Heterocyclic compounds in pharmaceutical applications

Abstract

The present invention aims to provide novel compounds and their salts that are effective in the treatment, prevention, and / or diagnosis of seizures in diseases accompanied by epileptic seizures or convulsive seizures. [Solution] Formula I: TIFF2026050464000087.tif2685 [In the formula, each symbol is as described in the specification.] This relates to the pharmaceutical uses of the compounds and salts thereof shown in [reference]. These compounds and salts are useful for the treatment, prevention, and / or diagnosis of seizures in diseases involving epileptic or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures, and status epilepticus).

Description

[Technical Field]

[0001] This invention relates to the pharmaceutical uses of heterocyclic compounds and their salts. The invention also relates to pharmaceuticals containing heterocyclic compounds or their salts as active ingredients, which are useful for the treatment, prevention, and / or diagnosis of seizures in diseases involving epileptic or convulsive seizures. [Background technology]

[0002] Epilepsy is a common neurological disorder affecting approximately 1% of the population, with about 1 million patients in Japan. The lifetime incidence rate is estimated at 3-4%, meaning tens of thousands of people develop epilepsy each year. About 70% of these patients can control their seizures with existing antiepileptic drugs and lead normal lives. However, the remaining 30% of epilepsy patients cannot adequately control their seizures and live with anxiety about when they might occur. Many existing antiepileptic drugs aim to correct the excitation-inhibition imbalance in nerve cells by suppressing excessive excitation or excessive synchronization. However, doses above the optimal level can disrupt this balance and induce motor impairment or epileptic seizures.

[0003] Patent Document 1 discloses a compound containing a pyrimidine in its structure, which is used in the treatment of diseases or conditions, 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 and pyridyloxypyrimidine in their structure as antagonists and / or inverse agonists of the cannabinoid-1 receptor, 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 [Overview of the project] [Problems that the invention aims to solve]

[0005] One of the objectives of the present invention is to provide novel compounds and salts thereof that are effective in the treatment, prevention, and / or diagnosis of seizures in diseases accompanied by epileptic seizures or convulsive seizures. Another objective of the present invention is to provide a drug that maintains an excitation-inhibition balance even at doses that completely suppress epileptic seizures, and has a broader therapeutic spectrum compared to existing antiepileptic drugs. [Means for solving the problem]

[0006] The inventors of this invention have diligently conducted research to solve the above problems and have succeeded in synthesizing a novel compound that has a broader therapeutic spectrum compared to existing antiepileptic drugs. This invention was completed based on this finding.

[0007] In other words, the present invention includes the following embodiments. [1] Equation I: TIFF2026050464000001.tif2685[in the formula, D is TIFF2026050464000002.tif2322 or C may be replaced with a halogen. 1-6 It is alkyl; Ring A is benzene, pyridine, indole, or indazole; Ring B is a pyrimidine, pyridazine, pyridine, pyrazole, benzene, or naphthalene, where, (i) When ring B is pyrimidine, ring C is selected from the following unsaturated rings and their oxides, dioxides (except for pyrimidine-2,4-dione and dihydropyrimidine-2,4-dione), and rings in which some or all of the unsaturated bonds in them are reduced with hydrogen; (a) A 3- to 8-membered monocyclic unsaturated heterocyclic ring containing only 1 to 4 nitrogen atoms as ring-constituting heteroatoms, (b) A 7- to 15-membered bicyclic or tricyclic unsaturated heterocyclic ring containing only 1 to 5 nitrogen atoms as ring-constituting heteroatoms, (c) A 7- to 12-membered bicyclic unsaturated heterocyclic ring containing only 1 to 3 oxygen atoms as ring-constituting heteroatoms, (d) A 3- to 8-membered monocyclic unsaturated heterocyclic ring containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms as ring-constituting heteroatoms, (e) A 7- to 12-membered bicyclic unsaturated heterocyclic ring containing 1 or 2 sulfur atoms and 1 to 3 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 C 1-6 alkyl, optionally substituted -O-C 1-6 alkyl, -CN or -SF5; R 2 is halogen, C 1-6 alkyl, -O-C 1-6 alkyl; R 3 is halogen, halogen or optionally substituted C 1-6 alkyl substituted with -O-C 1-6 alkyl, optionally substituted -O-C 1-6 alkyl, -C 1-6 alkyl-OH, -OH, -CN, -CONH2 or -NH2; L is a direct bond, C1-6 Alkylene, -O- or -S-; k is 0, 1, or 2, and if k is 2, R 1 Each of these independently represents the same or different substituent; m is 0, 1, or 2, and if m is 2, R 2 Each of these independently represents the same or different substituent; n is 0, 1, or 2, and if n is 2, R 3 Each of these independently represents the same or different substituent; A pharmaceutical product containing a compound represented by or a salt thereof. [2] In equation I, D is, The filename is TIFF2026050464000003.tif2322; Ring A is either benzene or pyridine; Ring B is a 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 those rings are reduced by hydrogen; Pyridine, Pyridazine, Pyrimidine, Indole, Pyrrolopyridine, Indazole, Benzimidazole, Pyrazolopyridine, Imidazopyridine, Imidazopyrazine, Imidazopyridazine, Triazolopyridine, Pyrazolopyrimidine, Imidazopyrimidine, Triazolopyrimidine, Quinoline, Isoquinoline, Naphthyridine, Kinazolin, Quinoxaline, Benzodioxol, oxazine, Oxazepine, Benzothiazole, benzene; R 1 C may be a halogen or a halogen-substituted C. 1-6 May be substituted with alkyl or halogen -OC 1-6 Alkyl or -CN; R 2 is, -OC 1-6 It is alkyl; R 3 is halogen, halogen or -OC 1-6 C may be substituted with alkyl. 1-6 May be substituted with alkyl or halogen -OC 1-6 Alkyl, -C 1-6 Alkyl-OH, -OH, -CN, -CONH2, or -NH2; L is -O-; k is 0, 1, or 2, and if k is 2, R 1 Each of these independently represents the same or different substituent; m is either 0 or 1; n is 0, 1, or 2, and if n is 2, R 3 Each of these independently represents the same or different substituent, as described in [1]. [3] In formula I, ring C is selected from the following unsaturated rings and their oxides and rings in which some or all of the unsaturated bonds in the ring are reduced by hydrogen; Pyridine, Pyridazine, Pyrrolopyridine, Indazole, Pyrazolopyridine, Imidazopyridine, Imidazopyrazine, Imidazopyridazine, Pyrazolopyrimidine, Triazolopyrimidine, Quinoline, Isoquinoline, Naphthyridine, Quinoxaline, benzene; R 1C may be a halogen or a halogen-substituted C 1-6 It is alkyl; R 3 C may be substituted with a halogen. 1-6 May be substituted with alkyl or halogen -OC 1-6 It is alkyl, -OH, -CONH2, or -NH2; L is -O-; k and n are either 0 or 1; m is 0, as described in [2]. [4] In formula I, ring C is selected from the following unsaturated rings and their oxides and rings in which some or all of the unsaturated bonds in the ring are reduced by hydrogen; Pyridine, Pyridazine, Pyrazolopyridine, Imidazopyridine; R 3 is -OH or -NH2; L is -O-; k and m are 0; The pharmaceutical product described in [3], wherein n is 0 or 1. [5] In equation I, D is TIFF2026050464000004.tif2322 or C may be replaced with a halogen. 1-6 It is alkyl; Ring A is either 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 C may be a halogen or a halogen-substituted C. 1-6 May be substituted with alkyl or halogen -OC 1-6 Alkyl, -CN, or -SF5; R 2 is halogen, C 1-6 Alkyl, -OC 1-6 It is alkyl; R 3 C1-6 It is alkyl; L is directly bonded, C 1-6 Alkylene, -O- or -S-; k is 0, 1, or 2, and if k is 2, R 1 Each of these independently represents the same or different substituent; m is 0, 1, or 2, and if m is 2, R 2 Each of these independently represents the same or different substituent; n is 0, 1, or 2, and if n is 2, R 3 Each of these independently represents the same or different substituent, as described in [1]. [6] In formula I, ring A is benzene; Ring B is benzene, pyridine, or pyridazine; Ring C is dihydropyrimidine-2,4-dione; R 1 It is a halogen; L is -O-; k is either 0 or 1; The pharmaceutical product described in [5], wherein m and n are 0. [7] A pharmaceutical product comprising a compound selected from the group consisting of the following compounds or a salt thereof. TIFF2026050464000005.tif140151 TIFF2026050464000006.tif135147 TIFF2026050464000007.tif154148[8] The pharmaceutical product according to [7], comprising a compound selected from the group consisting of the following compounds or a salt thereof. TIFF2026050464000008.tif113145[9] A pharmaceutical composition comprising any of the compounds described in [1] to [8] or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

[10] A compound or salt thereof described in any of [1] to [8], for the treatment, prevention and / or diagnosis of seizures in diseases involving epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus (status epilepticus)).

[11] Epileptic seizures include motor-initiated seizures (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures and tonic seizures) and non-motor-initiated seizures (including autonomic seizures, cessation seizures, cognitive seizures, emotional seizures and sensory seizures), seizures that progress from a focal seizure to a bilateral tonic-clonic seizure (secondary generalization of a partial seizure); motor seizures in generalized seizures (tonic-clonic seizures, clonic seizures, A therapeutic, prophylactic and / or diagnostic agent as described in

[10] , selected from tonic seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures, atonic seizures and epileptic-spasmodic seizures) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and blepharoplastic myoclonic seizures); and motor seizures (including tonic-clonic seizures and epileptic-spasmodic seizures) and non-motor seizures (including arrest seizures) in seizures of unknown origin.

[12] Disorders that involve epileptic 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, and hemiplegia. A therapeutic, prophylactic and / or diagnostic agent selected from among lateral convulsive, hemiplegic, and epileptic syndromes, medial temporal lobe epilepsy syndrome, epilepsy attributable to structural or metabolic causes (post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disease, epilepsy associated with brain tumor, epilepsy associated with neurodegenerative disease, Sturge-Weber syndrome, etc.), as well as congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial disease, lysosomal storage disease, etc.) and congenital genetic abnormalities (e.g., Rett syndrome, Angelman syndrome, 5p- syndrome, 4p- syndrome, Down syndrome, etc.)

[10] .

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

[14] Epileptic seizures include motor-initiated seizures (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures and tonic seizures) and non-motor-initiated seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, emotional seizures and sensory seizures), seizures that progress from a focal seizure to a bilateral tonic-clonic seizure (secondary generalization of a partial seizure); motor seizures in generalized seizures (tonic-clonic seizures, A pharmaceutical composition according to

[13] , selected from clonic seizures, tonic seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures, atonic seizures and epileptic spasmodic seizures) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and blepharomyoclonic seizures); and motor seizures (including tonic-clonic seizures and epileptic spasmodic seizures) and non-motor seizures (including behavioral arrest seizures) in seizures of unknown origin.

[15] Disorders that involve epileptic 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, and Geschwind syndrome. A pharmaceutical composition according to

[13] selected from syndromes, hemiplegia / hemiplegia syndrome, medial temporal lobe epilepsy syndrome, epilepsy attributable to structural or metabolic causes (post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disease, epilepsy associated with brain tumor, epilepsy associated with neurodegenerative disease, Sturge-Weber syndrome, etc.), as well as congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial disease, lysosomal storage disease, 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 involving epileptic or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus), characterized by administering an effective amount of any of the compounds or salts thereof described in [1] to [8] to a human.

[17] Epileptic seizures include motor-initiated seizures (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures and tonic seizures) and non-motor-initiated seizures (including autonomic seizures, cessation seizures, cognitive seizures, emotional seizures and sensory seizures), seizures that progress from a focal seizure to a bilateral tonic-clonic seizure (secondary generalization of a partial seizure); motor seizures in generalized seizures (tonic-clonic seizures) The method described in

[16] , comprising: clonic seizures, tonic seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures, atonic seizures and epileptic spasmodic seizures) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and blepharomyoclonic seizures); and selection from motor seizures (including tonic-clonic seizures and epileptic spasmodic seizures) and non-motor seizures (including behavioral arrest seizures) in seizures of unknown origin.

[18] Disorders that involve epileptic 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, and Geschwind syndrome. The method described in

[16] , selected from ) syndromes, hemiplegic epilepsy syndrome, medial temporal lobe epilepsy syndrome, epilepsy attributable to structural or metabolic causes (e.g., post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disease, epilepsy associated with brain tumor, epilepsy associated with neurodegenerative disease, Sturge-Weber syndrome), as well as congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial disease, lysosomal storage disease, etc.) and congenital genetic abnormalities (e.g., Rett syndrome, Angelman syndrome, 5p- syndrome, 4p- syndrome, Down syndrome, etc.).

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

[20] Epileptic seizures include motor-initiated seizures (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures and tonic seizures) and non-motor-initiated seizures (including autonomic seizures, cessation seizures, cognitive seizures, emotional seizures and sensory seizures), seizures that progress from a focal seizure to a bilateral tonic-clonic seizure (secondary generalization of a partial seizure); motor seizures in generalized seizures (tonic-clonic seizures, clonic seizures) A compound or salt thereof selected from seizures (including tonic seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures, atonic seizures and epileptic spasmodic seizures) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and blepharomyoclonic seizures); and motor seizures (including tonic-clonic seizures and epileptic spasmodic seizures) and non-motor seizures (including arrest seizures) in seizures of unknown origin

[19] .

[21] Disorders that involve epileptic 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, and Geschwind syndrome. Compounds or salts thereof selected from syndromes, hemiplegic syndrome, medial temporal lobe epilepsy syndrome, epilepsy attributable to structural or metabolic causes (e.g., post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disease, epilepsy associated with brain tumor, epilepsy associated with neurodegenerative disease, Sturge-Weber syndrome), and congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial disease, lysosomal storage disease), and congenital genetic abnormalities (e.g., Rett syndrome, Angelman syndrome, 5p- syndrome, 4p- syndrome, Down syndrome)

[19] .

[22] Use of any of the compounds or salts thereof described in [1] to [8] in the manufacture of a medicament for the treatment, prevention and / or diagnosis of seizures in diseases involving epileptic or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus).

[23] Epileptic seizures include motor-initiated seizures (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures and tonic seizures) and non-motor-initiated seizures (including autonomic seizures, cessation seizures, cognitive seizures, emotional seizures and sensory seizures), seizures that progress from a focal seizure to a bilateral tonic-clonic seizure (secondary generalization of a partial seizure); motor seizures in generalized seizures (tonic-clonic seizures) Use as described in

[22] , selected from motor seizures (including tonic seizures and epileptic spasms) and non-motor seizures (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and blepharomyoclonic seizures); and non-motor seizures (including arrest seizures) in seizures of unknown origin.

[24] Disorders that involve epileptic 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, and Geschwind syndrome. Use as described in

[22] , selected from: (t) syndromes, hemiplegic epilepsy syndrome, medial temporal lobe epilepsy syndrome, epilepsy attributable to structural or metabolic causes (e.g., post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disease, epilepsy associated with brain tumor, epilepsy associated with neurodegenerative disease, Sturge-Weber syndrome), and congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial disease, lysosomal storage disease, etc.) and congenital genetic abnormalities (e.g., Rett syndrome, Angelman syndrome, 5p- syndrome, 4p- syndrome, Down syndrome, etc.). [Effects of the Invention]

[0008] The compounds and salts of the present invention have excellent effects in the treatment, prevention, and / or diagnosis of diseases accompanied by epileptic seizures or convulsive seizures. Furthermore, the compounds and salts of the present invention have excellent characteristics for use as active ingredients in pharmaceuticals, such as having few side effects and excellent tolerability and stability (storage stability, metabolic stability, etc.). Moreover, the compounds and salts of the present invention have a broader therapeutic spectrum compared to existing antiepileptic drugs. [Modes for carrying out the invention]

[0009] The terms and phrases used in this specification are described in detail below. In this specification, "C 1-6 Examples of alkyl groups include those with 1 to 6 carbon atoms (C 1-6 It includes linear or branched alkyl groups, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, etc. Also, "C 1-6 "Alkyl" refers to a C molecule in which 1 to 3 hydrogen atoms are replaced by deuterium atoms. 1-6 Alkyl compounds are also included.

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

[0011] "C that can be substituted with halogens" 1-6 Examples of alkyl groups include those with 1 to 6 carbon atoms, which may be substituted with 1 to 4 halogens. 1-6) contains linear or branched alkyl groups, and specific examples 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, etc.

[0012] "C 1-6 Examples of alkylenes include those with 1 to 6 carbon atoms (C 1-6 It contains linear or branched alkylene groups, and specific examples include methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, dimethylmethylene, tetramethylene, pentamethylene, hexamethylene, etc. Also, "C 1-6 "Alkylene" is a compound in which 1 to 3 hydrogen atoms are replaced by deuterium atoms. 1-6 Alkylenes are also included.

[0013] Each group defined herein may be bonded to another group as appropriate via linkers such as -O-, -CO-, -COO-, -S-, -SO-, -SO2-, -Si-, -O-CO-, etc.

[0014] Each substituent in the compound represented by the general formula [I] of the present invention (hereinafter referred to as "compound [I] of the present invention") will be described below.

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

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

[0017] In compound [I] of the present invention, 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 are reduced by hydrogen, when ring B is a pyrimidine: (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-forming heteroatoms, (f) A monocyclic unsaturated hydrocarbon ring with 3 to 8 members.

[0018] As specific examples of monocyclic unsaturated heterocycles with 3 to 8 members containing only 1 to 4 nitrogen atoms as ring constituent heteroatoms as described in (a) above, 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 are reduced by hydrogen, Pyridine, piperidine, pyridine-1-oxide, pyridine-2(1H)-one, pyrimidine, tetrahydropyrimidine, tetrahydropyrimidine-2(1H)-one, pyridazine, pyridazine-3(2H)-one, 4,5-dihydropyridazine, 4,5-dihydropyridazine-3(2H)-one Examples include:

[0019] As specific examples of 7- to 15-membered bicyclic or tricyclic unsaturated heterocycles containing only 1 to 5 nitrogen atoms as ring constituent heteroatoms in (b) above, and their oxides, dioxides, and rings in which some or all of the unsaturated bonds in the ring are reduced by hydrogen, Indole, indoline, indoline-2-one, indoline-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, quinoline-2(1H)-one, dihydroquinoline (e.g., 1,2-dihydroquinoline, 3,4-dihydroquinoline), 3 ,4-dihydroquinoline-2(1H)-one, tetrahydroquinoline (e.g., 1,2,3,4-tetrahydroquinoline), isoquinoline, isoquinoline-1(2H)-one, 1,3-dihydroisoquinoline, 3,4-dihydroisoquinoline, 3,4-dihydroisoquinoline-1(2H)-one, triazolopyrimidine (e.g., [1,2,4]triazolo[1,5-a]pyrimidine), triazolopyridine (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) Noxaline, tetrahydroquinoxaline (e.g., 1,2,3,4-tetrahydroquinoxaline), quinazoline, quinazoline-4(3H)-one, dihydroquinazoline (e.g., 2,3-dihydroquinazoline), pyrazolopyridine (e.g., pyrazolo[1,5-a]pyridine, pyrazolo[3,4-b]pyridine), pyrrolopyridine (e.g., pyrrolo[2,3-b]pyridine), pyrrolo[2,3-b]pyridine-2(3H)-one, pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine) Examples include:

[0020] As specific examples of 7- to 12-membered bicyclic unsaturated heterocycles containing only 1 to 3 oxygen atoms as ring constituent heteroatoms in (c) above, and their oxides, dioxides, and rings in which some or all of the unsaturated bonds in the ring are reduced by hydrogen, Benzodioxoles (e.g., benzo[d][1,3]dioxole, benzo[c][1,2]dioxole) Examples include:

[0021] As specific examples of monocyclic unsaturated heterocycles with 3 to 8 members containing one or two oxygen atoms and one to three nitrogen atoms as ring constituent heteroatoms in (d) above, and their oxides, dioxides, and rings in which some or all of the unsaturated bonds in the ring are reduced by hydrogen, Oxazepines (e.g., 1,2-oxazepine, 1,3-oxazepine, 1,4-oxazepine), dihydrooxazepine, tetrahydrooxazepine, oxazepan (e.g., 1,2-oxazepan, 1,3-oxazepan, 1,4-oxazepan), 1,4-oxazepan-2-one, Oxazines (e.g., 1,4-oxazine), dihydrooxazines (3,4-dihydro2H-1,4-oxazepine), morpholine, morpholine-3-one Examples include:

[0022] As specific examples of 7- to 12-membered bicyclic unsaturated heterocycles containing one or two sulfur atoms and one to three nitrogen atoms as ring constituent heteroatoms in (e) above, and their oxides, dioxides, and rings in which some or all of the unsaturated bonds in the ring are reduced by hydrogen, Benzothiazole (e.g., benzo[d]thiazole) Examples include:

[0023] As specific examples of the 3- to 8-membered monocyclic unsaturated hydrocarbon rings described in (f) above, as well as their oxides, dioxides, and rings in which some or all of the unsaturated bonds in the ring are reduced by hydrogen, Benzene, cyclohexene, cyclohexane Examples include:

[0024] Preferably, 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 are reduced by hydrogen, when ring B is a pyrimidine: Pyridine, Pyridazine, Pyrimidine, Indole, Pyrrolopyridine, Indazole, Benzimidazole, Pyrazolopyridine, Imidazopyridine, Imidazopyrazine, Imidazopyridazine, Triazolopyridine, Pyrazolopyrimidine, Imidazopyrimidine, Triazolopyrimidine, Quinoline, Isoquinoline, Naphthyridine, Kinazolin, Quinoxaline, Benzodioxol, oxazine, Oxazepine, Benzothiazole, benzene.

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

[0026] R 1 C may be a halogen or a halogen-substituted C. 1-6 May be substituted with alkyl or halogen -OC 1-6It is alkyl, -CN, or -SF5. Preferably halogen, or C which may be substituted with a halogen. 1-6 May be substituted with alkyl or halogen -OC 1-6 It is an alkyl group, and more preferably fluorine, methyl, trifluoromethyl, or -O-trifluoromethyl.

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

[0028] R 3 is halogen, halogen or C 1-6 C may be substituted with alkyl-O- 1-6 May be substituted with alkyl or halogen -OC 1-6 Alkyl, -C 1-6 The C is alkyl-OH, -OH, -CN, -CONH2, or -NH2. Preferably, it may be substituted with a halogen. 1-6 Alkyl, -OC 1-6 The alkyl, -OH, -CONH2, or -NH2 is more preferably methyl, trifluoromethyl, -O-methyl, -OH, -CONH2, or -NH2.

[0029] L is directly bonded, C 1-6 The alkylene is -O- or -S-, preferably directly bonded or -O-, and more preferably -O-.

[0030] k is 0, 1, or 2, and if k is 2, R 1 Each of these independently represents the same or different substituent. Preferably, it is 0 or 1, and more preferably 0.

[0031] m is 0, 1, or 2, and if m is 2, R 2 Each of these independently represents the same or different substituent. Preferably, it is 0 or 1, and more preferably 0.

[0032] n is 0, 1, or 2, and if n is 2, R 3 Each of these independently represents the same or different substituent. Preferably, it is 0 or 1.

[0033] The compound [I] of the present invention includes all combinations of the above substituents, provided that the options and preferred embodiments are consistent with these substituents.

[0034] Preferred embodiments of compound [I] of the present invention are shown below. (1-1) In equation I, D is The filename is TIFF2026050464000009.tif2322; Ring A is either benzene or pyridine; Ring B is a 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 those rings are reduced by hydrogen; Pyridine, Pyridazine, Pyrimidine, Indole, Pyrrolopyridine, Indazole, Benzimidazole, Pyrazolopyridine, Imidazopyridine, Imidazopyrazine, Imidazopyridazine, Triazolopyridine, Pyrazolopyrimidine, Imidazopyrimidine, Triazolopyrimidine, Quinoline, Isoquinoline, Naphthyridine, Kinazolin, Quinoxaline, Benzodioxol, oxazine, Oxazepine, Benzothiazole, Benzene; R 1 is halogen, optionally substituted C 1-6 alkyl, optionally substituted -O-C 1-6 alkyl or -CN; R 2 is -O-C 1-6 alkyl; R 3 is halogen, halogen or optionally substituted -O-C 1-6 alkyl-substituted C 1-6 alkyl, optionally substituted -O-C 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 substituents; m is 0 or 1; n is 0, 1 or 2, and when n is 2, R 3 each independently represents the same or different substituents. (1-2) In formula I, ring C is selected from the following unsaturated rings and their oxides and rings in which some or all of the unsaturated bonds in the rings are reduced with hydrogen; Pyridine, Pyridazine, Pyrrolopyridine, Indazole, Pyrazolopyridine, Imidazopyridine,<00​​​​​​​​​​​​​​​​​​​​​​is alkyl; R 3 is optionally substituted C 1-6 alkyl, optionally substituted -O-C 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 and their oxides and rings in which some or all of the unsaturated bonds in them are reduced with hydrogen; pyridine, pyridazine, pyrazolopyridine, imidazopyridine; R 3 [[ID=2*]]is -OH, or -NH2; L is -O-;[[ID=*1]] 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. TIFF2026050464000010.tif140148 TIFF2026050464000011.tif140153 TIFF20*6050464000012.tif84146(1-5) A compound selected from the group consisting of the following compounds or a salt thereof. TIFF2026050464000013.tif100151

[0035] Another preferred embodiment of the compound [I] of the present invention is shown below. (2-1) In formula I, D is TIFF2026050464000014.tif2322 or optionally substituted C 1-6 alkyl; ring A is benzene or pyridine; y ring B is pyridazine, pyridine, pyrazole, benzene or naphthalene; It should be noted that there seems to be an error in the original text where "TIFF2026050464000012.tif84146(1-5)" has an asterisk in the middle of the file name which might be a mistake. Also, in the translation, I've tried to keep the text as close to the original format as possible while making it grammatically correct in English. If there are specific requirements regarding how to handle such file name-like text, it might need further clarification.Ring C is pyrimidine-2,4-dione or dihydropyrimidine-2,4-dione; R 1 C may be a halogen or a halogen-substituted C. 1-6 May be substituted with alkyl or halogen -OC 1-6 Alkyl, -CN, or -SF5; R 2 is halogen, C 1-6 Alkyl, -OC 1-6 It is alkyl; R 3 C 1-6 It is alkyl; L is directly bonded, C 1-6 Alkylene, -O- or -S-; k is 0, 1, or 2, and if k is 2, R 1 Each of these independently represents the same or different substituent; m is 0, 1, or 2, and if m is 2, R 2 Each of these independently represents the same or different substituent; n is 0, 1, or 2, and if n is 2, R 3 Each of these independently represents the same or different substituent. (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 It is a halogen; L is -O-; k is either 0 or 1; m and n are zero. (2-3) A compound selected from the group consisting of the following compounds, or a salt thereof. TIFF2026050464000015.tif50106(2-4) The following compounds or salts thereof. TIFF2026050464000016.tif3263

[0036] In this specification, the presentation of preferred embodiments and options relating to different characteristics of the compounds, methods, and compositions of the present invention also includes the presentation of combinations of preferred embodiments and options relating to such different characteristics, provided that they are combinatorial and inconsistent.

[0037] The following describes a method for producing compound [I] of the present invention. Compound [I] of the present invention can be produced, for example, based on the production method shown below. The production method shown below is illustrative, and the method for producing compound [I] is not limited to these.

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

[0039] Reaction Equation 1-1 TIFF2026050464000017.tif32167 (In the formula, Y and Y' are leaving groups, and the other symbols are equivalent to those above.)

[0040] Compound [I] of the present invention can be produced by the reaction shown in reaction formula 1-1 above. Specifically, compound [I] can be produced by adding a cyclic pinacol ester ((BPin)2) of a boronic acid to compound [IIa] to form compound [IIa'], and then bonding compound [IIIa] to it via a Suzuki cross coupling.

[0041] Specifically, the "leaving groups" used in the above reaction include halogens and C. 1-18 Examples of leaving groups include alkanesulfonyls, lower alkanesulfonyloxys, arylsulfonyloxys, aralkylsulfonyloxys, perhaloalkanesulfonyloxys, sulfonios, and toluenesulfoxys. Preferred leaving groups in this reaction include halogens.

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

[0043] The above "C 1-18 Examples of "alkanesulfonyls" include linear or branched alkanesulfonyls with 1 to 18 carbon atoms, and specific examples include methanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl, butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl, etc.

[0044] Examples of the above-mentioned "lower alkanesulfonyloxy" include linear or branched alkanesulfonyloxy with 1 to 6 carbon atoms, and specific examples include methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy, 2-propanesulfonyloxy, 1-butanesulfonyloxy, 3-butanesulfonyloxy, 1-pentanesulfonyloxy, 1-hexanesulfonyloxy, etc.

[0045] Examples of the above-mentioned "arylsulfonyloxy" include phenylsulfonyloxy and naphthylsulfonyloxy, which may have 1 to 3 substituents on the phenyl ring, selected from the group consisting of linear or branched alkyl groups having 1 to 6 carbon atoms, linear or branched alkoxy groups having 1 to 6 carbon atoms, nitro groups, and halogen groups. Specific examples of the above-mentioned "phenylsulfonyloxy that may have substituents" include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2-nitrophenylsulfonyloxy, and 3-chlorophenylsulfonyloxy. Specific examples of the above-mentioned "naphthylsulfonyloxy" include α-naphthylsulfonyloxy and β-naphthylsulfonyloxy.

[0046] Examples of the above-mentioned "aralkylsulfonyloxy" include phenyl-substituted linear or branched alkanesulfonyloxy with 1 to 6 carbon atoms, which may have 1 to 3 substituents on the phenyl ring selected from the group consisting of linear or branched alkyl, linear or branched alkoxy, nitro, and halogen; and naphthyl-substituted linear or branched alkanesulfonyloxy with 1 to 6 carbon atoms. Specific examples of the above-mentioned "phenyl-substituted alkanesulfonyloxy" include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, and 3-chlorobenzylsulfonyloxy. Specific examples of the above-mentioned "naphthyl-substituted alkanesulfonyloxy" include α-naphthylmethylsulfonyloxy and β-naphthylmethylsulfonyloxy.

[0047] Examples of the "perhaloalkanesulfonyloxy" mentioned above include trifluoromethanesulfonyloxy.

[0048] Specific examples of the above-mentioned "sulfonio" include dimethyl sulfonio, diethyl sulfonio, dipropyl sulfonio, 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, or diphenyl sulfonio.

[0049] The "palladium compound" used in this reaction is not particularly limited, but examples include tetravalent palladium catalysts such as sodium hexachloropalladium(IV) tetrahydrate and potassium hexachloropalladium(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 (XPhosPd Examples include divalent palladium catalysts such as G3), palladium(II) chloride, palladium(II) bromide, palladium(II) acetate (PD(OAc)2), palladium acetylacetonate (II), dichlorobis(benzonitrile)palladium (II), dichlorobis(acetonitrile)palladium (II), dichlorobis(triphenylphosphine)palladium (II), dichlorotetraamminepalladium (II), dichloro(cycloocta-1,5-diene)palladium (II), palladium trifluoroacetate (II), and 1,1'-bis(diphenylphosphine)ferrocenedichloropalladium(II)-dichloromethane complex; and zero-valent palladium catalysts such as tris(dibenzylideneacetone)dipalladium(O) (Pd2(dba)3), tris(dibenzylideneacetone)dipalladiumchloroform complex (O), and tetrakis(triphenylphosphine)palladium(O) (Pd(PPh3)4). These palladium compounds are used individually or in combination of two or more.

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

[0051] The "bases" used in this reaction include, for example, inorganic bases and organic bases. Examples of "inorganic bases" 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), and alkaline earth metal phosphates (e.g., sodium phosphate, potassium phosphate). Examples of "organic bases" include trialkylamines (e.g., trimethylamine, triethylamine, and diisopropylethylamine), dialkylamines (e.g., diethylamine, 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]undeca-7-ene (DBU). These bases are used individually or in combination of two or more.

[0052] The "boronic acid" or "boronic acid ester" used in this reaction may be prepared separately, isolated, and purified, or, for example, bispinacol diborane may be reacted with a precursor halogenated compound in the presence of a palladium compound and used in the Suzuki cross coupling reaction without isolation or purification.

[0053] The "solvent" used in this reaction can be any solvent that is inert to the reaction, and examples include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether), 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), hexamethylphosphate triamide, acetonitrile), ketones (e.g., acetone, methyl ethyl ketone), and esters (e.g., methyl acetate, ethyl acetate). These solvents can be used individually or in combination of two or more.

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

[0055] Reaction Equation 1-2 TIFF2026050464000018.tif38127 (In the formula, Y is a leaving group, and the other symbols are equivalent to those above.)

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

[0057] The palladium compounds, bases, solvents, etc. that can be used in reaction equation 1-2 are the same as those that can be used in reaction equation 1-1.

[0058] Reaction Equation 1-3 TIFF2026050464000019.tif38121 (In the formula, Y is a leaving group, and the other symbols are equivalent to those above.)

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

[0060] The palladium compounds, bases, solvents, etc. that can be used in reaction equations 1-3 above are the same as those that can be used in reaction equation 1-1.

[0061] Reaction Equation 2-1 TIFF2026050464000020.tif35119 (In this formula, 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 reaction formula 2-1 above. Specifically, compound [Ia] can be produced by adding compound [VI] to the amino group of compound [IIb], and then removing the chlorine from the product and cyclizing it.

[0063] The "bases" used in this reaction include, for example, inorganic bases and organic bases. 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 bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate), sodium hydride (NaH), sodium hexamethyldisilazide (NaHMDS), etc. Examples of "organic bases" include trialkylamines (e.g., trimethylamine, triethylamine), Hünig bases (N,N-diisopropylethylamine), pyridine, N-methylmorpholine, etc.

[0064] The "solvent" used in this reaction can be any solvent that is inert to the reaction, and examples include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether), 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), hexamethylphosphate triamide, acetonitrile), ketones (e.g., acetone, methyl ethyl ketone), and esters (e.g., methyl acetate, ethyl acetate). These solvents can be used individually or in combination of two or more.

[0065] Other reaction conditions (reaction temperature, reaction time, etc.) can be appropriately determined based on known condensation reactions, but 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 Equation 2-2 TIFF2026050464000021.tif28115 (In this formula, 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 reaction formula 2-2 above. Specifically, compound [Ib] can be produced by 1,4-adding compound [III] (acrylic acid) to the amino group of compound [IIb], and then converting the amino group of the product into a urea derivative using urea and cyclizing (intramolecular amidation).

[0068] The "solvent" used in the above reaction can be any solvent that is inert to the reaction, and examples include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether), 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), hexamethylphosphate triamide, acetonitrile), ketones (e.g., acetone, methyl ethyl ketone), and esters (e.g., methyl acetate, ethyl acetate). These solvents can be used individually or in combination of two or more.

[0069] Examples of "acids" used in the above reaction include inorganic acids and organic acids. Examples of "inorganic acids" include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and phosphoric acid. 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, and 10-camphorsulfonic acid.

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

[0071] Reaction Equation 3-1 TIFF2026050464000022.tif33153 (wherein Y is a leaving group and L1 is -O-, -S- or C) 1-6 It is an alkylene, and the other symbols are synonymous with those above.

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

[0073] The "bases" used in this reaction include, for example, inorganic bases. 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 bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate), sodium hydride (NaH), sodium hexamethyldisilazide (NaHMDS), etc. Examples of "organic bases" include trialkylamines (e.g., trimethylamine, triethylamine), Hünig bases (N,N-diisopropylethylamine), pyridine, N-methylmorpholine, etc.

[0074] The "solvent" used in this reaction can be any solvent that is inert to the reaction, and examples include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether), 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), hexamethylphosphate triamide, acetonitrile), ketones (e.g., acetone, methyl ethyl ketone), and esters (e.g., methyl acetate, ethyl acetate). These solvents can be used individually or in combination of two or more.

[0075] Other reaction conditions (reaction temperature, reaction time, etc.) can be appropriately determined based on known condensation reactions, but for example, the reaction temperature can range from room temperature to 100°C, and the reaction time can range from 1 to 10 hours.

[0076] In each reaction in the above reaction equation, the product can be used in the next reaction as is, or as a crude product. However, it can also be isolated from the reaction mixture according to conventional methods and easily purified by ordinary separation means. Examples of ordinary separation means include recrystallization, distillation, and chromatography.

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

[0078] Compound [I] of the present invention can be produced by the synthesis methods shown in the above reaction formulas or by similar methods.

[0079] Unless otherwise specified, the raw materials used in the production of compound [I] of the present invention may be commercially available or produced according to a known method or a similar method.

[0080] The starting material compounds and target compounds in each of the above processes can be used in appropriate salt forms. Examples of such salts are similar to those exemplified below as salts of compound [I] of the present invention.

[0081] If the compounds obtained in each step or the commercial product are free compounds, they can be converted to the desired salt by methods known to the public. If the compounds obtained in each step or the commercial product are salts, they can be converted to free forms or other types of salts of the desired nature by methods known to the public.

[0082] Furthermore, compound [I] of the present invention includes pharmaceutically acceptable salt forms thereof, and depending on the type of acid addition salt or substituent, it may also form salts with bases. 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. It 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 polymorphs of compound [I] and its salts.

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

[0085] Compound [I] of the present invention also includes pharmaceutically acceptable prodrugs. Substituents modified to form prodrugs include reactive functional groups such as -OH, -COOH, and amino. These functional group modifiers may be appropriately selected from the "substituents" as defined herein.

[0086] The compound [I] of the present invention or a salt thereof may be a pharmaceutically acceptable cocrystal or cocrystalline salt. Here, a cocrystal or cocrystalline salt means a crystalline substance composed of two or more unique solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, etc.). Cocrystals and cocrystalline salts can be produced by applying known cocrystallization methods.

[0087] Compound [I] and its salts of the present invention have excellent effects on the treatment, prevention and / or diagnosis of seizures in diseases involving epileptic or convulsive seizures. The invention is applicable to any seizure type classified as follows: In focal seizures (sometimes called partial seizures), motor-initiated seizures (including automatisms, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor-initiated seizures (including autonomic seizures, behavioral arrest seizures, cognitive seizures, emotional seizures, and sensory seizures), seizures that progress from focal seizures to bilateral tonic-clonic seizures (secondary generalization of partial seizures); in generalized seizures, motor seizures (including 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 eyelid myoclonic seizures); in seizures of unknown origin, motor seizures (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral arrest seizures). Diseases associated with epileptic 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, and Geschwind syndrome. Examples of conditions that may be classified as epilepsy include syndromes, unilateral seizure / hemiplegia / epileptic syndromes, medial temporal lobe epilepsy syndromes, epilepsy attributable to structural or metabolic causes (e.g., post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disease, epilepsy associated with brain tumors, epilepsy associated with neurodegenerative diseases, Sturge-Weber syndrome, etc.), as well as congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial diseases, lysosomal storage diseases, etc.) and congenital genetic abnormalities (e.g., Rett syndrome, Angelman syndrome, 5p- syndrome, 4p- syndrome, Down syndrome, etc.). Furthermore, compound [I] of the present invention and its salts are also effective in the treatment, prevention and / or diagnosis of multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus. In the present invention, multidrug-resistant seizures or refractory seizures refer to seizures that cannot be controlled due to the ineffectiveness or insufficient efficacy of one or more antiepileptic drugs, regardless of the above-mentioned type of epileptic seizure. Furthermore, compound [I] and its salts possess excellent characteristics for use as active ingredients in pharmaceuticals, such as having few side effects and excellent tolerability and stability (storage stability, metabolic stability, etc.). These group of compounds of the present invention are also effective as preventive and / or therapeutic agents for intractable epileptic seizures that do not respond to conventional drug treatments.

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

[0089] The above-mentioned medical formulation is a formulation of compound [I] of the present invention or a salt thereof in the form of a conventional medical formulation, and is prepared using compound [I] of the present invention or a salt thereof and a pharmaceutically acceptable carrier. Examples of such carriers include commonly used fillers, bulking agents, binders, humectants, disintegrants, surfactants, lubricants, and other diluents or excipients.

[0090] Such medical preparations can be selected from various forms depending on the therapeutic purpose, and examples include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions, etc.).

[0091] A wide range of known carriers can be used when forming tablets, including, for example, excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorption enhancers such as sodium lauryl sulfate; humectants 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 a standard tablet shell as needed, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double-layered tablets.

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

[0094] When forming the formulation into liquid, emulsion, and suspension forms, a wide range of known diluents can be used, such as water. In addition, conventional solubilizers, buffers, etc., may be added, and if necessary, colorants, preservatives, fragrances, flavorings, sweeteners, or other pharmaceuticals may be included.

[0095] A wide range of known carriers can be used when forming the suppository, such as cocoa butter.

[0096] When prepared as an injectable preparation, the solution, emulsion, and suspension are preferably sterilized and isotonic with blood. The injectable preparation may contain sufficient sodium chloride or other substances to adjust for isotonicity, or it may 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 generally preferable to contain 1 to 70% by weight of compound [I] of the present invention or a salt thereof in the medical preparation.

[0098] There are no particular restrictions on the method of administering the medical preparation according to the present invention, and it may be administered in a manner appropriate to the 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. Injectable preparations and sustained-release injectable preparations may be administered intravenously alone or mixed with conventional infusion fluids such as glucose and amino acids, or, if necessary, alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. Suppositories may be administered rectally.

[0099] The dosage of the above-mentioned medical preparation may be appropriately selected according to the method of use, the patient's age, sex, the severity of the disease, and other conditions. Typically, 0.01 to 100 mg, preferably 0.1 to 50 mg, per kg of body weight per day may be administered in one to several divided doses.

[0100] The above dosages vary depending on various conditions; therefore, a lower dosage may be sufficient in some cases, while a dosage exceeding the above range may be necessary in others.

[0101] Compound [I] of the present invention or a salt thereof can be used in combination with various therapeutic or prophylactic agents for diseases in which the aforementioned compound [I] is considered effective. This combination may involve simultaneous administration, or separate administrations consecutively or at desired time intervals. The simultaneous administration formulation may be a combination formulation or separately formulated formulations.

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

[0103] In another embodiment, an agent for the treatment, prevention and / or diagnosis of seizures in diseases involving epileptic or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus) is provided, comprising compound [I] of the present invention or a salt thereof and a pharmaceutically acceptable carrier and / or excipient.

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

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

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

[0107] In yet another embodiment, the use of compound [I] or a salt thereof of the present invention in the manufacture of therapeutic agents, prophylactic agents and / or diagnostic agents for seizures and other seizures in diseases involving epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus). [Examples]

[0108] The present invention will be further described in detail by the following reference examples, embodiments, and test examples, but these are not intended to limit the present invention and may be modified without departing from the scope of the present invention. In this specification, the following abbreviations may be used.

[0109] TIFF2026050464000023.tif227160 TIFF2026050464000024.tif213160

[0110] In the following examples, "room temperature" typically refers to a temperature range of approximately 10°C to 35°C. Ratios given for mixed solvents are volume ratios unless otherwise specified. Percentages (%) refer to weight percentages unless otherwise specified. 1 1HNMR (proton nuclear magnetic resonance spectroscopy) was measured using a Fourier transform NMR (either Bruker AVANCE III 400 (400 MHz) or Bruker AVANCE III HD (500 MHz)). In silica gel column chromatography, when basic conditions were mentioned, aminopropylsilane-bonded silica gel was used. The absolute configuration of the compounds was determined by known X-ray crystallography methods (e.g., Shigeru Ohba and Shigenobu Yano, "Basic Course for Chemists 12: X-ray Crystallography" (1st edition, 1999)), or estimated from 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 5-bromo-2-chloropyrimidine (25.0 g) was added to a suspension of phenol (13.6 mL), K2CO3 (26.8 g), and DMF (250 mL), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting crystals were filtered 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 under a nitrogen atmosphere under reflux for 10 hours. Water and AcOEt were added to the reaction mixture and filtered by Celite. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in IPE, insoluble matter was filtered off, and the filtrate was concentrated to obtain the solid, which was washed with hexane to obtain the target compound (646 mg).

[0113] Reference example 18 Synthesis of 3-Methoxy-6-(2-(methylthio)pyrimidine-5-yl)pyridazine A mixture of 3-chloro-6-methoxypyridazine (206.3 mg), 2-(methylthio)pyrimidinyl-5-boronic acid pinacol ester (425.4 mg), K3PO4 (663.4 mg), PdCl2(dppf)DCM (48.6 mg), 1,4-dioxane (20 mL), and water (2 mL) was heated under a nitrogen atmosphere under reflux for 1.5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (Hexane / AcOEt) to obtain the target compound (242.6 mg).

[0114] Reference example 19 Synthesis of 3-Methoxy-6-(2-(methylsulfonyl)pyrimidine-5-yl)pyridazine A mixture of 3-methoxy-6-(2-(methylthio)pyrimidine-5-yl)pyridazine (242.6 mg), 77% hydrated m-CPBA (627.9 mg), and DCM (20 mL) was stirred at 0°C for 1 hour, and then stirred overnight at room temperature. The reaction mixture was poured into ice and saturated NaHCO3 aqueous solution, 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 obtain the target compound (166.7 mg).

[0115] Reference example 21 Synthesis of 5-(2-(methylthio)pyrimidine-5-yl)pyridine-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), K3PO4 (3.86 g), PdCl2(dppf)DCM (273.3 mg), 1,4-dioxane (30 mL), and water (3 mL) was heated under a nitrogen atmosphere under reflux 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)pyrimidine-5-yl)pyridine-2-amine A mixture of 5-(2-(methylthio)pyrimidine-5-yl)pyridine-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 stirred at room temperature for 2.75 hours. The reaction mixture was poured over ice and saturated NaHCO3 aqueous solution, and the product was extracted by DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (AcOEt, AcOEt / MeOH) to obtain 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 overnight at room temperature. 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 obtain the target compound (3.56 g).

[0118] Reference example 24 Synthesis of 5-(2-(dodecylthio)pyrimidine-5-yl)pyridine-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), K3PO4 (1.82 g), PdCl2(dppf)DCM (107.7 mg), 1,4-dioxane (20 mL), and water (2 mL) was heated under a nitrogen atmosphere under reflux 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)pyrimidine-5-yl)pyridine-2-amine A mixture of 5-(2-(dodecylthio)pyrimidine-5-yl)pyridine-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 overnight at room temperature. The reaction mixture was poured over ice, a mixture of saturated NaHCO3 aqueous solution 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-phenoxypyrimidine-5-yl)pyridazine A mixture of 5-bromo-2-phenoxypyrimidine (2.96 g), (BPin)2 (3.68 g), PdCl2(dppf)DCM (0.370 g), AcOK (1.78 g), and 1,4-dioxane (20 mL) was heated under a nitrogen atmosphere under reflux for 3 hours. 3-(benzyloxy)-6-chloropyridazine (2.00 g), PdCl2(dppf)DCM (0.370 g), K3PO4 (3.85 g), and water (5 mL) were added to the reaction mixture and heated under reflux for 2 hours. Water and AcOEt were added to the reaction mixture and filtered by 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 obtain the target compound (2.54 g).

[0121] Reference example 35 Synthesis of 4-(2-phenoxypyrimidine-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazine-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), PdCl2(dppf)DCM (0.063 g), K3PO4 (1.229 g), 1,4-dioxane (10 mL), and water (3 mL) was stirred overnight at 100°C. Water was added to the reaction mixture, and the product was extracted with AcOEt. The organic layer was dried over anhydrous sodium sulfate and then 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 (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 added to 60% NaH (0.933 g) under stirring at 0°C. After 20 minutes, chlorotriisopropylsilane (4.99 mL) was added and the mixture was 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 under a nitrogen atmosphere for 3 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 (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)pyrimidine-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), PdCl2(dppf)DCM (0.301 g), K3PO4 (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 obtain the target compound (2.05 g).

[0126] Reference example 42 Synthesis of 6-(2-(dodecylsulfonyl)pyrimidine-5-yl)imidazo[1,2-a]pyridine A mixture of 6-(2-(dodecylthio)pyrimidine-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 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 overnight at room temperature. Water was added to the reaction mixture, and the resulting crystals were filtered off and washed with water to obtain the target compound (6.55 g).

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

[0129] Reference example 45 Synthesis of 1-(3-chloropropyl)-3-(2-phenoxypyrimidine-5-yl)urea A solution of 2-phenoxypyrimidine-5-amine (1.00 g) in THF (10 mL) was mixed with 3-chloropropyl isocyanate (0.713 mL) at room temperature and stirred overnight. The precipitated solid was filtered 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 overnight at room temperature. 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 obtain the target compound (8.63 g).

[0131] Reference example 47 Synthesis of 2-(3-fluorophenoxy)pyrimidine-5-amine 2-(3-fluoromethoxyphenoxy)nitropyrimidine (8.65 g) and 50% hydrated 10% Pd / C (3 g) were suspended in EtOH (100 mL) and stirred at room temperature under a hydrogen atmosphere 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 obtain the target compound (3.77 g).

[0132] Reference example 50 Synthesis of 2-phenoxy-5-(4-(triisopropylsilyloxy)piperidine-1-yl)pyrimidine A mixture of 5-bromo-2-phenoxypyrimidine (400 mg), 4-(triisopropylsilyloxy)piperidine (451 mg), Pd(OAc)2 (17.9 mg), tBu3P·HBF4 (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-phenoxypyrimidine-5-yl)-4-(triisopropylsilyloxy)piperidine-2-one A mixture of 5-iodo-2-phenoxypyrimidine (500 mg), (R)-4-(triisopropylsilyloxy)piperidine-2-one (501 mg), copper(I) iodide (5.68 μl), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.053 mL), K3PO4 (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 obtain 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 at 80°C for 6 hours. The reaction mixture was poured into ice water, the precipitate was filtered off, and washed with water to obtain the target compound (80.7 g).

[0135] Reference example 59 Synthesis of 4-(3-fluorophenoxy)aniline A mixture of 1-fluoro-3-(4-nitrophenoxy)benzene (30 g), ammonium chloride (41.3 g), a mixture of EtOH (225 mL) and water (75 mL) was stirred at room temperature, and zinc powder (50.5 g) was added. The mixture was further stirred at 60 °C for 1 hour. The 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 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 toluene (50 mL) solution of 4-bromoaniline (7.66 g) and acrylic acid (3.05 mL) was stirred at 80 °C overnight. The reaction solution was concentrated, urea (5.35 g) and acetic acid (20 mL) were added, and the mixture was heated 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)2 (3.15 g), AcOK (3.04 g), PdCl2(dppf)DCM (0.422 g), and DMSO (30 mL) was stirred at 100 °C for 5 hours under an argon atmosphere. The reaction solution 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 obtain the target compound (0.82 g).

[0138] Reference Example 76 Synthesis of 1-[4-(3-hydroxyphenoxy)phenyl]dihydropyrimidine-2,4(1H,3H)-dione A solution of 1-[4-(3-methoxyphenoxy)phenyl]dihydropyrimidine-2,4(1H,3H)-dione (3.86 g) in AcOH (25 mL) was added with HBr (12.5 mL) 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, they were purified by silica gel column chromatography (DCM / MeOH), and the obtained solid was washed with MeOH to obtain 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), K3PO4 (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 solution, 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<( A solution of 2-chloro-5-nitropyridine (16.0 g) in DMF (80 mL) was added with sodium phenoxide (12.3 g) under ice-cooling and stirring, and stirred at room temperature overnight. The reaction solution 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 at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution 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 (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 at 70 °C overnight. Water was added to the reaction solution, and the resulting solid was collected by filtration and washed with water and EtOH to obtain the target compound (9.51 g).

[0143] 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 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 each prepared. 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] <00009;65> <0000;-70> ; 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-phenoxypyrimidine-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), PdCl2(dppf)DCM (0.137 g), K3PO4 (7.12 g), 1,4-dioxane (50 mL), and water (25 mL) was heated under a nitrogen atmosphere under reflux 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 obtain the target compound (4.42 g).

[0146] Example 4 Synthesis of 3-(2-(3-fluorophenoxy)pyrimidine-5-yl)-6-methoxypyridazine A mixture of 5-bromo-2-(3-fluorophenoxy)pyrimidine (2.234 g), (BPin)2 (2.63 g), PdCl2(dppf)DCM (0.282 g), AcOK (1.358 g), and 1,4-dioxane (20 mL) was heated under a nitrogen atmosphere under reflux for 2 hours. 3-chloro-6-methoxypyridazine (1.00 g), PdCl2(dppf)DCM (0.282 g), K3PO4 (2.94 g), and water (5 mL) were added to the reaction mixture and heated under a nitrogen atmosphere under reflux overnight. Water and AcOEt were added to the reaction mixture, and the mixture was filtered by 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-methoxypyridine-3-yl)-2-phenoxypyrimidine A mixture of 5-bromo-2-phenoxypyrimidine (1.0 g), 2-methoxy-5-pyridineboronic acid (0.914 g), PdCl2(dppf)DCM (0.163 g), K3PO4 (1.691 g), 1,4-dioxane (10 mL), and water (5 mL) was heated under a nitrogen atmosphere under reflux 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 obtain the target compound (821 mg).

[0148] Example 7 Synthesis of 2-phenoxy-5-(pyridine-3-yl)pyrimidine A mixture of 5-bromo-2-phenoxypyrimidine (1.0 g), 3-pyridineboronic acid (0.734 g), PdCl2(dppf)DCM (0.163 g), K3PO4 (1.691 g), 1,4-dioxane (10 mL), and water (5 mL) was heated under a nitrogen atmosphere under reflux 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 obtain the target compound (386 mg).

[0149] Example 11 Synthesis of 3-(2-phenoxypyrimidine-5-yl)pyridine 1-oxide A mixture of 2-phenoxy-5-(pyridin-3-yl)pyrimidine (749 mg), 77% hydrated m-CPBA (1616 mg), and DCM (15 mL) was stirred overnight at room temperature. Dimethyl sulfide (309 μl) was added to the reaction mixture and stirred for a while, then saturated aqueous NaHCO3 solution 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 obtain the target compound (118 mg).

[0150] Example 24 Synthesis of 6-(2-(3-fluorophenoxy)pyrimidine-5-yl)pyridazine-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), K3PO4 (1.11 g), PdCl2(dppf)DCM (68 mg), 1,4-dioxane (20 mL), and water (2 mL) was heated under a nitrogen atmosphere under reflux 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 obtain the target compound (100 mg).

[0151] Example 30 Synthesis of 6-(2-phenoxypyrimidine-5-yl)pyridazine-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), K3PO4 (1.11 g), PdCl2(dppf)DCM (65.2 mg), 1,4-dioxane (10 mL), and water (2 mL) was heated under a nitrogen atmosphere under reflux for 5.5 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, AcOEt / MeOH) to obtain the target compound (180 mg).

[0152] Example 36 Synthesis of 5-(2-phenoxypyrimidine-5-yl)pyridine-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), K3PO4 (1.0 g), PdCl2(dppf)DCM (43.7 mg), 1,4-dioxane (20 mL), and water (2 mL) was heated under a nitrogen atmosphere under reflux 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 obtain the target compound (161 mg).

[0153] Example 38 Synthesis of 3-(2-phenoxypyrimidine-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), K3PO4 (780 mg), PdCl2(dppf)DCM (29.3 mg), 1,4-dioxane (20 mL), and water (2 mL) was heated under a nitrogen atmosphere under reflux 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 obtain the target compound (107 mg).

[0154] Example 60 Synthesis of 3-(2-(2-fluorophenoxy)pyrimidine-5-yl)pyridine 1-oxide A mixture of 3-(2-(2-fluorophenoxy)pyrimidine-5-yl)pyridine (998 mg), 77% hydrated m-CPBA (1255 mg), and DCM (15 mL) was stirred overnight at room temperature. Dimethyl sulfide and saturated NaHCO3 aqueous solution 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 obtain the target compound (383 mg).

[0155] Example 63 Synthesis of 3-(2-(2,5-difluorophenoxy)pyrimidine-5-yl)-6-methoxypyridazine A mixture of 2,5-difluorophenol (132 mg), 3-methoxy-6-(2-(methylsulfonyl)pyrimidine-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 filtered off to obtain the target compound (187 mg).

[0156] Example 69 Synthesis of 2-(6-(2-phenoxypyrimidine-5-yl)pyridazine-3-yl)propan-2-ol Ethyl 6-(2-phenoxypyrimidine-5-yl)pyridazine-3-carboxylate (200 mg) was suspended in THF (3 mL), and under ice cooling, a THF solution of 0.96 M methylmagnesium bromide (1.6 mL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was poured into a saturated aqueous solution of 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 obtain the target compound (45 mg).

[0157] Example 72 Synthesis of (6-(2-phenoxypyrimidine-5-yl)pyridazine-3-yl)methanol A mixture of calcium chloride (551 mg), NaBH4 (117 mg), THF (2 mL), and EtOH (2 mL) was cooled on ice, and ethyl 6-(2-phenoxypyrimidine-5-yl)pyridazine-3-carboxylate (400 mg) was added and the mixture was stirred for 30 minutes. An 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 purified by silica gel column chromatography (Hexane / AcOEt), and the resulting solid was washed with IPE to obtain the target compound (81 mg).

[0158] Example 84 Synthesis of 5-(2-(2,5-difluorophenoxy)pyrimidine-5-yl)pyridine-2-amine A mixture of 5-(2-(methylsulfinyl)pyrimidine-5-yl)pyridine-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 concentrated. The residue was purified by basic silica gel chromatography (Hexane / AcOEt), and the resulting solid was washed with Hexane / IPE to obtain the target compound (44 mg).

[0159] Example 88 Synthesis of 5-(2-(m-tolyloxy)pyrimidine-5-yl)pyridine-2-amine A mixture of 5-(2-(dodecylsulfinyl)pyrimidine-5-yl)pyridine-2-amine (163 mg), m-cresol (0.10 mL), K2CO3 (483 mg), and DMF (10 mL) was stirred at 80°C under a nitrogen atmosphere for 4 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 concentrated. The residue was purified by basic silica gel chromatography (Hexane / AcOEt), and the resulting solid was washed with IPE to obtain the target compound (50 mg).

[0160] Example 91 Synthesis of 6-(2-phenoxypyrimidine-5-yl)pyridazine-3(2H)-one A mixture of 3-(benzyloxy)-6-(2-phenoxypyrimidine-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 obtain the target compound (1.38 g).

[0161] Example 92 Synthesis of 6-(2-phenoxypyrimidine-5-yl)-4,5-dihydropyridazine-3(2H)-one A mixture of 6-(2-phenoxypyrimidine-5-yl)pyridazine-3(2H)-one (1.08 g), zinc powder (0.53 g), and AcOH (10 mL) was heated under reflux for 1 hour. 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 concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH) and washed with EtOH to obtain the target compound (583 mg).

[0162] Example 94 Synthesis of 6-(2-(3-fluorophenoxy)pyrimidine-5-yl)-4,5-dihydropyridazine-3(2H)-one A mixture of 6-(2-(3-fluorophenoxy)pyrimidine-5-yl)pyridazin-3(2H)-one (1.02 g), zinc powder (0.56 g), and AcOH (10 mL) was heated under 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 concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt), and the resulting solid was washed with EtOH to obtain the target compound (587 mg).

[0163] Example 106 Synthesis of 5-(2-(m-tolyloxy)pyrimidine-5-yl)pyridine-2(1H)-one A mixture of 5-(6-methoxypyridine-3-yl)-2-(m-tolyloxy)pyrimidine (425 mg), sodium iodide (652 mg), chlorotrimethylsilane (0.552 mL), and MeCN (5 mL) was stirred overnight at room temperature. 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 the target compound (204 mg) was crystallized from EtOH.

[0164] Example 114 Synthesis of 4-(2-phenoxypyrimidine-5-yl)pyridazine-3(2H)-one A mixture of 4-(2-phenoxypyrimidine-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 NaHCO3 aqueous 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 obtain the target compound (672 mg).

[0165] Example 118 Synthesis of 4-(2-phenoxypyrimidine-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), K3PO4 (712 mg), PdCl2(dppf)DCM (13.70 mg), 1,4-dioxane (5 mL), and water (2.5 mL) was heated under a nitrogen atmosphere under reflux 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 then concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt), and the resulting solid was washed with IPE to obtain the target compound (413 mg).

[0166] Example 119 Synthesis of 6-(2-phenoxypyrimidine-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), PdCl2(dppf)DCM (110 mg), K3PO4 (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 and filtered by 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-phenoxypyrimidine-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-chloroimidazo[1,2-b]pyridazine (227 mg), PdCl2(dppf)DCM (110 mg), K3PO4 (570 mg), 1,4-dioxane (4 mL), and water (2 mL) was stirred at 95°C for 3 hours under a nitrogen atmosphere. AcOEt and water were added to the reaction mixture and filtered by 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-phenoxypyrimidine-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), PdCl2(dppf)DCM (110 mg), K3PO4 (570 mg), 1,4-dioxane (4 mL), and water (2 mL) was stirred at 90°C for 3 hours under a nitrogen atmosphere. AcOEt and water were added to the reaction mixture and filtered by Celite. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in THF (5 mL), 1N-TBAF (1.34 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (DCM / AcOEt) to obtain the target compound (325 mg).

[0169] Example 139 Synthesis of 4-(2-phenoxypyrimidine-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), K3PO4 (427 mg), PdCl2(dppf)DCM (6.56 mg), 1,4-dioxane (4 mL), and water (2 mL) was heated under a nitrogen atmosphere under reflux 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 then concentrated. The residue was purified by silica gel column chromatography (MeOH / DCM), and the resulting solid was recrystallized from AcOEt to obtain the target compound (167 mg).

[0170] Example 163 Synthesis of 6-(2-(3-chlorophenoxy)pyrimidine-5-yl)imidazo[1,2-a]pyridine A mixture of 6-(2-(dodecylsulfonyl)pyrimidine-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-phenoxypyrimidine-5-yl)-1H-pyrrolo[3,2-b]pyridine-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]pyridine-2-one (200 mg), PdCl2(dppf)DCM (38.3 mg), K3PO4 (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 and filtered by 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 (98 mg).

[0172] Example 173 Synthesis of 6-(2-phenoxypyrimidine-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), PdCl2(dppf)DCM (45.2 mg), K3PO4 (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 and filtered by Celite. The filtrate was separated, 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 (250 mg).

[0173] Example 198 Synthesis of 5-methyl-6-(2-phenoxypyrimidine-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-methylimidazo[1,2-a]pyridine (257 mg), PdCl2(dppf)DCM (45.2 mg), K3PO4 (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 and filtered by 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 oily substance was dissolved in EtOH, 3 mL of 1N-HCl EtOH solution was added and stirred, and 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-phenoxypyrimidine-5-yl)tetrahydropyrimidine-2(1H)-one A solution of 1-(3-chloropropyl)-3-(2-phenoxypyrimidine-5-yl)urea (1.25 g) in DMF (12 mL) was stirred under ice-cold conditions, and 60% NaH (0.148 g) was added. 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)pyrimidine-5-yl)tetrahydropyrimidine-2(1H)-one 1.00 g of 2-(3-fluorophenoxy)pyrimidine-5-amine was dissolved in 10 mL of THF and 10 mL of DMF, and 0.800 mL of 3-chloropropyl isocyanate was added. The mixture was stirred at 50°C for 3 hours. Water was added to the reaction mixture, and the precipitated crystals were filtered to obtain an intermediate (1.41 g). The intermediate was dissolved in 14 mL of DMF, and 0.214 g of 60% NaH 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-(piperidine-1-yl)pyrimidine A mixture of 5-bromo-2-phenoxypyrimidine (500 mg), piperidine (0.256 mL), Pd(OAc)2 (447 mg), tBu3P·HBF4 (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 and filtered by 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-phenoxypyrimidine-5-yl)piperidine-4-ol 2-Phenoxy-5-(4-(triisopropylsilyloxy)piperidine-1-yl)pyrimidine (240 mg) was mixed with TBAF (0.56 mL) in THF (6 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (Hexane / AcOEt). The target compound (110 mg) was crystallized from Hexane / AcOEt.

[0178] Example 229 Synthesis of 4-(2-phenoxypyrimidine-5-yl)morpholin-3-one A mixture of 5-iodo-2-phenoxypyrimidine (500 mg), 3-ketomorpholine (254 mg), copper(I) iodide (31.9 mg), K3PO4 (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-phenoxypyrimidine-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 at room temperature under a hydrogen atmosphere 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 obtain the target compound (2.5 g) as a white solid.

[0180] Example 240 Synthesis of 6-(2-phenoxypyrimidine-5-yl)benzo[d]thiazole-2-amine 600 mg of 4-(2-phenoxypyrimidine-5-yl)aniline and 382 mg of ammonium thiocyanate were added to a 6 mL solution of acetic acid. Under ice-cold stirring, a 2 mL solution of acetic acid containing 0.140 mL of bromine was added. After 1 hour, the reaction mixture was poured into ice water, and 28% aqueous ammonia was added until the reaction system 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-phenoxypyrimidine-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), PdCl2(dppf)DCM (110 mg), K3PO4 (570 mg), 1,4-dioxane (4 mL), and water (2 mL) was stirred at 95°C for 3 hours under a nitrogen atmosphere. AcOEt and water were added to the reaction mixture and filtered by 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 oily substance was dissolved in ethanol and an ethanol solution of oxalic acid (80 mg) (1 mL) was added. The precipitate was filtered and dried to obtain the target compound (250 mg).

[0182] Example 262 Synthesis of 5-(2-phenoxypyrimidine-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), PdCl2(dppf)DCM (110 mg), K3PO4 (570 mg), 1,4-dioxane (4 mL), and water (2 mL) was stirred at 80°C under a nitrogen atmosphere for 3 hours. AcOEt and water were added to the reaction mixture and filtered by Celite. The filtrate was separated, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in THF (10 mL), to which TBAF (1.342 mL) was added and stirred at room temperature for 1 hour. After concentrating the reaction mixture, it was purified by silica gel column chromatography (Hexane / AcOEt) to obtain 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 overnight at 80°C. The reaction mixture was concentrated, urea (4.43 g) and AcOH (20 mL) were added, and the mixture was heated under reflux for 3 hours. Water was added, and the precipitate was filtered off. 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), K3PO4 (0.252 g), PdCl2(dppf)DCM (6.46 mg), DME (6.6 mL), and water (3.3 mL) was heated under a nitrogen atmosphere under reflux 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 A solution of 1-(4-(3-fluorophenoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg) in DMF (5 mL) was stirred at 0°C, and 60% NaH (32.0 mg) was added and the mixture was stirred for 30 minutes. Methyl iodide (0.046 mL) was added at 0°C and stirred, 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 a further 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 solution, and water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (Hexane / AcOEt), and crystallization was carried out with the addition of EtOH. The mixture was washed with EtOH to obtain the target compound (79 mg).

[0187] Example 321 Synthesis of 1-[4-(6-fluoropyridine-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 filtered off. The solid was purified by silica gel column chromatography (DCM / MeOH), and the resulting solid was washed with EtOH to obtain 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 overnight at room temperature. 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(Ph3P)4 (57.8 mg), Na2CO3 (212 mg), DME (5 mL), and water (1 mL) was heated under a nitrogen atmosphere under reflux for 12 hours. AcOEt and anhydrous magnesium sulfate were added to the reaction mixture, and the mixture was filtered by Celite. The filtrate was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH). The resulting solid was washed with EtOH to obtain 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 under reflux for 13 hours. Another 0.34 mL of crotonic acid was added, and the mixture was heated under reflux for a further 6 hours. The reaction mixture was concentrated, acetic acid (5 mL), and urea (0.324 g) were added, and the mixture was heated under reflux for 17 hours. Concentrated hydrochloric acid (0.23 mL) was added to the reaction mixture, and the mixture was heated under 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 NaHCO3 aqueous solution, and brine, dried over anhydrous magnesium sulfate, and then concentrated. EtOH (3 mL) and IPE (3 mL) were added to the residue, and crystallization occurred. The solid was filtered 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 heated under reflux for 5 hours. After adding water (20 mL) to the reaction mixture, saturated NaHCO3 aqueous solution was added to neutralize it. After extraction with AcOEt, the mixture was washed with saturated NaCl aqueous solution, 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 heated under reflux for 3 hours. Water and AcOEt were added to the reaction mixture and separated. The organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH), and EtOH (2 mL) was added to crystallize it. The solid was filtered 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 a further 1.5 hours. Water (15 mL) was added to the reaction mixture, and the precipitated solid was filtered off and washed with water and EtOH to obtain the target compound (35 mg).

[0194] Example 346 Synthesis of 1-(6-phenoxypyridazine-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 overnight at 130°C. 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-phenoxypyridazine-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 obtain the target compound (122 mg).

[0196] Examples 2, 3, 5, 8-10, 12-23, 25-29, 31-35, 37, 39-59, 61, 62, 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 are similarly represented in Examples 2, 3, 5, 8-10, 12-23, 25-29, 31-35, 37, 39-59, 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 manufactured, respectively. The structural formulas and physical properties of the compounds in 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] [Example Test] The following shows the results of pharmacological tests on representative compounds of the present invention and explains their pharmacological effects; however, the present invention is not limited to these test examples.

[0199] [Test Example 1] A model of auditory epileptic seizures The animal models used in this study are clinically predictive and represent phenotypes of partial seizures (including secondary generalization) and generalized tonic-clonic seizures. This study was conducted in accordance with 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 Tables 3-1 to 3-3 below were used as the test compounds. The test compound was suspended in 5% gum arabic / distilled water (w / v) and force-administered to male and female DBA / 2 mice (SLC Japan, 3 weeks old, 8 mice per group) at doses of 3, 5, 10, or 30 mg / kg. One hour later, the mice were placed in a transparent acrylic cylinder with a diameter of 23 cm and a height of 30 cm. After 30 seconds of acclimatization, they were exposed to 12.6 kHz, 100-110 dB sound stimuli for 1 minute or until a tonic seizure occurred. The severity of seizures was categorized as follows: 0: no seizure, 1: wild running, 2: clonic seizure, 3: tonic seizure, 4: respiratory arrest. The highest score among these categories 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] Rotor Rod Test This test evaluates the synergistic effects of the compound on motor coordination. Male ICR mice (Nippon SLC Co., Ltd., 5-6 weeks old, 8 mice per group) were placed on a rotorod device (Muromachi Machinery Co., Ltd.) and trained to walk for 2 minutes without falling from a rod rotating at a speed of 15 revolutions / minute. The test compound was suspended in 5% gum arabic / distilled water (w / v) and force-administered orally to the trained mice at doses of 3, 5, 10, or 30 mg / kg. One hour later, the mice were placed on the same rotorod device as above and observed for 200 seconds to see if they could walk in time with the rotation of the rod, which accelerated from 4 revolutions / minute to 40 revolutions / minute over 5 minutes. The fall latency was measured. The relative fall latency of the compound-administered group was calculated to the average fall latency of the solvent-administered group. The results are shown in Tables 4-1 and 4-2. Furthermore, a score of "A" indicates that the degree of coordination disorder was 25% or less, while a score of "B" indicates that it was greater than 25% but 50% or less. [Table 4-1] [Table 4-2]

[0201] [Test Example 3] Maximum Electric Shock Convulsion Model This study evaluates the anticonvulsant effect of the compound. The animal models used in this study are those exhibiting generalized tonic-clonic seizures and secondary generalized partial seizures. This study was conducted in accordance with the report by Hill AJ et al. (Br J Pharmacol. 2012 Dec;167(8):1629-42. Cannabidivarin is anticonvulsant in mouse and rat. Hill AJ, et al.). The test compound was suspended in 5% gum arabic / distilled water (w / v) and force-administered to male ICR mice (Nippon SLC Co., Ltd., 5-6 weeks old, 8 mice per group) at doses of 5 or 30 mg / kg. One hour later, electrical stimulation (100 Hz, 30 mA, 0.2 seconds) was applied using a small animal electroconvulsive stimulator (UgoBasile) via electrodes attached to both auricles, and the occurrence of induced tonic extension spasms of the hind limbs was observed. In the above study, tonic extension spasms of the hind limbs were induced in all cases in the solvent administration group, whereas the occurrence of spasms was suppressed in the test compound administration group.

[0202] [Test Example 4] Subcutaneous injection pentylenetetrazol model This study, like Study Example 3, evaluates the anticonvulsant effect of the compound. The animal model used in this study differs from the phenotype in Study Example 3, exhibiting generalized absence seizures and myoclonic seizures. The test compound was suspended in 5% gum arabic / distilled water (w / v) and administered orally to male ICR mice (SLC Japan, 5-6 weeks old, 10 mice per group) at doses of 5 or 30 mg / kg. One hour later, 85 mg / kg of pentylenetetrazol dissolved in physiological saline was administered subcutaneously, and the presence or absence of clonic seizures was observed for 30 minutes. In the above study, clonic seizures were induced in all cases in the solvent administration group, whereas the occurrence of seizures was suppressed in the test compound administration group.

[0203] As described above, the compounds of the present invention exhibit anticonvulsant activity in multiple animal models used to evaluate antiepileptic drugs, making them useful as antiepileptic drugs with a broad therapeutic spectrum (preventive and / or therapeutic agents for seizures in diseases involving epileptic 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 agents for diseases involving epileptic 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 Alternatively, C may be substituted with a halogen. 1-6 It is alkyl; Ring A is benzene, pyridine, indole, or indazole; Ring B is a pyrimidine, pyridazine, pyridine, pyrazole, benzene, or naphthalene, where, (i) If ring B is a pyrimidine, ring C is selected from the following unsaturated rings and their oxides and dioxides (except pyrimidine-2,4-dione and dihydropyrimidine-2,4-dione) and rings in which some or all of the unsaturated bonds in those rings are reduced by 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) Monocyclic unsaturated hydrocarbon rings with 3 to 8 members; (ii) If ring B is pyridazine, pyridine, pyrazole, benzene, or naphthalene, then ring C is pyrimidine-2,4-dione or dihydropyrimidine-2,4-dione; R 1 C may be a halogen or a halogen-substituted C. 1-6 May be substituted with alkyl or halogen -OC 1-6 Alkyl, -CN, or -SF 5 And; R 2 is halogen, C 1-6 Alkyl, -OC 1-6 It is alkyl; R 3 is halogen, halogen or -O-C 1-6 alkyl optionally substituted by C 1-6 alkyl, -O-C 1-6 alkyl optionally substituted by halogen, -C 1-6 alkyl-OH, -OH, -CN, -CONH 2 or -NH 2 and; L is directly bonded, C 1-6 Alkylene, -O- or -S-; k is 0, 1, or 2, and if k is 2, R 1 Each of these independently represents the same or different substituent; m is 0, 1, or 2, and if m is 2, R 2 Each of these independently represents the same or different substituent; n is 0, 1, or 2, and if n is 2, R 3 Each of these independently represents the same or different substituent; A pharmaceutical product containing a compound represented by or a salt thereof.

2. In equation I, D is And; Ring A is benzene or pyridine; Ring B is a 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 those rings are reduced by hydrogen; Pyridine, Pyridazine, Pyrimidine, Indole, Pyrrolopyridine, Indazole, Benzimidazole, Pyrazolopyridine, Imidazopyridine, Imidazopyrazine, Imidazopyridazine, Triazolopyridine, Pyrazolopyrimidine, Imidazopyrimidine, Triazolopyrimidine, Quinoline, Isoquinoline, Naphthyridine, Kinazolin, Quinoxaline, Benzodioxol, oxazine, Oxazepine, Benzothiazole, benzene; R 1 C may be a halogen or a halogen-substituted C. 1-6 May be substituted with alkyl or halogen -OC 1-6 Alkyl or -CN; R 2 is, -OC 1-6 It is alkyl; R 3 is halogen, halogen or -OC 1-6 C may be substituted with alkyl. 1-6 May be substituted with alkyl or halogen -OC 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 if k is 2, R 1 Each of these independently represents the same or different substituent; m is either 0 or 1; n is 0, 1, or 2, and if n is 2, R 3 The pharmaceutical product according to claim 1, wherein each of the substituents independently represents the same or different substituents.

3. In formula I, ring C is selected from the following unsaturated rings and their oxides and rings in which some or all of the unsaturated bonds in the ring are reduced by hydrogen; Pyridine, Pyridazine, Pyrrolopyridine, Indazole, Pyrazolopyridine, Imidazopyridine, Imidazopyrazine, Imidazopyridazine, Pyrazolopyrimidine, Triazolopyrimidine, Quinoline, Isoquinoline, Naphthyridine, Quinoxaline, benzene; R 1 C may be a halogen or a halogen-substituted C 1-6 It is alkyl; R 3 C may be substituted with a halogen. 1-6 May be substituted with alkyl or halogen -OC 1-6 Alkyl, -OH, -CONH 2 or -NH 2 And; L is -O-; k and n are either 0 or 1; The pharmaceutical product according to claim 2, wherein m is 0.

4. In formula I, ring C is selected from the following unsaturated rings and their oxides and rings in which some or all of the unsaturated bonds in the ring are reduced by hydrogen; Pyridine, Pyridazine, Pyrazolopyridine, Imidazopyridine; R 3 is -OH or -NH 2 And; L is -O-; k and m are 0; The pharmaceutical product according to claim 3, wherein n is 0 or 1.

5. In equation I, D is Alternatively, C may be substituted with a halogen. 1-6 It 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 C may be a halogen or a halogen-substituted C. 1-6 May be substituted with alkyl or halogen -OC 1-6 Alkyl, -CN, or -SF 5 And; R 2 is halogen, C 1-6 Alkyl, -OC 1-6 It is alkyl; R 3 C 1-6 It is alkyl; L is directly bonded, C 1-6 Alkylene, -O- or -S-; k is 0, 1, or 2, and if k is 2, R 1 Each of these independently represents the same or different substituent; m is 0, 1, or 2, and if m is 2, R 2 Each of these independently represents the same or different substituent; n is 0, 1, or 2, and if n is 2, R 3 The pharmaceutical product according to claim 1, wherein each of the substituents independently represents 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 It is a halogen; L is -O-; k is either 0 or 1; The pharmaceutical product according to claim 5, wherein m and n are 0.

7. A pharmaceutical product comprising a compound selected from the group consisting of the following compounds, or a salt thereof.

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

9. A pharmaceutical composition comprising a 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. An agent for the treatment, prevention, and / or diagnosis of seizures in diseases involving epileptic or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures, and status epilepticus (status epilepticus)), comprising a compound or salt thereof according to any one of claims 1 to 8.

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

12. Use of a 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 involving epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile seizures and status epilepticus).

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