Heterocyclic compounds for the treatment of epilepsy

Abstract

To provide a new compound useful for treatment, prevention and / or diagnosis of seizure or the like in diseases accompanied by epileptic seizure or convulsive seizure (including multidrug-resistant seizure, intractable seizure, acute symptomatic seizure, febrile seizure and status epilepticus).SOLUTION: There are provided a compound represented by formula [I] and a salt thereof. Ring C is selected from pyridazine, pyrimidine, indole, pyrrolopyridine, indazole, pyrazolopyridine, imidazopyridine, imidazopyrazine, imidazopyridazine, triazolopyridine, pyrazolopyrimidine, imidazopyrimidine, triazolopyrimidine, isoquinoline, naphthyridine, quinazoline, quinoxaline, benzodioxole, oxazine, oxazepine, benzothiazole, and triazolopyridazine, with the proviso that pyrimidine-2, 4-dione and dihydropyrimidine-2, 4-dione are excluded.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a heterocyclic compound and a salt thereof. The present invention also relates to a pharmaceutical agent containing the heterocyclic compound or a salt thereof as an active ingredient, which is useful for treating, preventing, and / or diagnosing seizures and the like in diseases accompanied by epileptic seizures or convulsive seizures. [Background technology]

[0002] Epilepsy is a common neurological disorder affecting approximately 1% of the population, with approximately 1 million patients in Japan. Its lifetime prevalence is estimated at 3-4%, with tens of thousands of people developing epilepsy annually. While approximately 70% of patients are able to control their seizures with existing antiepileptic drugs and are able to lead normal daily lives, the remaining 30% are unable to adequately control their seizures and live with anxiety about the possibility of a seizure occurring at any time. Many existing antiepileptic drugs aim to correct the imbalance between neuronal excitation and inhibition by suppressing neuronal hyperexcitation and hypersynchronization. However, doses above the optimal dose can disrupt this balance, potentially leading to movement disorders and epileptic seizures.

[0003] Patent Document 1 discloses compounds containing pyrimidine in their structures as compounds to be used in the treatment of diseases or disorders, including epilepsy, that require modulators of Kv3.1 and / or Kv3.2 channels. Patent Documents 2 and 3 disclose compounds containing a pyrimidine skeleton as kynurenine-3-monooxygenase inhibitors for treating neurodegenerative conditions including epilepsy. Patent Document 4 discloses compounds containing phenoxypyrimidine or pyridyloxypyrimidine in their structures as antagonists and / or inverse agonists of cannabinoid-1 receptors, including those for epilepsy. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2011 / 069951 [Patent Document 2] International Publication No. 2013 / 016488 [Patent Document 3] International Publication No. 2011 / 091153 [Patent Document 4] International Publication No. 2004 / 029204 Summary of the Invention [Problem to be solved by the invention]

[0005] One object of the present invention is to provide pharmaceutical uses of novel compounds and salts thereof that are effective in treating, preventing and / or diagnosing seizures and the like in diseases accompanied by epileptic seizures or convulsive seizures. Another object of the present invention is to provide a pharmaceutical agent that maintains an excitation-inhibition balance even at a dose that completely suppresses epileptic seizures and has a broader therapeutic spectrum than existing antiepileptic drugs.

[0006] The present inventors have conducted extensive research to solve the above problems and have succeeded in synthesizing novel pyrimidine compounds that have a broader therapeutic spectrum than existing antiepileptic drugs. The present invention was completed based on this finding.

[0007] That is, the present invention includes the following aspects. [1] Formula I: TIFF2026031948000001.tif2685[in the formula, D is TIFF2026031948000002.tif2322 or C optionally substituted with halogen 1-6 is alkyl; Ring A is benzene, pyridine, indole, or indazole; Ring B is pyrimidine, pyridazine, pyridine, pyrazole, benzene or naphthalene, wherein: (i) When ring B is pyrimidine, ring C is selected from the following unsaturated rings and their oxides and dioxides (excluding pyrimidine-2,4-dione and dihydropyrimidine-2,4-dione), and rings in which some or all of the unsaturated bonds in the ring have been reduced with hydrogen; (a) a 3- to 8-membered monocyclic unsaturated heterocycle containing only 1 to 4 nitrogen atoms as ring-constituting heteroatoms; (b) a 7- to 15-membered bicyclic or tricyclic unsaturated heterocycle containing only 1 to 5 nitrogen atoms as ring-constituting heteroatoms; (c) a 7- to 12-membered bicyclic unsaturated heterocycle containing only 1 to 3 oxygen atoms as ring-constituting heteroatoms; (d) a 3- to 8-membered monocyclic unsaturated heterocycle containing one or two oxygen atoms and one to three nitrogen atoms as ring-constituting heteroatoms; (e) a 7- to 12-membered bicyclic unsaturated heterocycle containing one or two sulfur atoms and one to three nitrogen atoms as ring-constituting heteroatoms; and (f) 3- to 8-membered monocyclic unsaturated hydrocarbon ring; (ii) when ring B is pyridazine, pyridine, pyrazole, benzene or naphthalene, ring C is pyrimidine-2,4-dione or dihydropyrimidine-2,4-dione; R 1 is halogen, optionally substituted with halogen, 1-6 -OC optionally substituted with alkyl or halogen 1-6 alkyl, -CN or -SF5; R 2 is a halogen, C 1-6 Alkyl, -OC 1-6 is alkyl; R 3 is halogen, halogen or -OC 1-6 C optionally substituted with alkyl 1-6 -OC optionally substituted with alkyl or halogen 1-6 Alkyl, -C 1-6 alkyl -OH, -OH, -CN, -CONH2 or -NH2; L is a bond, C1-6 alkylene, -O- or -S-; k is 0, 1 or 2, and when k is 2, R 1 each independently represents the same or different substituent; m is 0, 1 or 2, and when m is 2, R 2 each independently represents the same or different substituent; n is 0, 1 or 2, and when n is 2, R 3 each independently represents the same or different substituent; A compound represented by the formula (I) or a salt thereof. [2] In formula I, D is TIFF2026031948000003.tif2322; Ring A is benzene or pyridine; Ring B is a pyrimidine; Ring C is selected from the following unsaturated rings, their oxides and dioxides (excluding pyrimidine-2,4-dione and dihydropyrimidine-2,4-dione), and rings in which some or all of the unsaturated bonds in the ring have been reduced with hydrogen: pyridine, pyridazine, pyrimidine, Indore, pyrrolopyridine, indazole, benzimidazole, pyrazolopyridines, imidazopyridine, imidazopyrazine, imidazopyridazine, triazolopyridines, pyrazolopyrimidines, imidazopyrimidines, triazolopyrimidines, quinoline, isoquinoline, naphthyridine, quinazoline, quinoxaline, benzodioxoles, oxazine, oxazepine, benzothiazole, benzene; R 1 is halogen, optionally substituted with halogen, 1-6 -OC optionally substituted with alkyl or halogen 1-6 alkyl or -CN; R 2 -OC 1-6 is alkyl; R 3 is halogen, halogen or -OC 1-6 C optionally substituted with alkyl 1-6 -OC optionally substituted with alkyl or halogen 1-6 Alkyl, -C 1-6 alkyl -OH, -OH, -CN, -CONH2 or -NH2; L is -O-; k is 0, 1 or 2, and when k is 2, R 1 each independently represents the same or different substituent; m is 0 or 1; n is 0, 1 or 2, and when n is 2, R 3 are each independently the same or different substituents, [3] In formula I, ring C is selected from the following unsaturated rings, their oxides, and rings in which some or all of the unsaturated bonds in the rings have been reduced with hydrogen: pyridine, pyridazine, pyrrolopyridine, indazole, pyrazolopyridines, imidazopyridine, imidazopyrazine, imidazopyridazine, pyrazolopyrimidines, triazolopyrimidines, quinoline, isoquinoline, naphthyridine, quinoxaline, benzene; R 1is halogen or optionally halogen-substituted C 1-6 is alkyl; R 3 C optionally substituted with halogen 1-6 -OC optionally substituted with alkyl or halogen 1-6 alkyl, -OH, -CONH2 or -NH2; L is -O-; k and n are 0 or 1; [2] The compound or salt thereof according to [2], wherein m is 0. [4] In formula I, ring C is selected from the following unsaturated rings, their oxides, and rings in which some or all of the unsaturated bonds in the rings have been reduced with hydrogen: pyridine, pyridazine, pyrazolopyridines, Imidazopyridine; R 3 is -OH or -NH; L is -O-; k and m are 0; [3] The compound or salt thereof according to [3], wherein n is 0 or 1. [5] In Formula I, D is TIFF2026031948000004.tif2322 or C optionally substituted with halogen 1-6 is alkyl; Ring A is benzene or pyridine; Ring B is pyridazine, pyridine, pyrazole, benzene, or naphthalene; Ring C is pyrimidine-2,4-dione or dihydropyrimidine-2,4-dione; R 1 is halogen, optionally substituted with halogen, 1-6 -OC optionally substituted with alkyl or halogen 1-6 alkyl, -CN or -SF5; R 2 is a halogen, C 1-6 Alkyl, -OC 1-6 is alkyl; R3 is C 1-6 is alkyl; L is a bond, C 1-6 alkylene, -O- or -S-; k is 0, 1 or 2, and when k is 2, R 1 each independently represents the same or different substituent; m is 0, 1 or 2, and when m is 2, R 2 each independently represents the same or different substituent; n is 0, 1 or 2, and when n is 2, R 3 are each independently the same or different substituents, [6] In Formula I, ring A is benzene; Ring B is benzene, pyridine, or pyridazine; Ring C is dihydropyrimidine-2,4-dione; R 1 is a halogen; L is -O-; k is 0 or 1; [5] The compound or salt thereof according to [5], wherein m and n are 0. [7] A compound selected from the group consisting of the following compounds or a salt thereof: TIFF2026031948000005.tif140151 TIFF2026031948000006.tif135147 TIFF2026031948000007.tif154148[8] The compound according to [7] or a salt thereof, selected from the group consisting of the following compounds: TIFF2026031948000008.tif113145[9] A pharmaceutical composition comprising a compound according to any one of [1] to [8] or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

[10] A therapeutic, preventive and / or diagnostic agent for seizures in diseases accompanied by epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus), comprising the compound according to any one of [1] to [8] or a salt thereof.

[11] Epileptic seizures include motor-onset seizures (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor-onset seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, affective seizures, and perceptual seizures) in focal seizures (sometimes called partial seizures), seizures that progress from focal seizures to bilateral tonic-clonic seizures (secondary generalization of partial seizures), motor seizures in generalized seizures (tonic-clonic seizures, clonic seizures, The therapeutic, preventive and / or diagnostic agent according to

[10] , wherein the seizures are selected from tonic seizures, myoclonic seizures, myoclonic tonic-clonic seizures, myoclonic atonic seizures, atonic seizures and epileptic spasms) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and lid myoclonic seizures); motor seizures of unknown onset (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral arrest seizures).

[12] Diseases accompanied by epileptic seizures or convulsive seizures include Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (infantile spasms), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, and hemiconvulsions / hemiplegia. The therapeutic, preventive and / or diagnostic agent according to

[10] , which is selected from epilepsy syndromes, mesial temporal lobe epilepsy syndromes, epilepsy attributable to structural or metabolic causes (post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disorders, epilepsy associated with brain tumors, epilepsy associated with neurodegenerative diseases, epilepsy associated with autoimmune diseases, etc.), as well as congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (Rett syndrome, Angelman syndrome, 5p syndrome, 4p syndrome, Down syndrome, etc.).

[13] A pharmaceutical composition for the treatment, prevention and / or diagnosis of seizures in diseases accompanied by epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus), comprising the compound according to any one of [1] to [8] or a salt thereof as an active ingredient.

[14] Epileptic seizures include motor-onset seizures (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor-onset seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, affective seizures, and perceptual seizures) in focal seizures (sometimes called partial seizures), seizures that progress from focal seizures to bilateral tonic-clonic seizures (secondary generalization of partial seizures), and motor seizures in generalized seizures (tonic-clonic seizures). The composition described in

[13] is selected from motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures, and eyelid myoclonic seizures) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures, and eyelid myoclonic seizures); motor seizures of unknown onset (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral arrest seizures).

[15] Diseases accompanied by epileptic seizures or convulsive seizures include Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (infantile spasms), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, and hemiconvulsions.

[13] The composition according to

[13] , which is selected from epilepsy caused by structural or metabolic causes (post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disorders, epilepsy associated with brain tumors, epilepsy associated with neurodegenerative diseases, epilepsy associated with autoimmune diseases, etc.), congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (e.g., Rett syndrome, Angelman syndrome, 5p syndrome, 4p syndrome, Down syndrome, etc.).

[16] A method for treating, preventing, and / or diagnosing seizures in diseases accompanied by epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures, and status epilepticus), comprising administering to a human an effective amount of the compound according to any one of [1] to [8] or a salt thereof.

[17] Epileptic seizures include focal seizures (sometimes called partial seizures) with motor onset (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor onset seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, affective seizures, and perceptual seizures), focal seizures that progress to bilateral tonic-clonic seizures (secondary generalization of partial seizures), and motor seizures in generalized seizures (tonic-clonic seizures). , clonic seizures, tonic seizures, myoclonic seizures, myoclonic tonic-clonic seizures, myoclonic atonic seizures, atonic seizures and epileptic spasms) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and lid myoclonic seizures); motor seizures of unknown onset (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral arrest seizures).

[18] The disease accompanied by epileptic seizures or convulsive seizures is Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (infantile spasms), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, hemispasm,

[16] The method according to

[16] , wherein the epilepsy is selected from convulsion / hemiplegia / epilepsy syndrome, mesial temporal lobe epilepsy syndrome, epilepsy attributable to structural or metabolic causes (post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disorders, epilepsy associated with brain tumors, epilepsy associated with neurodegenerative diseases, epilepsy associated with autoimmune diseases, etc.), congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (Rett syndrome, Angelman syndrome, 5p syndrome, 4p syndrome, Down syndrome, etc.).

[19] The compound or salt thereof according to any one of [1] to [8] for use in the treatment, prevention and / or diagnosis of seizures in diseases accompanied by epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus).

[20] Epileptic seizures include motor-onset seizures (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor-onset seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, affective seizures, and perceptual seizures) in focal seizures (sometimes called partial seizures), seizures that progress from focal seizures to bilateral tonic-clonic seizures (secondary generalization of partial seizures), motor seizures in generalized seizures (tonic-clonic seizures, clonic seizures), and The compound or salt thereof according to

[19] , which is selected from motor seizures (including tonic seizures, myoclonic seizures, myoclonic tonic-clonic seizures, myoclonic atonic seizures, atonic seizures, and epileptic spasms) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures, and lid myoclonic seizures); motor seizures of unknown onset (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral arrest seizures).

[21] Diseases accompanied by epileptic seizures or convulsive seizures include Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (infantile spasms), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, and hemiconvulsions. The compound or salt thereof according to

[19] is selected from hemiplegia epilepsy syndrome, mesial temporal lobe epilepsy syndrome, epilepsy attributable to structural or metabolic causes (post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disorders, epilepsy associated with brain tumors, epilepsy associated with neurodegenerative diseases, epilepsy associated with autoimmune diseases, etc.), as well as congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (e.g., Rett syndrome, Angelman syndrome, 5p syndrome, 4p syndrome, Down syndrome, etc.).

[22] Use of the compound or salt thereof according to any one of [1] to [8] in the manufacture of a medicament for treating, preventing and / or diagnosing seizures in diseases accompanied by epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus).

[23] Epileptic seizures include motor-onset seizures (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor-onset seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, affective seizures, and perceptual seizures) in focal seizures (sometimes called partial seizures), seizures that progress from focal seizures to bilateral tonic-clonic seizures (secondary generalization of partial seizures), and motor seizures in generalized seizures (tonic-clonic seizures). , clonic seizures, tonic seizures, myoclonic seizures, myoclonic tonic-clonic seizures, myoclonic atonic seizures, atonic seizures and epileptic spasms) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and lid myoclonic seizures); motor seizures of unknown onset (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral arrest seizures).

[22] The use described in

[24] Disorders accompanied by epileptic seizures or convulsive seizures include Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (infantile spasms), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, unilateral epilepsy,

[22] The use according to

[22] , wherein the condition is selected from convulsion / hemiplegia / epilepsy syndrome, mesial temporal lobe epilepsy syndrome, epilepsy attributable to structural or metabolic causes (post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disorders, epilepsy associated with brain tumors, epilepsy associated with neurodegenerative diseases, epilepsy associated with autoimmune diseases, etc.), as well as congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (e.g., Rett syndrome, Angelman syndrome, 5p syndrome, 4p syndrome, Down syndrome, etc.).

[0008] The compounds of the present invention and salts thereof have excellent effects in the treatment, prevention, and / or diagnosis of diseases accompanied by epileptic seizures or convulsive seizures. Furthermore, the compounds of the present invention and salts thereof have excellent characteristics suitable for use as active ingredients in pharmaceuticals, such as fewer side effects and excellent characteristics in terms of tolerability and stability (storage stability, metabolic stability, etc.). Furthermore, the compounds of the present invention and salts thereof have a broader therapeutic spectrum than existing antiepileptic drugs. DETAILED DESCRIPTION OF THE INVENTION

[0009] The terms and phrases used in this specification are explained in detail below. "C 1-6 "Alkyl" is C 1-6 Specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, and the like. In addition, C in which 1 to 3 hydrogen atoms are replaced by deuterium atoms 1-6 Alkyl is also included.

[0010] "Halogen" refers to fluorine, chlorine, bromine or iodine. Preferably, it is fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0011] "Optionally halogen-substituted C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms (C 1-6) is a straight-chain or branched alkyl group, specific examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromohexyl, and the like.

[0012] "C 1-6 Alkylene is a group containing 1 to 6 carbon atoms (C 1-6 ) is a straight-chain or branched alkylene group, and specific examples thereof include methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, dimethylmethylene, tetramethylene, pentamethylene, hexamethylene, and the like. Also, "C 1-6 "Alkylene" includes C alkylenes in which one to three hydrogen atoms are replaced by deuterium atoms. 1-6 Alkylene is also included.

[0013] Each group defined herein may be optionally linked to another group via a linker such as -O-, -CO-, -COO-, -S-, -SO-, -SO2-, -Si-, or -O-CO-.

[0014] Various substituents in the compound of the present invention represented by the general formula [I] (hereinafter referred to as "compound [I] of the present invention") are explained below.

[0015] D in the compound [I] of the present invention is (R 1 )k Ring A optionally substituted with or C optionally substituted with halogen 1-6 It is alkyl.

[0016] Ring A in the compound [I] of the present invention is benzene, pyridine, indole or indazole, preferably benzene or pyridine.

[0017] In the compound [I] of the present invention, when the ring B is pyrimidine, the ring C is selected from the following unsaturated rings, their oxides and dioxides (excluding pyrimidine-2,4-dione and dihydropyrimidine-2,4-dione), and rings in which some or all of the unsaturated bonds in the ring have been reduced with hydrogen: (a) a 3- to 8-membered monocyclic unsaturated heterocycle containing only 1 to 4 nitrogen atoms as ring-constituting heteroatoms; (b) a 7- to 15-membered bicyclic or tricyclic unsaturated heterocycle containing only 1 to 5 nitrogen atoms as ring-constituting heteroatoms; (c) a 7- to 12-membered bicyclic unsaturated heterocycle containing only 1 to 3 oxygen atoms as ring-constituting heteroatoms; (d) a 3- to 8-membered monocyclic unsaturated heterocycle containing one or two oxygen atoms and one to three nitrogen atoms as ring-constituting heteroatoms; (e) a 7- to 12-membered bicyclic unsaturated heterocycle containing one or two sulfur atoms and one to three nitrogen atoms as ring-constituting heteroatoms; (f) 3- to 8-membered monocyclic unsaturated hydrocarbon ring.

[0018] Specific examples of the above (a) 3- to 8-membered monocyclic unsaturated heterocycle containing only 1 to 4 nitrogen atoms as ring-constituting heteroatoms, as well as oxides and dioxides thereof (excluding pyrimidine-2,4-dione and dihydropyrimidine-2,4-dione), and rings in which part or all of the unsaturated bonds in the ring have been reduced with hydrogen include: Pyridine, piperidine, pyridine-1-oxide, pyridin-2(1H)-one, pyrimidine, tetrahydropyrimidine, tetrahydropyrimidin-2(1H)-one, pyridazine, pyridazin-3(2H)-one, 4,5-dihydropyridazine, 4,5-dihydropyridazin-3(2H)-one The following can be mentioned:

[0019] Specific examples of the above (b) 7- to 15-membered bicyclic or tricyclic unsaturated heterocycle containing only 1 to 5 nitrogen atoms as ring-constituting heteroatoms, as well as their oxides, dioxides, and rings in which part or all of the unsaturated bonds in the ring have been reduced with hydrogen include: indole, indoline, indolin-2-one, indolin-3-one, indoline-2,3-dione, benzimidazole (e.g., 1H-benzo[d]imidazole), dihydrobenzimidazole (e.g., 2,3-dihydro-1H-benzo[d]imidazole), indazole, dihydroindazole (e.g., 2,3-dihydro-1H-indazole), quinoline, quinolin-2(1H)-one, dihydroquinoline (e.g., 1,2-dihydroquinoline, 3,4-dihydroquinoline), 3 ,4-dihydroquinolin-2(1H)-one, tetrahydroquinoline (e.g., 1,2,3,4-tetrahydroquinoline), isoquinoline, isoquinolin-1(2H)-one, 1,3-dihydroisoquinoline, 3,4-dihydroisoquinoline, 3,4-dihydroisoquinolin-1(2H)-one, triazolopyrimidines (e.g., [1,2,4]triazolo[1,5-a]pyrimidine), triazolopyridines (e.g., [1,2,3]triazolo[1,5-a]pyridine, [1,2,4]triazolo[ [1,5-a]pyridine, [1,2,4]triazolo[4,3-a]pyridine, imidazopyridine (e.g., imidazo[1,5-a]pyridine), imidazopyrazine (e.g., imidazo[1,2-a]pyrazine), imidazopyrimidine (e.g., imidazo[1,2-a]pyrimidine), imidazopyridazine (e.g., imidazo[1,2-b]pyridazine), naphthyridine (e.g., 1,5-naphthyridine, 1,8-naphthyridine), quinoxaline, dihydroquinoxaline (e.g., 1,2-dihydroquinoxaline), quinoxaline), tetrahydroquinoxaline (e.g., 1,2,3,4-tetrahydroquinoxaline), quinazoline, quinazolin-4(3H)-one, dihydroquinazoline (e.g., 2,3-dihydroquinazoline), pyrazolopyridines (e.g., pyrazolo[1,5-a]pyridine, pyrazolo[3,4-b]pyridine), pyrrolopyridines (e.g., pyrrolo[2,3-b]pyridine), pyrrolo[2,3-b]pyridin-2(3H)-one, pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine) The following can be mentioned:

[0020] Specific examples of the above (c) 7- to 12-membered bicyclic unsaturated heterocycle containing only 1 to 3 oxygen atoms as ring-constituting heteroatoms, as well as their oxides, dioxides, and rings in which part or all of the unsaturated bonds in the ring have been reduced with hydrogen include: Benzodioxoles (e.g., benzo[d][1,3]dioxole, benzo[c][1,2]dioxole) The following can be mentioned:

[0021] Specific examples of the above (d) 3- to 8-membered monocyclic unsaturated heterocycle containing one or two oxygen atoms and one to three nitrogen atoms as ring-constituting heteroatoms, as well as oxides and dioxides thereof and rings in which part or all of the unsaturated bonds in the ring have been reduced with hydrogen include: Oxazepines (e.g., 1,2-oxazepine, 1,3-oxazepine, 1,4-oxazepine), dihydrooxazepines, tetrahydrooxazepines, oxazepanes (e.g., 1,2-oxazepane, 1,3-oxazepane, 1,4-oxazepane), 1,4-oxazepan-2-ones, oxazines (e.g., 1,4-oxazine), dihydrooxazines (3,4-dihydro-2H-1,4-oxazepines), morpholine, morpholin-3-one The following can be mentioned:

[0022] Specific examples of the above (e) 7- to 12-membered bicyclic unsaturated heterocycle containing one or two sulfur atoms and one to three nitrogen atoms as ring-constituting heteroatoms, as well as oxides and dioxides thereof and rings in which part or all of the unsaturated bonds in the ring have been reduced with hydrogen include: Benzothiazoles (e.g., benzo[d]thiazole) The following can be mentioned:

[0023] Specific examples of the 3- to 8-membered monocyclic unsaturated hydrocarbon rings of the above (f), as well as their oxides, dioxides, and rings in which part or all of the unsaturated bonds in the rings have been reduced with hydrogen include: Benzene, cyclohexene, cyclohexane The following can be mentioned:

[0024] Preferably, when ring B is pyrimidine, ring C is selected from the following unsaturated rings, their oxides and dioxides (excluding pyrimidine-2,4-dione and dihydropyrimidine-2,4-dione), and rings in which some or all of the unsaturated bonds in the ring have been reduced with hydrogen: pyridine, pyridazine, pyrimidine, Indore, pyrrolopyridine, indazole, benzimidazole, pyrazolopyridines, imidazopyridine, imidazopyrazine, imidazopyridazine, triazolopyridines, pyrazolopyrimidines, imidazopyrimidines, triazolopyrimidines, quinoline, isoquinoline, naphthyridine, quinazoline, quinoxaline, benzodioxoles, oxazine, oxazepine, benzothiazole, benzene.

[0025] In the compound [I] of the present invention, when ring B is benzene, naphthalene, pyridine, pyrazole or pyridazine, ring C is pyrimidine-2,4-dione or dihydropyrimidine-2,4-dione. Preferably, ring B is benzene or pyridine.

[0026] R 1 is halogen, optionally substituted with halogen, 1-6 -OC optionally substituted with alkyl or halogen 1-6 alkyl, -CN or -SF5. Preferably halogen, optionally halogen-substituted C1-6 -OC optionally substituted with alkyl or halogen 1-6 It is alkyl, and more preferably fluorine, methyl, trifluoromethyl or -O-trifluoromethyl.

[0027] R 2 is a halogen, C 1-6 Alkyl or -OC 1-6 It is alkyl, preferably fluorine, methyl or -O-methyl.

[0028] R 3 is halogen, halogen or C 1-6 C optionally substituted with alkyl-O- 1-6 -OC optionally substituted with alkyl or halogen 1-6 Alkyl, -C 1-6 Alkyl-OH, -OH, -CN, -CONH2 or -NH2. Preferably, C optionally substituted with halogen. 1-6 Alkyl, -OC 1-6 It is preferably alkyl, -OH, -CONH2 or -NH2, and more preferably methyl, trifluoromethyl, -O-methyl, -OH, -CONH2 or -NH2.

[0029] L is a bond, C 1-6 It is alkylene, —O— or —S—, preferably a bond or —O—, and more preferably —O—.

[0030] k is 0, 1 or 2, and when k is 2, R 1 are each independently the same or different substituents, preferably 0 or 1, and more preferably 0.

[0031] m is 0, 1 or 2, and when m is 2, R 2 are each independently the same or different substituents, preferably 0 or 1, and more preferably 0.

[0032] n is 0, 1 or 2, and when n is 2, R 3are each independently the same or different substituents, preferably 0 or 1.

[0033] In the compound [I] of the present invention, the above-mentioned options and preferred embodiments regarding the substituents include all combinations thereof, so long as they are not contradictory combinations.

[0034] Preferred embodiments of the compound [I] of the present invention are shown below. (1-1) In formula I, D is TIFF2026031948000009.tif2322; Ring A is benzene or pyridine; Ring B is a pyrimidine; Ring C is selected from the following unsaturated rings, their oxides and dioxides (excluding pyrimidine-2,4-dione and dihydropyrimidine-2,4-dione), and rings in which some or all of the unsaturated bonds in the ring have been reduced with hydrogen: pyridine, pyridazine, pyrimidine, Indore, pyrrolopyridine, indazole, benzimidazole, pyrazolopyridines, imidazopyridine, imidazopyrazine, imidazopyridazine, triazolopyridines, pyrazolopyrimidines, imidazopyrimidines, triazolopyrimidines, quinoline, isoquinoline, naphthyridine, quinazoline, quinoxaline, benzodioxoles, oxazine, oxazepine, benzothiazole, benzene; R1 is halogen, optionally substituted with halogen, 1-6 -OC optionally substituted with alkyl or halogen 1-6 alkyl or -CN; R 2 -OC 1-6 is alkyl; R 3 is halogen, halogen or -OC 1-6 C optionally substituted with alkyl 1-6 -OC optionally substituted with alkyl or halogen 1-6 Alkyl, -C 1-6 alkyl -OH, -OH, -CN, -CONH2 or -NH2; L is -O-; k is 0, 1 or 2, and when k is 2, R 1 each independently represents the same or different substituent; m is 0 or 1; n is 0, 1 or 2, and when n is 2, R 3 are each independently the same or different substituents. (1-2) In formula I, ring C is selected from the following unsaturated rings, oxides thereof, and rings in which some or all of the unsaturated bonds in the rings have been reduced with hydrogen: pyridine, pyridazine, pyrrolopyridine, indazole, pyrazolopyridines, imidazopyridine, imidazopyrazine, imidazopyridazine, pyrazolopyrimidines, triazolopyrimidines, quinoline, isoquinoline, naphthyridine, quinoxaline, benzene; R 1 is halogen or optionally halogen-substituted C 1-6 is alkyl; R3 C optionally substituted with halogen 1-6 -OC optionally substituted with alkyl or halogen 1-6 alkyl, -OH, -CONH2 or -NH2; L is -O-; k and n are 0 or 1; m is 0. (1-3) In formula I, ring C is selected from the following unsaturated rings, their oxides, and rings in which some or all of the unsaturated bonds in the rings have been reduced with hydrogen: pyridine, pyridazine, pyrazolopyridines, Imidazopyridine; R 3 is -OH or -NH; L is -O-; k and m are 0; n is 0 or 1. (1-4) A compound selected from the group consisting of the following compounds or a salt thereof: TIFF2026031948000010.tif140148 TIFF2026031948000011.tif140153 TIFF2026031948000012.tif84146(1-5) A compound or a salt thereof selected from the group consisting of the following compounds: TIFF2026031948000013.tif100151

[0035] Another preferred embodiment of the compound [I] of the present invention is shown below. (2-1) In formula I, D is TIFF2026031948000014.tif2322 or C optionally substituted with halogen 1-6 is alkyl; Ring A is benzene or pyridine; Ring B is pyridazine, pyridine, pyrazole, benzene, or naphthalene; Ring C is pyrimidine-2,4-dione or dihydropyrimidine-2,4-dione; R 1 is halogen, optionally substituted with halogen, 1-6 -OC optionally substituted with alkyl or halogen 1-6 alkyl, -CN or -SF5; R 2 is a halogen, C 1-6 Alkyl, -OC 1-6 is alkyl; R 3 is C 1-6 is alkyl; L is a bond, C 1-6 alkylene, -O- or -S-; k is 0, 1 or 2, and when k is 2, R 1 each independently represents the same or different substituent; m is 0, 1 or 2, and when m is 2, R 2 each independently represents the same or different substituent; n is 0, 1 or 2, and when n is 2, R 3 are each independently the same or different substituents. (2-2) In formula I, ring A is benzene; Ring B is benzene, pyridine, or pyridazine; Ring C is dihydropyrimidine-2,4-dione; R 1 is a halogen; L is -O-; k is 0 or 1; m and n are 0. (2-3) A compound selected from the group consisting of the following compounds or a salt thereof: TIFF2026031948000015.tif50106(2-4) The following compounds or salts thereof: TIFF2026031948000016.tif3263

[0036] In this specification, the presentation of preferred aspects and options for different features of the compounds, methods, and compositions of the present invention also includes the presentation of combinations of preferred aspects and options for the different features, as long as they are combinable and not contradictory.

[0037] The production method of the compound [I] of the present invention will be explained below. The compound [I] of the present invention can be produced, for example, by the production method shown below. The production methods shown below are merely examples, and the production method of the compound [I] is not limited to these.

[0038] In the following reaction schemes, alkylation, hydrolysis, amination, esterification, amidation, etherification, nucleophilic substitution, addition, oxidation, reduction, and other reactions are carried out according to methods known per se. Examples of such methods include those described in Experimental Chemistry Lectures (5th ed., edited by the Chemical Society of Japan, Maruzen Co., Ltd.), Organic Functional Group Preparations, 2nd ed., Academic Press, Inc., 1989; Comprehensive Organic Transformations, VCH Publishers Inc., 1989; and Greene's Protective Groups in Organic Synthesis, 4th ed., 2006, by P.G. M. Uts and T.W. Greene.

[0039] Reaction Scheme 1-1 TIFF2026031948000017.tif32167 (wherein Y and Y′ are leaving groups, and the other symbols are as defined above.)

[0040] The compound [I] of the present invention can be produced by the reaction shown in the above reaction formula 1-1. Specifically, compound [IIa] is added with a cyclic pinacol ester of boronic acid ((BPin)2) to form compound [IIa'], and compound [IIIa] is then coupled thereto by Suzuki cross-coupling to produce compound [I].

[0041] The "leaving group" used in the above reaction is specifically halogen, C 1-18 Alkanesulfonyl, C 1-8 Alkanesulfonyloxy, arylsulfonyloxy, aralkylsulfonyloxy, trihalomethanesulfonyloxy, sulfonio, toluenesulfoxy, etc. Preferred leaving groups in this reaction include halogens.

[0042] The above "halogen" is fluorine, chlorine, bromine or iodine.

[0043] The above "C 1-18 Examples of "alkanesulfonyl" include C 1-18 It includes straight-chain or branched-chain alkanesulfonyl, specific examples of which include methanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl, butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl, and the like.

[0044] Examples of the above "lower alkanesulfonyloxy" include C 1-6 It includes straight-chain or branched-chain alkanesulfonyloxy, and specific examples thereof are methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy, 2-propanesulfonyloxy, 1-butanesulfonyloxy, 3-butanesulfonyloxy, 1-pentanesulfonyloxy, 1-hexanesulfonyloxy, and the like.

[0045] Examples of the above "arenesulfonyloxy" include halogen, nitro, C 1-6 Linear or branched alkoxy groups and C 1-6It includes benzenesulfonyloxy, naphthalenesulfonyloxy, etc., which may have 1 to 3 substituents selected from the group consisting of straight-chain or branched-chain alkyl groups on the phenyl ring. Specific examples of these "benzenesulfonyloxy which may have a substituent" include benzenesulfonyloxy, 4-methylbenzenesulfonyloxy, 2-methylbenzenesulfonyloxy, 4-nitrobenzenesulfonyloxy, 4-methoxybenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, 3-chlorobenzenesulfonyloxy, etc. Specific examples of the above "naphthalenesulfonyloxy" include α-naphthylsulfonyloxy, β-naphthylsulfonyloxy, etc.

[0046] Examples of the above "aralkanesulfonyloxy" include halogen, nitro, C 1-6 Linear or branched alkoxy groups and C 1-6 C substituted with phenyl, which may have 1 to 3 substituents on the phenyl ring selected from the group consisting of straight-chain or branched-chain alkyl groups 1-6 Linear or branched alkanesulfonyloxy, naphthyl-substituted C 1-6 It includes straight-chain or branched-chain alkanesulfonyloxy. Specific examples of these "alkanesulfonyloxy substituted with phenyl" include phenylmethanesulfonyloxy, 2-phenylethanesulfonyloxy, 4-phenylbutanesulfonyloxy, 4-tolylmethanesulfonyloxy, 2-tolylmethanesulfonyloxy, (4-nitrophenyl)methanesulfonyloxy, (4-methoxyphenyl)methanesulfonyloxy, (3-chlorophenyl)methanesulfonyloxy, etc. Examples of the above "alkanesulfonyloxy substituted with naphthyl" include α-naphthylmethanesulfonyloxy, β-naphthylmethanesulfonyloxy, etc.

[0047] A specific example of the above-mentioned "trihaloalkanesulfonyloxy" is trifluoromethanesulfonyloxy.

[0048] Specific examples of the above "sulfonio" include dimethylsulfonio, diethylsulfonio, dipropylsulfonio, di(2-cyanoethyl)sulfonio, di(2-nitroethyl)sulfonio, di-(aminoethyl)sulfonio, di(2-methylaminoethyl)sulfonio, di-(2-dimethylaminoethyl)sulfonio, di-(2-hydroxyethyl)sulfonio, di-(3-hydroxypropyl)sulfonio, di-(2-methoxyethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2-carboxyethyl)sulfonio, di-(2-methoxycarbonylethyl)sulfonio, diphenylsulfonio, and the like.

[0049] The "palladium compound" used in this reaction is not particularly limited, but examples thereof include tetravalent palladium catalysts such as sodium hexachloropalladate(IV) tetrahydrate and potassium hexachloropalladate(IV); [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (PdCl2(dppf)DCM), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd Examples of suitable catalysts include divalent palladium catalysts such as palladium(II) chloride, palladium(II) bromide, palladium(II) acetate (PD(OAc)), palladium acetylacetonate(II), dichlorobis(benzonitrile)palladium(II), dichlorobis(acetonitrile)palladium(II), dichlorobis(triphenylphosphine)palladium(II), dichlorotetraamminepalladium(II), dichloro(cycloocta-1,5-diene)palladium(II), and palladium(II) trifluoroacetate; and zero-valent palladium catalysts such as tris(dibenzylideneacetone)dipalladium(0) (Pd(dba)), tris(dibenzylideneacetone)dipalladium(0) chloroform complex, and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh)). These palladium compounds can be used alone or in combination.

[0050] In this reaction, the amount of the palladium compound used is not particularly limited, but is usually in the range of 0.000001 to 20 moles in terms of palladium per mole of compound [IIa]. The more preferred amount of the palladium compound used is in the range of 0.0001 to 5 moles in terms of palladium per mole of compound [IIa].

[0051] The "base" used in this reaction includes, for example, inorganic bases, organic bases, etc. Examples of the "inorganic base" include alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate), alkali metal phosphates (e.g., sodium phosphate, potassium phosphate), alkaline earth metal phosphates (e.g., sodium phosphate, potassium phosphate), etc. Examples of the "organic base" include trialkylamines (e.g., trimethylamine, triethylamine, and diisopropylethylamine), dialkylamines (e.g., diethylamine and diisopropylamine), picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc. These bases may be used alone or in combination.

[0052] The "boronic acid" or "boronic acid ester" used in this reaction may be separately produced, isolated, and purified before use. Alternatively, for example, a precursor halogenated compound or the like may be reacted with bis-pinacoldiborane in the presence of a palladium compound, and then used in the Suzuki cross-coupling without isolation or purification.

[0053] The "solvent" used in this reaction may be any solvent inert to the reaction, and examples thereof include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether), hydrocarbons (e.g., hexane), halohydrocarbons (e.g., methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, xylene), lower alcohols (e.g., methanol, ethanol, isopropanol), polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, acetonitrile), ketones (e.g., acetone, methyl ethyl ketone), and esters (e.g., methyl acetate, ethyl acetate). These solvents may be used alone or in combination.

[0054] Other reaction conditions (reaction temperature, reaction time, etc.) can be appropriately determined based on known Suzuki cross-coupling reactions.

[0055] Reaction Scheme 1-2 TIFF2026031948000018.tif38127 (wherein Y is a leaving group, and the other symbols are as defined above.)

[0056] The compound [I] of the present invention can be produced by the reaction shown in the above reaction formula 1-2. Specifically, the compound [I] can be produced by coupling the compound [IIa] to the compound [IIIb] by Suzuki cross-coupling.

[0057] The palladium compound, base, solvent, etc. that can be used in the above reaction scheme 1-2 are the same as those that can be used in reaction scheme 1-1.

[0058] Reaction Scheme 1-3 TIFF2026031948000019.tif38121 (wherein Y is a leaving group, and the other symbols are as defined above.)

[0059] The compound [I] of the present invention can be produced by the reaction shown in the above reaction scheme 1-3. Specifically, the compound [I] can be produced by coupling the compound [IIa] to the compound [IIIc] by Suzuki cross-coupling.

[0060] The palladium compound, base, solvent, etc. that can be used in the above reaction scheme 1-3 are the same as those that can be used in reaction scheme 1-1.

[0061] Reaction Scheme 2-1 TIFF2026031948000020.tif35119 (wherein each symbol has the same meaning as above.)

[0062] Compound [Ia], which is included in compound [I] of the present invention, can be produced by the reaction shown in the above reaction formula 2-1. Specifically, compound [VI] is added to the amino group of compound [IIb], and then the chlorine in the product is eliminated and cyclized to produce compound [Ia].

[0063] The "base" used in this reaction includes, for example, inorganic bases, organic bases, etc. Examples of "inorganic bases" include alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), alkali metal hydrogencarbonates (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate), sodium hydride (NaH), sodium hexamethyldisilazide (NaHMDS), etc. Examples of "organic bases" include trialkylamines (e.g., trimethylamine, triethylamine), Hunig's base (N,N-diisopropylethylamine), pyridine, N-methylmorpholine, etc.

[0064] The "solvent" used in this reaction may be any solvent inert to the reaction, and examples thereof include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether), hydrocarbons (e.g., hexane), halohydrocarbons (e.g., methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, xylene), lower alcohols (e.g., methanol, ethanol, isopropanol), polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, acetonitrile), ketones (e.g., acetone, methyl ethyl ketone), and esters (e.g., methyl acetate, ethyl acetate). These solvents may be used alone or in combination.

[0065] Other reaction conditions (such as reaction temperature and reaction time) can be appropriately determined based on known condensation reactions. For example, the reaction temperature is from room temperature to the reflux temperature of the solvent, and the reaction time is from 10 minutes to 10 hours.

[0066] Reaction Scheme 2-2 TIFF2026031948000021.tif28115 (wherein each symbol has the same meaning as above.)

[0067] Compound [Ib], which is included in compound [I] of the present invention, can be produced by the reaction shown in the above reaction formula 2-2. Specifically, compound [III] (acrylic acid) is added to the amino group of compound [IIb] in a 1,4-addition reaction, and then the amino group of the product is converted to a urea derivative using urea, followed by cyclization (intramolecular amidation) to produce compound [Ib].

[0068] The "solvent" used in the above reaction may be any solvent inert to the reaction, and examples thereof include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether), hydrocarbons (e.g., hexane), halohydrocarbons (e.g., methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, xylene), lower alcohols (e.g., methanol, ethanol, isopropanol), polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidine (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, acetonitrile), ketones (e.g., acetone, methyl ethyl ketone), and esters (e.g., methyl acetate, ethyl acetate). These solvents may be used alone or in combination.

[0069] The "acid" used in the above reaction includes, for example, inorganic acids, organic acids, etc. Examples of "inorganic acids" include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc. Examples of "organic acids" include acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.

[0070] Other reaction conditions (reaction temperature, reaction time, etc.) can be appropriately determined based on the known 1,4-addition reaction and amidation reaction.

[0071] Reaction Scheme 3-1 TIFF2026031948000022.tif33153 (wherein Y is a leaving group, L1 is -O-, -S- or C 1-6 alkylene, and the other symbols are as defined above.

[0072] The compound [Ic] included in the compound [I] of the present invention can be produced by the reaction shown in the above reaction formula 3-1. Specifically, the compound [Ic] can be produced by eliminating the leaving group Y of the compound [V] and replacing it with the compound [IV].

[0073] The "base" used in this reaction may, for example, be an inorganic base. Examples of the "inorganic base" include alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), alkali metal hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate), sodium hydride (NaH), sodium hexamethyldisilazide (NaHMDS), etc. Examples of the "organic base" include trialkylamines (e.g., trimethylamine, triethylamine), Hunig's base (N,N-diisopropylethylamine), pyridine, N-methylmorpholine, etc.

[0074] The "solvent" used in this reaction may be any solvent inert to the reaction, and examples thereof include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether), hydrocarbons (e.g., hexane), halohydrocarbons (e.g., methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, xylene), lower alcohols (e.g., methanol, ethanol, isopropanol), polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, acetonitrile), ketones (e.g., acetone, methyl ethyl ketone), and esters (e.g., methyl acetate, ethyl acetate). These solvents may be used alone or in combination.

[0075] Other reaction conditions (reaction temperature, reaction time, etc.) can be appropriately determined based on known condensation reactions, and examples include a reaction temperature of room temperature to 100°C and a reaction time of 1 to 10 hours.

[0076] In each reaction in the above reaction scheme, the product can be used in the next reaction either as the reaction mixture or as a crude product, or it can be isolated from the reaction mixture in a conventional manner or easily purified by conventional separation means, such as recrystallization, distillation, and chromatography.

[0077] The starting compounds, intermediate compounds, and target compounds in each of the above steps, as well as the compound [I] of the present invention, include geometric isomers, stereoisomers, optical isomers, and tautomers. Various isomers can be separated by common optical resolution methods. Alternatively, the compounds can be prepared from suitable optically active starting compounds.

[0078] The compound [I] of the present invention can be produced by the synthesis methods shown in the above reaction schemes or by methods analogous thereto.

[0079] In the production of the compound [I] of the present invention, the starting compounds may be commercially available compounds, or compounds produced by known methods or methods analogous thereto, unless a specific production method is described.

[0080] The starting compounds and target compounds in each of the above steps can be used in the form of suitable salts, such as those exemplified below as salts of compound [I] of the present invention.

[0081] When the compound obtained in each step or a commercially available product is a free compound, it can be converted into the desired salt by a method known per se. When the compound obtained in each step or a commercially available product is a salt, it can be converted into the free form or another type of desired salt by a method known per se.

[0082] Compound [I] of the present invention also includes pharmaceutically acceptable salts, and may form acid addition salts or salts with bases depending on the type of substituents. Examples of such "acids" include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid; and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, and lactic acid. Examples of such "bases" include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; and organic bases such as methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline, and choline; and ammonium salts. Compounds may also form salts with amino acids such as lysine, arginine, aspartic acid, and glutamic acid.

[0083] The present invention also includes various hydrates, solvates and crystalline polymorphic substances of Compound [I] and its salts.

[0084] The compound [I] of the present invention includes compounds in which one or more atoms are substituted with one or more isotope atoms. Examples of isotope atoms include deuterium ( 2 H), tritium ( 3 H), 13 C. 15 N, 18 O and others.

[0085] The compound [I] of the present invention also includes pharmaceutically acceptable prodrugs. Substituents that can be modified to form prodrugs include reactive functional groups such as -OH, -COOH, and amino. Modification groups for these functional groups may be appropriately selected from the "substituents" in this specification.

[0086] The compound [I] of the present invention or a salt thereof may be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or a co-crystal salt refers to a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, etc.). Co-crystals and co-crystal salts can be prepared by applying known co-crystallization methods.

[0087] The compound [I] and its salts of the present invention have excellent effects in the treatment, prevention and / or diagnosis of epileptic seizures or convulsive seizures, which can be applied to any of the following types of epileptic seizures: Motor-onset seizures (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor onset seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, affective seizures, and perceptual seizures) in focal seizures (sometimes called partial seizures), seizures that progress from focal seizures to bilateral tonic-clonic seizures (secondarily generalized partial seizures); motor seizures (including tonic-clonic seizures, clonic seizures, tonic seizures, myoclonic tonic-clonic seizures, myoclonic atonic seizures, atonic seizures, and epileptic spasms) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures, and lid myoclonic seizures) in generalized seizures; motor seizures (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral arrest seizures) in seizures of unknown onset. Diseases accompanied by epileptic seizures or convulsive seizures include, for example, Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (infantile spasms), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, Examples include hemiconvulsion-hemiplegia-epilepsy syndrome, mesial temporal lobe epilepsy syndrome, epilepsy attributable to structural or metabolic causes (e.g., post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disorders, epilepsy associated with brain tumors, epilepsy associated with neurodegenerative diseases, epilepsy associated with autoimmune diseases, etc.), as well as congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (Rett syndrome, Angelman syndrome, 5p syndrome, 4p syndrome, Down syndrome, etc.). In addition, compound [I] and its salts of the present invention are also effective in the treatment, prevention, and / or diagnosis of multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures, and status epilepticus. Multidrug-resistant seizures or refractory seizures in the present invention refer to seizures that cannot be controlled due to ineffectiveness or insufficient effect of one or more antiepileptic drugs, regardless of the above-mentioned epileptic seizure type. Furthermore, the compound [I] of the present invention and its salts have excellent characteristics suitable for use as active ingredients in pharmaceuticals, such as fewer side effects and excellent characteristics in terms of tolerability and stability (storage stability, metabolic stability, etc.). These compounds of the present invention are also effective as prophylactic and / or therapeutic agents for intractable epileptic seizures that are refractory to conventional drug treatments.

[0088] Next, a medical preparation (hereinafter also referred to as a "pharmaceutical composition") containing the compound [I] of the present invention or a salt thereof as an active ingredient will be described.

[0089] The above-mentioned medical preparation is prepared by formulating the compound [I] of the present invention or a salt thereof in the form of a conventional medical preparation, using the compound [I] of the present invention or a salt thereof and a pharmaceutically acceptable carrier, which may include commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc.

[0090] Such medical preparations can be selected from a variety of forms depending on the purpose of treatment, including, for example, tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions, etc.).

[0091] A wide variety of known carriers can be used when forming tablets, including excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorption promoters such as sodium lauryl sulfate; moisturizers such as glycerin and starch; adsorbents such as colloidal silicic acid; and lubricants such as magnesium stearate and polyethylene glycol.

[0092] Furthermore, the tablets may be coated with conventional tablets as needed, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multi-layered tablets.

[0093] A wide range of known carriers can be used when forming the tablets into pills, including excipients such as glucose; binders such as gum arabic; and disintegrants such as laminaran.

[0094] Diluents used in forming the formulation into a liquid, emulsion, or suspension can be a wide variety of known diluents, such as water, etc. In addition, conventional solubilizers, buffers, etc. may also be added, and colorants, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may also be added as needed.

[0095] As the carrier used for forming into a suppository, a wide variety of known carriers can be used, for example, cacao butter.

[0096] When prepared as an injection, the solution, emulsion, or suspension is preferably sterilized and isotonic with blood. The injection may contain sufficient salt or the like to adjust the injection to isotonicity, and may also contain analgesics or other pharmaceuticals.

[0097] The amount of compound [I] of the present invention or a salt thereof contained in the medical preparation is not particularly limited and can be appropriately selected from a wide range, but it is usually preferable that the medical preparation contains 1 to 70% by weight of compound [I] of the present invention or a salt thereof.

[0098] The method of administration of the medical preparation of the present invention is not particularly limited, and may be administered by a method depending on various formulation forms, the patient's age, sex, disease state, and other conditions. For example, tablets, pills, liquids, suspensions, emulsions, granules, and capsules may be administered orally. Injections may be administered intravenously alone or in combination with common replacement fluids such as glucose and amino acids, or may be administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally as needed. Suppositories may be administered rectally.

[0099] The dosage of the above medical preparation may be selected appropriately depending on the method of use, the patient's age, sex, severity of the disease, and other conditions, and is usually 0.01 to 100 mg, preferably 0.1 to 50 mg per kg of body weight per day, which may be administered once or in divided doses.

[0100] The dosage varies depending on various conditions, and therefore, in some cases a dosage less than the above range is sufficient, and in other cases a dosage exceeding the above range is required.

[0101] Compound [I] or a salt thereof of the present invention can be used in combination with various therapeutic or prophylactic agents for diseases for which the aforementioned compound [I] is considered effective. Such combinations may be administered simultaneously, or separately, consecutively, or at a desired time interval. The simultaneous administration preparations may be formulated as a combined preparation or as separate preparations.

[0102] In one embodiment of the present invention, there is provided a pharmaceutical composition comprising compound [I] of the present invention or a salt thereof and a pharmaceutically acceptable carrier and / or excipient.

[0103] In another aspect, there is provided an agent for treating, preventing and / or diagnosing seizures in diseases accompanied by epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus), comprising compound [I] of the present invention or a salt thereof and a pharmaceutically acceptable carrier and / or excipient.

[0104] In yet another aspect, there is provided a pharmaceutical composition for the treatment, prevention and / or diagnosis of seizures in diseases accompanied by epileptic or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus), comprising compound [I] of the present invention or a salt thereof and a pharmaceutically acceptable carrier and / or excipient.

[0105] In yet another aspect, there is provided a method for treating, preventing and / or diagnosing seizures in diseases accompanied by epileptic or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus), which comprises administering to a human an effective amount of compound [I] of the present invention or a salt thereof.

[0106] In yet another aspect, there is provided compound [I] of the present invention or a salt thereof for treating, preventing and / or diagnosing seizures in diseases accompanied by epileptic or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus).

[0107] In yet another aspect, there is provided use of compound [I] of the present invention or a salt thereof in the manufacture of an agent for treating, preventing and / or diagnosing seizures in diseases accompanied by epileptic or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus). [Example]

[0108] The present invention will be further explained in detail by the following Reference Examples, Examples and Test Examples, but these do not limit the present invention and may be modified within the scope of the present invention. The following abbreviations may be used in this specification:

[0109] TIFF2026031948000023.tif227160 TIFF2026031948000024.tif213160

[0110] In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. Ratios shown for mixed solvents are by volume unless otherwise specified. % refers to % by weight unless otherwise specified. 1 H NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier transform NMR (either Bruker AVANCE III 400 (400 MHz) or Bruker AVANCE III HD (500 MHz)). In silica gel column chromatography, when basic is mentioned, aminopropylsilane-bonded silica gel was used. The absolute configuration of the compounds was determined by known X-ray crystal structure analysis methods (e.g., Shigeru Ohba and Shigenobu Yano, "Basic Lectures for Chemists 12: X-Ray Crystal Structure Analysis" (1st ed., 1999)), or estimated from the empirical rules of asymmetric epoxidation (Waldemar Adam, Rainer T. Fell, Chantu R. Saha-Moller and Cong-Gui Zhao: Tetrahedron: Asymmetry 1998, 9, 397-401; Yuanming Zhu, Yong Tu, Hongwu Yu, Yian Shi: Tetrahedron Lett. 1988, 29, 2437-2440).

[0111] [Reference example] Reference example 1 Synthesis of 5-bromo-2-phenoxypyrimidine To a suspension of phenol (13.6 mL), K2CO3 (26.8 g), and DMF (250 mL), 5-bromo-2-chloropyrimidine (25.0 g) was added and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting crystals were collected by filtration and washed with water to obtain the target compound (27.7 g).

[0112] Reference example 2 Synthesis of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine A mixture of 5-bromo-2-phenoxypyrimidine (1.00 g), (BPin)2 (1.315 g), PdCl2(dppf)DCM (0.163 g), AcOK (0.782 g), and 1,4-dioxane (10 mL) was heated to reflux under a nitrogen atmosphere for 10 hours. Water and AcOEt were added to the reaction mixture, which was then filtered through Celite. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in IPE, and insoluble materials were removed by filtration. The filtrate was concentrated, and the resulting solid was washed with hexane to give the target compound (646 mg).

[0113] Reference example 18 Synthesis of 3-methoxy-6-(2-(methylthio)pyrimidin-5-yl)pyridazine A mixture of 3-chloro-6-methoxypyridazine (206.3 mg), 2-(methylthio)pyrimidinyl-5-boronic acid pinacol ester (425.4 mg), KPO (663.4 mg), PdCl(dppf)DCM (48.6 mg), 1,4-dioxane (20 mL), and water (2 mL) was refluxed under nitrogen for 1.5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (Hexane / AcOEt) to give the target compound (242.6 mg).

[0114] Reference example 19 Synthesis of 3-methoxy-6-(2-(methylsulfonyl)pyrimidin-5-yl)pyridazine A mixture of 3-methoxy-6-(2-(methylthio)pyrimidin-5-yl)pyridazine (242.6 mg), aqueous 77% m-CPBA (627.9 mg), and DCM (20 mL) was stirred at 0°C for 1 hour and then at room temperature overnight. The reaction mixture was poured into ice and saturated aqueous NaHCO3, and the product was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (Hexane / AcOEt) to give the target compound (166.7 mg).

[0115] Reference example 21 Synthesis of 5-(2-(methylthio)pyrimidin-5-yl)pyridin-2-amine A mixture of 2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (1.96 g), 2-amino-5-bromopyridine (1.037 g), KPO (3.86 g), PdCl(dppf)DCM (273.3 mg), 1,4-dioxane (30 mL), and water (3 mL) was heated to reflux under a nitrogen atmosphere for 6 hours. Water was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by basic silica gel chromatography (hexane / AcOEt) to obtain the target compound (1.175 g).

[0116] Reference example 22 Synthesis of 5-(2-(methylsulfinyl)pyrimidin-5-yl)pyridin-2-amine A mixture of 5-(2-(methylthio)pyrimidin-5-yl)pyridin-2-amine (1.175 g), Oxone® (2.43 g), THF (30 mL), and water (10 mL) was stirred under a nitrogen atmosphere at 0°C for 10 minutes and then at room temperature for 2.75 hours. The reaction mixture was poured into ice and saturated aqueous NaHCO3, and the product was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (AcOEt, AcOEt / MeOH) to give the target compound (462 mg).

[0117] Reference example 23 Synthesis of 5-bromo-2-(dodecylthio)pyrimidine A mixture of 5-bromo-2-chloropyrimidine (2.30 g), 1-dodecanethiol (3.2 mL), K2CO3 (2.57 g), and DMF (20 mL) was stirred at room temperature overnight. Water was added, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (Hexane / AcOEt) to give the target compound (3.56 g).

[0118] Reference example 24 Synthesis of 5-(2-(dodecylthio)pyrimidin-5-yl)pyridin-2-amine A mixture of 5-bromo-2-(dodecylthio)pyrimidine (1.008 g), 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (811.6 mg), KPO (1.82 g), PdCl(dppf)DCM (107.7 mg), 1,4-dioxane (20 mL), and water (2 mL) was heated to reflux under a nitrogen atmosphere for 2.25 hours. Water was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (Hexane / AcOEt) to obtain the target compound (1.01 g).

[0119] Reference example 25 Synthesis of 5-(2-(dodecylsulfinyl)pyrimidin-5-yl)pyridin-2-amine A mixture of 5-(2-(dodecylthio)pyrimidin-5-yl)pyridin-2-amine (1.010 g), Oxone® (1.97 g), THF (40 mL), and water (10 mL) was stirred at 0°C for 25 minutes, and then stirred at room temperature overnight. The reaction mixture was poured into a mixture of ice, saturated aqueous NaHCO3, and DCM, and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (Hexane / AcOEt) to obtain the target compound (163 mg).

[0120] Reference example 26 Synthesis of 3-(benzyloxy)-6-(2-phenoxypyrimidin-5-yl)pyridazine A mixture of 5-bromo-2-phenoxypyrimidine (2.96 g), (BPin) (3.68 g), PdCl(dppf)DCM (0.370 g), AcOK (1.78 g), and 1,4-dioxane (20 mL) was heated to reflux for 3 hours under a nitrogen atmosphere. 3-(benzyloxy)-6-chloropyridazine (2.00 g), PdCl(dppf)DCM (0.370 g), KPO (3.85 g), and water (5 mL) were added to the reaction mixture and heated to reflux for 2 hours. Water and AcOEt were added to the reaction mixture, which was then filtered through Celite. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt), and the resulting solid was washed with AcOEt to give the target compound (2.54 g).

[0121] Reference example 35 Synthesis of 4-(2-phenoxypyrimidin-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (1.496 g), 4-bromo-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (1.00 g), PdCl(dppf)DCM (0.063 g), KPO (1.229 g), 1,4-dioxane (10 mL), and water (3 mL) was stirred at 100 °C overnight. Water was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt), and the resulting solid was washed with EtOH to give the target compound (1.087 g).

[0122] Reference example 38 Synthesis of 5-bromo-1-triisopropylsilyl-1H-pyrazolo[3,4-b]pyridine A solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (4.20 g) in DMF (20 mL) was stirred at 0°C and 60% NaH (0.933 g) was added. After 20 minutes, chlorotriisopropylsilane (4.99 mL) was added and stirred for 30 minutes. The reaction mixture was poured into ice water, and the precipitated solid was collected by filtration. The solid was dissolved in AcOEt, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt) to obtain the target compound (6.70 g).

[0123] Reference example 39 Synthesis of 4-methoxy-2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine A mixture of 5-bromo-4-methoxy-2-phenoxypyrimidine (15.00 g), (BPin)2 (14.9 g), AcOK (10.5 g), PdCl2(dppf)DCM (2.18 g), and DMSO (60 mL) was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was poured into ice water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt) to obtain the target compound (9.61 g).

[0124] Reference example 40 Synthesis of 2-(dodecylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine A mixture of 5-bromo-2-(dodecylthio)pyrimidine (2.548 g), (BPin)2 (2.17 g), AcOK (1.48 g), PdCl2(dppf)DCM (280.1 mg), and DMSO (20 mL) was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into ice water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt) to obtain the target compound (1.90 g).

[0125] Reference example 41 Synthesis of 6-(2-(dodecylthio)pyrimidin-5-yl)imidazo[1,2-a]pyridine A mixture of 2-(dodecylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (3.00 g), 6-bromoimidazo(1,2-a)pyridine (1.53 g), PdCl(dppf)DCM (0.301 g), KPO (3.13 g), 1,4-dioxane (20 mL), and water (10 mL) was stirred at 95 °C for 1 hour. The reaction mixture was poured into ice water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt) to give the target compound (2.05 g).

[0126] Reference example 42 Synthesis of 6-(2-(dodecylsulfonyl)pyrimidin-5-yl)imidazo[1,2-a]pyridine A mixture of 6-(2-(dodecylthio)pyrimidin-5-yl)imidazo[1,2-a]pyridine (2.00 g), Oxone® (7.75 g), THF (40 mL), and water (20 mL) was stirred at room temperature for 5 hours. The reaction mixture was poured into ice water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt) to obtain the target compound (910 mg).

[0127] Reference example 43 Synthesis of 5-nitro-2-phenoxypyrimidine A mixture of phenol (6.61 mL), potassium carbonate (12.99 g), 2-chloro-5-nitropyrimidine (10 g), and DMF (80 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the resulting crystals were collected by filtration and washed with water to obtain the target compound (6.55 g).

[0128] Reference example 44 Synthesis of 2-phenoxypyrimidin-5-amine 5-Nitro-2-phenoxypyrimidine (7.45 g) and aqueous 10% Pd / C (3 g) were suspended in EtOH (100 mL) and stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The resulting solid was washed with IPE to give the target compound (4.73 g).

[0129] Reference example 45 Synthesis of 1-(3-chloropropyl)-3-(2-phenoxypyrimidin-5-yl)urea To a solution of 2-phenoxypyrimidin-5-amine (1.00 g) in THF (10 mL) was added 3-chloropropyl isocyanate (0.713 mL) at room temperature under stirring, and the mixture was stirred overnight. The precipitated solid was collected by filtration and washed with THF to obtain the target compound (756 mg).

[0130] Reference example 46 Synthesis of 2-(3-fluoromethoxyphenoxy)-5-nitropyrimidine A mixture of m-fluorophenol (5.45 mL), potassium carbonate (10.40 g), 2-chloro-5-nitropyrimidine (8.00 g), and DMF (80 mL) was stirred at room temperature overnight. Water was added to the residue, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give the target compound (8.63 g).

[0131] Reference example 47 Synthesis of 2-(3-fluorophenoxy)pyrimidin-5-amine 2-(3-Fluoromethoxyphenoxy)nitropyrimidine (8.65 g) and 50% aqueous 10% Pd / C (3 g) were suspended in EtOH (100 mL) and stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by medium-pressure column chromatography (DCM / AcOEt), and the resulting solid was washed with hexane to give the target compound (3.77 g).

[0132] Reference example 50 Synthesis of 2-phenoxy-5-(4-(triisopropylsilyloxy)piperidin-1-yl)pyrimidine A mixture of 5-bromo-2-phenoxypyrimidine (400 mg), 4-(triisopropylsilyloxy)piperidine (451 mg), Pd(OAc) (17.9 mg), tBuP·HBF (23.1 mg), NaOtBu (153 mg), and toluene (6 mL) was stirred at 100°C under a nitrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt) to obtain the target compound (250 mg).

[0133] Reference example 56 Synthesis of (R)-1-(2-phenoxypyrimidin-5-yl)-4-(triisopropylsilyloxy)piperidin-2-one A mixture of 5-iodo-2-phenoxypyrimidine (500 mg), (R)-4-(triisopropylsilyloxy)piperidin-2-one (501 mg), copper(I) iodide (5.68 μL), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.053 mL), KPO (712 mg), and 1,4-dioxane (6 mL) was stirred at 95°C under a nitrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt) to give the target compound (340 mg).

[0134] Reference example 58 Synthesis of 1-fluoro-3-(4-nitrophenoxy)benzene A mixture of m-fluorophenol (41.7 g), 4-fluoronitrobenzene (50.0 g), K2CO3 (63.7 g), and DMF (250 mL) was stirred for 6 hours at 80 °C. The reaction mixture was poured into ice water, and the precipitate was collected by filtration and washed with water to obtain the target compound (80.7 g).

[0135] Reference example 59 Synthesis of 4-(3-fluorophenoxy)aniline To a mixture of 1-fluoro-3-(4-nitrophenoxy)benzene (30 g), ammonium chloride (41.3 g), EtOH (225 mL), and water (75 mL) was added zinc powder (50.5 g) under stirring at room temperature, followed by further stirring at 60°C for 1 hour. Insoluble matter was filtered through Celite, and the filtrate was concentrated. The residue was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt) to obtain the target compound (26 g).

[0136] Reference example 60 Synthesis of 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione A solution of 4-bromoaniline (7.66 g) and acrylic acid (3.05 mL) in toluene (50 mL) was stirred overnight at 80°C. The reaction mixture was concentrated, and urea (5.35 g) and acetic acid (20 mL) were added, followed by heating under reflux for 3 hours. The precipitated solid was collected by filtration and washed with EtOH to obtain the target compound (5.44 g).

[0137] Reference example 61 Synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione (2.78 g), (BPin) (3.15 g), AcOK (3.04 g), PdCl(dppf) DCM (0.422 g), and DMSO (30 mL) was stirred at 100 °C for 5 hours under an argon atmosphere. The reaction mixture was poured into ice water and extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH) to give the target compound (0.82 g).

[0138] Reference example 76 Synthesis of 1-[4-(3-hydroxyphenoxy)phenyl]dihydropyrimidine-2,4(1H,3H)-dione To a solution of 1-[4-(3-methoxyphenoxy)phenyl]dihydropyrimidine-2,4(1H,3H)-dione (3.86 g) in AcOH (25 mL), HBr (12.5 mL) was added under ice cooling and stirred for 3 hours. Water (100 mL) was added to the reaction solution and stirred, and the precipitated crystals were collected by filtration. After washing with water and drying, the crystals were purified by silica gel column chromatography (DCM / MeOH). The resulting solid was washed with MeOH to give the target compound (1.11 g).

[0139] Reference example 77 Synthesis of 3-(3-fluorophenoxy)aniline A mixture of 3-fluoroiodobenzene (0.587 mL), 3-aminophenol (818 mg), KPO (2.12 g), picolinic acid (123 mg), copper(I) iodide (95 mg), and DMSO (15 mL) was stirred at 90°C for 24 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt) to obtain the target compound (865 mg).

[0140] Reference example 83 Synthesis of 5-nitro-2-phenoxypyridine To a solution of 2-chloro-5-nitropyridine (16.0 g) in DMF (80 mL) was added sodium phenoxide (12.3 g) under ice-cooling and stirring, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration and washed with water to obtain the target compound (21.1 g).

[0141] Reference example 84 Synthesis of 6-phenoxypyridin-3-amine A mixture of 5-nitro-2-phenoxypyridine (21 g), 10% Pd / C (2 g), and EtOH (200 mL) was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt) to give the target compound (15 g).

[0142] Reference example 111 Synthesis of 1-(6-chloropyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione A mixture of 3,6-dichloropyridazine (10.00 g), uracil (8.28 g), and DMSO (100 mL) was stirred overnight at 70° C. Water was added to the reaction mixture, and the resulting solid was collected by filtration and washed with water and EtOH to obtain the target compound (9.51 g).

[0143] The compounds of Reference Examples 3 to 17, 20, 27 to 34, 36, 37, 48, 49, 51 to 55, 57, 62 to 75, 78 to 82, 85 to 95, and 97 to 110 were produced in the same manner as in Reference Examples 1, 2, 18, 19, 21 to 26, 35, 38 to 47, 50, 56, 58 to 61, 76, 77, 83, 84, and 111. The structural formulas and physical property data of the compounds of Reference Examples 1 to 111 are shown in Tables 1-1 to 1-11, respectively.

[0144] Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 [Table 1-10] [Table 1-11]

[0145] Example 1 Synthesis of 3-methoxy-6-(2-phenoxypyrimidin-5-yl)pyridazine A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (5.00 g), 3-chloro-6-methoxypyridazine (3.64 g), PdCl(dppf)DCM (0.137 g), KPO (7.12 g), 1,4-dioxane (50 mL), and water (25 mL) was heated to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt) to give the target compound (4.42 g).

[0146] Example 4 Synthesis of 3-(2-(3-fluorophenoxy)pyrimidin-5-yl)-6-methoxypyridazine A mixture of 5-bromo-2-(3-fluorophenoxy)pyrimidine (2.234 g), (BPin) (2.63 g), PdCl(dppf)DCM (0.282 g), AcOK (1.358 g), and 1,4-dioxane (20 mL) was heated to reflux under a nitrogen atmosphere for 2 hours. 3-Chloro-6-methoxypyridazine (1.00 g), PdCl(dppf)DCM (0.282 g), KPO (2.94 g), and water (5 mL) were added to the reaction mixture, and the mixture was heated to reflux overnight under a nitrogen atmosphere. Water and AcOEt were added to the reaction mixture, which was then filtered through Celite. The product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The precipitated crystals were washed with EtOH to obtain the target compound (947 mg).

[0147] Example 6 Synthesis of 5-(6-methoxypyridin-3-yl)-2-phenoxypyrimidine A mixture of 5-bromo-2-phenoxypyrimidine (1.0 g), 2-methoxy-5-pyridineboronic acid (0.914 g), PdCl(dppf)DCM (0.163 g), KPO (1.691 g), 1,4-dioxane (10 mL), and water (5 mL) was heated to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt), and the resulting solid was washed with EtOH to give the target compound (821 mg).

[0148] Example 7 Synthesis of 2-phenoxy-5-(pyridin-3-yl)pyrimidine A mixture of 5-bromo-2-phenoxypyrimidine (1.0 g), 3-pyridineboronic acid (0.734 g), PdCl(dppf)DCM (0.163 g), KPO (1.691 g), 1,4-dioxane (10 mL), and water (5 mL) was heated to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt), and the resulting solid was washed with EtOH to give the target compound (386 mg).

[0149] Example 11 Synthesis of 3-(2-phenoxypyrimidin-5-yl)pyridine 1-oxide A mixture of 2-phenoxy-5-(pyridin-3-yl)pyrimidine (749 mg), 77% aqueous m-CPBA (1616 mg), and DCM (15 mL) was stirred at room temperature overnight. Dimethyl sulfide (309 μL) was added to the reaction mixture and stirred for a while. After stirring, saturated aqueous NaHCO3 was added, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt), and the resulting solid was washed with AcOEt to give the target compound (118 mg).

[0150] Example 24 Synthesis of 6-(2-(3-fluorophenoxy)pyrimidin-5-yl)pyridazin-3-amine A mixture of 2-(3-fluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (581 mg), 3-amino-6-chloropyridazine (202 mg), KPO (1.11 g), PdCl(dppf) in DCM (68 mg), 1,4-dioxane (20 mL), and water (2 mL) was heated to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (Hexane / AcOEt, AcOEt / MeOH), and the resulting solid was washed with IPE to give the target compound (100 mg).

[0151] Example 30 Synthesis of 6-(2-phenoxypyrimidin-5-yl)pyridazin-3-amine A mixture of 3-amino-6-chloropyridazine (205 mg), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (526 mg), KPO (1.11 g), PdCl(dppf) DCM (65.2 mg), 1,4-dioxane (10 mL), and water (2 mL) was heated to reflux for 5.5 hours under a nitrogen atmosphere. The reaction mixture was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (Hexane / AcOEt, AcOEt / MeOH) to give the target compound (180 mg).

[0152] Example 36 Synthesis of 5-(2-phenoxypyrimidin-5-yl)pyridin-2-amine A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (386 mg), 2-amino-5-bromopyridine (209 mg), KPO (1.0 g), PdCl(dppf) in DCM (43.7 mg), 1,4-dioxane (20 mL), and water (2 mL) was heated to reflux under a nitrogen atmosphere for 2.75 hours. The reaction mixture was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane / AcOEt), and the resulting solid was washed with IPE to give the target compound (161 mg).

[0153] Example 38 Synthesis of 3-(2-phenoxypyrimidin-5-yl)-6-(trifluoromethyl)pyridazine A mixture of 3-chloro-6-(trifluoromethyl)pyridazine (209 mg), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (373 mg), KPO (780 mg), PdCl(dppf)DCM (29.3 mg), 1,4-dioxane (20 mL), and water (2 mL) was heated to reflux under a nitrogen atmosphere for 5 hours. The reaction mixture was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (Hexane / AcOEt), and the resulting solid was washed with AcOEt to give the target compound (107 mg).

[0154] Example 60 Synthesis of 3-(2-(2-fluorophenoxy)pyrimidin-5-yl)pyridine 1-oxide A mixture of 3-(2-(2-fluorophenoxy)pyrimidin-5-yl)pyridine (998 mg), aqueous 77% m-CPBA (1255 mg), and DCM (15 mL) was stirred at room temperature overnight. Dimethyl sulfide and saturated aqueous NaHCO3 were added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (AcOEt / MeOH), and the resulting solid was washed with EtOH to give the target compound (383 mg).

[0155] Example 63 Synthesis of 3-(2-(2,5-difluorophenoxy)pyrimidin-5-yl)-6-methoxypyridazine A mixture of 2,5-difluorophenol (132 mg), 3-methoxy-6-(2-(methylsulfonyl)pyrimidin-5-yl)pyridazine (167 mg), K2CO3 (176 mg), and DMF (5 mL) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration to obtain the target compound (187 mg).

[0156] Example 69 Synthesis of 2-(6-(2-phenoxypyrimidin-5-yl)pyridazin-3-yl)propan-2-ol Ethyl 6-(2-phenoxypyrimidin-5-yl)pyridazine-3-carboxylate (200 mg) was suspended in THF (3 mL), and then a 0.96 M THF solution (1.6 mL) of methylmagnesium bromide was added under ice cooling and stirred overnight at room temperature. The reaction mixture was poured into saturated aqueous ammonium chloride, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt), and the resulting solid was washed with IPE to give the target compound (45 mg).

[0157] Example 72 Synthesis of (6-(2-phenoxypyrimidin-5-yl)pyridazin-3-yl)methanol To a mixture of calcium chloride (551 mg), NaBH4 (117 mg), THF (2 mL), and EtOH (2 mL) was added ethyl 6-(2-phenoxypyrimidin-5-yl)pyridazine-3-carboxylate (400 mg) under ice-cooling and stirred for 30 minutes. Aqueous citric acid was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt), and the resulting solid was washed with IPE to give the target compound (81 mg).

[0158] Example 84 Synthesis of 5-(2-(2,5-difluorophenoxy)pyrimidin-5-yl)pyridin-2-amine A mixture of 5-(2-(methylsulfinyl)pyrimidin-5-yl)pyridin-2-amine (100 mg), 2,5-difluorophenol (130 mg), K2CO3 (236 mg), and DMF (7 mL) was stirred at 80 °C under a nitrogen atmosphere for 3.5 hours. Water was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by basic silica gel chromatography (Hexane / AcOEt), and the resulting solid was washed with hexane / IPE to give the target compound (44 mg).

[0159] Example 88 Synthesis of 5-(2-(m-tolyloxy)pyrimidin-5-yl)pyridin-2-amine A mixture of 5-(2-(dodecylsulfinyl)pyrimidin-5-yl)pyridin-2-amine (163 mg), m-cresol (0.10 mL), K2CO3 (483 mg), and DMF (10 mL) was stirred at 80 °C for 4 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by basic silica gel chromatography (Hexane / AcOEt), and the resulting solid was washed with IPE to give the target compound (50 mg).

[0160] Example 91 Synthesis of 6-(2-phenoxypyrimidin-5-yl)pyridazin-3(2H)-one A mixture of 3-(benzyloxy)-6-(2-phenoxypyrimidin-5-yl)pyridazine (2.54 g), 10% Pd / C (2 g), EtOH (25 mL), and THF (75 mL) was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was crystallized from EtOH to give the target compound (1.38 g).

[0161] Example 92 Synthesis of 6-(2-phenoxypyrimidin-5-yl)-4,5-dihydropyridazin-3(2H)-one A mixture of 6-(2-phenoxypyrimidin-5-yl)pyridazin-3(2H)-one (1.08 g), zinc powder (0.53 g), and AcOH (10 mL) was heated to reflux for 1 hour. The reaction mixture was concentrated, and water was added to the residue. The product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH) and washed with EtOH to give the target compound (583 mg).

[0162] Example 94 Synthesis of 6-(2-(3-fluorophenoxy)pyrimidin-5-yl)-4,5-dihydropyridazin-3(2H)-one A mixture of 6-(2-(3-fluorophenoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (1.02 g), zinc powder (0.56 g), and AcOH (10 mL) was heated to reflux for 3 hours. The reaction mixture was concentrated, water was added to the residue, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt), and the resulting solid was washed with EtOH to give the target compound (587 mg).

[0163] Example 106 Synthesis of 5-(2-(m-tolyloxy)pyrimidin-5-yl)pyridin-2(1H)-one A mixture of 5-(6-methoxypyridin-3-yl)-2-(m-tolyloxy)pyrimidine (425 mg), sodium iodide (652 mg), chlorotrimethylsilane (0.552 mL), and MeCN (5 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH) and crystallized from EtOH to give the target compound (204 mg).

[0164] Example 114 Synthesis of 4-(2-phenoxypyrimidin-5-yl)pyridazin-3(2H)-one A mixture of 4-(2-phenoxypyrimidin-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (1.085 g), TFA (10 mL), and DCM (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was neutralized with saturated aqueous NaHCO3 solution. The product was then extracted with DCM. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt), and the resulting solid was washed with EtOH to give the target compound (672 mg).

[0165] Example 118 Synthesis of 4-(2-phenoxypyrimidin-5-yl)quinoline A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (500 mg), 4-bromoquinoline (419 mg), KPO (712 mg), PdCl(dppf) in DCM (13.70 mg), 1,4-dioxane (5 mL), and water (2.5 mL) was heated to reflux under a nitrogen atmosphere for 1.5 hours. Water was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt), and the resulting solid was washed with IPE to give the target compound (413 mg).

[0166] Example 119 Synthesis of 6-(2-phenoxypyrimidin-5-yl)imidazo[1,2-a]pyridine A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (400 mg), 6-bromoimidazo[1,2-a]pyridine (291 mg), PdCl(dppf)DCM (110 mg), KPO (570 mg), 1,4-dioxane (4 mL), and water (2 mL) was stirred at 100°C for 3 hours under a nitrogen atmosphere. AcOEt and water were added to the reaction mixture, which was then filtered through Celite. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (DCM / AcOEt) to obtain the target compound (318 mg).

[0167] Example 123 Synthesis of 6-(2-phenoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (400 mg), 6-chloro-imidazo[1,2-b]pyridazine (227 mg), PdCl(dppf)DCM (110 mg), KPO (570 mg), 1,4-dioxane (4 mL), and water (2 mL) was stirred at 95°C under a nitrogen atmosphere for 3 hours. AcOEt and water were added to the reaction mixture, which was then filtered through Celite. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (hexane / AcOEt) to obtain the target compound (329 mg).

[0168] Example 137 Synthesis of 6-(2-phenoxypyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridine A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (400 mg), 6-bromo-1-(triisopropylsilyl)-1H-pyrrolo[3,2-b]pyridine (522 mg), PdCl(dppf)DCM (110 mg), KPO (570 mg), 1,4-dioxane (4 mL), and water (2 mL) was stirred at 90°C under a nitrogen atmosphere for 3 hours. AcOEt and water were added to the reaction mixture, which was then filtered through Celite. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in THF (5 mL), and 1N-TBAF (1.34 mL) was added. The mixture was stirred at room temperature for 1 hour, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (DCM / AcOEt) to give the target compound (325 mg).

[0169] Example 139 Synthesis of 4-(2-phenoxypyrimidin-5-yl)-1,8-naphthyridine A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (300 mg), 4-chloro-[1,8]naphthyridine (199 mg), KPO (427 mg), PdCl(dppf) in DCM (6.56 mg), 1,4-dioxane (4 mL), and water (2 mL) was heated to reflux under a nitrogen atmosphere for 3 hours. Water was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (MeOH / DCM), and the resulting solid was recrystallized from AcOEt to give the target compound (167 mg).

[0170] Example 163 Synthesis of 6-(2-(3-chlorophenoxy)pyrimidin-5-yl)imidazo[1,2-a]pyridine A mixture of 6-(2-(dodecylsulfonyl)pyrimidin-5-yl)imidazo[1,2-a]pyridine (300 mg), 1-chloro-3-hydroxybenzene (0.089 mL), K2CO3 (193 mg), and DMF (3 mL) was stirred at 80 °C for 5 hours. The reaction mixture was poured into ice water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by basic column chromatography (DCM / AcOEt) to obtain the target compound (194 mg).

[0171] Example 172 Synthesis of 5-(2-phenoxypyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-2(3H)-one A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (560 mg), 5-bromo-1H,2H,3H-pyrrolo[3,2-b]pyridin-2-one (200 mg), PdCl(dppf)DCM (38.3 mg), KPO (399 mg), 1,4-dioxane (4 mL), and water (2 mL) was stirred at 90°C for 5 hours under a nitrogen atmosphere. AcOEt and water were added to the reaction mixture, which was then filtered through Celite. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (DCM / AcOEt) to give the target compound (98 mg).

[0172] Example 173 Synthesis of 6-(2-phenoxypyrimidin-5-yl)-[1,2,3]triazolo[1,5-a]pyridine A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (330 mg), 6-bromo-[1,2,3]triazolo[1,5-a]pyridine (241 mg), PdCl(dppf)DCM (45.2 mg), KPO (470 mg), 1,4-dioxane (4 mL), and water (2 mL) was stirred at 90 °C for 5 hours. AcOEt and water were added to the reaction mixture, which was then filtered through Celite. The filtrate was separated, and the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (DCM / AcOEt) to give the target compound (250 mg).

[0173] Example 198 Synthesis of 5-methyl-6-(2-phenoxypyrimidin-5-yl)imidazo[1,2-a]pyridine hydrochloride A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (330 mg), 6-bromo-5-methyl-imidazo[1,2-a]pyridine (257 mg), PdCl(dppf)DCM (45.2 mg), KPO (470 mg), 1,4-dioxane (4 mL), and water (2 mL) was stirred at 90 °C for 5 h. AcOEt and water were added to the reaction mixture, which was then filtered through Celite. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (DCM / AcOEt). The resulting oil was dissolved in EtOH, and 3 mL of 1N HCl in EtOH was added. After stirring, the reaction mixture was concentrated. The precipitated crystals were recrystallized from EtOH / AcOEt to obtain the target compound (349 mg).

[0174] Example 220 Synthesis of 1-(2-phenoxypyrimidin-5-yl)tetrahydropyrimidin-2(1H)-one To a solution of 1-(3-chloropropyl)-3-(2-phenoxypyrimidin-5-yl)urea (1.25 g) in DMF (12 mL) was added 60% NaH (0.148 g) under ice-cooling and stirring, and the mixture was stirred at room temperature for 2 days. Water was added to the residue, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The precipitated crystals were washed with EtOH to obtain the target compound (181 mg).

[0175] Example 221 Synthesis of 1-(2-(3-fluorophenoxy)pyrimidin-5-yl)tetrahydropyrimidin-2(1H)-one 2-(3-Fluorophenoxy)pyrimidin-5-amine (1.00 g) was dissolved in THF (10 mL) and DMF (10 mL), and 3-chloropropyl isocyanate (0.800 mL) was added. The mixture was stirred at 50°C for 3 hours. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration to obtain the intermediate (1.41 g). The intermediate was dissolved in DMF (14 mL), and 60% NaH (0.214 g) was added under ice-cooling. The mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (AcOEt / MeOH), and the resulting solid was washed with EtOH to obtain the target compound (460 mg).

[0176] Example 223 Synthesis of 2-phenoxy-5-(piperidin-1-yl)pyrimidine A mixture of 5-bromo-2-phenoxypyrimidine (500 mg), piperidine (0.256 mL), Pd(OAc) (447 mg), tBuP·HBF (578 mg), NaOtBu (191 mg), and toluene (10 mL) was stirred at 100°C for 1 hour under a nitrogen atmosphere. AcOEt and water were added to the reaction mixture, which was then filtered through Celite. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (Hexane / AcOEt) to obtain the target compound (53 mg).

[0177] Example 226 Synthesis of 1-(2-phenoxypyrimidin-5-yl)piperidin-4-ol To a solution of 2-phenoxy-5-(4-(triisopropylsilyloxy)piperidin-1-yl)pyrimidine (240 mg) in THF (6 mL) was added TBAF (0.56 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (Hexane / AcOEt) and crystallized from Hexane / AcOEt to give the target compound (110 mg).

[0178] Example 229 Synthesis of 4-(2-phenoxypyrimidin-5-yl)morpholin-3-one A mixture of 5-iodo-2-phenoxypyrimidine (500 mg), 3-ketomorpholine (254 mg), copper(I) iodide (31.9 mg), KPO (712 mg), (1R,2R)-N,N-dimethyl-1,2-cyclohexanediamine (0.053 mL), and 1,4-dioxane (6 mL) was stirred at 90 °C for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt) to obtain the target compound (368 mg).

[0179] Example 239 Synthesis of 4-(2-phenoxypyrimidin-5-yl)aniline A mixture of 5-(4-nitrophenyl)-2-phenoxypyrimidine (3.8 g), 10% Pd / C (0.4 g), and EtOH (80 mL) was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt) to give the target compound (2.5 g) as a white solid.

[0180] Example 240 Synthesis of 6-(2-phenoxypyrimidin-5-yl)benzo[d]thiazol-2-amine To a solution of 4-(2-phenoxypyrimidin-5-yl)aniline (600 mg) and ammonium thiocyanate (382 mg) in acetic acid (6 mL) was added a solution of bromine (0.140 mL) in acetic acid (2 mL) under ice-cooling and stirring. After 1 hour, the reaction mixture was poured into ice water, and 28% aqueous ammonia was added until the reaction mixture became basic. The product was then extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt) to obtain the target compound (542 mg).

[0181] Example 257 Synthesis of 5-(2-phenoxypyrimidin-5-yl)-1H-benzo[d]imidazole oxalate A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (400 mg), 5-bromo-1H-benzo[d]imidazole (291 mg), PdCl(dppf)DCM (110 mg), KPO (570 mg), 1,4-dioxane (4 mL), and water (2 mL) was stirred at 95°C under a nitrogen atmosphere for 3 hours. AcOEt and water were added to the reaction mixture, which was then filtered through Celite. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt). The resulting oil was dissolved in ethanol, and a solution of oxalic acid (80 mg) in ethanol (1 mL) was added. The precipitate was collected by filtration and dried to give the target compound (250 mg).

[0182] Example 262 Synthesis of 5-(2-phenoxypyrimidin-5-yl)-1H-indole A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (400 mg), 5-bromo-1-(triisopropylsilyl)-1H-indole (520 mg), PdCl(dppf)DCM (110 mg), KPO (570 mg), 1,4-dioxane (4 mL), and water (2 mL) was stirred at 80°C for 3 hours under a nitrogen atmosphere. AcOEt and water were added to the reaction mixture, which was then filtered through Celite. The filtrate was separated, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in THF (10 mL), and TBAF (1.342 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by silica gel column chromatography (hexane / AcOEt) to give the target compound (319 mg).

[0183] Example 302 Synthesis of 1-(4-(3-fluorophenoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of 4-(3-fluorophenoxy)aniline (5.00 g), acrylic acid (2.53 mL), and toluene (40 mL) was stirred at 80°C overnight. The reaction mixture was concentrated, and urea (4.43 g) and AcOH (20 mL) were added, followed by heating to reflux for 3 hours. Water was added, and the precipitate was collected by filtration. The precipitate was purified by silica gel column chromatography (DCM / MeOH) to obtain the target compound (2.33 g).

[0184] Example 305 Synthesis of 1-(4-(3-fluorobenzyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of m-fluorobenzyl chloride (0.11 mL), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (0.25 g), KPO (0.252 g), PdCl(dppf), DCM (6.46 mg), DME (6.6 mL), and water (3.3 mL) was heated to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into ice water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt) to obtain the target compound (30 mg).

[0185] Example 308 Synthesis of 1-(4-(3-fluorophenoxy)phenyl)-3-methyldihydropyrimidine-2,4(1H,3H)-dione To a solution of 1-(4-(3-fluorophenoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg) in DMF (5 mL) was added 60% NaH (32.0 mg) and stirred at 0°C for 30 minutes. Methyl iodide (0.046 mL) was added with stirring at 0°C, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (Hexane / AcOEt) to obtain the target compound (50 mg).

[0186] Example 314 Synthesis of 1-{4-[3-(difluoromethoxy)phenoxy]phenyl}dihydropyrimidine-2,4(1H,3H)-dione A mixture of 1-[4-(3-hydroxy)phenyl]dihydropyrimidine-2,4(1H,3H)-dione (337 mg), sodium chlorodifluoroacetate (344 mg), K2CO3 (234 mg), and DMF (1.7 mL) was stirred at 90 °C for 4 hours. Sodium chlorodifluoroacetate (344 mg) was added and the mixture was stirred for an additional 2 hours. Hydrochloric acid was added to the reaction mixture, and the product was extracted with AcOEt. The mixture was washed with water, aqueous NaOH, and water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt) and crystallized from EtOH. The target compound (79 mg) was obtained by washing with EtOH.

[0187] Example 321 Synthesis of 1-[4-(6-fluoropyridin-2-yloxy)phenyl]dihydropyrimidine-2,4(1H,3H)-dione A mixture of 1-(4-hydroxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (412 mg), 2,6-difluoropyridine (0.218 mL), K2CO3 (553 mg), and DMSO (2 mL) was stirred at 100 °C for 2 hours. Water (10 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was purified by silica gel column chromatography (DCM / MeOH), and the resulting solid was washed with EtOH to give the target compound (244 mg).

[0188] Example 322 Synthesis of 1-(4-phenoxyphenyl)pyrimidine-2,4(1H,3H)-dione A mixture of 4-phenoxyphenylboronic acid (1.27 g), uracil (0.798 g), N,N,N',N'-tetramethylethylenediamine (0.896 mL), copper(II) acetate (0.539 g), MeOH (40 mL), and water (10 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt) to obtain the target compound (160 mg).

[0189] Example 327 Synthesis of 1-((1,1'-biphenyl)-4-yl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of monobromobenzene (0.158 mL), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]dihydropyrimidine-2,4(1H,3H)-dione (316 mg), Pd(PhP) (57.8 mg), NaCO (212 mg), DME (5 mL), and water (1 mL) was heated to reflux under a nitrogen atmosphere for 12 hours. AcOEt and anhydrous magnesium sulfate were added to the reaction mixture, which was then filtered through Celite. The filtrate was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH). The resulting solid was washed with EtOH to give the target compound (35 mg).

[0190] Example 328 Synthesis of 6-methyl-1-(4-phenoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of 4-phenoxyaniline (0.50 g), toluene (5 mL), and crotonic acid (0.34 mL) was heated to reflux for 13 hours. Crotonic acid (0.34 mL) was added and the mixture was heated to reflux for an additional 6 hours. The reaction mixture was concentrated, and acetic acid (5 mL) and urea (0.324 g) were added, followed by heating to reflux for 17 hours. Concentrated hydrochloric acid (0.23 mL) was added to the reaction mixture, and the mixture was heated to reflux for 30 minutes. Water was added to the reaction mixture, and the product was extracted with AcOEt. The mixture was washed with water, saturated aqueous NaHCO3, and brine, dried over anhydrous magnesium sulfate, and then concentrated. EtOH (3 mL) and IPE (3 mL) were added to the residue, causing crystallization. The solid was collected by filtration and washed with IPE to obtain the target compound (272 mg).

[0191] Example 337 Synthesis of 6,6-dimethyl-1-(4-phenoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of 4-phenoxyaniline (1.0 g) and 3,3-dimethylacrylic acid (2.70 g) was stirred at 70-80°C for 75 hours. Urea (0.648 g) and AcOH (6 mL) were added to the reaction mixture, and the mixture was heated to reflux for 5 hours. Water (20 mL) was added to the reaction mixture, and then saturated aqueous NaHCO3 was added to neutralize it. After extraction with AcOEt, the mixture was washed with saturated aqueous NaCl, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt), and the resulting solid was washed with EtOH to obtain the target compound (103 mg).

[0192] Example 343 Synthesis of 6-ethyl-1-(4-phenoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of 4-phenoxyaniline (0.50 g) and trans-2-pentenoic acid (1.37 mL) was stirred at 120°C for 5 hours. AcOH (5 mL) and urea (0.324 g) were added to the reaction mixture, and the mixture was heated to reflux for 3 hours. Water and AcOEt were added to the reaction mixture, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH) and crystallized from EtOH (2 mL). The solid was collected by filtration and washed with EtOH and IPE to obtain the target compound (204 mg).

[0193] Example 344 Synthesis of 1-[4-(3,5-difluoromethoxy)phenyl]dihydropyrimidine-2,4(1H,3H)-dione A mixture of 1-(4-hydroxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (330 mg), 1,3,5-trifluorobenzene (0.199 mL), K2CO3 (442 mg), and DMSO (2 mL) was stirred at 100 °C for 3.5 hours. 1,3,5-Trifluorobenzene (0.199 mL) was added, and the mixture was stirred for an additional 1.5 hours. Water (15 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water and EtOH to obtain the target compound (35 mg).

[0194] Example 346 Synthesis of 1-(6-phenoxypyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione A mixture of phenol (1.017 mL), 1-(6-chloropyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (2.00 g), Cs2CO3 (4.35 g), and DMSO (20 mL) was stirred at 130 °C overnight. Aqueous citric acid solution was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was washed with EtOH to obtain the target compound (588 mg).

[0195] Example 347 Synthesis of 1-(6-phenoxypyridazin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-Phenoxypyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (577 mg) was dissolved in DMF (10 mL), and 50% aqueous 10% Pd / C (500 mg) was added. The mixture was stirred at 50°C for 6 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by medium-pressure column chromatography (DCM / AcOEt), and the resulting solid was washed with EtOH to give the target compound (122 mg).

[0196] In the same manner as in Examples 1, 4, 6, 7, 11, 24, 30, 36, 38, 60, 63, 69, 72, 84, 88, 91, 92, 94, 106, 114, 118, 119, 123, 137, 139, 163, 172, 173, 198, 220, 221, 223, 226, 229, 239, 240, 257, 262, 302, 305, 308, 314, 321, 322, 327, 328, 337, 343, 344, 346, and 347, Examples 2, 3, 5, 8 to 10, 12 to 23, 25 to 29, 31 to 35, 37, 39 to 59, 61, 62, Compounds 64-68, 70, 71, 73-83, 85-87, 89, 90, 93, 95-105, 107-113, 115-117, 120-122, 124-136, 138, 140-162, 164-171, 174-197, 199-219, 222, 224, 225, 227, 228, 230-238, 241-256, 258-261, 263-301, 303, 304, 306, 307, 309-313, 315-320, 323-326, 329-336, 338-342, 345 and 348-350 were produced, respectively. The structural formulas and physical property data of the compounds of Examples 1 to 347 are shown in Tables 2-1 to 2-37, respectively.

[0197] Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 [Table 2-37]

[0198] [Test example] The pharmacological test results of representative compounds of the present invention are shown below, and the pharmacological actions of the compounds are explained, but the present invention is not limited to these test examples.

[0199] [Test Example 1] Audiogenic epileptic seizure model The animal model used in this study is highly clinically predictive and represents partial seizures (including secondarily generalized seizures) and generalized tonic-clonic seizures. This study was performed according to the report by De Sarro et al. (Br J Pharmacol. 1988 Feb; 93(2): 247-56. Anticonvulsant effects of some calcium entry blockers in DBA / 2 mice. De Sarro GB, Meldrum BS, Nistico G.). In this test example, the example compounds shown in the following Tables 3-1 to 3-3 were used as test compounds. The test compound was suspended in 5% gum arabic / distilled water (w / v) and administered orally at a dose of 30 mg / kg to male and female DBA / 2 mice (Japan SLC Co., Ltd., 3 weeks old, 8 mice per group). One hour later, the mice were placed in a clear acrylic cylinder 23 cm in diameter and 30 cm in height. After 30 seconds of acclimation, a 12.6 kHz, 100-110 dB tone stimulus was applied for 1 minute or until tonic seizures occurred. The severity of the seizures was rated as 0: no seizure, 1: wild running, 2: clonic seizure, 3: tonic seizure, and 4: respiratory arrest, and the maximum of these points was recorded as the seizure severity score. The seizure suppression rate for each compound administration group was calculated using the following formula.

number

[0200] [Test Example 2] Rotarod test This test is a test to evaluate the coordination disorder effects of compounds. In this test example, the example compounds shown in Table 4 below were used as test compounds. Male ICR mice (Japan SLC Co., Ltd., 5-6 weeks old, 8 mice per group) were placed on a rotarod apparatus (Muromachi Kikai Co., Ltd.) and trained to walk from a rod rotating at a fixed speed (15 rpm) for 2 minutes without falling. A test compound was suspended in 5% gum arabic / distilled water (w / v) and administered orally at a dose of 30 mg / kg to the trained mice. One hour later, the mice were placed on the same rotarod apparatus as above. The mice were observed for 200 seconds to see whether they could walk in time with the rotation of the rod, which accelerated from 4 rpm to 40 rpm over 5 minutes, and the falling latency was measured. The falling latency of the compound-treated group was calculated relative to the average falling latency of the vehicle-treated group. The results are shown in Tables 4-1 and 4-2. Coordination impairment of 25% or less was designated as "A," and coordination impairment of more than 25% but less than 50% was designated as "B." [Table 4-1] [Table 4-2]

[0201] [Test Example 3] Maximum electric shock convulsion model This test evaluates the anticonvulsant activity of compounds. The animal models used in this test are phenotypes of generalized tonic-clonic seizures and secondarily generalized partial seizures. This test was performed according to the report by Hill AJ et al. (Br J Pharmacol. 2012 Dec;167(8):1629-42. Cannabidivarin is anticonvulsant in mice and rats. Hill AJ, et al.). The test compound was suspended in 5% gum arabic / distilled water (w / v) and administered orally at a dose of 30 mg / kg to male ICR mice (Japan SLC, 5-6 weeks old, 8 mice per group). One hour later, electrical stimulation (100 Hz, 30 mA, 0.2 seconds) was administered via electrodes attached to both ears using an electroconvulsive convulsion stimulator for small animals (UgoBasile), and the occurrence of tonic extensor convulsions of the hind limbs was observed. In the above test, it can be confirmed that tonic extension convulsions of the hind limbs are induced in all animals in the vehicle-administered group, whereas the onset of convulsions is suppressed in the test compound-administered group.

[0202] [Test Example 4] Subcutaneous injection pentylenetetrazole model This test is a test to evaluate the anticonvulsant activity of a compound, similar to Test Example 3. The animal model used in this test is a phenotype of generalized absence seizures and myoclonic seizures, which is different from the phenotype in Test Example 3. The test compound was suspended in 5% gum arabic / distilled water (w / v) and administered orally at a dose of 30 mg / kg to male ICR mice (Japan SLC Co., Ltd., 5-6 weeks old, 10 mice per group). One hour later, 85 mg / kg of pentylenetetrazole dissolved in saline was administered subcutaneously, and the occurrence of clonic convulsions was observed for 30 minutes. In the above test, it can be confirmed that clonic convulsions are induced in all animals in the vehicle-administered group, whereas the onset of convulsions is suppressed in the test compound-administered group.

[0203] As described above, the compounds of the present invention exhibit anticonvulsant effects in all of the multiple model animals used in the evaluation of antiepileptic drugs, and are therefore useful as antiepileptic drugs exhibiting a broad therapeutic spectrum (compounds for preventing and / or treating seizures in diseases accompanied by epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures, and status epilepticus)). Furthermore, the compounds of the present invention are also useful as diagnostic compounds for diseases accompanied by epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures, and status epilepticus).

Claims

1. Formula I: [In the formula, D is or C optionally substituted with halogen 1-6 is alkyl; Ring A is benzene, pyridine, indole, or indazole; Ring B is pyrimidine, pyridazine, pyridine, pyrazole, benzene or naphthalene, wherein: (i) When ring B is pyrimidine, ring C is selected from the following unsaturated rings and their oxides and dioxides (excluding pyrimidine-2,4-dione and dihydropyrimidine-2,4-dione), and rings in which some or all of the unsaturated bonds in the ring have been reduced with hydrogen: (a) a 3- to 8-membered monocyclic unsaturated heterocycle containing only 1 to 4 nitrogen atoms as ring-constituting heteroatoms; (b) a 7- to 15-membered bicyclic or tricyclic unsaturated heterocycle containing only 1 to 5 nitrogen atoms as ring-constituting heteroatoms; (c) a 7- to 12-membered bicyclic unsaturated heterocycle containing only 1 to 3 oxygen atoms as ring-constituting heteroatoms; (d) a 3- to 8-membered monocyclic unsaturated heterocycle containing one or two oxygen atoms and one to three nitrogen atoms as ring-constituting heteroatoms; (e) a 7- to 12-membered bicyclic unsaturated heterocycle containing one or two sulfur atoms and one to three nitrogen atoms as ring-constituting heteroatoms; and (f) a 3- to 8-membered monocyclic unsaturated hydrocarbon ring; (ii) when ring B is pyridazine, pyridine, pyrazole, benzene or naphthalene, ring C is pyrimidine-2,4-dione or dihydropyrimidine-2,4-dione; R 1 is halogen, optionally substituted with halogen, 1-6 -OC optionally substituted with alkyl or halogen 1-6 Alkyl, -CN or -SF 5 and R 2 is a halogen, C 1-6 Alkyl, -OC 1-6 is alkyl; R 3 is halogen, halogen or -OC 1-6 C optionally substituted with alkyl 1-6 -OC optionally substituted with alkyl or halogen 1-6 Alkyl, -C 1-6 Alkyl-OH, -OH, -CN, -CONH 2 or -NH 2 and L is a bond, C 1-6 alkylene, -O-, or -S-; k is 0, 1 or 2, and when k is 2, R 1 each independently represents the same or different substituent; m is 0, 1 or 2, and when m is 2, R 2 each independently represents the same or different substituent; n is 0, 1 or 2, and when n is 2, R 3 each independently represents the same or different substituent; A compound represented by the formula (I) or a salt thereof.

2. In formula I, D is and Ring A is benzene or pyridine; Ring B is pyrimidine; Ring C is selected from the following unsaturated rings, their oxides and dioxides (excluding pyrimidine-2,4-dione and dihydropyrimidine-2,4-dione), and rings in which some or all of the unsaturated bonds in the ring have been reduced with hydrogen: pyridine, pyridazine, pyrimidine, Indore, pyrrolopyridine, indazole, benzimidazole, pyrazolopyridines, imidazopyridine, imidazopyrazine, imidazopyridazine, triazolopyridines, pyrazolopyrimidines, imidazopyrimidines, triazolopyrimidines, quinoline, isoquinoline, naphthyridine, quinazoline, quinoxaline, benzodioxoles, oxazine, oxazepine, benzothiazole, benzene; R 1 is halogen, optionally substituted with halogen, 1-6 -OC optionally substituted with alkyl or halogen 1-6 alkyl or -CN; R 2 -OC 1-6 is alkyl; R 3 is halogen, halogen or -OC 1-6 C optionally substituted with alkyl 1-6 -OC optionally substituted with alkyl or halogen 1-6 Alkyl, -C 1-6 Alkyl-OH, -OH, -CN, -CONH 2 or -NH 2 and L is -O-; k is 0, 1 or 2, and when k is 2, R 1 each independently represents the same or different substituent; m is 0 or 1; n is 0, 1 or 2, and when n is 2, R 3 The compound or salt thereof according to claim 1, wherein each independently represents the same or different substituent.

3. In formula I, ring C is selected from the following unsaturated rings, oxides thereof, and rings in which some or all of the unsaturated bonds in the rings have been reduced with hydrogen: pyridine, pyridazine, pyrrolopyridine, indazole, pyrazolopyridines, imidazopyridine, imidazopyrazine, imidazopyridazine, pyrazolopyrimidines, triazolopyrimidines, quinoline, isoquinoline, naphthyridine, quinoxaline, benzene; R 1 is halogen or optionally halogen-substituted C 1-6 is alkyl; R 3 C optionally substituted with halogen 1-6 -OC optionally substituted with alkyl or halogen 1-6 Alkyl, -OH, -CONH 2 or -NH 2 and L is -O-; k and n are 0 or 1; The compound or salt thereof according to claim 2, wherein m is 0.

4. In formula I, ring C is selected from the following unsaturated rings, oxides thereof, and rings in which some or all of the unsaturated bonds in the rings have been reduced with hydrogen: pyridine, pyridazine, pyrazolopyridines, Imidazopyridine; R 3 is -OH or -NH 2 and L is -O-; k and m are 0; 4. The compound or salt thereof according to claim 3, wherein n is 0 or 1.

5. In formula I, D is or C optionally substituted with halogen 1-6 is alkyl; Ring A is benzene or pyridine; Ring B is pyridazine, pyridine, pyrazole, benzene, or naphthalene; Ring C is pyrimidine-2,4-dione or dihydropyrimidine-2,4-dione; R 1 is halogen, optionally substituted with halogen, 1-6 -OC optionally substituted with alkyl or halogen 1-6 Alkyl, -CN or -SF 5 and R 2 is a halogen, C 1-6 Alkyl, -OC 1-6 is alkyl; R 3 is C 1-6 is alkyl; L is a bond, C 1-6 alkylene, -O-, or -S-; k is 0, 1 or 2, and when k is 2, R 1 each independently represents the same or different substituent; m is 0, 1 or 2, and when m is 2, R 2 each independently represents the same or different substituent; n is 0, 1 or 2, and when n is 2, R 3 The compound or salt thereof according to claim 1, wherein each independently represents the same or different substituent.

6. In Formula I, ring A is benzene; Ring B is benzene, pyridine, or pyridazine; Ring C is dihydropyrimidine-2,4-dione; R 1 is a halogen; L is -O-; k is 0 or 1; The compound or salt thereof according to claim 5, wherein m and n are 0.

7. A compound selected from the group consisting of the following compounds or a salt thereof:

8. 8. The compound according to claim 7, or a salt thereof, selected from the group consisting of the following compounds:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

10. A therapeutic, preventive and / or diagnostic agent for seizures in diseases accompanied by epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus), comprising the compound according to any one of claims 1 to 8 or a salt thereof.

11. Epileptic seizures include motor-onset seizures (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor-onset seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, affective seizures, and perceptual seizures) in focal seizures (sometimes called partial seizures), seizures that progress from focal seizures to bilateral tonic-clonic seizures (secondary generalization of partial seizures), and motor seizures in generalized seizures (tonic-clonic seizures, clonic seizures, tonic-clonic seizures, and tonic-clonic seizures).

11. The therapeutic, preventive and / or diagnostic agent according to claim 10, wherein the seizures are selected from motor seizures (including tonic seizures, myoclonic seizures, myoclonic tonic-clonic seizures, myoclonic atonic seizures, atonic seizures and epileptic spasms) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and lid myoclonic seizures); motor seizures of unknown onset (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral arrest seizures).

12. Diseases accompanied by epileptic seizures or convulsive seizures include Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (infantile spasms), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, unilateral convulsions, hemiplegia, 11. The therapeutic, preventive and / or diagnostic agent according to claim 10, wherein the therapeutic, preventive and / or diagnostic agent is selected from epilepsy syndromes, mesial temporal lobe epilepsy syndromes, epilepsy attributable to structural or metabolic causes (post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disorders, epilepsy associated with brain tumors, epilepsy associated with neurodegenerative diseases, epilepsy associated with autoimmune diseases, etc.), congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (e.g., Rett syndrome, Angelman syndrome, 5p syndrome, 4p syndrome, Down syndrome, etc.).

13. A pharmaceutical composition for the treatment, prevention and / or diagnosis of seizures in diseases accompanied by epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus), comprising the compound according to any one of claims 1 to 8 or a salt thereof as an active ingredient.

14. Epileptic seizures include focal seizures (sometimes called partial seizures) with motor onset (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor onset seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, affective seizures, and perceptual seizures), focal seizures that progress to bilateral tonic-clonic seizures (secondary generalization of partial seizures), motor seizures in generalized seizures (tonic-clonic seizures, The composition of claim 13, wherein the seizures are selected from non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and eyelid myoclonic seizures); motor seizures of unknown onset (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral arrest seizures).

15. Diseases accompanied by epileptic seizures or convulsive seizures include Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (infantile spasms), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, and hemiconvulsions. The composition according to claim 13, wherein the epilepsy is selected from hemiplegia-epilepsy syndrome, mesial temporal lobe epilepsy syndrome, epilepsy attributable to structural or metabolic causes (post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disorders, epilepsy associated with brain tumors, epilepsy associated with neurodegenerative diseases, epilepsy associated with autoimmune diseases, etc.), congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (Rett syndrome, Angelman syndrome, 5p syndrome, 4p syndrome, Down syndrome, etc.).

16. A method for treating, preventing and / or diagnosing seizures in diseases accompanied by epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus), comprising administering to a human an effective amount of the compound according to any one of claims 1 to 8 or a salt thereof.

17. Epileptic seizures include focal seizures (sometimes called partial seizures) with motor onset (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor onset seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, affective seizures, and perceptual seizures), focal seizures that progress to bilateral tonic-clonic seizures (secondary generalization of partial seizures), motor seizures in generalized seizures (tonic-clonic seizures, 17. The method of claim 16, wherein the seizures are selected from: non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures, and eyelid myoclonic seizures); motor seizures (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral arrest seizures) of unknown onset.

18. Diseases accompanied by epileptic seizures or convulsive seizures include Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (infantile spasms), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, and hemiconvulsions.

17. The method of claim 16, wherein the epilepsy is selected from epilepsy caused by hemiplegia, cerebrovascular disease, brain tumor, neurodegenerative disease, autoimmune disease, etc., including hemiplegia, cerebrovascular disease, hemiplegia, and mesial temporal lobe epilepsy syndrome, structural or metabolic causes (e.g., post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, cerebrovascular disease, brain tumor, neurodegenerative disease, autoimmune disease, etc.), congenital malformation, congenital metabolic disorder (e.g., phenylketonuria, mitochondrial disease, lysosomal disease, Sturge-Weber syndrome, etc.), and congenital genetic abnormality (e.g., Rett syndrome, Angelman syndrome, 5p syndrome, 4p syndrome, Down syndrome, etc.).

19. 9. The compound or salt thereof according to any one of claims 1 to 8 for use in the treatment, prevention and / or diagnosis of seizures in diseases accompanied by epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus).

20. Epileptic seizures include focal seizures (sometimes called partial seizures) with motor onset (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor onset seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, affective seizures, and perceptual seizures), focal seizures that progress to bilateral tonic-clonic seizures (secondary generalization of partial seizures), and motor seizures in generalized seizures (tonic-clonic seizures, clonic seizures).

20. The compound or salt thereof according to claim 19, wherein the compound or salt is selected from motor seizures (including typical absence seizures, tonic seizures, myoclonic seizures, myoclonic tonic-clonic seizures, myoclonic atonic seizures, atonic seizures and epileptic spasms) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and lid myoclonic seizures); motor seizures of unknown onset (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral arrest seizures).

21. Diseases accompanied by epileptic seizures or convulsive seizures include Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (infantile spasms), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, unilateral convulsions / unilateral spasms, 20. The compound or salt thereof according to claim 19, which is selected from paralysis-epilepsy syndrome, mesial temporal lobe epilepsy syndrome, epilepsy attributable to structural or metabolic causes (post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disorders, epilepsy associated with brain tumors, epilepsy associated with neurodegenerative diseases, epilepsy associated with autoimmune diseases, etc.), congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (e.g., Rett syndrome, Angelman syndrome, 5p syndrome, 4p syndrome, Down syndrome, etc.).

22. Use of the compound or salt thereof according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment, prevention and / or diagnosis of seizures in diseases accompanied by epileptic or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus).

23. Epileptic seizures include focal seizures (sometimes called partial seizures) with motor onset (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor onset seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, affective seizures, and perceptual seizures), focal seizures that progress to bilateral tonic-clonic seizures (secondary generalization of partial seizures), motor seizures in generalized seizures (tonic-clonic seizures, 23. The use according to claim 22, wherein the seizures are selected from: non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and eyelid myoclonic seizures); motor seizures of unknown onset (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral arrest seizures).

24. Diseases accompanied by epileptic seizures or convulsive seizures include Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (infantile spasms), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, and hemiconvulsions.

23. The use according to claim 22, wherein the epilepsy is selected from epilepsy caused by hemiplegia, cerebrovascular disease, brain tumor, neurodegenerative disease, autoimmune disease, etc., including hemiplegia, cerebrovascular disease, hemiplegia, and mesial temporal lobe epilepsy, structural or metabolic causes (e.g., post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, cerebrovascular disease, brain tumor, neurodegenerative disease, autoimmune disease, etc.), congenital malformation, congenital metabolic disorder (e.g., phenylketonuria, mitochondrial disease, lysosomal disease, Sturge-Weber syndrome, etc.), and congenital genetic abnormality (e.g., Rett syndrome, Angelman syndrome, 5p syndrome, 4p syndrome, Down syndrome, etc.).

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