta 1b, natalizumab, etc.) Antiepileptic drugs (phenytoin, carbamazepine, phenobarbital, primidone, zonizamide, sodium valproate, ethosuximide, diazepam, nitrazepam, clonazepam, clobazam, gabapentin, topiramate, lamotrigine, levetiracetam, stiripentol, rufinamide, etc.), cholesterol-lowering drugs and other dyslipidemia drugs (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors),Drugs for treating abnormal behavior or suppressing wandering habits due to dementia (sedatives, anti-anxiety drugs, etc.), apoptosis inhibitors, anti-obesity drugs, drugs for treating diabetes, drugs for treating high blood pressure, drugs for treating low blood pressure, drugs for treating rheumatism (DMARDs), anti-cancer drugs, drugs for treating parathyroid gland (PTH), calcium receptor antagonists, sex hormones or derivatives thereof (progesterone, estradiol, estradiol benzoate, etc.), drugs for promoting neuronal differentiation, drugs for promoting neuronal regeneration, non-steroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroids (dexamethasone, cortisone acetate, etc.), anti-cytokine drugs (TNF inhibitors, MAP kinase inhibitors, etc.), antibody drugs, nucleic acids or nucleic acid derivatives, aptamer drugs, etc.

[0236] By combining the compound of the present invention with a concomitant drug, (1) The dose of the compound of the present invention or a concomitant drug can be reduced compared to when the compound is administered alone. (2) Drugs to be used in combination with the compounds of the present invention can be selected depending on the symptoms of the patient (mild, severe, etc.). (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be extended. (4) By selecting a concomitant drug having a different mechanism of action from that of the compound of the present invention, the therapeutic effect can be sustained. (5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.

[0237] Hereinafter, the combined use of the compound of the present invention and a concomitant drug will be referred to as "the combined drug of the present invention." When using the combination drug of the present invention, the administration time of the compound of the present invention and the combination drug is not limited, and the compound of the present invention or its pharmaceutical composition and the combination drug or its pharmaceutical composition may be administered to the subject at the same time or at a time lag. The dosage of the combination drug may be in accordance with the dosage used in clinical practice, and may be appropriately selected depending on the subject, administration route, disease, combination, etc. The administration form of the combination drug of the present invention is not particularly limited, and it is sufficient that the compound of the present invention and the combination drug are combined at the time of administration.Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the combination drug, (2) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug by the same administration route, (3) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug by the same administration route with a time difference, (4) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug by the different administration routes, (5) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug by the different administration routes with a time difference (for example, administration in the order of the compound of the present invention; administration in the reverse order).

[0238] The combination drug of the present invention has low toxicity, and for example, the compound of the present invention or (and) the combination drug described above can be mixed with a pharma- ceutically acceptable carrier according to a known method and safely administered orally or parenterally (e.g., topically, rectally, intravenously, etc.) as a pharmaceutical composition, for example, a tablet (including sugar-coated tablet, film-coated tablet), powder, granule, capsule (including soft capsule), liquid, injection, suppository, sustained-release agent, etc. Injection can be administered intravenously, intramuscularly, subcutaneously or intraorgan, or directly to the lesion. Examples of the pharma- ceutically acceptable carrier that may be used in the production of the combination drug of the present invention include the same as those mentioned above.

[0239] The mixing ratio of the compound of the present invention to the concomitant drug in the combination agent of the present invention can be appropriately selected depending on the subject of administration, the administration route, the disease, etc. For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the formulation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight based on the total formulation. The content of the concomitant drug in the concomitant agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight based on the total preparation. EXAMPLES

[0240] The present invention will be further explained in detail by the following examples, test examples and formulation examples, but these are not intended to limit the present invention and may be modified without departing from the scope of the present invention. In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. Ratios shown in mixed solvents are by volume unless otherwise specified. % refers to weight % unless otherwise specified.

[0241] In the examples, elution in column chromatography was performed under observation by TLC (Thin Layer Chromatography) unless otherwise specified. In the TLC observation, a 60 F TLC plate manufactured by Merck was used. 254 The developing solvent was the same as that used as the elution solvent in column chromatography. A UV detector was used for detection. In silica gel column chromatography, when NH is used, aminopropylsilane-bonded silica gel was used, and when Diol is used, 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel was used. In preparative HPLC (high performance liquid chromatography), when C18 is used, octadecyl-bonded silica gel was used. The ratios shown in the elution solvents are by volume unless otherwise specified.

[0242] 1 H NMR analysis was performed using ACD / SpecManager (trade name) software, etc. Peaks with very gentle proton peaks such as hydroxyl and amino groups may not be recorded. MS was measured by LC / MS. ESI or APCI was used as the ionization method. Data shown are actual measurements (found). Molecular ion peaks are usually observed, but may be observed as fragment ions. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.

[0243] The following abbreviations are used in the following examples: mp: melting point MS: Mass spectrum M: Molar concentration N: Normality CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide 1 H NMR: Proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer ESI: electrospray ionization APCI: atomic pressure chemical ionization HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate DPPA: Diphenyl phosphoryl azide DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide THF: Tetrahydrofuran MeOH: Methanol EtOH: Ethanol DMSO: Dimethyl sulfoxide TEA: Triethylamine

[0244] Example 1 1-(2-Methoxyphenyl)-6-methyl-2-oxo-N-(4-phenoxyphenyl)-1,2-dihydropyridine-3-carboxamide

[0245] A) Ethyl 3-[(2-methoxyphenyl)amino]-3-oxopropionate A solution of ethyl 3-chloro-3-oxopropionate (27.0 mL) in acetone (25 mL) was added dropwise to a mixture of 2-methoxyaniline (24.74 g), TEA (29.4 mL), and acetone (250 mL) under ice-cooling. The mixture was stirred for 30 minutes under ice-cooling, and then stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with ethyl acetate / hexane to obtain the title compound (20.50 g). MS: [M+H] + 238.0.

[0246] B) 1-(2-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 4,4-Dimethoxybutan-2-one (6.68 g) and 20% sodium ethoxide-EtOH solution (47.3 g) were added to a solution of ethyl 3-[(2-methoxyphenyl)amino]-3-oxopropionate (10 g) in EtOH (100 mL), and the mixture was stirred overnight at 50° C. The reaction mixture was acidified with 1M hydrochloric acid, and the precipitate was collected by filtration and washed with EtOH and ethyl acetate to obtain the title compound (6.48 g). MS: [M+H] + 260.0.

[0247] C) 1-(2-methoxyphenyl)-6-methyl-2-oxo-N-(4-phenoxyphenyl)-1,2-dihydropyridine-3-carboxamide HATU (110 mg) was added to a mixture of 1-(2-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (50 mg) and DMF (5 mL), and the mixture was stirred at room temperature for 30 minutes. DIPEA (62 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. 4-Phenoxyaniline (43 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (0.05% ammonia water containing acetonitrile / 0.1% ammonia water) to obtain the title compound (50 mg). 1 H NMR (400 MHz, CDCl3) δ 2.07 (3H, s), 3.84 (3H, s), 6.45 (1H, d, J = 7.6 Hz), 6.93-7.01 (4H, m), 7.06 (1H, t, J = 7.6 Hz), 7.11-7.21 (3H, m), 7.30 (2H, t, J = 8.0 Hz), 7.47-7.55 (1H, m), 7.68 (2H, d, J = 8.8 Hz), 8.61 (1H, d, J = 7.2 Hz), 11.78 (1H, brs).

[0248] Example 54 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[1-(oxan-4-yl)-1H-pyrazol-3-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide

[0249] A) 3-nitro-1-(oxan-4-yl)-1H-pyrazole 20% di-tert-butyl azodicarboxylate-toluene solution (6.10 g) was added to a mixture of 3-nitro-1H-pyrazole (500 mg), triphenylphosphine (1392 mg), tetrahydro-2H-pyran-4-ol (542 mg), and THF (10 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SI and NH, ethyl acetate / hexane) to obtain the title compound (597 mg). MS: [M+H] + 198.0.

[0250] B) 1-(oxan-4-yl)-1H-pyrazol-3-amine 10% palladium-carbon (55% wet, 100 mg) was added to a solution of 3-nitro-1-(oxan-4-yl)-1H-pyrazole (597 mg) in MeOH (10 mL), and the mixture was stirred at room temperature under normal pressure under a hydrogen atmosphere overnight. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (330 mg). MS: [M+H] + 168.0.

[0251] C) 4-Fluoro-1-nitro-2-(2,2,2-trifluoroethoxy)benzene 2,2,2-Trifluoroethyl trifluoromethanesulfonate (16.11 mL) was added to a mixture of 5-fluoro-2-nitrophenol (16.73 g), cesium carbonate (52.0 g), and DMF (200 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (24.2 g). 1H NMR (300 MHz, DMSO-d6) δ 5.02 (2H, q, J = 8.7 Hz), 7.05-7.19 (1H, m), 7.49 (1H, dd, J = 10.7, 2.4 Hz), 8.10 (1H, dd, J = 9.0, 6.0 Hz).

[0252] D) 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylate methyl 10% palladium-carbon (55% wet, 500 mg) was added to a solution of 4-fluoro-1-nitro-2-(2,2,2-trifluoroethoxy)benzene (24.2 g) in MeOH (100 mL), and the mixture was stirred overnight at room temperature under hydrogen atmosphere at normal pressure. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 4-fluoro-2-(2,2,2-trifluoroethoxy)aniline (20.21 g) as a crude product. DMF (150 mL) and 3-carbomethoxy-2-pyrone (13.47 g) were added to the obtained crude product, and the mixture was stirred at room temperature for 3 days. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.79 g) and N,N-dimethyl-4-aminopyridine (2.67 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The obtained crude product was washed with ethyl acetate / hexane to obtain the title compound (9.13 g). MS: [M+H] + 345.9.

[0253] E) 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid To a mixture of 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (9.13 g), MeOH (100 mL), and THF (50 mL), 4M aqueous lithium hydroxide solution (25 mL) was added and stirred at room temperature for 5 hours. The reaction mixture was adjusted to pH = 2 with 1M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to obtain the title compound (6.91 g). MS: [M+H] + 331.9.

[0254] F) 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[1-(oxan-4-yl)-1H-pyrazol-3-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide HATU (86 mg) was added to a mixture of 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (50 mg), 1-(oxan-4-yl)-1H-pyrazol-3-amine (30.3 mg), TEA (0.032 mL), and DMF (0.8 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane). The crude product obtained was recrystallized from diethyl ether / hexane to obtain the title compound (41.0 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.75-1.85 (2H, m), 1.88-2.12 (2H, m), 3.39 (2H, brs), 3.93 (2H, d, J = 11.7 Hz), 4.19 (1H, t, J = 11.3 Hz), 4.78-5.01 (2H, m), 6.42 (1H, d, J = 1.5 Hz), 6.73 (1H, t, J = 7.0 Hz), 7.12 (1H, td, J = 8.6, 2.4 Hz), 7.36-7.50 (2H, m), 7.62 (1H, dd, J = 8.7, 6.0 Hz), 8.06 (1H, dd, J = 6.6, 2.1 Hz), 8.58 (1H, dd, J = 7.2, 1.9 Hz), 12.08 (1H, s).

[0255] Example 60 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxy-2-methylpropoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

[0256] A) 2-Methyl-1-(4-nitrophenoxy)propan-2-ol A mixture of 4-nitrophenol (0.696 g), sodium dihydrogen phosphate (0.600 g), potassium carbonate (0.691 g), acetonitrile (5 mL) and water (2 mL) was stirred at room temperature for 5 minutes, then 2,2-dimethyloxirane (0.668 mL) was added and stirred at 150°C for 3 hours under microwave irradiation. Ethyl acetate was added to the reaction mixture, which was washed with saturated aqueous ammonium chloride solution and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.023 g). MS: [M+H] + 212.0.

[0257] B) 1-(4-aminophenoxy)-2-methylpropan-2-ol To a mixture of 2-methyl-1-(4-nitrophenoxy)propan-2-ol (1.023 g) and MeOH (10 mL), 10% palladium carbon (55% wet, 102 mg) was added and stirred at room temperature under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.845 g). MS: [M+H] + 182.0.

[0258] C) 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxy-2-methylpropoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide HATU (72.6 mg) was added to a mixture of 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (42.2 mg), 1-(4-aminophenoxy)-2-methylpropan-2-ol (30 mg), TEA (0.036 mL) and DMF (0.5 mL) at room temperature, and the mixture was stirred at the same temperature for 17 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride solution and saturated saline, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the residue was crystallized using ethyl acetate / hexane to obtain the title compound (48 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.19 (6H, s), 3.68 (2H, s), 4.60 (1H, s), 4.87 (2H, qd, J = 8.7, 1.5 Hz), 6.64-6.73 (1H, m), 6.88-6.97 (2H, m), 7.10 (1H, td, J = 8.5, 2.6 Hz), 7.41 (1H, dd, J = 10.6, 2.6 Hz), 7.53-7.65 (3H, m), 7.97 (1H, dd, J = 6.6, 2.3 Hz), 8.56 (1H, dd, J = 7.3, 2.2 Hz), 11.73 (1H, s).

[0259] Example 62 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1,2-dihydropyridine-3-carboxamide

[0260] A) 4-nitro-1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazole 2,2,3,3,3-Pentafluoropropyl trifluoromethanesulfonate (2.62 g) was added to a mixture of 4-nitro-1H-pyrazole (1.0 g), cesium carbonate (4.32 g), and DMF (20 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.850 g). 1 H NMR (300 MHz, DMSO-d6) δ 5.35 (2H, t, J = 15.3 Hz), 8.44 (1H, s), 9.05 (1H, s).

[0261] B) 1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-amine To a mixture of 4-nitro-1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazole (1.85 g) and MeOH (20 mL), 10% palladium-carbon (55% wet, 200 mg) was added and stirred overnight at room temperature under hydrogen atmosphere at atmospheric pressure. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.390 g). MS: [M+H] + 215.9.

[0262] C) 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1,2-dihydropyridine-3-carboxamide HATU (86 mg) was added to a mixture of 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (50 mg), 1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-amine (42.2 mg), TEA (0.032 mL), and DMF (0.8 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / hexane to obtain the title compound (49.0 mg). 1 H NMR (300 MHz, DMSO-d6) δ 4.86 (2H, qd, J = 8.6, 4.0 Hz), 5.18 (2H, t, J = 15.3 Hz), 6.68 (1H, t, J = 7.0 Hz), 7.10 (1H, td, J = 8.6, 2.4 Hz), 7.41 (1H, dd, J = 10.5, 2.6 Hz), 7.60 (1H, dd, J = 8.9, 6.2 Hz), 7.76 (1H, s), 7.97 (1H, dd, J = 6.6, 1.7 Hz), 8.29 (1H, s), 8.53 (1H, dd, J = 7.3, 1.7 Hz), 11.62 (1H, s).

[0263] Example 69 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(1-hydroxycyclopropyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

[0264] A) {[1-(4-bromophenyl)cyclopropyl]oxy}(tert-butyl)dimethylsilane Imidazole (188 mg) was added to a mixture of 1-(4-bromophenyl)cyclopropan-1-ol (490 mg), tert-butyldimethylchlorosilane (381 mg), and DMF (5.0 mL), and the mixture was stirred at room temperature for 3 days. Ethyl acetate was added to the reaction mixture, which was then poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (678 mg). 1 H NMR (300 MHz, CDCl3) δ -0.01 (6H, s), 0.87 (9H, s), 0.91 - 0.99 (2H, m), 1.14-1.22 (2H, m), 7.18 (2H, d, J = 8.7 Hz), 7.41 (2H, d, J = 8.7 Hz).

[0265] B) 1-(4-aminophenyl)cyclopropan-1-ol Benzophenone imine (88 μL), sodium tert-butoxide (63.0 mg), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (82 mg), and tris(dibenzylideneacetone)dipalladium(0) (40.0 mg) were added to a solution of {[1-(4-bromophenyl)cyclopropyl]oxy}(tert-butyl)dimethylsilane (143 mg) in toluene (6 mL), and the mixture was stirred overnight at 100°C under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, and insoluble matter was removed by filtration. The filtrate was washed with saturated aqueous ammonium chloride solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. THF (3 mL) and 1M hydrochloric acid (6 mL) were added to the residue, and the mixture was stirred at room temperature for 1.5 hours. Aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (28.0 mg). MS: [M+H] + 150.0.

[0266] C) 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(1-hydroxycyclopropyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide HATU (86 mg) was added to a mixture of 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (50 mg), 1-(4-aminophenyl)cyclopropan-1-ol (27 mg), TEA (42 μL), and DMF (0.5 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride solution and saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate / hexane), and crystallized from ethyl acetate / hexane to obtain the title compound (24 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.83-0.95 (2H, m), 0.97-1.10 (2H, m), 4.87 (2H, dd, J = 8.7, 1.1 Hz), 5.88 (1H, s), 6.69 (1H, t, J = 7.0 Hz), 7.06-7.15 (1H, m), 7.21 (2H, d, J = 7.8 Hz), 7.41 (1H, dd, J = 10.5, 2.6 Hz), 7.53-7.65 (3H, m), 7.98 (1H, dd, J = 6.8, 2.3 Hz), 8.57 (1H, dd, J = 7.5, 2.3 Hz), 11.83 (1H, s).

[0267] Example 72 2-Oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl]-1,2-dihydropyridine-3-carboxamide

[0268] A) 1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-amine To a mixture of 5-nitro-1-(3,3,3-trifluoropropyl)-1H-pyrazole (531 mg) and EtOH (10 mL), 10% palladium on carbon (50 mg) was added and stirred at room temperature under a hydrogen atmosphere for 16 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give the title compound (324 mg). MS: [M+H] + 179.8.

[0269] B) Ethyl 3-oxo-3-{[1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl]amino}propanoate To a mixture of 1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-amine (490 mg), TEA (415 mg) and dichloromethane (5 mL), ethyl 3-chloro-3-oxopropanoate (453 mg) was added at 0°C and stirred at room temperature for 12 hours. Ethyl 3-chloro-3-oxopropanoate (205 mg) was added at 0°C and stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (510 mg). MS: [M+H] + 293.8.

[0270] C) Ethyl 2-oxo-1-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl]-1,2-dihydropyridine-3-carboxylate A mixture of ethyl 3-oxo-3-{[1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl]amino}propanoate (510 mg), 3-(dimethylamino)acrolein (345 mg), EtOH (5 mL) and acetic acid (188 mg) was stirred at 80° C. for 48 hours. The reaction mixture was poured into water, neutralized with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (280 mg). MS: [M+H] + 329.7.

[0271] D) 2-oxo-1-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl]-1,2-dihydropyridine-3-carboxylic acid A mixture of ethyl 2-oxo-1-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl]-1,2-dihydropyridine-3-carboxylate (280 mg), lithium hydroxide monohydrate (71 mg), THF (1 mL), MeOH (1 mL) and water (1 mL) was stirred at room temperature for 12 hours. The reaction mixture was poured into water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (210 mg). MS: [M+H] + 302.0.

[0272] E) 2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl]-1,2-dihydropyridine-3-carboxamide HATU (256 mg) and DIPEA (145 mg) were added to a mixture of 2-oxo-1-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl]-1,2-dihydropyridine-3-carboxylic acid (135 mg) and DMF (5 mL), and the mixture was stirred at room temperature for 30 minutes. Then, 6-(2,2,2-trifluoroethoxy)pyridin-3-amine (86 mg) was added and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (acetonitrile / water containing 0.05% ammonia water) to obtain the title compound (27 mg). 1 H NMR (400 MHz, CDCl3) δ 2.66-3.09 (2H, m), 4.10-4.26 (2H, m), 4.77 (2H, q, J = 8.4 Hz), 6.38 (1H, d, J = 1.6 Hz), 6.69 (1H, t, J = 6.8 Hz), 6.90 (1H, d, J = 9.2 Hz), 7.53 (1H, dd, J = 6.8, 2.4 Hz), 7.73 (1H, d, J = 1.6 Hz), 8.14 (1H, dd, J = 8.8, 2.8 Hz), 8.42 (1H, d, J = 2.4 Hz), 8.81 (1H, dd, J = 7.2, 2.0 Hz), 11.45 (1H, brs).

[0273] Example 73 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-{6-[(2,2,2-trifluoroethoxy)methyl]pyridin-3-yl}-1,2-dihydropyridine-3-carboxamide

[0274] A) (5-Bromopyridin-2-yl)methyl 4-methylbenzene-1-sulfonate 4-Methylbenzenesulfonyl chloride (2.231 g) was added to a mixture of (5-bromopyridin-2-yl)methanol (2.0 g), TEA (2.97 mL), and THF (30 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.040 g). MS: [M+H] + 341.8.

[0275] B) 5-Bromo-2-[(2,2,2-trifluoroethoxy)methyl]pyridine Sodium hydride (60% in oil, 93 mg) was added to a solution of 2,2,2-trifluoroethanol (0.278 mL) in DMF (10 mL) under ice-cooling, and the mixture was stirred for 15 minutes under ice-cooling. (5-bromopyridin-2-yl)methyl 4-methylbenzene-1-sulfonate (660 mg) was added to the reaction mixture under ice-cooling, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (496 mg). MS: [M+H] + 269.8.

[0276] C) 6-[(2,2,2-trifluoroethoxy)methyl]pyridin-3-amine A mixture of 5-bromo-2-[(2,2,2-trifluoroethoxy)methyl]pyridine (496 mg), benzophenone imine (0.339 mL), sodium tert-butoxide (265 mg), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (686 mg), tris(dibenzylideneacetone)dipalladium(0) (336 mg), and toluene (10 mL) was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. THF (10.00 mL), EtOH (10.00 mL), and 2M hydrochloric acid (2 mL) were added to the residue, stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (279 mg). MS: [M+H] + 207.0.

[0277] D) 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-{6-[(2,2,2-trifluoroethoxy)methyl]pyridin-3-yl}-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (74.1 mg), 6-[(2,2,2-trifluoroethoxy)methyl]pyridin-3-amine (60 mg), TEA (0.047 mL), DMF (0.8 mL) was added to the mixture and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / hexane to obtain the title compound (56.0 mg). 1H NMR (300 MHz, DMSO-d6) δ 4.19 (2H, q, J = 9.4 Hz), 4.70 (2H, s), 4.80-4.95 (2H, m), 6.72 (1H, t, J = 7.0 Hz), 7.11 (1H, td, J = 8.6, 2.4 Hz), 7.37-7.49 (2H, m), 7.62 (1H, dd, J = 8.7, 6.4 Hz), 8.03 (1H, dd, J = 6.4, 1.9 Hz), 8.22 (1H, dd, J = 8.5, 2.4 Hz), 8.59 (1H, dd, J = 7.5, 1.9 Hz), 8.79 (1H, d, J = 2.3 Hz), 12.00 (1H, s).

[0278] Example 75 rac-N-{6-[cyclopropyl(hydroxy)methyl]pyridin-3-yl}-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

[0279] A) rac-(5-bromopyridin-2-yl)(cyclopropyl)methanol 0.5M cyclopropylmagnesium bromide-THF solution (14.90 mL) was added to a solution of 5-bromopyridine-2-carbaldehyde (1.26 g) in THF (100 mL) under ice cooling, and the mixture was stirred for 20 minutes under ice cooling, and then stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.130 g). MS: [M+H] + 227.9.

[0280] B) rac-N-{6-[cyclopropyl(hydroxy)methyl]pyridin-3-yl}-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide A mixture of rac-(5-bromopyridin-2-yl)(cyclopropyl)methanol (580 mg), benzophenone imine (0.469 mL), sodium tert-butoxide (367 mg), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (950 mg), tris(dibenzylideneacetone)dipalladium(0) (466 mg), and toluene (10 mL) was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane). THF (10.00 mL), EtOH (10.00 mL), and 2M hydrochloric acid (1.526 mL) were added to the resulting residue, stirred at room temperature for 30 minutes, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH / ethyl acetate) to give rac-(5-aminopyridin-2-yl)(cyclopropyl)methanol (367 mg) as a crude product. The crude product (80 mg), 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (72.0 mg), TEA (0.045 mL), and DMF (0.8 mL) were mixed with HATU (124 mg) and stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from diethyl ether / hexane to give the title compound (61.0 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.30-0.46 (4H, m), 1.03-1.20 (1H, m), 4.01-4.16 (1H, m), 4.75-4.97 (2H, m), 5.27 (1H, d, J = 4.5 Hz), 6.71 (1H, t, J = 6.8 Hz), 7.11 (1H, td, J = 8.4, 2.4 Hz), 7.35-7.51 (2H, m), 7.62 (1H, dd, J = 8.9, 6.2 Hz), 8.02 (1H, dd, J = 6.6, 2.1 Hz), 8.14 (1H, dd, J = 8.5, 2.4 Hz), 8.59 (1H, dd, J = 7.2, 1.9 Hz), 8.71 (1H, d, J = 2.3 Hz), 11.93 (1H, s).

[0281] Example 80 N-[6-(cyanomethyl)pyridin-3-yl]-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

[0282] A) (5-Nitropyridin-2-yl)acetonitrile To a mixture of 2-chloro-5-nitropyridine (2.05 g) and THF (30 mL), tert-butyl cyanoacetate (2.215 mL) and potassium carbonate (3.57 g) were added, and the mixture was stirred at 70° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain rac-tert-butyl cyano(5-nitropyridin-2-yl)acetate as a crude product. To a mixture of the obtained crude product and toluene (50 mL), 4-methylbenzenesulfonic acid monohydrate (0.246 g) was added, and the mixture was stirred at 110° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.24 g). 1H NMR (300 MHz, DMSO-d6) δ 4.46 (2H, s), 7.71 (1H, d, J = 8.7 Hz), 8.64 (1H, dd, J = 8.7, 2.6 Hz), 9.37 (1H, d, J = 2.3 Hz).

[0283] B) (5-aminopyridin-2-yl)acetonitrile A mixture of (5-nitropyridin-2-yl)acetonitrile (930 mg), 3.5-6.5% palladium carbon-ethylenediamine complex (93 mg) and EtOH (15 mL) was stirred at room temperature under hydrogen atmosphere for 8 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give the title compound (420 mg). MS: [M+H] + 134.0.

[0284] C) N-[6-(cyanomethyl)pyridin-3-yl]-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide A mixture of 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (60 mg), (5-aminopyridin-2-yl)acetonitrile (31.4 mg), HATU (103 mg), TEA (0.050 mL) and DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane), and the solid was washed with ethyl acetate / diisopropyl ether to obtain the title compound (26.2 mg). 1H NMR (300 MHz, DMSO-d6) δ 4.16 (2H, s), 4.80-4.95 (2H, m), 6.66-6.77 (1H, m), 7.11 (1H, td, J = 8.5, 2.6 Hz), 7.36-7.46 (2H, m), 7.62 (1H, dd, J = 8.7, 6.0 Hz), 8.03 (1H, dd, J = 6.8, 2.3 Hz), 8.22 (1H, dd, J = 8.3, 2.6 Hz), 8.59 (1H, dd, J = 7.3, 2.1 Hz), 8.80 (1H, d, J = 1.9 Hz), 12.01 (1H, s).

[0285] Example 94 1-(4-Methoxy-1-methyl-1H-pyrazol-5-yl)-2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide

[0286] A) 4-Bromo-1-methyl-5-nitro-1H-pyrazole 4-Bromo-1-methyl-1H-pyrazole (25.0 g) was added dropwise to a mixture of concentrated nitric acid (9.87 g) and concentrated sulfuric acid (100 mL) at 0°C, and the mixture was stirred at 100°C for 1 hour. The reaction mixture was poured into ice water, and 25% aqueous ammonia was added to adjust the pH to 7-8, followed by extraction with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (10.2 g). 1 H NMR (400 MHz, CDCl3) δ 4.23 (3H, s), 7.54 (1H, s).

[0287] B) 4-Methoxy-1-methyl-5-nitro-1H-pyrazole Sodium tomoxide (13.4 g) was added to a mixture of 4-bromo-1-methyl-5-nitro-1H-pyrazole (10.2 g) and MeOH (100 mL), and the mixture was stirred at 65° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (432 mg). 1 H NMR (400 MHz, CDCl3) δ 3.97 (3H, s), 4.19 (3H, s), 7.30 (1H, s).

[0288] C) 4-Methoxy-1-methyl-1H-pyrazol-5-amine hydrochloride 10% palladium-carbon (100 mg) was added to a solution of 4-methoxy-1-methyl-5-nitro-1H-pyrazole (712 mg) in MeOH (10 mL), and the mixture was stirred at room temperature for 1 hour under hydrogen atmosphere at normal pressure. The catalyst was removed by filtration, and 4M hydrogen chloride-dioxane solution (10 mL) was added to the filtrate, which was then concentrated under reduced pressure to give the title compound (623 mg). 1 H NMR (400 MHz, DMSO-d6) δ 3.71 (3H, s), 3.73 (3H, s), 7.88 (1H, s).

[0289] D) Ethyl 3-[(4-methoxy-1-methyl-1H-pyrazol-5-yl)amino]-3-oxopropanoate To a mixture of 4-methoxy-1-methyl-1H-pyrazol-5-amine hydrochloride (623 mg) and dichloromethane (10 mL), TEA (771 mg) and ethyl 3-chloro-3-oxopropanoate (631 mg) were added and stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (310 mg). MS: [M+H] + 241.8.

[0290] E) Ethyl 1-(4-methoxy-1-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate A mixture of ethyl 3-[(4-methoxy-1-methyl-1H-pyrazol-5-yl)amino]-3-oxopropanoate (310 mg), 3-(dimethylamino)acrolein (382 mg), EtOH (4 mL), and acetic acid (100 μL) was stirred for 16 hours at 80° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (224 mg). MS: [M+H] + 277.8.

[0291] F) 1-(4-methoxy-1-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid Lithium hydroxide monohydrate (39 mg) was added to a mixture of ethyl 1-(4-methoxy-1-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (224 mg), MeOH (2 mL), THF (2 mL), and water (2 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. 1M hydrochloric acid was added to the aqueous layer to adjust the pH to 6, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the title compound (86 mg). MS: [M+H] + 249.8.

[0292] G) 1-(4-Methoxy-1-methyl-1H-pyrazol-5-yl)-2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide HATU (92 mg) and DIPEA (52 mg) were added to a mixture of 1-(4-methoxy-1-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (40 mg) and DMF (5 mL), and the mixture was stirred at room temperature for 30 minutes. 6-(2,2,2-trifluoroethoxy)pyridin-3-amine (34 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (0.05% ammonia water containing acetonitrile / 0.1% ammonia water) to obtain the title compound (21 mg). 1 H NMR (400 MHz, CDCl3) δ 3.72 (3H, s), 3.81 (3H, s), 4.74 (2H, q, J = 8.8 Hz), 6.64 (1H, t, J = 6.8 Hz), 6.86 (1H, d, J = 8.8 Hz), 7.40 (1H, s), 7.48 (1H, dd, J = 6.8, 2.0 Hz), 8.12 (1H, dd, J = 8.8, 2.4 Hz), 8.40 (1H, d, J = 2.4 Hz), 8.76 (1H, dd, J = 7.2, 2.0 Hz), 11.55 (1H, brs).

[0293] Example 98 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0294] A) 4-Fluoro-1-isothiocyanato-2-(2,2,2-trifluoroethoxy)benzene 4-Fluoro-2-(2,2,2-trifluoroethoxy)aniline (8.10 g), THF (100 mL) was added with 1,1'-thiocarbonyldiimidazole (7.59 g) and stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (6.90 g). 1 H NMR (400 MHz, DMSO-d6) δ 4.95 (2H, q, J = 8.8 Hz), 6.95 (1H, t, J = 8.4 Hz), 7.31 (1H, dd, J = 10.4, 2.8 Hz), 7.40 (1H, dd, J = 8.8, 6.0 Hz).

[0295] B) N-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]thiourea A mixture of 4-fluoro-1-isothiocyanato-2-(2,2,2-trifluoroethoxy)benzene (6.90 g) and MeOH (10 mL) was added with 7N ammonia-MeOH solution (50 mL) and stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (6.95 g). MS: [M+H] + 268.8.

[0296] C) Ethyl 3-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate A mixture of N-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]thiourea (5.90 g), diethyl ethoxymethylenemalonate (14.3 g), concentrated hydrochloric acid (6 mL), and EtOH (60 mL) was stirred at 100° C. for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (5.90 g). MS: [M+H] + 393.1.

[0297] D) Ethyl 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate A mixture of ethyl 3-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6.77 g), sodium carbonate (5.49 g), methyl iodide (2.94 g), and DMF (100 mL) was stirred at room temperature for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (5.15 g). MS: [M+H] + 406.7.

[0298] E) Ethyl 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylate A mixture of ethyl 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (5.15 g), triethylsilane (3.09 g), copper(I) 2-thiophenecarboxylate (5.36 g), tetrakis(triphenylphosphine)palladium(0) (1.54 g), and dioxane (60 mL) was stirred at 80°C for 15 hours under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (3.15 g). MS: [M+H] + 360.8.

[0299] F) 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxamide A mixture of ethyl 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylate (370 mg), tributyltin hydride (1.22 g), and toluene (10 mL) was stirred at 110° C. for 15 hours. The reaction mixture was poured into water, adjusted to pH = 5-6 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid as a crude product. A mixture of the obtained crude product, 2-(4-aminophenyl)propan-2-ol (300 mg), HATU (500 mg), DIPEA (400 mg), and DMF (5 mL) was stirred at room temperature for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (0.225% formic acid in acetonitrile / 0.225% formic acid in water) to obtain a crude product. The obtained crude product was purified by thin layer chromatography (ethyl acetate / petroleum ether) to obtain the title compound (38 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.40 (6H, s), 4.90 (2H, q, J = 8.8 Hz), 5.00 (1H, brs), 7.16 (1H, t, J = 8.4 Hz), 7.35-7.50 (3H, m), 7.58 (2H, d, J = 8.4 Hz), 7.71 (1H, dd, J = 8.8, 6.0 Hz), 8.76 (1H, s), 8.88 (1H, s), 11.04 (1H, brs).

[0300] Example 108 1-[4,5-difluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide

[0301] A) 4,5-difluoro-2-(2,2,2-trifluoroethoxy)aniline 2,2,2-Trifluoroethyl trifluoromethanesulfonate (3.92 mL) was added to a mixture of 2-bromo-4,5-difluorophenol (5.17 g), cesium carbonate (12.09 g), and DMF (100 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 1-bromo-4,5-difluoro-2-(2,2,2-trifluoroethoxy)benzene (8.43 g) as a crude product. Benzophenone imine (4.49 mL), sodium tert-butoxide (3.50 g), tris(dibenzylideneacetone)dipalladium(0) (1.113 g), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.270 g), and toluene (100 mL) were added to the obtained crude product, and the mixture was refluxed for 4 hours. Tris(dibenzylideneacetone)dipalladium(0) (0.556 g) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.135 g) were added to the reaction mixture, and the mixture was refluxed for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was added with THF (80 mL), EtOH (80 mL), and 2M hydrochloric acid (30 mL), stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (1.850 g). MS: [M+H] + 227.9.

[0302] B) Ethyl 3-[4,5-difluoro-2-(2,2,2-trifluoroethoxy)anilino]-3-oxopropanoate Ethyl 3-chloro-3-oxopropanoate (1.251 mL) was added to a mixture of 4,5-difluoro-2-(2,2,2-trifluoroethoxy)aniline (1.85 g), TEA (1.703 mL), and THF (30 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.51 g). MS: [M+H] + 341.9.

[0303] C) Ethyl 1-[4,5-difluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylate To a mixture of ethyl 3-[4,5-difluoro-2-(2,2,2-trifluoroethoxy)anilino]-3-oxopropanoate (2.184 g), EtOH (30 mL), and acetic acid (1.500 mL), 3-(dimethylamino)acrolein (3.20 mL) was added, and the mixture was stirred at 80°C for 2 hours, and then at 70°C overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.20 g). MS: [M+H] + 378.0.

[0304] D) 1-[4,5-difluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid To a mixture of ethyl 1-[4,5-difluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (985 mg) and MeOH (10 mL), 4M aqueous lithium hydroxide solution (1.958 mL) was added and stirred for 5 days. The reaction mixture was neutralized with 2M hydrochloric acid, and the precipitate was collected by filtration and washed with water to obtain the title compound (699 mg). MS: [M+H] + 349.9.

[0305] E) 1-[4,5-difluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4,5-difluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (65.4 mg), 2-(4-aminophenyl)propan-2-ol (34 mg), TEA (0.039 mL), DMF (0.8 mL) was added with HATU (107 mg) and stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / hexane to obtain the title compound (50.0 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.41 (6H, s), 4.77-4.91 (2H, m), 4.95 (1H, s), 6.71 (1H, t, J = 7.0 Hz), 7.34-7.49 (2H, m), 7.58 (2H, d, J = 8.7 Hz), 7.70 (1H, dd, J = 12.0, 7.2 Hz), 7.92 (1H, dd, J = 10.5, 8.3 Hz), 8.00 (1H, dd, J = 6.6, 2.1 Hz), 8.57 (1H, dd, J = 7.2, 2.3 Hz), 11.75 (1H, s).

[0306] Example 109 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide

[0307] A) 1-(2,2-difluoroethoxy)-2-nitrobenzene 2,2-Difluoroethyl trifluoromethanesulfonate (76 g) was added to a mixture of 2-nitrophenol (47 g), cesium carbonate (143 g) and DMF (500 mL) under ice-cooling. After stirring overnight at room temperature, water was added to the mixture. The resulting solid was collected by filtration to obtain the title compound (67.2 g). 1 H NMR (300 MHz, DMSO-d6) δ 4.43-4.61 (2H, m), 6.17-6.61 (1H, m), 7.13-7.26 (1H, m), 7.38-7.48 (1H, m), 7.62-7.74 (1H, m), 7.85-7.96 (1H, m).

[0308] B) 2-(2,2-difluoroethoxy)aniline 10% palladium-carbon (55% wet, 3.0 g) was added to a solution of 1-(2,2-difluoroethoxy)-2-nitrobenzene (67.2 g) in MeOH (700 mL). The mixture was stirred overnight under hydrogen atmosphere at normal pressure. The mixture was filtered through Celite with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the title compound (57.0 g). MS: [M+H] + 174.1.

[0309] C) [2-(2,2-difluoroethoxy)phenyl]hydrazine A mixture of concentrated hydrochloric acid (500 mL) and 2-(2,2-difluoroethoxy)aniline (57 g) was stirred at 0°C for 30 minutes, and then a mixture of sodium nitrate (27.3 g) and water (100 mL) was added dropwise to the mixture at 0°C, and the mixture was stirred at 0°C for 30 minutes. Then, a mixture of tin chloride (187 g) and concentrated hydrochloric acid (300 mL) was added dropwise to the mixture at 0°C, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was filtered without washing, and the filter cake was dissolved in 2N aqueous sodium hydroxide solution (500 mL). The mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was collected by filtration using hexane to obtain the title compound (43.3 g). MS: [M+H] + 189.0.

[0310] D) rac-Ethyl 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate To a solution of [2-(2,2-difluoroethoxy)phenyl]hydrazine (35.0 g) in THF (400 mL) and acetic acid (40.0 mL), diethyl acetonylmalonate (40.2 g) was added at 0°C. The mixture was stirred at room temperature for 5 hours. The mixture was diluted with toluene and concentrated under reduced pressure. To a solution of the residue in toluene (400 mL), p-toluenesulfonic acid monohydrate (7.08 g) was added at room temperature. The mixture was stirred at 100°C overnight. p-toluenesulfonic acid monohydrate (7.08 g) was added to the mixture again. The mixture was stirred at 100°C for 5 hours. The mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SI then NH, ethyl acetate / hexane) to obtain the title compound (16.8 g). MS: [M+H] + 341.1.

[0311] E) Ethyl 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylate 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (11.21 g) was added to a solution of rac-ethyl 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate (16.8 g) in toluene (400 mL) at room temperature. The mixture was stirred at 100°C for 2 hours. The mixture was filtered over NH silica gel using ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (11.2 g). MS: [M+H] + 339.1.

[0312] F) 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid To a solution of ethyl 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylate (11.2 g) in EtOH (300 mL), 2M aqueous sodium hydroxide solution (83 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the resulting solid was dissolved in water. The solution was acidified with 1N hydrochloric acid at 0°C, and the precipitate was collected by filtration to obtain the title compound (9.05 g). MS: [M+H] + 311.1.

[0313] G) 1,1,3,3-tetrafluoro-2-(5-nitropyridin-2-yl)propan-2-ol To a mixture of 5-nitropyridine-2-carboxylic acid (1.0 g) and THF (20 mL), oxalyl chloride (0.604 mL) and DMF (1 drop) were added under ice cooling. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to obtain 5-nitropyridine-2-carbonyl chloride as a crude product. To a mixture of the obtained crude product and acetonitrile (15 mL), [bromo(difluoro)methyl](trimethyl)silane (1.922 mL), triphenylphosphine (2.70 g), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.987 mL) were added at 0°C. The mixture was stirred at room temperature overnight. To the mixture, water (10 mL) and pyridine (2 mL) were added at room temperature. The mixture was stirred at 80°C for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (0.606 g). MS: [M+H] + 254.9.

[0314] H) 2-(5-aminopyridin-2-yl)-1,1,3,3-tetrafluoropropan-2-ol To a mixture of 1,1,3,3-tetrafluoro-2-(5-nitropyridin-2-yl)propan-2-ol (606 mg), EtOH (6 mL), and water (6 mL), ammonium chloride (638 mg) and iron powder (666 mg) were added at room temperature. The mixture was refluxed for 3 hours. Insoluble materials were removed by filtration. A saturated aqueous solution of sodium bicarbonate was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (235 mg). MS: [M+H] + 224.9.

[0315] I) 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide HATU (110 mg) was added to a solution of 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (60 mg), 2-(5-aminopyridin-2-yl)-1,1,3,3-tetrafluoropropan-2-ol (52.0 mg) in DMF (1 mL) and TEA (0.040 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from ethyl acetate / diisopropyl ether / hexane to obtain the title compound (62.0 mg). 1 H NMR (300 MHz, DMSO) δ 2.44 (3H, s), 4.37 (2H, t, J = 14.9 Hz), 5.99-6.75 (3H, m), 7.12 (1H, s), 7.19 (1H, td, J = 7.7, 1.1 Hz), 7.35 (1H, d, J = 7.5 Hz), 7.43-7.58 (2H, m), 7.73 (1H, d, J = 8.7 Hz), 8.25-8.34 (2H, m), 8.88 (1H, d, J = 1.9 Hz), 11.85 (1H, s).

[0316] Example 114 N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-2'-(2,2,2-trifluoroethoxy)-2H-[1,3'-bipyridine]-3-carboxamide

[0317] A) 3-nitro-2-(2,2,2-trifluoroethoxy)pyridine To a mixture of 2,2,2-trifluoroethanol (3.38 g) and THF (10 mL), 1.3M lithium bis(trimethylsilyl)amide-THF solution (23.82 mL) was added under ice-cooling, and the mixture was stirred under ice-cooling for 15 minutes. 2-Fluoro-3-nitropyridine (4 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (3.03 g). MS: [M+H] + 222.9.

[0318] B) 2-(2,2,2-trifluoroethoxy)pyridin-3-amine To a mixture of 3-nitro-2-(2,2,2-trifluoroethoxy)pyridine (3.03 g) and MeOH (40 mL), 10% palladium-carbon (55% wet, 400 mg) was added and the mixture was stirred at room temperature under normal pressure under a hydrogen atmosphere overnight. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.490 g). MS: [M+H] + 192.9.

[0319] C) Ethyl 3-oxo-3-{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]amino}propanoate Ethyl 3-chloro-3-oxopropanoate (1.991 mL) was added to a mixture of 2-(2,2,2-trifluoroethoxy)pyridin-3-amine (2.49 g), TEA (2.71 mL), and THF (40 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.480 g). MS: [M+H] + 306.9.

[0320] D) 2-oxo-2'-(2,2,2-trifluoroethoxy)-2H-[1,3'-bipyridine]-3-carboxylic acid To a mixture of ethyl 3-oxo-3-{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]amino}propanoate (2.48 g), EtOH (40 mL), and acetic acid (2.000 mL), 3-(dimethylamino)acrolein (4.05 mL) was added, and the mixture was refluxed for 3 hours and then stirred at 70°C overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain ethyl 2-oxo-2'-(2,2,2-trifluoroethoxy)-2H-[1,3'-bipyridine]-3-carboxylate (1.88 g) as a crude product. MeOH (20 mL) and 4M lithium hydroxide aqueous solution (4 mL) were added to the obtained crude product, and the mixture was stirred for 5 days. The reaction mixture was neutralized with 1M hydrochloric acid, and the precipitate was collected by filtration and washed with water to obtain a crude product. The crude product was recrystallized from ethyl acetate / hexane to obtain the title compound (807 mg). MS: [M+H] + 314.9.

[0321] E) N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-2'-(2,2,2-trifluoroethoxy)-2H-[1,3'-bipyridine]-3-carboxamide 2-Oxo-2'-(2,2,2-trifluoroethoxy)-2H-[1,3'-bipyridine]-3-carboxylic acid (70 mg), 2-(4-aminophenyl)propan-2-ol (40 mg), TEA (0.047 mL), DMF (0.8 mL) was added to a mixture and stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from diethyl ether / hexane to obtain the title compound (42.0 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.41 (6H, s), 4.95 (1H, s), 4.99-5.16 (2H, m), 6.66-6.80 (1H, m), 7.30-7.48 (3H, m), 7.53-7.65 (2H, m), 8.08 (2H, dd, J = 7.2, 5.7, 2.1 Hz), 8.38 (1H, dd, J = 4.9, 1.5 Hz), 8.59 (1H, dd, J = 7.2, 2.3 Hz), 11.73 (1H, s).

[0322] Example 119 N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-2-oxo-1-[5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-1,2-dihydropyridine-3-carboxamide

[0323] A) 5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine A mixture of 4-aminopyrimidin-5-ol (2.00 g), 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.21 g), cesium carbonate (7.04 g), and DMF (15 mL) was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (2.40 g). 1 H NMR (400 MHz, DMSO-d6) δ 4.79 (2H, q, J = 9.2 Hz), 6.81 (2H, brs), 7.96 (1H, s), 8.08 (1H, s).

[0324] B) Ethyl 3-oxo-3-{[5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]amino}propanoate To a mixture of 5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine (1.20 g), TEA (943 mg), and dichloromethane (20 mL), ethyl 3-chloro-3-oxopropanoate (1.03 g) was added at 0° C. and stirred at room temperature for 4 hours. To the reaction mixture, ethyl 3-chloro-3-oxopropanoate (1.03 g) was added at 0° C. and stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (1.09 g). MS: [M+H] + 307.8.

[0325] C) Ethyl 2-oxo-1-[5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-1,2-dihydropyridine-3-carboxylate A mixture of ethyl 3-oxo-3-{[5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]amino}propanoate (480 mg), 3-(dimethylamino)acrolein (310 mg), EtOH (5 mL), and acetic acid (169 mg) was stirred at 60° C. for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (370 mg). MS: [M+H] + 344.1.

[0326] D) 2-oxo-1-[5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-1,2-dihydropyridine-3-carboxylic acid Lithium hydroxide monohydrate (33 mg) was added to a mixture of ethyl 2-oxo-1-[5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-1,2-dihydropyridine-3-carboxylate (270 mg), THF (3 mL), and water (3 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and 1M hydrochloric acid was added to the residue to adjust the pH to 6, and the precipitate was collected by filtration. Water was added to the obtained crude product, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (113 mg). MS: [M+H] + 315.9.

[0327] E) 2-(5-bromopyridin-2-yl)propan-2-ol To a mixture of methyl 5-bromopyridine-2-carboxylate (7.29 g) and THF (100 mL), 1M methylmagnesium bromide-2-methyltetrahydrofuran solution (23.62 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (3.59 g). MS: [M+H] + 216.0.

[0328] F) 2-(5-aminopyridin-2-yl)propan-2-ol A mixture of 2-(5-bromopyridin-2-yl)propan-2-ol (1.62 g), benzophenone imine (1.510 mL), cesium carbonate (7.33 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.868 g), tris(dibenzylideneacetone)dipalladium(0) (0.687 g), and 1,2-dimethoxyethane (30 mL) was refluxed under nitrogen atmosphere for 4 hours. Ethyl acetate was added to the reaction mixture, and insoluble matter was removed by filtration. The filtrate was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. THF (15 mL), MeOH (15 mL), and 2M hydrochloric acid (10 mL) were added to the residue, stirred at room temperature for 30 minutes, neutralized with 2M aqueous sodium hydroxide solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (0.713 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.35 (6H, s), 4.89 (1H, s), 5.07 (2H, s), 6.89 (1H, dd, J = 8.5, 2.8 Hz), 7.26 (1H, d, J = 9.0 Hz), 7.82 (1H, dd, J = 2.6, 0.8 Hz).

[0329] G) N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-2-oxo-1-[5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-1,2-dihydropyridine-3-carboxamide 2-Oxo-1-[5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-1,2-dihydropyridine-3-carboxylic acid (50 mg), 2-(5-aminopyridin-2-yl)propan-2-ol (30 mg), TEA (0.033 mL), DMF (0.8 mL) was added to the mixture and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and recrystallized from diethyl ether / hexane to obtain the title compound (28.0 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.42 (6H, s), 5.03-5.21 (3H, m), 6.76-6.90 (1H, m), 7.64 (1H, d, J = 8.7 Hz), 8.11 (1H, dd, J = 8.7, 2.6 Hz), 8.18 (1H, dd, J = 6.8, 2.3 Hz), 8.63 (1H, dd, J = 7.2, 2.3 Hz), 8.68 (1H, d, J = 2.3 Hz), 9.06 (1H, s), 9.09 (1H, s), 11.56 (1H, s).

[0330] Example 121 rac-2-oxo-1-[3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]-N-[6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide

[0331] A) rac-2-(5-bromopyridin-2-yl)-1,1,1-trifluoropropan-2-ol 1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethan-1-one (1.0 g) in THF (20 mL) was added with 3M methylmagnesium bromide-2-methyltetrahydrofuran solution (1.444 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (0.190 g). MS: [M+H] + 269.8.

[0332] B) rac-2-(5-aminopyridin-2-yl)-1,1,1-trifluoropropan-2-ol To a mixture of rac-2-(5-bromopyridin-2-yl)-1,1,1-trifluoropropan-2-ol (190 mg), benzophenone imine (0.142 mL), cesium carbonate (688 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (163 mg), and 1,2-dimethoxyethane (4 mL), tris(dibenzylideneacetone)dipalladium(0) (129 mg) was added and the mixture was refluxed under nitrogen atmosphere for 4 hours. Ethyl acetate was added to the reaction mixture, insoluble matter was removed by filtration, and the mixture was concentrated under reduced pressure. THF (4 mL), MeOH (4 mL), and 2M hydrochloric acid (2 mL) were added to the residue, and the mixture was stirred at room temperature for 30 minutes, neutralized by adding 2M aqueous sodium hydroxide solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (110 mg). MS: [M+H] + 207.0.

[0333] C) tert-Butyl (3,6-dichloropyridazin-4-yl)carbamate A mixture of 3,6-dichloropyridazine-4-carboxylic acid (3 g), TEA (2.383 mL), DPPA (3.69 mL) and tert-butyl alcohol (30 mL) was stirred overnight at 80° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.61 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.51 (9H, s), 8.22 (1H, d, J = 0.8 Hz), 9.64 (1H, brs).

[0334] D) 3,6-Dichloropyridazin-4-amine A mixture of tert-butyl (3,6-dichloropyridazin-4-yl)carbamate (2.61 g), 4M hydrogen chloride / ethyl acetate (37.1 mL), and ethyl acetate (20 mL) was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (1.85 g). MS: [M+H] + 163.9.

[0335] E) 6-chloro-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine A mixture of 3,6-dichloropyridazin-4-amine (1.85 g), 2,2,2-trifluoroethanol (1.620 mL), lithium hydroxide monohydrate (1.041 g), DMSO (20 mL) and water (2.000 mL) was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and washed with water to obtain the title compound (2.20 g). MS: [M+H] + 227.9.

[0336] F) 3-(2,2,2-trifluoroethoxy)pyridazin-4-amine A mixture of 6-chloro-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine (2.20 g), 10% palladium on carbon (49% wet, 220 mg) and MeOH (40 mL) was stirred at room temperature for 5 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (1.84 g). MS: [M+H] + 193.9.

[0337] G) Ethyl 3-oxo-3-{[3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]amino}propanoate To a mixture of 3-(2,2,2-trifluoroethoxy)pyridazin-4-amine (1.3 g), TEA (1.407 mL) and THF (6 mL), ethyl 3-chloro-3-oxopropanoate (1.034 mL) was added at 0°C and stirred at room temperature overnight. TEA (0.7 mL) and ethyl 3-chloro-3-oxopropanoate (0.5 mL) were added to the reaction mixture at room temperature and stirred at the same temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.534 g). MS: [M+H] + 308.0.

[0338] H) Ethyl 2-oxo-1-[3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]-1,2-dihydropyridine-3-carboxylate To a mixture of ethyl 3-oxo-3-{[3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]amino}propanoate (271 mg), EtOH (4 mL) and acetic acid (0.200 mL), 3-(dimethylamino)acrolein (0.422 mL) was added at room temperature and stirred at 70°C overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (105 mg). MS: [M+H] + 343.9.

[0339] I) 2-oxo-1-[3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]-1,2-dihydropyridine-3-carboxylic acid A mixture of ethyl 2-oxo-1-[3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]-1,2-dihydropyridine-3-carboxylate (105 mg), 1M aqueous sodium hydroxide solution (0.918 mL), and MeOH (1.5 mL) was stirred at room temperature overnight. The reaction mixture was acidified with 1M hydrochloric acid, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration and washed with water and diisopropyl ether to obtain the title compound (44 mg). MS: [M+H] + 315.9.

[0340] J) rac-2-oxo-1-[3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]-N-[6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide 2-Oxo-1-[3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]-1,2-dihydropyridine-3-carboxylic acid (50 mg), rac-2-(5-aminopyridin-2-yl)-1,1,1-trifluoropropan-2-ol (50 mg), TEA (0.033 mL), DMF (0.8 mL) was added to the mixture and stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography (SI and NH, ethyl acetate / hexane) to obtain the title compound (3.70 mg). 1 H NMR (400 MHz, CDCl3) δ1.72 (3H, s), 5.08 (2H, q, J = 8.3 Hz), 6.12 (1H, s), 6.70 (1H, t, J = 7.2 Hz), 7.44-7.55 (2H, m), 7.64 (1H, d, J = 4.9 Hz), 8.32 (1H, dd, J = 8.7, 2.6 Hz), 8.73-8.83 (2H, m), 9.21 (1H, d, J = 5.3 Hz), 11.66 (1H, s).

[0341] Example 127 N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide HATU (182 mg) was added to a mixture of 3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid (100 mg), 2-(4-aminophenyl)propan-2-ol (69 mg), TEA (48.3 mg), and DMF (0.8 mL) at room temperature. After stirring overnight at room temperature, the mixture was purified by silica gel column chromatography (SI then NH, ethyl acetate / hexane) and recrystallized from diethyl ether / hexane to obtain the title compound (67 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.41 (6H, s), 4.82 (2H, brs), 4.98 (1H, s), 7.25 (1H, td, J = 7.5, 1.1 Hz), 7.39 (1H, d, J = 7.5 Hz), 7.43-7.50 (2H, m), 7.51-7.64 (4H, m), 8.30 (1H, d, J = 4.1 Hz), 8.34-8.40 (1H, m), 11.53 (1H, s).

[0342] Example 133 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0343] A) (2E)-{2-[2-(2,2-difluoroethoxy)phenyl]hydrazinylidene}acetaldehyde To a mixture of [2-(2,2-difluoroethoxy)phenyl]hydrazine (2.53 g), acetic acid (15 mL), and water (15.00 mL), 40% aqueous glyoxal solution (7.80 g) was added and stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with water to obtain a crude product. Ethyl acetate was added to the crude product, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (2.76 g). MS: [M+H] + 229.0.

[0344] B) 5-[(2E)-2-{2-[2-(2,2-difluoroethoxy)phenyl]hydrazinylidene}ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione To a mixture of (2E)-{2-[2-(2,2-difluoroethoxy)phenyl]hydrazinylidene}acetaldehyde (2.76 g) and toluene (50 mL), 2,2-dimethyl-1,3-dioxane-4,6-dione (1.743 g), piperidine (0.239 mL), and acetic acid (0.138 mL) were added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (3.65 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.69 (6H, s), 4.43 (2H, td, J = 14.3, 3.8 Hz), 6.19-6.65 (1H, m), 7.00-7.13 (2H, m), 7.15-7.23 (1H, m), 7.48-7.61 (1H, m), 7.96 (1H, d, J = 10.5 Hz), 9.06 (1H, d, J = 10.5 Hz), 11.95 (1H, s).

[0345] C) 2-[2-(2,2-difluoroethoxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid Sodium methoxide (0.668 g) was added to a solution of 5-[(2E)-2-{2-[2-(2,2-difluoroethoxy)phenyl]hydrazinylidene}ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (3.65 g) in MeOH (80 mL), and the mixture was stirred at 70°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, which was then washed with ethyl acetate. The organic layer was extracted with 1M aqueous sodium hydroxide solution. The aqueous layers were combined, acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to give the title compound (2.62 g). MS: [M+H] + 296.9.

[0346] D) 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (100 mg), 2-(4-aminophenyl)propan-2-ol (77 mg), TEA (0.071 mL), DMF (1 mL) was added with HATU (193 mg) and stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / hexane to obtain the title compound (83 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.41 (6H, s), 4.27-4.47 (2H, m), 4.98 (1H, s), 5.99-6.43 (1H, m), 7.20 (1H, td, J = 7.7, 1.1 Hz), 7.35 (1H, dd, J = 8.3, 1.1 Hz), 7.43-7.58 (4H, m), 7.58-7.65 (2H, m), 8.29 (1H, d, J = 4.1 Hz), 8.33-8.39 (1H, m), 11.54 (1H, s).

[0347] Example 135 2-[2-(2,2-difluoroethoxy)phenyl]-N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide A mixture of 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (100 mg), 2-(5-aminopyridin-2-yl)propan-2-ol (63.8 mg), TEA (65.2 mg), HATU (147 mg), and DMF (2 mL) was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (118 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.43 (6H, s), 2.44 (3H, s), 4.25-4.47 (2H, m), 5.19 (1H, s), 5.99-6.43 (1H, m), 7.16-7.24 (1H, m), 7.31-7.38 (1H, m), 7.44-7.56 (2H, m), 7.63-7.70 (1H, m), 8.14 (1H, dd, J = 8.5, 2.4 Hz), 8.26 (1H, s), 8.73 (1H, d, J = 2.3 Hz), 11.72 (1H, s).

[0348] Example 136 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-(4-aminophenyl)propan-2-ol (2.144 g), HATU (5.39 g) and TEA (2.61 g) were added to a solution of 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (4.00 g) in DMF (40 mL) at 0°C. The mixture was stirred at room temperature for 3 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane). After filtration to remove dust and concentration under reduced pressure, the resulting solid was recrystallized from ethyl acetate to obtain the title compound (3.80 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.41 (6H, s), 2.43 (3H, s), 4.25-4.49 (2H, m), 4.99 (1H, s), 6.00-6.42 (1H, m), 7.15-7.24 (1H, m), 7.31-7.37 (1H, m), 7.42-7.56 (4H, m), 7.57-7.65 (2H, m), 8.25 (1H, s), 11.67 (1H, s).

[0349] Example 140 rac-N-[5-(1-hydroxyethyl)pyridin-2-yl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide

[0350] A) [2-(2,2,2-trifluoroethoxy)phenyl]hydrazine A mixture of 2-(2,2,2-trifluoroethoxy)aniline (10.60 g) and concentrated hydrochloric acid (60 mL) was stirred at 0°C for 30 minutes, and a mixture of sodium nitrite (4.59 g) and water (10.0 mL) was added dropwise to the mixture at 0°C, and the mixture was stirred at 0°C for 30 minutes. Then, a mixture of tin(II) chloride (31.5 g) and concentrated hydrochloric acid (80 mL) was added dropwise to the mixture at 0°C, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was filtered without washing, and the filter cake was dissolved in 2N aqueous sodium hydroxide solution (100 mL). The mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with 2M aqueous sodium hydroxide solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was filtered using hexane to obtain the title compound (6.48 g). MS: [M+H] + 207.0.

[0351] B) (2E)-{2-[2-(2,2,2-trifluoroethoxy)phenyl]hydrazinylidene}acetaldehyde A mixture of [2-(2,2,2-trifluoroethoxy)phenyl]hydrazine (5.36 g), acetic acid (25 mL), and water (25.00 mL) was added to 40% aqueous glyoxal solution (15.09 g) at room temperature. The mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration and washed with water. The resulting solid was dissolved in ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (6.25 g). MS: [M+H] + 246.9.

[0352] C) 2,2-Dimethyl-5-[(2E)-2-{2-[2-(2,2,2-trifluoroethoxy)phenyl]hydrazinylidene}ethylidene]-1,3-dioxane-4,6-dione To a solution of (2E)-{2-[2-(2,2,2-trifluoroethoxy)phenyl]hydrazinylidene}acetaldehyde (6.25 g) in toluene (75 mL), 2,2-dimethyl-1,3-dioxane-4,6-dione (2.159 g), piperidine (0.296 mL), and acetic acid (0.171 mL) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). Ethyl acetate and hexane were added to the obtained crude product, and the resulting solid was collected by filtration to obtain the title compound (4.55 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.69 (6H, s), 4.86 (2H, q, J = 8.8 Hz), 7.01-7.15 (2H, m), 7.17-7.29 (1H, m), 7.50-7.63 (1H, m), 7.96 (1H, d, J = 10.5 Hz), 9.08 (1H, d, J = 10.5 Hz), 11.98 (1H, s).

[0353] D) 3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid To a mixture of 2,2-dimethyl-5-[(2E)-2-{2-[2-(2,2,2-trifluoroethoxy)phenyl]hydrazinylidene}ethylidene]-1,3-dioxane-4,6-dione (4.55 g) and MeOH (100 mL) was added 5M sodium methoxide-MeOH solution (2.93 mL) at room temperature. The mixture was stirred at 70°C for 5 hours. The mixture was concentrated under reduced pressure, and the resulting solid was dissolved in water. The solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate / hexane to obtain the title compound (3.53 g). MS: [M+H] + 314.9.

[0354] E) 1-(6-aminopyridin-3-yl)ethan-1-one A mixture of 1-(6-chloropyridin-3-yl)ethanone (1250 mg) and 28% aqueous ammonia (25 mL) was stirred at 120°C for 2 hours under microwave irradiation. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (767 mg). MS: [M+H] + 137.0.

[0355] F) rac-1-(6-aminopyridin-3-yl)ethan-1-ol Sodium borohydride (371 mg) was added to a mixture of 1-(6-aminopyridin-3-yl)ethan-1-one (667 mg) and MeOH (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH / ethyl acetate). The crude product obtained was washed with ethyl acetate / hexane to give the title compound (672 mg). MS: [M+H] + 139.0.

[0356] G) rac-N-[5-(1-hydroxyethyl)pyridin-2-yl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide 3-Oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid (100 mg), rac-1-(6-aminopyridin-3-yl)ethan-1-ol (66.0 mg), TEA (0.067 mL), DMF (0.8 mL) was added to the mixture and stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / hexane to obtain the title compound (75 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.35 (3H, d, J = 6.4 Hz), 4.67-4.92 (3H, m), 5.28 (1H, d, J = 4.1 Hz), 7.25 (1H, td, J = 7.5, 1.1 Hz), 7.40 (1H, d, J = 7.5 Hz), 7.49-7.62 (2H, m), 7.84 (1H, dd, J = 8.5, 2.4 Hz), 8.21 (1H, d, J = 8.7 Hz), 8.29-8.41 (3H, m), 11.89 (1H, s).

[0357] Example 144 rac-2-[2-(2,2-difluoroethoxy)phenyl]-3-oxo-N-[4-(oxolan-2-yl)phenyl]-2,3-dihydropyridazine-4-carboxamide

[0358] A) 2-(4-nitrophenyl)furan A mixture of 1-bromo-4-nitrobenzene (1 g), 2-furylboronic acid (0.554 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.362 g), potassium carbonate (1.710 g), 1,2-dimethoxyethane (10 mL), and water (0.250 mL) was stirred at 85° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane). The obtained crude product was washed with ethyl acetate / hexane to obtain the title compound (0.344 g). 1 H NMR (300 MHz, DMSO-d6) δ 6.72 (1H, dd, J = 3.6, 1.7 Hz), 7.32 (1H, d, J = 3.0 Hz), 7.89-8.01 (3H, m), 8.23-8.33 (2H, m).

[0359] B) rac-4-(oxolan-2-yl)aniline To a mixture of 2-(4-nitrophenyl)furan (344 mg) and MeOH (10 mL), 10% palladium-carbon (55% wet, 100 mg) was added and the mixture was stirred at room temperature under normal pressure hydrogen atmosphere overnight. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (129 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.54-1.69 (1H, m), 1.81-1.97 (2H, m), 2.05-2.19 (1H, m), 3.70 (1H, td, J = 7.9, 6.4 Hz), 3.83-3.96 (1H, m), 4.56 (1H, dd, J = 8.1, 6.6 Hz), 4.95 (2H, s), 6.45-6.53 (2H, m), 6.88-7.00 (2H, m).

[0360] C) rac-2-[2-(2,2-difluoroethoxy)phenyl]-3-oxo-N-[4-(oxolan-2-yl)phenyl]-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (100 mg), rac-4-(oxolan-2-yl)aniline (66.1 mg), TEA (0.071 mL), DMF (1 mL) was added with HATU (154 mg) and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / hexane to obtain the title compound (98 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.55-1.73 (1H, m), 1.86-2.01 (2H, m), 2.18-2.35 (1H, m), 3.72-3.85 (1H, m), 3.92-4.03 (1H, m), 4.37 (2H, br t, J = 14.1 Hz), 4.77 (1H, t, J = 7.2 Hz), 5.99-6.44 (1H, m), 7.20 (1H, td, J = 7.5, 1.1 Hz), 7.27-7.40 (3H, m), 7.46-7.58 (2H, m), 7.60-7.73 (2H, m), 8.24-8.31 (1H, m), 8.36 (1H, d, J = 4.5 Hz), 11.57 (1H, s).

[0361] Example 146 2-[2-(2,2-difluoroethoxy)phenyl]-N-[2-fluoro-4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0362] A) Methyl 3-fluoro-4-nitrobenzoate To a mixture of 3-fluoro-4-nitrobenzoic acid (10.0 g), potassium carbonate (14.93 g) and DMF (100 mL), iodomethane (5.04 mL) was added at room temperature and stirred at room temperature for 3 hours. The reaction mixture was poured into water at 0°C and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (10.62 g). 1 H NMR (300 MHz, DMSO-d6) δ 3.92 (3H, s), 7.91-8.00 (1H, m), 8.04 (1H, dd, J = 11.4, 1.5 Hz), 8.29 (1H, dd, J = 8.5, 7.5 Hz).

[0363] B) Methyl 4-amino-3-fluorobenzoate A mixture of methyl 3-fluoro-4-nitrobenzoate (2 g), 10% palladium on carbon (55% wet, 200 mg), ethyl acetate (10 mL) and EtOH (10 mL) was stirred at room temperature for 3 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (1.687 g). MS: [M+H] + 170.1.

[0364] C) 2-(4-amino-3-fluorophenyl)propan-2-ol A 3M methylmagnesium bromide-2-methyltetrahydrofuran solution (16.55 mL) was added dropwise to a mixture of methyl 4-amino-3-fluorobenzoate (1.68 g) and THF (20 mL) at 0°C, and the mixture was stirred at room temperature overnight. A 3M methylmagnesium bromide-2-methyltetrahydrofuran solution (3.31 mL) was added to the reaction mixture at 0°C, and the mixture was stirred at 40°C for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (540 mg). MS: [M+H] + 170.1.

[0365] D) 2-[2-(2,2-difluoroethoxy)phenyl]-N-[2-fluoro-4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide HATU (129 mg) was added to a mixture of 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (70 mg), 2-(4-amino-3-fluorophenyl)propan-2-ol (76 mg), TEA (0.047 mL) and DMF (1.5 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (90 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.41 (6H, s), 2.44 (3H, s), 4.26-4.48 (2H, m), 5.13 (1H, s), 5.96-6.42 (1H, m), 7.19 (1H, td, J = 7.6, 1.3 Hz), 7.27-7.40 (3H, m), 7.42-7.57 (2H, m), 8.24-8.38 (2H, m), 11.96 (1H, d, J = 1.9 Hz).

[0366] Example 148 N-[2-fluoro-4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide HATU (109 mg) was added to a mixture of 3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid (60 mg), 2-(4-amino-3-fluorophenyl)propan-2-ol (64.6 mg), TEA (0.040 mL) and DMF (1.5 mL) at room temperature, and the mixture was stirred at the same temperature for 2 days. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (26.5 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.41 (6H, s), 4.72-4.91 (2H, m), 5.13 (1H, s), 7.21-7.43 (4H, m), 7.50-7.61 (2H, m), 8.29-8.41 (3H, m), 11.82 (1H, d, J = 1.9 Hz).

[0367] Example 152 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,3-dihydropyridazine-4-carboxamide

[0368] A) 1,1,3,3-tetrafluoro-2-(4-nitrophenyl)propan-2-ol To a mixture of 4-nitrobenzoyl chloride (1.002 g) and acetonitrile (10 mL), [bromo(difluoro)methyl](trimethyl)silane (2.52 mL), triphenylphosphine (3.54 g), and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (2.60 mL) were added at 0°C, and the mixture was stirred at room temperature for 72 hours. Water (10 mL) and pyridine (2 mL) were added to the reaction mixture, and the mixture was stirred at 80°C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.218 g). MS: [MH] - 251.9.

[0369] B) 2-(4-aminophenyl)-1,1,3,3-tetrafluoropropan-2-ol 1,1,3,3-Tetrafluoro-2-(4-nitrophenyl)propan-2-ol (604.5 mg), water (6 mL), EtOH (6.00 mL), ammonium chloride (639 mg), and reduced iron (667 mg) were added and refluxed for 2 hours. Insoluble matter was removed by filtration, and saturated aqueous sodium bicarbonate solution was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (532 mg). MS: [M+H] + 224.0.

[0370] C) 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,3-dihydropyridazine-4-carboxamide HATU (165 mg) was added to a mixture of 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (90 mg), 2-(4-aminophenyl)-1,1,3,3-tetrafluoropropan-2-ol (97 mg), TEA (0.061 mL), and DMF (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (80 mg). 1 H NMR (300 MHz, DMSO) δ 2.44 (3H, s), 4.37 (2H, t, J = 14.3 Hz), 6.00-6.65 (3H, m), 6.98 (1H, s), 7.13-7.24 (1H, m), 7.30-7.37 (1H, m), 7.42-7.63 (4H, m), 7.75 (2H, d, J = 9.0 Hz), 8.26 (1H, s), 11.78 (1H, s).

[0371] Example 154 N-[2-cyano-4-(2-hydroxypropan-2-yl)phenyl]-2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0372] A) Methyl 3-cyano-4-nitrobenzoate A mixture of methyl 3-bromo-4-nitrobenzoate (2.05 g), copper(I) cyanide (1.059 g), and N-methylpyrrolidone (30 mL) was stirred at 150° C. for 7 hours under an argon atmosphere. Brine and ethyl acetate were added to the reaction mixture, which was then filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (770 mg). 1 H NMR (300 MHz, DMSO-d6) δ 3.94 (3H, s), 8.40-8.46 (1H, m), 8.48-8.53 (1H, m), 8.56 (1H, d, J = 1.9 Hz).

[0373] B) Methyl 4-amino-3-cyanobenzoate A mixture of methyl 3-cyano-4-nitrobenzoate (760 mg), 10% palladium on carbon (55% wet, 392 mg), MeOH (20 mL) and THF (10 mL) was stirred at room temperature under a hydrogen atmosphere for 4 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (480 mg). MS: [M+H] + 177.1.

[0374] C) 2-Amino-5-(2-hydroxypropan-2-yl)benzonitrile To a mixture of methyl 4-amino-3-cyanobenzoate (480 mg) and THF (5 mL), 2M methylmagnesium bromide - THF / 2-methyltetrahydrofuran solution (6.81 mL) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes and at room temperature for 21 hours. Diethyl ether and water were added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for 5 minutes, and then water and saturated saline were added. The reaction mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (336 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.35 (6H, s), 4.90 (1H, s), 5.83 (2H, s), 6.71-6.76 (1H, m), 7.35-7.43 (2H, m).

[0375] D) N-[2-cyano-4-(2-hydroxypropan-2-yl)phenyl]-2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide HATU (92 mg) was added to a mixture of 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg), 2-amino-5-(2-hydroxypropan-2-yl)benzonitrile (36.9 mg), TEA (0.034 mL) and DMF (0.5 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the residue was crystallized from ethyl acetate / diisopropyl ether / hexane to obtain the title compound (46 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.43 (6H, s), 2.45 (3H, s), 4.23-4.52 (2H, m), 5.24 (1H, s), 5.99-6.43 (1H, m), 7.21 (1H, td, J = 7.72, 1.13 Hz), 7.34 - 7.41 (1H, m), 7.45-7.59 (2H, m), 7.79-7.90 (2H, m), 8.27-8.37 (2H, m), 12.22 (1H, s).

[0376] Example 158 6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-methyl-5-oxo-2,5-dihydropyridazine-4-carboxamide

[0377] A) 1-(2,2-difluoroethoxy)-2-iodobenzene 2,2-Difluoroethyl trifluoromethanesulfonate (15.20 mL) and cesium carbonate (44.3 g) were added to a solution of 2-iodophenol (23 g) in DMF (150 mL) under ice-cooling, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was cooled to 0°C, water was added, and the mixture was extracted with diethyl ether. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue, washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (31 g). 1 H NMR (300 MHz, DMSO-d6) δ 4.37 (2H, td, J = 14.51, 3.77 Hz), 6.16-6.62 (1H, m), 6.81 (1H, td, J = 7.54, 1.51 Hz), 7.09 (1H, dd, J = 8.29, 1.51 Hz), 7.38 (1H, dd, J = 8.38, 7.06, 1.51 Hz), 7.80 (1H, dd, J = 7.54, 1.51 Hz).

[0378] B) 1-(2,2-difluoroethoxy)-2-(prop-1-yn-1-yl)benzene A mixture of 1-(2,2-difluoroethoxy)-2-iodobenzene (29.5 g), bis(triphenylphosphine)palladium(II) dichloride (4 g), copper(I) iodide (2.97 g), TEA (18 mL), and DMF (50 mL) was added with 1M prop-1-yne in THF solution (170 mL), stirred at room temperature for 24 hours under an argon atmosphere, and concentrated under reduced pressure. The residue was passed through a pad of silica gel and washed with ethyl acetate. The filtrate was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). Diethyl ether was added to the obtained crude product, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (23.90 g). 1H NMR (300 MHz, DMSO-d6) δ 2.05 (3H, s), 4.35 (2H, td, J =1 4.49, 3.76 Hz), 6.15 - 6.61 (1H, m), 6.96 (1H, td, J = 7.43, 0.94 Hz), 7.09 (1H, d, J = 7.91 Hz), 7.26 - 7.37 (2H, m).

[0379] C) 1-[2-(2,2-difluoroethoxy)phenyl]propane-1,2-dione Ruthenium(III) chloride (4.23 mg) was added to a mixture of 1-(2,2-difluoroethoxy)-2-(prop-1-yn-1-yl)benzene (200 mg), sodium bicarbonate (13.70 mg), magnesium sulfate (30.7 mg), sodium periodate (1090 mg), carbon tetrachloride (1.5 mL), acetonitrile (1.5 mL), and water (3 mL), and the mixture was stirred for 2 hours. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (190 mg). MS: [M+H] + 229.1.

[0380] D) (3E)-1-[2-(2,2-difluoroethoxy)phenyl]-4-(dimethylamino)but-3-ene-1,2-dione A mixture of 1-[2-(2,2-difluoroethoxy)phenyl]propane-1,2-dione (14.99 g), N,N-dimethylformamide dimethyl acetal (100 mL), and toluene (70 mL) was stirred at 120° C. for 4 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (13.50 g). MS: [M+H] + 284.1.

[0381] E) 3-[2-(2,2-difluoroethoxy)phenyl]pyridazin-4(1H)-one Hydrazine monohydrate (2.6 mL) was added to a solution of (3E)-1-[2-(2,2-difluoroethoxy)phenyl]-4-(dimethylamino)but-3-ene-1,2-dione (13.5 g) in EtOH (150 mL), and the mixture was stirred at 70° C. for 1 hour. The mixture was concentrated under reduced pressure, and the resulting solid was suspended in ethyl acetate / hexane and collected by filtration to obtain the title compound (9.38 g). MS: [M+H] + 253.1.

[0382] F) 5-Bromo-3-[2-(2,2-difluoroethoxy)phenyl]pyridazin-4(1H)-one N-Bromosuccinimide (9.27 g) was added to a solution of 3-[2-(2,2-difluoroethoxy)phenyl]pyridazin-4(1H)-one (9.38 g) in DMF (120 mL) at 0° C., and the mixture was stirred at 0° C. for 1.5 hours. Water was added to the reaction mixture at 0° C., and the suspension was stirred at room temperature for 10 minutes. The precipitate was collected by filtration and washed with water to obtain the title compound (10.71 g). MS: [M+H] + 331.0.

[0383] G) 5-Bromo-3-[2-(2,2-difluoroethoxy)phenyl]-1-methylpyridazin-4(1H)-one To a mixture of 5-bromo-3-[2-(2,2-difluoroethoxy)phenyl]pyridazin-4(1H)-one (600 mg) and THF (6 mL), sodium hydride (60% in oil, 94 mg) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. Iodomethane (0.170 mL) was added dropwise at 0°C, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a 5% aqueous solution of sodium thiosulfate and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (469 mg). MS: [M+H] + 345.0.

[0384] H) Methyl 6-[2-(2,2-difluoroethoxy)phenyl]-2-methyl-5-oxo-2,5-dihydropyridazine-4-carboxylate A mixture of 5-bromo-3-[2-(2,2-difluoroethoxy)phenyl]-1-methylpyridazin-4(1H)-one (464 mg), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (98 mg), TEA (375 μL), and MeOH (10 mL) was stirred at 85°C for 5 hours under carbon monoxide (0.5 MPa) atmosphere. The mixture was concentrated under reduced pressure, suspended in ethyl acetate, and filtered through a pad of NH silica and Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (377 mg). MS: [M+H] + 325.1.

[0385] I) 6-[2-(2,2-difluoroethoxy)phenyl]-2-methyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid To a mixture of methyl 6-[2-(2,2-difluoroethoxy)phenyl]-2-methyl-5-oxo-2,5-dihydropyridazine-4-carboxylate (169 mg), THF (1.5 mL), and MeOH (0.5 mL), 2M aqueous sodium hydroxide solution (0.274 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was acidified with 1M hydrochloric acid under ice-cooling, and then concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was crystallized from diisopropyl ether / ethyl acetate to obtain the title compound (151 mg). MS: [M+H] + 311.1.

[0386] J) 6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-methyl-5-oxo-2,5-dihydropyridazine-4-carboxamide HATU (110 mg) was added to a solution of 6-[2-(2,2-difluoroethoxy)phenyl]-2-methyl-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (60 mg), 2-(4-aminophenyl)propan-2-ol (38.0 mg), and TEA (54 μL) in DMF (0.8 mL) at room temperature, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / diisopropyl ether / heptane to obtain the title compound (60.6 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.41 (6H, s), 4.08 (3H, s), 4.34 (2H, td, J = 14.60, 3.58 Hz), 4.96 (1H, s), 5.98 - 6.43 (1H, m), 7.13 (1H, td, J = 7.44, 0.94 Hz), 7.25 (1H, d, J = 7.91 Hz), 7.35 (1H, dd, J = 7.54, 1.51 Hz), 7.41 - 7.54 (3H, m), 7.55 - 7.61 (2H, m), 9.12 (1H, s), 12.06 (1H, s).

[0387] Example 161 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide

[0388] A) 5-Bromo-3-[2-(2,2-difluoroethoxy)phenyl]-1-(difluoromethyl)pyridazin-4(1H)-one To a mixture of 5-bromo-3-[2-(2,2-difluoroethoxy)phenyl]pyridazin-4(1H)-one (350 mg) and DMF (5 mL), sodium chloro(difluoro)acetate (322 mg) and cesium carbonate (517 mg) were added and stirred at 100°C for 45 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (380 mg). MS: [M+H] + 381.0.

[0389] B) Methyl 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-2,5-dihydropyridazine-4-carboxylate A mixture of 5-bromo-3-[2-(2,2-difluoroethoxy)phenyl]-1-(difluoromethyl)pyridazin-4(1H)-one (423 mg), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (85 mg), TEA (0.32 mL), and MeOH (10 mL) was stirred at 85° C. for 5 hours under a carbon monoxide atmosphere of 0.5 MPa. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (308 mg). MS: [M+H] + 361.0.

[0390] C) 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-2,5-dihydropyridazine-4-carboxylic acid To a mixture of methyl 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-2,5-dihydropyridazine-4-carboxylate (304 mg), THF (2 mL), and MeOH (1.5 mL), 2M aqueous sodium hydroxide solution (0.47 mL) was added at 0°C, and the mixture was stirred at room temperature for 10 minutes. Water (3 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. 1M hydrochloric acid (5 mL) was added to the reaction mixture at 0°C to make it acidic, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (285 mg). MS: [M+H] + 347.1.

[0391] D) 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide HATU (99 mg) was added to a mixture of 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (60 mg), 2-(4-aminophenyl)propan-2-ol (34.1 mg), TEA (48 μL), and DMF (0.8 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from ethyl acetate / hexane to obtain the title compound (48 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.41 (6H, s), 4.36 (2H, td, J = 14.6, 3.6 Hz), 4.97 (1H, s), 5.93-6.45 (1H, m), 7.16 (1H, td, J = 7.4, 0.9 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.40 (1H, dd, J = 7.5, 1.9 Hz), 7.43-7.49 (2H, m), 7.50-7.62 (3H, m), 7.69-8.13 (1H, m), 9.42 (1H, s), 11.46 (1H, s).

[0392] Example 162 3-Oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide HATU (87 mg) was added to a solution of 2-(5-aminopyridin-2-yl)-1,1,3,3-tetrafluoropropan-2-ol (51.4 mg), 3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid (60 mg) in DMF (1 mL) and TEA (0.040 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from ethyl acetate / diisopropyl ether / hexane to obtain the title compound (61 mg). 1 H NMR (300 MHz, DMSO-d6) δ 4.82 (2H, brs), 6.28-6.89 (2H, m), 7.13 (1H, s), 7.21-7.83 (5H, m), 8.19-8.50 (3H, m), 8.88 (1H, d, J = 2.3 Hz), 11.70 (1H, s).

[0393] Example 163 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,5-dihydropyridazine-4-carboxamide HATU (99 mg) was added to a mixture of 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (60 mg), 2-(4-aminophenyl)-1,1,3,3-tetrafluoropropan-2-ol (50.3 mg), TEA (48 μL), and DMF (0.8 mL), and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from ethyl acetate / diisopropyl ether / heptane to obtain the title compound (78 mg). 1 H NMR (300 MHz, DMSO-d6) δ 4.36 (2H, td, J = 14.6, 3.6 Hz), 5.99-6.63 (3H, m), 6.97 (1H, s), 7.12-7.21 (1H, m), 7.27 (1H, d, J = 7.9 Hz), 7.40 (1H, dd, J = 7.5, 1.5 Hz), 7.51-7.62 (3H, m), 7.68-8.12 (3H, m), 9.43 (1H, s), 11.59 (1H, s).

[0394] Example 167 6-[2-(2,2-difluoroethoxy)phenyl]-N-(2,4-difluorophenyl)-2-(2-hydroxy-2-methylpropyl)-5-oxo-2,5-dihydropyridazine-4-carboxamide

[0395] A) Methyl 6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxylate A mixture of 5-bromo-3-[2-(2,2-difluoroethoxy)phenyl]pyridazin-4(1H)-one (9 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.989 g), TEA (8 mL), and MeOH (160 mL) was stirred at 85° C. for 5 hours under a carbon monoxide atmosphere of 0.5 MPa. MeOH was added to the reaction mixture, insoluble matter was removed by filtration, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the solid matter was collected by filtration and washed with water and acetonitrile to obtain the title compound (7.54 g). MS: [M+H] + 311.1.

[0396] B) Methyl 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2-hydroxy-2-methylpropyl)-5-oxo-2,5-dihydropyridazine-4-carboxylate To a mixture of methyl 6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxylate (500 mg) and DMF (4 mL), 1-chloro-2-methylpropan-2-ol (1 mL) and potassium carbonate (500 mg) were added, and the mixture was stirred at 80°C for 13 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SI and NH, ethyl acetate / hexane) to obtain the title compound (360 mg). MS: [M+H] + 383.1.

[0397] C) 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2-hydroxy-2-methylpropyl)-5-oxo-2,5-dihydropyridazine-4-carboxylic acid To a mixture of methyl 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2-hydroxy-2-methylpropyl)-5-oxo-2,5-dihydropyridazine-4-carboxylate (490 mg), THF (1.5 mL), and MeOH (2 mL), 2M aqueous sodium hydroxide solution (0.77 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 1M hydrochloric acid (0.75 mL) was added to the reaction mixture at 10°C, and the mixture was concentrated under reduced pressure. Water (1 mL) was added to the residue, and 1M hydrochloric acid (2 mL) was added to make the mixture acidic. The solid matter was collected by filtration to obtain the title compound (456 mg). MS: [M+H] + 369.1.

[0398] D) 6-[2-(2,2-difluoroethoxy)phenyl]-N-(2,4-difluorophenyl)-2-(2-hydroxy-2-methylpropyl)-5-oxo-2,5-dihydropyridazine-4-carboxamide HATU (77.4 mg) was added to a mixture of 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2-hydroxy-2-methylpropyl)-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (50.2 mg), 2,4-difluoroaniline (18 μL), TEA (38 μL) and DMF (0.7 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate / THF=4 / 1. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitate was collected by filtration and washed with a mixed solvent of ethyl acetate / hexane and diisopropyl ether to obtain the title compound (65.6 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.16 (6H, s), 4.23 (2H, s), 4.34 (2H, td, J = 14.5, 3.8 Hz), 4.97 (1H, s), 5.94-6.39 (1H, m), 7.07-7.19 (2H, m), 7.25 (1H, d, J = 7.9 Hz), 7.31 (1H, dd, J = 7.5, 1.5 Hz), 7.40 (1H, ddd, J = 11.3, 8.8, 2.8 Hz), 7.46-7.56 (1H, m), 8.43 (1H, td, J = 9.1, 6.2 Hz), 9.02 (1H,s), 12.32 (1H,s).

[0399] Example 168 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2-hydroxy-2-methylpropyl)-5-oxo-N-[4-(2,2,2-trifluoroethoxy)phenyl]-2,5-dihydropyridazine-4-carboxamide HATU (103 mg) was added to a mixture of 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2-hydroxy-2-methylpropyl)-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (57 mg), 4-(2,2,2-trifluoroethoxy)aniline (55 mg), TEA (0.043 mL), and DMF (0.7 mL), and the mixture was stirred at room temperature for 2 hours. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / diisopropyl ether to obtain the title compound (45 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.16 (6H, s), 4.22 (2H, s), 4.34 (2H, td, J = 14.6, 3.6 Hz), 4.73 (2H, q, J = 9.0 Hz), 4.96 (1H, s), 5.95-6.41 (1H, m), 7.03-7.16 (3H, m), 7.24 (1H, d, J = 8.3 Hz), 7.30 (1H, dd, J = 7.5, 1.9 Hz), 7.49 (1H, ddd, J = 8.6, 7.2, 1.9 Hz), 7.59-7.68 (2H, m), 9.00 (1H, s), 12.04 (1H, s).

[0400] Example 169 2-Cyclopropyl-6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide

[0401] A) 5-Bromo-3-[2-(2,2-difluoroethoxy)phenyl]-1-cyclopropylpyridazin-4(1H)-one To a mixture of 5-bromo-3-[2-(2,2-difluoroethoxy)phenyl]pyridazin-4(1H)-one (300 mg), cyclopropylboronic acid (207 mg), pyridine (0.730 mL), TEA (0.379 mL), DMF (1.5 mL), and acetonitrile (4.5 mL), copper(II) acetate (247 mg) was added and stirred at 60°C for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, which was washed with saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (267 mg). MS: [M+H] + 371.0.

[0402] B) Methyl 2-cyclopropyl-6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxylate A mixture of 5-bromo-3-[2-(2,2-difluoroethoxy)phenyl]-1-cyclopropylpyridazin-4(1H)-one (500 mg), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (99 mg), TEA (0.376 mL), and MeOH (5 mL) was stirred at 85° C. for 5 hours under a carbon monoxide atmosphere of 0.5 MPa. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (381 mg). MS: [M+H] + 351.1.

[0403] C) 2-Cyclopropyl-6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxylic acid To a mixture of methyl 2-cyclopropyl-6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxylate (33 mg), THF (0.4 mL), and MeOH (0.4 mL), 2M aqueous sodium hydroxide solution (52 μL) was added under ice cooling, and the mixture was stirred at room temperature for 10 minutes. Water (0.5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (30.0 mg). MS: [M+H] + 337.1.

[0404] D) 2-Cyclopropyl-6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide HATU (50.9 mg) was added to a mixture of 2-cyclopropyl-6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (30 mg), 2-(4-aminophenyl)propan-2-ol (17.54 mg), TEA (0.025 mL), and DMF (0.4 mL), and the mixture was stirred at room temperature for 1 hour. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and crystallized from ethyl acetate / hexane to obtain the title compound (27 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.00-1.10 (2H, m), 1.18-1.27 (2H, m), 1.41 (6H, s), 4.18 (1H, tt, J = 7.4, 3.7 Hz), 4.34 (2H, td, J = 14.6, 3.6 Hz), 4.95 (1H, s), 5.96-6.42 (1H, m), 7.13 (1H, td, J = 7.4, 0.9 Hz), 7.24 (1H, d, J = 8.3 Hz), 7.36 (1H, dd, J = 7.5, 1.9 Hz), 7.41-7.53 (3H, m), 7.55-7.62 (2H, m), 9.15 (1H, s), 12.00 (1H, s).

[0405] Example 175 6-[2-(2,2-difluoroethoxy)phenyl]-2-[(oxetan-3-yl)methyl]-5-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,5-dihydropyridazine-4-carboxamide

[0406] A) Methyl 6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxylate A mixture of 5-bromo-3-[2-(2,2-difluoroethoxy)phenyl]pyridazin-4(1H)-one (9 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.989 g), TEA (8 mL) and MeOH (160 mL) was stirred at 85°C for 5 hours under carbon monoxide (0.5 MPa) atmosphere. The reaction mixture was dissolved in hot methanol, and the catalyst was removed by filtration through Celite. The filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the solid was collected by filtration, then washed with water and acetonitrile to obtain the title compound (7.54 g). MS: [M+H] + 311.1.

[0407] B) Methyl 6-[2-(2,2-difluoroethoxy)phenyl]-2-[(oxetan-3-yl)methyl]-5-oxo-2,5-dihydropyridazine-4-carboxylate Potassium carbonate (346 mg) was added to a mixture of methyl 6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxylate (483 mg), 3-(bromomethyl)oxetane (260 mg) and DMF (3 mL), and the mixture was stirred at 75°C for 4 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (396 mg). MS: [M+H] + 381.1.

[0408] C) 6-[2-(2,2-difluoroethoxy)phenyl]-2-[(oxetan-3-yl)methyl]-5-oxo-2,5-dihydropyridazine-4-carboxylic acid To a solution of methyl 6-[2-(2,2-difluoroethoxy)phenyl]-2-[(oxetan-3-yl)methyl]-5-oxo-2,5-dihydropyridazine-4-carboxylate (393 mg) in methanol (2 mL), 2M aqueous sodium hydroxide solution (0.78 mL) was added and stirred at room temperature for 30 minutes. The reaction mixture was acidified with 6M hydrochloric acid, concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (379 mg). MS: [M+H] + 367.1.

[0409] D) 6-[2-(2,2-difluoroethoxy)phenyl]-2-[(oxetan-3-yl)methyl]-5-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,5-dihydropyridazine-4-carboxamide HATU (83 mg) was added to a mixture of 6-[2-(2,2-difluoroethoxy)phenyl]-2-[(oxetan-3-yl)methyl]-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (53 mg), 2-(4-aminophenyl)-1,1,3,3-tetrafluoropropan-2-ol (42.0 mg), TEA (0.040 mL) and DMF (0.6 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the resulting solid was washed with diisopropyl ether / hexane to obtain the title compound (58 mg). 1H NMR (300 MHz, DMSO-d6) δ 3.49-3.62 (1H, m), 4.34 (2H, td, J = 14.7, 3.4 Hz), 4.47 (2H, t, J = 6.4 Hz), 4.61-4.71 (4H, m), 5.98-6.62 (3H, m), 6.95 (1H, s), 7.09-7.18 (1H, m), 7.24 (1H, d, J = 7.9 Hz), 7.35 (1H, dd, J = 7.5, 1.5 Hz), 7.46-7.53 (1H, m), 7.57 (2H, d, J = 9.0 Hz), 7.72 (2H, d, J = 8.7 Hz), 9.21 (1H, s), 12.14 (1H, s).

[0410] Example 177 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (637 mg), 2-(5-aminopyridin-2-yl)-1,1,3,3-tetrafluoropropan-2-ol (495 mg), TEA (0.513 mL) and DMF (6 mL) were mixed and added with HATU (1049 mg), and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the target fraction was concentrated, and the solid was washed with ethyl acetate / heptane to obtain the title compound (515 mg). 1H NMR (300 MHz, DMSO-d6) δ 4.36 (2H, td, J = 14.6, 3.6 Hz), 6.00-6.75 (3H, m), 7.12 (1H, s), 7.17 (1H, td, J = 7.4, 0.9 Hz), 7.28 (1H, d, J = 7.9 Hz), 7.41 (1H, dd, J = 7.5, 1.9 Hz), 7.50-7.60 (1H, m), 7.68-8.12 (2H, m), 8.28 (1H, dd, J = 8.7, 2.3 Hz), 8.88 (1H, d, J = 1.9 Hz), 9.47 (1H, s), 11.67 (1H, s).

[0411] Example 179 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2,2-difluoroethyl)-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide

[0412] A) Methyl 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2,2-difluoroethyl)-5-oxo-2,5-dihydropyridazine-4-carboxylate 2,2-Difluoroethyl trifluoromethanesulfonate (0.330 mL) and potassium carbonate (334 mg) were added sequentially to a solution of methyl 6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxylate (500 mg) in DMF (6 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (587 mg). MS: [M+H] + 375.1.

[0413] B) 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2,2-difluoroethyl)-5-oxo-2,5-dihydropyridazine-4-carboxylic acid A mixture of methyl 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2,2-difluoroethyl)-5-oxo-2,5-dihydropyridazine-4-carboxylate (573 mg), THF (2 mL) and MeOH (2 mL) was cooled to 10°C, and then 2M aqueous sodium hydroxide solution (0.919 mL) was added and stirred at room temperature for 30 minutes. The reaction mixture was neutralized with 6M hydrochloric acid and concentrated under reduced pressure. Water was added to the residue, and the mixture was acidified with 1M hydrochloric acid, and then extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in diisopropyl ether, and the solid was collected by filtration to obtain the title compound (534 mg). MS: [M+H] + 361.1.

[0414] C) 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2,2-difluoroethyl)-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide HATU (95 mg) was added to a mixture of 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2,2-difluoroethyl)-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (60 mg), 2-(4-aminophenyl)propan-2-ol (36 mg), TEA (46 μL) and DMF (0.6 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the solid was washed with ethyl acetate / hexane to obtain the title compound (63 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.41 (6H, s), 4.35 (2H, td, J = 14.5, 3.8 Hz), 4.80-4.99 (3H, m), 5.97-6.74 (2H, m), 7.10-7.18 (1H, m), 7.25 (1H, d, J = 7.9 Hz), 7.37 (1H, dd, J = 7.5, 1.5 Hz), 7.42-7.47 (2H, m), 7.48-7.55 (1H, m), 7.55-7.61 (2H, m), 9.22 (1H, s), 11.86 (1H, s).

[0415] Example 182 6-[2-(2,2-difluoroethoxy)phenyl]-N-(2,4-difluorophenyl)-2-(oxetan-3-yl)-5-oxo-2,5-dihydropyridazine-4-carboxamide

[0416] A) Methyl 6-[2-(2,2-difluoroethoxy)phenyl]-2-(oxetan-3-yl)-5-oxo-2,5-dihydropyridazine-4-carboxylate 3-Iodooxetane (284 μL) and potassium carbonate (356 mg) were added in sequence to a solution of methyl 6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxylate (400 mg) in DMF (2.5 mL), and the mixture was stirred at 90°C for 5.5 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (398 mg). MS: [M+H] + 367.1.

[0417] B) 6-[2-(2,2-difluoroethoxy)phenyl]-2-(oxetan-3-yl)-5-oxo-2,5-dihydropyridazine-4-carboxylic acid To a solution of methyl 6-[2-(2,2-difluoroethoxy)phenyl]-2-(oxetan-3-yl)-5-oxo-2,5-dihydropyridazine-4-carboxylate (399 mg) in MeOH (3 mL), 2M aqueous sodium hydroxide solution (2 mL) was added and stirred at room temperature for 2 hours. MeOH (2 mL) and THF (2 mL) were added to the reaction mixture, which was stirred at room temperature for 12 hours and then concentrated under reduced pressure. Water was added to the residue, which was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with diisopropyl ether / diethyl ether to obtain the title compound (260 mg). MS: [M+H] + 353.1.

[0418] C) 6-[2-(2,2-difluoroethoxy)phenyl]-N-(2,4-difluorophenyl)-2-(oxetan-3-yl)-5-oxo-2,5-dihydropyridazine-4-carboxamide HATU (81 mg) was added to a mixture of 6-[2-(2,2-difluoroethoxy)phenyl]-2-(oxetan-3-yl)-5-oxo-2,5-dihydropyridazine-4-carboxylic acid (50 mg), 2,4-difluoroaniline (0.019 mL), TEA (0.040 mL) and DMF (0.6 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solid was washed with ethyl acetate to obtain the title compound (52 mg). 1H NMR (300 MHz, DMSO-d6) δ 4.37 (2H, td, J = 14.6, 3.6 Hz), 4.81-4.98 (4H, m), 5.81-5.94 (1H, m), 5.98-6.41 (1H, m), 7.07-7.22 (2H, m), 7.29 (1H, d, J = 7.9 Hz), 7.40 (1H, ddd, J = 11.5, 8.8, 3.0 Hz), 7.45-7.58 (2H, m), 8.43 (1H, td, J = 9.1, 6.2 Hz), 9.10 (1H, s), 12.23 (1H, d, J = 1.9 Hz).

[0419] Example 190 N-[4-(2-cyanopropan-2-yl)phenyl]-2-methyl-5-oxo-6-[2-(2,2,2-trifluoroethoxy)phenyl]-2,5-dihydropyridazine-4-carboxamide

[0420] A) 1-iodo-2-(2,2,2-trifluoroethoxy)benzene Cesium carbonate (28.9 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (11.79 mL) were added successively to a solution of 2-iodophenol (15 g) in DMF (110 mL), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was cooled to 0°C, water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was diluted with diethyl ether, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (22.5 g). 1 H NMR (300 MHz, DMSO-d6) δ 4.82 (2H, q, J = 8.7 Hz), 6.84 (1H, td, J = 7.6, 1.3 Hz), 7.14 (1H, dd, J = 8.3, 1.1 Hz), 7.40 (1H, ddd, J = 8.4, 7.1, 1.5 Hz), 7.82 (1H, dd, J = 7.5, 1.5 Hz).

[0421] B) 1-(prop-1-yn-1-yl)-2-(2,2,2-trifluoroethoxy)benzene Dichlorobis(triphenylphosphine)palladium(II) (2.5 g) and copper iodide (2.1 g) were added to a solution of 1-iodo-2-(2,2,2-trifluoroethoxy)benzene (20.59 g) in DMF (50 mL) under argon atmosphere, and prop-1-yne (100 mL) and TEA (11 mL) were added and stirred at room temperature for 6 hours. Prop-1-yne (15 mL) was added and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layers were combined, washed with water, aqueous sodium bicarbonate solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was filtered through a pad packed with silica gel, and the filtrate was concentrated under reduced pressure to obtain the title compound (12.65 g). 1 H NMR (300 MHz, DMSO-d6) δ 2.05 (3H, s), 4.79 (2H, q, J = 9.0 Hz), 7.00 (1H, td, J = 7.4, 0.9 Hz), 7.14 (1H, d, J = 7.9 Hz), 7.28-7.40 (2H, m)..

[0422] C) 1-[2-(2,2,2-trifluoroethoxy)phenyl]propane-1,2-dione Ruthenium (III) chloride (0.203 g) was added to a mixture of sodium hydrogen carbonate (0.824 g), anhydrous magnesium sulfate (1.475 g), sodium periodate (31.5 g), ethyl acetate (100 mL), acetonitrile (100 mL) and water (150 mL), and the mixture was cooled to 0°C. A solution of 1-(prop-1-yn-1-yl)-2-(2,2,2-trifluoroethoxy)benzene (10.5 g) in ethyl acetate (15 mL) was added at 0°C, and the mixture was stirred at 0°C for 5 minutes. Water was added to the reaction mixture, the supernatant was separated, and the insoluble matter was removed by filtration through Celite. The organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, and then the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (8.21 g). 1 H NMR (300 MHz, DMSO-d6) δ 2.37 (3H, s), 4.89 (2H, q, J = 8.7 Hz), 7.21-7.28 (1H, m), 7.32 (1H, d, J = 8.3 Hz), 7.70-7.80 (2H, m)..

[0423] D) (3E)-4-(Dimethylamino)-1-[2-(2,2,2-trifluoroethoxy)phenyl]but-3-ene-1,2-dione A mixture of 1-[2-(2,2,2-trifluoroethoxy)phenyl]propane-1,2-dione (8.21 g), 1,1-dimethoxy-N,N-dimethylmethanamine (25 mL) and toluene (80 mL) was stirred at 130° C. for 5 hours. N,N-Dimethylformamide dimethyl acetal (15 mL) was added and stirred at 130° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (6.7 g). MS: [M+H] + 302.1.

[0424] E) 3-[2-(2,2,2-trifluoroethoxy)phenyl]pyridazin-4(1H)-one Hydrazine monohydrate (1.1 mL) was added to a solution of (3E)-4-(dimethylamino)-1-[2-(2,2,2-trifluoroethoxy)phenyl]but-3-ene-1,2-dione (6.7 g) in ethanol (60 mL), and the mixture was stirred at 60°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in a hot mixture of ethyl acetate / hexane and cooled. The solid was collected by filtration to obtain the title compound (4.8 g). MS: [M+H] + 271.0.

[0425] F) 5-Bromo-3-[2-(2,2,2-trifluoroethoxy)phenyl]pyridazin-4(1H)-one To a solution of 3-[2-(2,2,2-trifluoroethoxy)phenyl]pyridazin-4(1H)-one (4.8 g) in DMF (75 mL), N-bromosuccinimide (4.1 g) was added over 30 minutes at 0°C, and the mixture was stirred at 0°C for 1.5 hours. N-bromosuccinimide (0.85 g) was added at 0°C, and the mixture was stirred at 0°C for 1.5 hours. Water was added to the reaction mixture, and the mixture was stirred at 0°C for 5 minutes. The solid was collected by filtration and washed with water to obtain the title compound (5.55 g). MS: [M+H] + 349.0.

[0426] G) Methyl 5-oxo-6-[2-(2,2,2-trifluoroethoxy)phenyl]-2,5-dihydropyridazine-4-carboxylate A mixture of 5-bromo-3-[2-(2,2,2-trifluoroethoxy)phenyl]pyridazin-4(1H)-one (750 mg), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (157 mg), TEA (0.599 mL) and MeOH (10 mL) was stirred at 85°C for 5 hours under carbon monoxide (0.5 MPa) atmosphere. After adding hot MeOH to the reaction mixture, the insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the solid was collected by filtration and washed with water and acetonitrile to obtain the title compound (626 mg). MS: [M+H] + 329.1.

[0427] H) Methyl 2-methyl-5-oxo-6-[2-(2,2,2-trifluoroethoxy)phenyl]-2,5-dihydropyridazine-4-carboxylate To a solution of methyl 5-oxo-6-[2-(2,2,2-trifluoroethoxy)phenyl]-2,5-dihydropyridazine-4-carboxylate (160 mg) in DMF (1.4 mL), iodomethane (0.076 mL) and potassium carbonate (101 mg) were added, and the mixture was stirred at 75°C for 1.5 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (181 mg). MS: [M+H] + 343.1.

[0428] I) 2-Methyl-5-oxo-6-[2-(2,2,2-trifluoroethoxy)phenyl]-2,5-dihydropyridazine-4-carboxylic acid To a mixture of methyl 2-methyl-5-oxo-6-[2-(2,2,2-trifluoroethoxy)phenyl]-2,5-dihydropyridazine-4-carboxylate (197 mg), THF (1.5 mL) and MeOH (1.5 mL), 2M aqueous sodium hydroxide solution (0.345 mL) was added at 0°C and stirred at room temperature for 30 minutes. The reaction mixture was neutralized with 1M hydrochloric acid, and the solvent was distilled off under reduced pressure. The residue was suspended in water and 1M hydrochloric acid, and the resulting solid was collected by filtration to obtain the title compound (180 mg). MS: [M+H] + 329.0.

[0429] J) N-[4-(2-cyanopropan-2-yl)phenyl]-2-methyl-5-oxo-6-[2-(2,2,2-trifluoroethoxy)phenyl]-2,5-dihydropyridazine-4-carboxamide HATU (60.8 mg) was added to a mixture of 2-methyl-5-oxo-6-[2-(2,2,2-trifluoroethoxy)phenyl]-2,5-dihydropyridazine-4-carboxylic acid (35 mg), 2-(4-aminophenyl)-2-methylpropanenitrile (25.6 mg), DIPEA (0.037 mL) and DMF (1 mL), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (41.5 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.68 (6H, s), 4.08 (3H, s), 4.76 (2H, q, J = 8.8 Hz), 7.18 (1H, td, J = 7.4, 0.9 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.39 (1H, dd, J = 7.5, 1.9 Hz), 7.48-7.56 (3H, m), 7.68-7.74 (2H, m), 9.14 (1H, s), 12.19 (1H, s).

[0430] Example 193 rac-6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2-(oxolan-3-yl)-2,5-dihydropyridazine-4-carboxamide

[0431] A) rac-Methyl 6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2-(oxolan-3-yl)-2,5-dihydropyridazine-4-carboxylate A mixture of methyl 6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxylate (200 mg), rac-tetrahydrofuran-3-ol (95 mg), triphenylphosphine (270 mg) and THF (2.5 mL) was added with bis(2-methoxyethyl) azodicarboxylate (226 mg) and stirred at room temperature for 3 hours. Water and saturated saline were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and silica gel column chromatography (methanol / ethyl acetate) to obtain the title compound (342 mg) as a crude product. MS: [M+H] + 381.1.

[0432] B) rac-6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2-(oxolan-3-yl)-2,5-dihydropyridazine-4-carboxylic acid To a mixture of rac-methyl 6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2-(oxolan-3-yl)-2,5-dihydropyridazine-4-carboxylate (342 mg), MeOH (3 mL) and THF (3 mL), 2M aqueous sodium hydroxide solution (0.4 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate / diisopropyl ether / hexane was added to the residue, and the resulting solid was collected by filtration to obtain the title compound (155 mg). MS: [M+H] + 367.1.

[0433] C) rac-6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2-(oxolan-3-yl)-2,5-dihydropyridazine-4-carboxamide HATU (70.1 mg) was added to a mixture of rac-6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2-(oxolan-3-yl)-2,5-dihydropyridazine-4-carboxylic acid (45 mg), 2-(4-aminophenyl)propan-2-ol (24.15 mg), TEA (0.034 mL) and DMF (0.5 mL), and the mixture was stirred at room temperature for 1 hour. Water and saturated saline were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.41 (6H, s), 2.22-2.46 (2H, m), 3.78 (1H, td, J = 8.1, 6.0 Hz), 3.91-4.00 (2H, m), 4.02-4.10 (1H, m), 4.35 (2H, td, J = 14.6, 3.6 Hz), 4.96 (1H, s), 5.24-5.40 (1H, m), 5.96-6.43 (1H, m), 7.09-7.19 (1H, m), 7.25 (1H, d, J = 7.9 Hz), 7.36-7.53 (4H, m), 7.54-7.61 (2H, m), 9.13 (1H, s), 12.02 (1H, s).

[0434] Example 197 6-Acetyl-N-[4-(difluoromethoxy)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide

[0435] A) 3-oxo-2-{2-[2-(2,2,2-trifluoroethoxy)phenyl]hydrazinylidene}butanal To a mixture of 2-(2,2,2-trifluoroethoxy)aniline (1.00 g) and 6M hydrochloric acid (5.3 mL), sodium nitrite (435.9 mg) aqueous solution (2 mL) was added dropwise at 0°C, and the mixture was stirred at 0°C for 15 minutes to prepare an aqueous diazonium salt solution. To a mixture of (3E)-4-(dimethylamino)but-3-en-2-one (600.5 mg), sodium acetate (3.01 g) and MeOH (12 mL), the above aqueous diazonium salt solution was added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. After removing MeOH under reduced pressure, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was filtered and washed with diisopropyl ether / hexane to obtain the title compound (884.7 mg). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (271.8 mg). MS: [M+H] + 289.0.

[0436] B) Ethyl 6-acetyl-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylate A mixture of 3-oxo-2-{2-[2-(2,2,2-trifluoroethoxy)phenyl]hydrazinylidene}butanal (1.16 g), diethyl malonate (740 μL), piperidine (0.2 mL) and pyridine (12 mL) was stirred at 120° C. for 3.5 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene to remove pyridine. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (622.5 mg). MS: [M+H] + 385.1.

[0437] C) 6-Acetyl-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid To a solution of ethyl 6-acetyl-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylate (620 mg) in EtOH (10 mL), 4M aqueous lithium hydroxide solution (0.6 mL) was added at room temperature and stirred at room temperature for 1 hour. The reaction mixture was acidified with 6M hydrochloric acid, and the precipitate was filtered to obtain the title compound (281.6 mg). The filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound (284.6 mg). MS: [M+H] + 357.0.

[0438] D) 6-Acetyl-N-[4-(difluoromethoxy)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide HATU (195.1 mg) was added to a mixture of 6-acetyl-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid (120.7 mg), 4-(difluoromethoxy)aniline (71.1 mg), TEA (193 μL) and DMF (1.5 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the obtained solid was collected by filtration to obtain the title compound (56.9 mg). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (34.1 mg). 1 H NMR (300 MHz, DMSO-d6) δ 2.46-2.54 (3H, m), 4.73-5.03 (2H, m), 6.93-7.48 (1H, m), 7.18-7.25 (2H, m), 7.29 (1H, td, J = 7.5, 1.1 Hz), 7.41-7.48 (1H, m), 7.58-7.66 (2H, m), 7.72-7.80 (2H, m), 8.58 (1H, s), 11.26 (1H, s).

[0439] Example 198 Ethyl 5-{[4-(difluoromethoxy)phenyl]carbamoyl}-6-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,6-dihydropyridazine-3-carboxylate

[0440] A) Ethyl 3-oxo-2-{2-[2-(2,2,2-trifluoroethoxy)phenyl]hydrazinylidene}propanoate To a mixture of 2-(2,2,2-trifluoroethoxy)aniline (1.01 g) and 6M hydrochloric acid (5.3 mL), an aqueous solution of sodium nitrite (443.3 mg) (2 mL) was slowly added at 0°C, and the mixture was stirred at 0°C for 15 minutes to prepare an aqueous solution of diazonium salt. To a mixture of ethyl 3-(dimethylamino)prop-2-enoate (765.6 mg), sodium acetate (3.03 g), and EtOH (12 mL), the above aqueous solution of diazonium salt was added at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.30 g). MS: [M+H] + 319.0.

[0441] B) 5-benzyl 3-ethyl 6-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,6-dihydropyridazine-3,5-dicarboxylate Piperidine (0.2 mL) was added to a mixture of ethyl 3-oxo-2-{2-[2-(2,2,2-trifluoroethoxy)phenyl]hydrazinylidene}propanoate (1.30 g), dibenzyl malonate (1.25 mL) and pyridine (13 mL), and the mixture was stirred at 120° C. for 2 hours. Piperidine (0.04 mL) was added and the mixture was stirred at 120° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the mixture was azeotroped with toluene to remove the residual pyridine. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (838.7 mg). MS: [M+H] + 477.1.

[0442] C) 6-(ethoxycarbonyl)-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid A mixture of 5-benzyl 3-ethyl 6-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,6-dihydropyridazine-3,5-dicarboxylate (438.4 mg), 10% palladium-carbon (55% wet, 50.5 mg) and EtOH (7 mL) was stirred at room temperature under hydrogen atmosphere at normal pressure for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallized from ethyl acetate / hexane to give the title compound (267.8 mg). The filtrate was concentrated under reduced pressure to give the title compound (82.8 mg). MS: [M+H] + 387.0.

[0443] D) Ethyl 5-{[4-(difluoromethoxy)phenyl]carbamoyl}-6-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,6-dihydropyridazine-3-carboxylate HATU (97.9 mg) was added to a mixture of 6-(ethoxycarbonyl)-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid (66 mg), 4-(difluoromethoxy)aniline (32.2 mg), TEA (48 μL) and DMF (1 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, which was then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (74.4 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.32 (3H, t, J = 7.2 Hz), 4.38 (2H, q, J = 7.2 Hz), 4.68-5.02 (2H, m), 6.93-7.47 (1H, m), 7.17-7.24 (2H, m), 7.28 (1H, td, J = 7.5, 1.1 Hz), 7.39-7.47 (1H, m), 7.53-7.66 (2H, m), 7.72-7.80 (2H, m), 8.61 (1H, s), 11.28 (1H, s).

[0444] Example 199 rac-N-[4-(difluoromethoxy)phenyl]-6-(1-hydroxyethyl)-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide 6-Acetyl-N-[4-(difluoromethoxy)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide (39.8 mg) in THF (0.8 mL) was added dropwise with 1.5M toluene solution of isobutylaluminum hydride (133.4 μL) at -78°C, and the mixture was stirred at -78°C for 2.5 hours. An aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (acetonitrile / 10 mM aqueous ammonium hydrogen carbonate solution) to obtain the title compound (9.4 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.37 (3H, d, J = 6.8 Hz), 4.63-4.93 (3H, m), 5.82 (1H, d, J = 5.3 Hz), 6.94-7.45 (1H, m), 7.10-7.28 (3H, m), 7.38 (1H, d, J = 8.7 Hz), 7.50-7.65 (2H, m), 7.71-7.82 (2H, m), 8.45 (1H, s), 11.53-11.76 (1H, m).

[0445] Example 200 N-[4-(difluoromethoxy)phenyl]-6-(2-hydroxypropan-2-yl)-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide

[0446] A) rac-Ethyl 5-{[4-(difluoromethoxy)phenyl]carbamoyl}-6-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,4,5,6-tetrahydropyridazine-3-carboxylate Sodium triacetoxyborohydride (55.8 mg) was added to a solution of ethyl 5-{[4-(difluoromethoxy)phenyl]carbamoyl}-6-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,6-dihydropyridazine-3-carboxylate (49.8 mg) in THF (1 mL) at 0°C, and the mixture was stirred at 0°C for 30 minutes. EtOH (0.007 mL) was added, and the mixture was stirred at room temperature for 30 minutes. EtOH (0.007 mL) was added, and the mixture was stirred at room temperature for 1 hour. EtOH (0.007 mL) was added, and the mixture was stirred at room temperature for 2 hours. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (52.4 mg). MS: [M+H] + 530.2.

[0447] B) rac-N-[4-(difluoromethoxy)phenyl]-6-(2-hydroxypropan-2-yl)-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3,4,5-tetrahydropyridazine-4-carboxamide To a solution of rac-ethyl 5-{[4-(difluoromethoxy)phenyl]carbamoyl}-6-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,4,5,6-tetrahydropyridazine-3-carboxylate (51.5 mg) in THF (1 mL), 3M 2-methyltetrahydrofuran solution of methylmagnesium bromide (0.161 mL) was added at 0°C and stirred at room temperature for 1 hour. Aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (30.3 mg). MS: [MH] - 514.1.

[0448] C) N-[4-(difluoromethoxy)phenyl]-6-(2-hydroxypropan-2-yl)-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide 4,5-Dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (16.5 mg) was added to a solution of rac-N-[4-(difluoromethoxy)phenyl]-6-(2-hydroxypropan-2-yl)-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3,4,5-tetrahydropyridazine-4-carboxamide (25.9 mg) in toluene (0.6 mL), and the mixture was stirred at 100°C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (19.7 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.42 (6H, br s), 4.68-4.94 (2H, m), 5.71 (1H, s), 6.92-7.46 (1H, m), 7.16-7.28 (3H, m), 7.39 (1H, d, J = 7.5 Hz), 7.48-7.61 (2H, m), 7.70-7.80 (2H, m), 8.60 (1H, s), 11.68 (1H, s).

[0449] The example compounds are shown in the following table. MS in the table indicates the actually measured value. According to the methods shown in the above examples or methods similar thereto, the compounds of Examples 2 to 53, 55 to 59, 61, 63 to 68, 70, 71, 74, 76 to 79, 81 to 93, 95 to 97, 99 to 107, 110 to 113, 115 to 118, 120, 122 to 126, 128 to 132, 134, 137 to 139, 141 to 143, 145, 147, 149 to 151, 153, 155 to 157, 159, 160, 164, 165 to 166, 170 to 174, 176, 178, 180, 181, 183 to 189, 191, 192, 194 to 196 and 201 to 203 in the following table were produced.

[0450] [Table 1-1]

[0451] [Table 1-2]

[0452] [Table 1-3]

[0453] [Table 1-4]

[0454] [Table 1-5]

[0455]

Table 1-6

[0456]

Table 1-7

[0457]

Table 1-8

[0458]

Table 1-9

[0459]

Table 1-10

[0460]

Table 1-11

[0461]

Table 1-12

[0462]

Table 1-13

[0463]

Table 1-14

[0464]

Table 1-15

[0465]

Table 1-16

[0466]

Table 1-17

[0467]

Table 1-18

[0468]

Table 1-19

[0469]

Table 1-20

[0470]

Table 1-21

[0471]

Table 1-22

[0472]

Table 1-23

[0473]

Table 1-24

[0474]

Table 1-25

[0475] [Table 1-26]

[0476] Test Example 1 Glucosylceramide synthase (GCS) assay In the enzyme assay, microsomal fractions obtained by transient expression in Expi293FTM cells (catalog number: A14527, Thermo Fisher Scientific) were used as a glucosylceramide synthase source. The substrates used were liposomal C8 ceramide and UDP-glucose. The substrate concentrations used were 1.7 μM UDP-glucose and 3 μM C8 ceramide, which were equal to the Km value. After the enzyme reaction, the compounds were analyzed using Rapidfire MS / MS (API-4000TM, SCIEX) to quantify C8 glucosylceramide, and the inhibitory activity of the test compounds against glucosylceramide synthase activity was evaluated. The pcDNA3.3TOPO vector (catalog number: K830001, Thermo Fisher Scientific) containing the human GCS gene was transfected with ExpiFectamine TM Expi293F was transfected using the 293 Transfection Kit (catalog number: A14525, Thermo Fisher Scientific). TM The cultured cells were then introduced into Thermo Fisher Scientific Cells (catalog number: A14527). The cultured cells were dissolved in D-PBS containing 1 mM PMSF (catalog number: 048-29805, Fujifilm Wako Pure Chemical Industries, Ltd.), left on ice for 30 minutes, and then disrupted (homogenized). The disrupted solution was centrifuged at 10,000xg for 20 minutes at 4°C, and the resulting supernatant was centrifuged at 142,400xg for 60 minutes at 4°C. The resulting precipitate was resuspended in D-PBS containing 1 mM PMSF, homogenized again, and prepared as a microsomal fraction. Protein quantification was performed by the CBB method. 100 nL of a 1 mM compound solution dissolved in DMSO was added to a 384-well plate so that the final concentration of the test compound was 10 μM. Next, 5 μL of a substrate solution consisting of 3.4 μM UDP-glucose and 6 μM C8 ceramide was added, followed by 5 μL of an enzyme solution consisting of 25 μg / mL microsome fraction. C8 ceramide was prepared from liposomes consisting of 15 mol% C8 ceramide and 85 mol% dioleoylphosphatidylcholine (1,2-Dioleoyl-sn-glycero-3-phosphocholine:DOPC). The enzyme reaction was carried out at room temperature for 60 minutes in a solution consisting of 20 mM Tris-HCl buffer (pH 7.5), 0.01% Tween 20, 0.01% bovine serum albumin, and 1 mM dithiothreitol. Then, 60μL of a solution consisting of 75% isopropanol and 1% formic acid containing 0.25μM N-Octadecanoyl-D35-psychosine (catalog number: 1914, Matreya) as an internal standard substance was added to stop the enzyme reaction. 5μL of the centrifuged supernatant of the obtained reaction product was analyzed by Rapidfire MS / MS (Agilent Technologies) using API-4000TM (SCIEX) and C8 glucosylceramide was quantified to evaluate the inhibitory activity of the test compound against glucosylceramide synthesis enzyme activity. The value of C8 glucosylceramide in the solution without enzyme was set to 100% inhibition, and the enzyme activity of the DMSO group in the absence of compound was set to 0% inhibition, and the inhibitory activity of the test compound was evaluated. The results are shown in Table 2 below.

[0477] [Table 2-1]

[0478] [Table 2-2]

[0479] [Table 2-3]

[0480] [Table 2-4]

[0481] [Table 2-5]

[0482] [Table 2-6]

[0483] [Table 2-7]

[0484] As shown in Table 2, it was confirmed that the compounds of the present invention have glucosylceramide synthase inhibitory activity.

[0485] Test Example 2 The glucosylceramide synthase inhibitory effect of the compound of the present invention in mice can be evaluated based on the glucosylceramide lowering action after oral administration as described below. For the experiment, C57BL / 6J mice are used, and the test compound is prepared in a 0.5% methylcellulose suspension and orally administered. After administration, blood and brain cortex are collected, and plasma is extracted from the blood and methanol is added to the brain cortex to prepare homogenates. A mixture of isopropanol and ethanol is added to the resulting methanol homogenates of plasma and brain cortex to extract lipids. The glucosylceramide concentration of the extracted samples is measured by LC / MS / MS, and the glucosylceramide lowering effect (% control) is calculated as (glucosylceramide concentration in the test compound group) / (glucosylceramide concentration in the 0.5% methylcellulose suspension group)×100.

[0486] Test Example 3 The glucosylsphingosine lowering effect of the compound of the present invention in mice due to its glucosylceramide synthase inhibitory effect can be evaluated by measuring the glucosylceramide and glucosylsphingosine concentrations after oral administration as described below. For the experiment, Gba D409V KI mice, a Gaucher disease model mouse with ac...

Claims

1. A compound selected from the following, or a salt thereof: 1-(2-Methoxyphenyl)-6-methyl-2-oxo-N-(4-phenoxyphenyl)-1,2-dihydropyridine-3-carboxamide 1-(2-Methoxyphenyl)-2-oxo-N-(4-phenoxyphenyl)-1,2-dihydropyridine-3-carboxamide 1-(4-fluoro-2-methoxyphenyl)-2-oxo-N-(4-phenoxyphenyl)-1,2-dihydropyridine-3-carboxamide 1-[2-(morpholin-4-yl)phenyl]-2-oxo-N-(4-phenoxyphenyl)-1,2-dihydropyridine-3-carboxamide 1-(4-Fluoro-2-methoxyphenyl)-2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide 1-(4-Fluoro-2-methoxyphenyl)-2-oxo-N-[4-(trifluoromethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide N-(6-cyclopropylpyridin-3-yl)-1-(4-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(4-Fluoro-2-methoxyphenyl)-N-[1-(4-fluorophenyl)-1H-pyrazol-3-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(4-Fluoro-2-methoxyphenyl)-N-(6-methoxypyridin-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-[4-(difluoromethoxy)phenyl]-1-(4-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(4-Fluoro-2-methoxyphenyl)-2-oxo-N-[4-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide N-[1-(4-fluorophenyl)-1H-pyrazol-3-yl]-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide N-(6-Methoxypyridin-3-yl)-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide N-(4-chlorophenyl)-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide 2-Oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide N-[6-(difluoromethoxy)pyridin-3-yl]-1-(4-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(morpholin-4-yl)phenyl]-2-oxo-N-(4-phenoxyphenyl)-1,2-dihydropyridine-3-carboxamide 2-(4-Fluoro-2-methoxyphenyl)-3-oxo-N-(4-phenoxyphenyl)-2,3-dihydropyridazine-4-carboxamide 1-(4-Fluoro-2-methoxyphenyl)-N-[4-(morpholin-4-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 2-Oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-N-[6-(trifluoromethyl)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide N-(5-cyclopropylpyridin-2-yl)-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide 2-Oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-N-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-1,2-dihydropyridine-3-carboxamide 2-(4-Fluoro-2-methoxyphenyl)-3-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide N-(6-cyanopyridin-3-yl)-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(morpholin-4-yl)phenyl]-2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2-methoxyethoxy)phenyl]-2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2-methoxyethoxy)phenyl]-N-[1-(4-fluorophenyl)-1H-pyrazol-3-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide 2-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-3-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide 1-(2-cyano-4-fluorophenyl)-2-oxo-N-(4-phenoxyphenyl)-1,2-dihydropyridine-3-carboxamide N-(5-cyanopyridin-2-yl)-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-(1-cyclopropyl-1H-pyrazol-4-yl)-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-{4-[(morpholin-4-yl)methyl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[2-(trifluoromethyl)pyrimidin-5-yl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[5-(trifluoromethyl)pyrazin-2-yl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[6-(trifluoromethyl)pyridazin-3-yl]-1,2-dihydropyridine-3-carboxamide N-(1-tert-butyl-1H-pyrazol-3-yl)-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-(4-cyanophenyl)-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[4-(piperidine-1-carbonyl)phenyl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[1-(difluoromethyl)-1H-pyrazol-4-yl]-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[5-(trifluoromethyl)-1,2-oxazol-3-yl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-1,2-dihydropyridine-3-carboxamide N-[6-(difluoromethyl)pyridin-3-yl]-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[4-(cyclopropylmethoxy)phenyl]-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[2-(difluoromethoxy)pyrimidin-5-yl]-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(2-cyano-4-fluorophenyl)-2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide 1-[1-(oxan-4-yl)-1H-pyrazol-5-yl]-2-oxo-N-(4-phenoxyphenyl)-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[1-(oxan-4-yl)-1H-pyrazol-3-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide rac-N-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-3-yl}-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,3,3,3-pentafluoropropoxy)phenyl]-2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide N-[4-(cyanomethyl)phenyl]-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,3,3,3-pentafluoropropoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[1-(oxan-4-yl)-1H-pyrazol-5-yl]-2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxy-2-methylpropoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxy-2-methylpropyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1,2-dihydropyridine-3-carboxamide N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[6-(3,3,3-trifluoropropoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide N-{1-[(3-fluorooxetan-3-yl)methyl]-1H-pyrazol-4-yl}-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-{1-[(1-fluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2-hydroxy-2-methylpropoxy)phenyl]-2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide N-[4-(2-hydroxypropan-2-yl)phenyl]-1-[2-methyl-6-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(1-hydroxycyclopropyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[4-(2-hydroxy-2-methylpropoxy)phenyl]-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide 1-(2-cyano-4-fluorophenyl)-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 2-Oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-{6-[(2,2,2-trifluoroethoxy)methyl]pyridin-3-yl}-1,2-dihydropyridine-3-carboxamide 2-Oxo-N-{6-[(2,2,2-trifluoroethoxy)methyl]pyridin-3-yl}-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide rac-N-{6-[cyclopropyl(hydroxy)methyl]pyridin-3-yl}-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide rac-N-{6-[cyclopropyl(hydroxy)methyl]pyridin-3-yl}-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide 2-Oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide 2-Oxo-1-[3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide N-[6-(cyanomethyl)pyridin-3-yl]-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[1-(4-fluorophenyl)-1H-pyrazol-3-yl]-2-oxo-1-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl]-1,2-dihydropyridine-3-carboxamide N-[3-fluoro-4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide N-[3-fluoro-4-(2-hydroxypropan-2-yl)phenyl]-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[6-(cyanomethyl)pyridin-3-yl]-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide N-[6-(2-cyanopropan-2-yl)pyridin-3-yl]-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[6-(2-cyanopropan-2-yl)pyridin-3-yl]-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1-[3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[6-(2-methoxypropan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[6-(2-methoxypropan-2-yl)pyridin-3-yl]-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-6-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,6-dihydropyrimidine-5-carboxamide 1-(4-Methoxy-1-methyl-1H-pyrazol-5-yl)-2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide 2-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide N-[4-(1-hydroxycyclobutyl)phenyl]-2-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(1-hydroxycyclobutyl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxamide 1-[2-(2,2-difluoropropoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[2-(2,2-difluoroethoxy)-4-fluorophenyl]-2-oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide 1-[2-(2,2-difluoroethoxy)-4-fluorophenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-(2-cyano-4-fluorophenyl)-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4-fluoro-2-(2-hydroxy-2-methylpropoxy)phenyl]-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 2-[4-Fluoro-2-(2,2,3,3,3-pentafluoropropoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide 1-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1-[4,5-difluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide 2-Oxo-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1-[5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-1,2-dihydropyridine-3-carboxamide 1-[3,4-difluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 2-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide 1-[5-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[4-(2-hydroxypropan-2-yl)phenyl]-2-oxo-2'-(2,2,2-trifluoroethoxy)-2H-[1,3'-bipyridine]-3-carboxamide (R or S)-N-{6-[cyclopropyl(hydroxy)methyl]pyridin-3-yl}-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide (R or S)-N-{6-[cyclopropyl(hydroxy)methyl]pyridin-3-yl}-1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 2-[4-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-3-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide 1-[4,5-difluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-2-oxo-1-[5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]-1,2-dihydropyridine-3-carboxamide N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-2-oxo-2'-(2,2,2-trifluoroethoxy)-2H-[1,3'-bipyridine]-3-carboxamide rac-2-oxo-1-[3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]-N-[6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide 2-Oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-1-[3-(2,2,2-trifluoroethoxy)pyridazin-4-yl]-1,2-dihydropyridine-3-carboxamide 2-Oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2'-(2,2,2-trifluoroethoxy)-2H-[1,3'-bipyridine]-3-carboxamide 1-[5-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-2-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-1,2-dihydropyridine-3-carboxamide 1-[5-Fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide N-[5-(2-hydroxypropan-2-yl)pyridin-2-yl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6-methyl-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide N-[5-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-methyl-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide N-[4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[5-(2-hydroxypropan-2-yl)pyridin-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[5-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide rac-N-[4-(1-hydroxyethyl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide rac-2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(1-hydroxyethyl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide rac-N-[5-(1-hydroxyethyl)pyridin-2-yl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-N-[4-(oxetan-3-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)-3-methylphenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)-2-methylphenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide rac-2-[2-(2,2-difluoroethoxy)phenyl]-3-oxo-N-[4-(oxolan-2-yl)phenyl]-2,3-dihydropyridazine-4-carboxamide rac-2-[2-(2,2-difluoroethoxy)phenyl]-3-oxo-N-[4-(oxolan-3-yl)phenyl]-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[2-fluoro-4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[2-fluoro-4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide N-[2-fluoro-4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide N-[2-chloro-4-(2-hydroxypropan-2-yl)phenyl]-2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[2,6-difluoro-4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)-2-methoxyphenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-3-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,3-dihydropyridazine-4-carboxamide N-[2-cyano-4-(2-hydroxypropan-2-yl)phenyl]-2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide 3-Oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[2-fluoro-4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide 2-[2-(2,2-difluoroethoxy)phenyl]-N-[2-fluoro-4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-methyl-5-oxo-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-methyl-5-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,5-dihydropyridazine-4-carboxamide N-[2-chloro-4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2-[2-(2,2-difluoroethoxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide 3-Oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxy-2-methylpropoxy)phenyl]-2-methyl-5-oxo-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-N-[4-(2-hydroxy-2-methylpropoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide N-[4-(2-hydroxypropan-2-yl)phenyl]-2-methyl-5-oxo-6-[2-(2,2,2-trifluoroethoxy)phenyl]-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-N-(2,4-difluorophenyl)-2-(2-hydroxy-2-methylpropyl)-5-oxo-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2-hydroxy-2-methylpropyl)-5-oxo-N-[4-(2,2,2-trifluoroethoxy)phenyl]-2,5-dihydropyridazine-4-carboxamide 2-Cyclopropyl-6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide Ethyl 5-({2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carbonyl}amino)thiophene-2-carboxylate 6-[2-(2,2-difluoroethoxy)phenyl]-N-(4-fluorophenyl)-2-(2-hydroxy-2-methylpropyl)-5-oxo-2,5-dihydropyridazine-4-carboxamide N-[4-(2-cyanopropan-2-yl)phenyl]-6-[2-(2,2-difluoroethoxy)phenyl]-2-methyl-5-oxo-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(difluoromethoxy)phenyl]-2-(2-hydroxy-2-methylpropyl)-5-oxo-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2-hydroxy-2-methylpropyl)-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-[(oxetan-3-yl)methyl]-5-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-methyl-5-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2-hydroxy-2-methylpropyl)-5-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2,2-difluoroethyl)-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-[(oxetan-3-yl)methyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-N-(2,4-difluorophenyl)-2-[(oxetan-3-yl)methyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-N-(2,4-difluorophenyl)-2-(oxetan-3-yl)-5-oxo-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-(oxetan-3-yl)-5-oxo-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-(oxetan-3-yl)-5-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(difluoromethyl)phenyl]-2-methyl-5-oxo-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-(2,2-difluoroethyl)-5-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-(oxetan-3-yl)-5-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,5-dihydropyridazine-4-carboxamide 6-[2-(2,2-difluoroethoxy)phenyl]-2-[(oxetan-3-yl)methyl]-5-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,5-dihydropyridazine-4-carboxamide 2-Cyclopropyl-6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,5-dihydropyridazine-4-carboxamide N-[4-(2-cyanopropan-2-yl)phenyl]-2-methyl-5-oxo-6-[2-(2,2,2-trifluoroethoxy)phenyl]-2,5-dihydropyridazine-4-carboxamide N-[4-(2-cyanopropan-2-yl)phenyl]-6-[2-(2,2-difluoroethoxy)phenyl]-2-(oxetan-3-yl)-5-oxo-2,5-dihydropyridazine-4-carboxamide N-[4-(2-cyanopropan-2-yl)phenyl]-2-cyclopropyl-6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide rac-6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2-(oxolan-3-yl)-2,5-dihydropyridazine-4-carboxamide Ethyl 4-({2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carbonyl}amino)benzoate rac-6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2-(oxolan-3-yl)-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,5-dihydropyridazine-4-carboxamide rac-6-[2-(2,2-difluoroethoxy)phenyl]-5-oxo-2-(oxolan-3-yl)-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,5-dihydropyridazine-4-carboxamide 6-Acetyl-N-[4-(difluoromethoxy)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide Ethyl 5-{[4-(difluoromethoxy)phenyl]carbamoyl}-6-oxo-1-[2-(2,2,2-trifluoroethoxy)phenyl]-1,6-dihydropyridazine-3-carboxylate rac-N-[4-(difluoromethoxy)phenyl]-6-(1-hydroxyethyl)-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide N-[4-(difluoromethoxy)phenyl]-6-(2-hydroxypropan-2-yl)-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide N-[4-(2-cyanopropan-2-yl)phenyl]-6-(2-hydroxypropan-2-yl)-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide 6-(2-hydroxypropan-2-yl)-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide, and 6-(2-hydroxypropan-2-yl)-3-oxo-N-[4-(prop-1-en-2-yl)phenyl]-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide.

2. 2-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide, or a salt thereof. 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide, or a salt thereof; N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide, or a salt thereof, 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide, or a salt thereof, 2-[2-(2,2-difluoroethoxy)phenyl]-N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide, or a salt thereof; 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide, or a salt thereof, 2-[2-(2,2-difluoroethoxy)phenyl]-N-[2-fluoro-4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide, or a salt thereof; N-[2-fluoro-4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide, or a salt thereof; 2-[2-(2,2-difluoroethoxy)phenyl]-6-methyl-3-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,3-dihydropyridazine-4-carboxamide, or a salt thereof, 6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-2-methyl-5-oxo-2,5-dihydropyridazine-4-carboxamide, or a salt thereof, 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide, or a salt thereof; 3-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide, or a salt thereof; 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-N-[4-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)phenyl]-2,5-dihydropyridazine-4-carboxamide, or a salt thereof; 2-Cyclopropyl-6-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-5-oxo-2,5-dihydropyridazine-4-carboxamide, or a salt thereof, 6-[2-(2,2-difluoroethoxy)phenyl]-2-(difluoromethyl)-5-oxo-N-[6-(1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]-2,5-dihydropyridazine-4-carboxamide, or a salt thereof.

3. N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide or a salt thereof.

4. 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide or a salt thereof.

5. 2-[2-(2,2-difluoroethoxy)phenyl]-N-[4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide or a salt thereof.

6. A medicine comprising a compound according to any one of claims 1 to 5 or a salt thereof.

7. The pharmaceutical according to claim 6, which is a glucosylceramide synthase inhibitor.

8. The pharmaceutical agent according to claim 6, which is a preventive or therapeutic agent for a lysosomal disease or a neurodegenerative disease.

9. The pharmaceutical composition according to claim 8, wherein the lysosomal disease is Gaucher disease, Fabry disease, GM1-gangliosidosis, GM2 activator deficiency, Tay-Sachs disease or Sandhoff disease.

10. The pharmaceutical composition according to claim 8, wherein the neurodegenerative disease is Parkinson's disease, dementia with Lewy bodies or multiple system atrophy.

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