Heterocyclic compound

Abstract

This invention provides novel heterocyclic compounds and their salts represented by formula [I], wherein the symbols are as defined in the specification, and these heterocyclic compounds and their salts are used for the treatment, prevention, and / or diagnosis of seizures or convulsive episodes involving epileptic seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile epilepsy, and status epilepticus), along with their medical uses. [Formula I]

Description

Technical Field

[0001] This invention relates to a heterocyclic compound and its salt. It also relates to a medicament having a heterocyclic compound or its salt as an active ingredient for the treatment, prevention, and / or diagnosis of seizures in diseases involving epileptic seizures or convulsive seizures. Prior Technology

[0002] Epilepsy affects approximately 1% of the population. It is considered a common neurological disorder, with about one million patients in Japan and a lifetime prevalence of 3% to 4%, with an estimated tens of thousands of new cases each year. About 70% of these patients can control their seizures with existing antiepileptic drugs and lead their daily lives without problems; however, the remaining 30% of epilepsy patients cannot adequately control their seizures and fear that a seizure will occur without warning. Most existing antiepileptic drugs aim to regulate the excitation / inhibition imbalance in neural activity by inhibiting excessive excitation and oversynchronization of neuronal activity; however, doses higher than optimal can disrupt the balance of neuronal activity and induce motor dysfunction and seizures.

[0003] PTL 1 discloses compounds containing pyrimidines in their structure, as compounds for the treatment of diseases or conditions (including epilepsy) that require modulators of Kv3.1 and / or Kv3.2 channels. PTL 2 and 3 revealed compounds with a pyrimidine skeleton as kynurenine-3-monooxygenase inhibitors for the treatment of neurodegenerative diseases, including epilepsy. PTL 4 discloses compounds containing phenoxypyrimidine or pyridoxypyrimidine structures as antagonists and / or inverse agonists of cannabinoid-1 receptors for the treatment of diseases including epilepsy. Reference List Patent documents

[0004] [PLT1] WO 2011 / 069951 [PLT2] WO 2013 / 016488 [PLT3] WO 2011 / 091153 [PLT4] WO 2004 / 029204 Summary of the Invention

[0005] The object of this invention is to provide novel pyrimidine compounds or salts thereof for the treatment, prevention and / or diagnosis of seizures in diseases involving epileptic seizures or convulsive seizures, and their medical uses. Another object of the present invention is to provide a drug with a broad therapeutic spectrum compared to existing antiepileptic drugs, thereby maintaining the balance of neuronal excitation / inhibition even at doses that completely suppress epileptic seizures. Solution to the problem

[0006] As a result of extensive research aimed at solving the aforementioned problems, the inventors successfully synthesized novel pyrimidine compounds with a broad therapeutic spectrum compared to existing antiepileptic drugs. This invention is based on these findings.

[0007] In other words, the present invention includes the following embodiments. [1] A compound represented by formula I: [Formula I] in D series Or, depending on the need, C1-6 alkyl groups that can be halogenated; A-ring benzene, pyridine, indole, or indazole; Cyclic B-type pyrimidines, pyridoxines pyridine, pyrazole, benzene or naphthalene, in, (i) When ring B is pyrimidine, ring C is selected from the group consisting of: the following unsaturated rings and their oxides and dioxides (conditionally excluding pyrimidine-2,4-diones and dihydropyrimidine-2,4-diones), and those in which some or all of the unsaturated bonds in these rings are reduced by hydrogen: (a) Unsaturated 3- to 8-membered monocyclic heterocycles containing only 1 to 4 nitrogen atoms as heteroatoms constituting the ring. (b) Unsaturated 7- to 15-membered bicyclic or tricyclic heterocycles containing only 1 to 5 nitrogen atoms as heteroatoms constituting the ring. (c) Unsaturated 7- to 12-membered bicyclic heterocycles containing only 1 to 3 oxygen atoms as heteroatoms constituting the ring. (d) Unsaturated 3- to 8-membered monocyclic heterocycles containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms as heteroatoms constituting the ring. (e) Unsaturated 7- to 12-membered bicyclic heterocycles containing one or two sulfur atoms and one to three nitrogen atoms as heteroatoms constituting the ring, and (f) Unsaturated 3- to 8-membered monocyclic hydrocarbon rings; (ii) When ring B system When pyridine, pyrazole, benzene or naphthalene are present, the cyclic C-type is pyrimidine-2,4-dione or dihydropyrimidine-2,4-dione; R1-series halogens, C1-6 alkyl groups to be halogenated as needed, -O-C1-6 alkyl groups to be halogenated as needed, -CN or -SF5; R2-series halogens, C1-6 alkyl groups, or -O-C1-6 alkyl groups; R3 halogens, C1-6 alkyl groups to be halogenated as needed, or -O-C1-6 alkyl groups, -O-C1-6 alkyl groups to be halogenated as needed, -C1-6 alkyl groups -OH, -OH, -CN, -CONH2 or -NH2; L-series bonds, C1-6 alkyl groups, -O- or -S-; k-system 0, 1, or 2, and when k-system 2, each R1 independently represents the same or different substituents; m-system 0, 1, or 2, and when m-system 2, each R2 independently represents the same or different substituents; and The n-system can be 0, 1, or 2, and when the n-system is 2, each R3 independently represents the same or different substituents; Or its salt. [2] According to the compound described in [1], wherein, in formula I, D is a series ; A-ring benzene or pyridine; Cyclic β-pyrimidines; Ring C is selected from the group consisting of: the following unsaturated rings and their oxides and dioxides (excluding pyrimidine-2,4-diones and dihydropyrimidine-2,4-diones), and those in which some or all of the unsaturated bonds in these rings are reduced by hydrogen: Pyridine despair , Pyrimidine Indole, Pyrrolopyridine Indazole, Benzimidazole, Pyrazolopyridine, Imidazolidine, Imidazolium , Imidazolidinedazole , Triazopyridine, Pyrazolopyrimidine, Imidazorprine, Triazoropyrimidine, Quinoline, Isoquinoline, Oral-Nystatin Quinazoline, Quinine porphyrin, benzodioxole , Oxygen and nitrogen phosphate benzothiazole, and benzene; R1-series halogens, C1-6 alkyl groups to be halogenated as needed, -O-C1-6 alkyl groups or -CN groups to be halogenated as needed; R2-O-C1-6 alkyl; R3 halogens, C1-6 alkyl groups to be halogenated as needed, or -O-C1-6 alkyl groups, -O-C1-6 alkyl groups to be halogenated as needed, -C1-6 alkyl groups -OH, -OH, -CN, -CONH2 or -NH2; L-series-O-; and k-system 0, 1, or 2, and when k-system 2, each R1 independently represents the same or different substituents; m is either 0 or 1; The n-system can be 0, 1, or 2, and when the n-system is 2, each R3 independently represents the same or different substituents; Or its salt. [3] According to the compound described in [2], wherein, in formula I, ring C is selected from the group consisting of: the following unsaturated rings and their oxides, and those in which some or all of the unsaturated bonds in such rings are reduced by hydrogen: Pyridine despair , Pyrrolopyridine Indazole, Pyrazolopyridine, Imidazolidine, Imidazolium , Imidazolidinedazole , Pyrazolopyrimidine, Triazoropyrimidine, Quinoline, Isoquinoline, Oral-Nystatin Quinine porphyrin, and benzene; R1 series halogens or C1-6 alkyl groups that may be halogenated as needed; The R3 series consists of C1-6 alkyl groups that need to be halogenated, -O-C1-6 alkyl groups, -OH, -CONH2, or -NH2 that need to be halogenated. L-series-O-; k and n are either 0 or 1; and m series 0; Or its salt. [4] According to the compound described in [3], wherein, in formula I, ring C is selected from the group consisting of: the following unsaturated rings and their oxides, and those in which some or all of the unsaturated bonds in such rings are reduced by hydrogen: Pyridine despair , Pyrazolopyridine, and Imidazolidine; R3 series -OH or -NH2; L-series-O-; k and m are related to 0; and n is either 0 or 1; Or its salt. [5] According to the compound described in [1], wherein, in formula I, D is a series of Or, depending on the need, C1-6 alkyl groups that can be halogenated; A-ring benzene or pyridine; Ring B series pyridine, pyrazole, benzene, or naphthalene; Cyclic C-type pyrimidine-2,4-dione or dihydropyrimidine-2,4-dione; R1-series halogens, C1-6 alkyl groups to be halogenated as needed, -O-C1-6 alkyl groups to be halogenated as needed, -CN or -SF5; R2-series halogens, C1-6 alkyl groups, or -O-C1-6 alkyl groups; R3 series C1-6 alkyl; L-series bonds, C1-6 alkyl groups, -O- or -S-; k-system 0, 1, or 2, and when k-system 2, each R1 independently represents the same or different substituents; m-system 0, 1, or 2, and when m-system 2, each R2 independently represents the same or different substituents; and The n-system can be 0, 1, or 2, and when the n-system is 2, each R3 independently represents the same or different substituents; Or its salt. [6] According to the compound or its salt described in [5], In formula I, cyclic A-type benzene; BO-type benzene, pyridine, or terpinen ; Cyclic C-system dihydropyrimidine-2,4-dione; R1 series halogens; L-series-O-; k is either 0 or 1; and m and n are related to 0; Or its salt. [7] A compound selected from the group consisting of the following compounds: ; Or its salt. [8] The compounds according to [7] are selected from the group consisting of the following compounds: Or its salt. [9] A pharmaceutical composition comprising a compound or a salt thereof as an active ingredient according to any one of [1] to [8], and a pharmaceutically acceptable carrier or excipient.

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

[11] According to the therapeutic, preventive and / or diagnostic agents described in

[10] , the epileptic seizures are selected from focal onset seizures (also known as partial seizures) with motor onset (including automatism, atonic seizures, clonic seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures and tonic seizures) and non-motor onset (including autonomic seizures, behavioral arrest seizures, cognitive seizures, emotional seizures and sensory seizures) and focal to bilateral tonic-clonic seizures (secondary generalization of partial seizures). Seizures include generalized seizures, including motor seizures (including intermodal tonic seizures, intermodal 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); and seizures of unknown origin, including motor seizures (including intermodal tonic seizures and epileptic spasms) and non-motor seizures (including behaviorally inhibited seizures).

[12] According to the therapeutic, preventive and / or diagnostic agents described in

[10] , wherein the diseases involving epileptic seizures or convulsive seizures are selected from Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (epilepsia nutans), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, hemiconvulsion-hemiplegia-epilepsy syndrome, and mesial temporal epilepsy. Epilepsy includes conditions such as lobe epilepsy, epilepsy with structural / metabolic causes (e.g., post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy related to cerebrovascular disorders, epilepsy related to brain tumors, epilepsy related to neurodegenerative diseases, epilepsy related to autoimmune disorders, etc.), congenital malformations, congenital metabolic abnormalities (e.g., phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (e.g., Rett's syndrome, Angelman's syndrome, 5p syndrome, 4p syndrome, Down's syndrome, etc.).

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

[14] According to the composition described in

[13] , the epileptic seizures are selected from focal seizures (also known as partial seizures) with motor onset (including automatisms, atonic seizures, intergenerational seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor onset (including autonomic epilepsy, behavioral inhibition seizures, cognitive impairment seizures, emotional seizures, and sensory seizures) and focal to bilateral tonic intergenerational seizures (secondary spread of partial seizures); including motor seizures (including tonic intergenerational seizures, intergenerational 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, and myoclonic absence seizures). Generalized seizures including myoclonic seizures and eyelid myoclonic seizures; and seizures of unknown origin including motor seizures (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral inhibition seizures).

[15] According to the composition described in

[13] , the diseases involving epileptic seizures or convulsive seizures are selected from Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (epilepsia nutans), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, hemiconvulsion-hemiplegia-epilepsy syndrome, and mesial temporal lobe epilepsy. Epilepsy, including epilepsy with structural / metabolic causes (such as post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy related to cerebrovascular disorders, epilepsy related to brain tumors, epilepsy related to neurodegenerative diseases, epilepsy related to autoimmune disorders, etc.), congenital malformations, congenital metabolic abnormalities (such as phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (such as Rett's syndrome, Angelman's syndrome, 5p syndrome, 4p syndrome, Down's syndrome, etc.).

[16] A method for treating, preventing and / or diagnosing the onset of a disease involving seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile epilepsy and status epilepticus), wherein the method comprises administering to a human in need an effective amount of a compound or a salt thereof according to any one of [1] to [8].

[17] According to the method described in

[16] , the epileptic seizures are selected from focal seizures (also known as partial seizures) with motor onset (including automatisms, atonic seizures, intergenerational seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor onset (including autonomic epilepsy, behavioral inhibition seizures, cognitive impairment seizures, emotional seizures, and sensory seizures), and focal to bilateral tonic intergenerational seizures (secondary spread of partial seizures); including motor seizures (including tonic intergenerational seizures, intergenerational 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, and myoclonic absence seizures). Generalized seizures including myoclonic seizures and eyelid myoclonic seizures; and seizures of unknown origin including motor seizures (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral inhibition seizures).

[18] According to the method described in

[16] , the diseases involving epileptic seizures or convulsive seizures are selected from Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (epilepsia nutans), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, hemiconvulsion-hemiplegia-epilepsy syndrome, and mesial temporal lobe epilepsy. Epilepsy, including epilepsy with structural / metabolic causes (such as post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy related to cerebrovascular disorders, epilepsy related to brain tumors, epilepsy related to neurodegenerative diseases, epilepsy related to autoimmune disorders, etc.), congenital malformations, congenital metabolic abnormalities (such as phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (such as Rett's syndrome, Angelman's syndrome, 5p syndrome, 4p syndrome, Down's syndrome, etc.).

[19] The compound or salt thereof according to any one of [1] to [8], the compound or salt thereof being used to treat, prevent and / or diagnose the onset of a disease involving seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile epilepsy and status epilepticus).

[20] According to the compound or salt thereof described in

[19] , wherein the epileptic seizures are selected from focal seizures (also known as partial seizures) with motor onset (including automatisms, atonic seizures, intergenerational seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures and tonic seizures) and non-motor onset (including autonomic epilepsy, behavioral inhibition seizures, cognitive impairment seizures, emotional seizures and sensory seizures) and non-motor onset (including autonomic symptoms epilepsy, behavioral inhibition seizures, cognitive impairment seizures, emotional seizures and sensory seizures); and focal to bilateral tonic intergenerational seizures (secondary spread of partial seizures); including generalized seizures with motor onset (including tonic intergenerational seizures, intergenerational seizures, tonic seizures, myoclonic seizures, myoclonic tonic intergenerational seizures, myoclonic atonic seizures, atonic seizures and epileptic spasms) and non-motor onset (including typical absence seizures, atypical absence seizures, myoclonic absence seizures and eyelid myoclonic seizures); and seizures with unknown onset (including tonic intergenerational seizures and epileptic spasms) and non-motor onset (including behavioral inhibition seizures).

[21] According to the compound or salt thereof described in

[19] , wherein the disease involving epileptic seizures or convulsive seizures is selected from Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (epilepsia nutans), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, hemiconvulsion-hemiplegia-epilepsy syndrome, and mesial temporal lobe epilepsy. Epilepsy, including epilepsy with structural / metabolic causes (such as post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy related to cerebrovascular disorders, epilepsy related to brain tumors, epilepsy related to neurodegenerative diseases, epilepsy related to autoimmune disorders, etc.), congenital malformations, congenital metabolic abnormalities (such as phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (such as Rett's syndrome, Angelman's syndrome, 5p syndrome, 4p syndrome, Down's syndrome, etc.).

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

[23] According to the use described in

[22] , the epileptic seizures are selected from focal seizures (also known as partial seizures) with motor onset (including automatisms, atonic seizures, intergenerational seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor onset (including autonomic epilepsy, behavioral inhibition seizures, cognitive impairment seizures, emotional seizures, and sensory seizures), and focal to bilateral tonic intergenerational seizures (secondary spread of partial seizures); including motor seizures (including tonic intergenerational seizures, intergenerational 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, and myoclonic absence seizures). Generalized seizures including myoclonic seizures and eyelid myoclonic seizures; and seizures of unknown origin including motor seizures (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral inhibition seizures).

[24] According to the use described in

[22] , the diseases involving epileptic seizures or convulsive seizures are selected from Dravet syndrome, Lennox-Gastaut syndrome, West syndrome (epilepsia nutans), Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome, hemiconvulsion-hemiplegia-epilepsy syndrome, and mesial temporal lobe epilepsy. Epilepsy, including epilepsy with structural / metabolic causes (such as post-stroke epilepsy, traumatic epilepsy, infectious epilepsy, epilepsy related to cerebrovascular disorders, epilepsy related to brain tumors, epilepsy related to neurodegenerative diseases, epilepsy related to autoimmune disorders, etc.), congenital malformations, congenital metabolic abnormalities (such as phenylketonuria, mitochondrial diseases, lysosomal diseases, Sturge-Weber syndrome, etc.), and congenital genetic abnormalities (such as Rett's syndrome, Angelman's syndrome, 5p syndrome, 4p syndrome, Down's syndrome, etc.).

[0008] The compounds and their salts of the present invention are highly effective in treating, preventing, and / or diagnosing diseases involving epileptic seizures, convulsive seizures, etc. Furthermore, the compounds and their salts of the present invention, when used as active ingredients in pharmaceuticals, possess excellent characteristics, such as fewer side effects, tolerability, and stability (storage stability, metabolic stability, etc.). Moreover, compared to existing antiepileptic drugs, the compounds and their salts of the present invention have a broad therapeutic spectrum. Simple Explanation of the Diagram

[0009] none Implementation

[0010] The phrases and terms used in this specification are explained in detail below. "C1-6 alkyl" refers to C1-6 straight-chain or branched alkyl groups, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, etc. It also includes C1-6 alkyl groups having one to three hydrogen atoms substituted with deuterium atoms.

[0011] "Halogen" refers to fluorine, chlorine, bromine, or iodine. Fluorine, chlorine, or bromine are preferred, and fluorine or chlorine are even more preferred.

[0012] "C1-6 alkyl groups to be halogenated as desired" refers to straight-chain or branched alkyl groups having 1 to 6 carbon atoms (C1-6) that are to be substituted with 1 to 4 halogens (preferably 1 to 3 halogens), and specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, dibutyl, 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.

[0013] "C1-6 alkyl groups" are linear or branched alkyl groups having 1 to 6 carbon atoms (C1-6). Specific examples include methylene, ethyl alkyl, 1-methylethyl alkyl, 2-methylethyl alkyl, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, dimethylmethylene, tetramethylene, pentamethylene, and hexamethylene. In addition, "C1-6 alkyl groups" also include C1-6 alkyl groups in which one to three hydrogen atoms are replaced by deuterium atoms.

[0014] Each of the groups defined in this specification may be suitably linked to another group via a linker (such as -O-, -CO-, -COO-, -S-, -SO-, -SO2-, -Si-, -O-CO-, etc.).

[0015] The various substituents in the compounds represented by the general formula [I] of the present invention (hereinafter referred to as "compounds [I] of the present invention") are explained below.

[0016] In the compounds [I] of the present invention, the D-series may be substituted with (R1)k ring A or C1-6 alkyl may be substituted with halogen.

[0017] The compound [I] of the present invention is a cyclic A-type benzene, pyridine, indole, or indazole, preferably benzene or pyridine.

[0018] When ring B is pyrimidine, ring C in the compound [I] of the present invention is selected from the group consisting of: the following unsaturated rings and their oxides and dioxides (excluding pyrimidine-2,4-diones and dihydropyrimidine-2,4-diones), and those in which some or all of the unsaturated bonds in such rings are reduced by hydrogen; (a) Unsaturated 3- to 8-membered monocyclic heterocycles containing only 1 to 4 nitrogen atoms as heteroatoms constituting the ring. (b) Unsaturated 7- to 15-membered bicyclic or tricyclic heterocycles containing only 1 to 5 nitrogen atoms as heteroatoms constituting the ring. (c) Unsaturated 7- to 12-membered bicyclic heterocycles containing only 1 to 3 oxygen atoms as heteroatoms constituting the ring. (d) Unsaturated 3- to 8-membered monocyclic heterocycles containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms as heteroatoms constituting the ring. (e) Unsaturated 7- to 12-membered bicyclic heterocycles containing one or two sulfur atoms and one to three nitrogen atoms as heteroatoms constituting the ring, and (f) Unsaturated 3- to 8-membered monocyclic hydrocarbon rings.

[0019] Specific examples of unsaturated 3- to 8-membered monocyclic heterocycles and their oxides and dioxides (excluding pyrimidine-2,4-diones and dihydropyrimidine-2,4-diones) containing only 1 to 4 nitrogen atoms as heteroatoms constituting the ring, and heterocycles in which some or all of the unsaturated bonds in the ring are reduced by hydrogen, may include pyridine, piperidine, pyridine-1-oxide, pyridine-2(1H)-one, pyrimidine, tetrahydropyrimidine, tetrahydropyrimidine-2(1H)-one, and pyridoxine. ,despair -3(2H)-ketone, 4,5-dihydroketone , and 4,5-dihydrotadalafil -3(2H)-ketone.

[0020] Specific examples of unsaturated 7- to 15-membered bicyclic or tricyclic heterocycles and their oxides and dioxides containing only 1 to 5 nitrogen atoms as heteroatoms constituting the ring, and heterocycles in which some or all of the unsaturated bonds in the ring are reduced by hydrogen, may include indole, indoline, indoline-2-one, indoline-3-one, indoline-2,3-dione, benzimidazole (e.g., 1H-benzimidazole), dihydrobenzimidazole (e.g., 2,3-dihydro-1H-benzimidazole), indazole, dihydroindazole (e.g., 2,3-dihydro-1H-indazole), quinoline, quinoline-2(1H)-one, dihydroquinoline (e.g., 1,2-dihydroquinoline, 3,4-dihydroquinoline ... [1,2,4]triazolopyrimidine (e.g., [1,2,3,4]triazolo[1,5-a]pyrimidine), [1,3-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), imidazopyridine (For example, imidazo[1,2-a]pyrene) ), imidazopyrimidine (e.g., imidazo[1,2-a]pyrimidine), imidazopyridine (e.g., imidazo[1,2-b]tadalafil) ), nabendazole (e.g., 1,5-nabendazole, 1,8-nabendazole), quinine Phosphorus, dihydroquinone porphyrins (e.g., 1,2-dihydroquinone) (P- ... porphyrins (e.g., 1,2,3,4-tetrahydroquinone) Phosphoric acid, 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, and pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine).

[0021] Specific examples of unsaturated 7- to 12-membered bicyclic heterocycles and their oxides and dioxides containing only 1 to 3 oxygen atoms as heteroatoms constituting the ring, and heterocycles in which some or all of the unsaturated bonds in the ring are reduced by hydrogen, may include benzo[d][1,3]-dioxane (e.g., benzo[d][1,3]-dioxane, benzo[c][1,2]-dioxane).

[0022] Specific examples of unsaturated 3- to 8-membered monocyclic heterocycles and their oxides and dioxides containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms as heteroatoms constituting the ring, as well as heterocycles in which some or all of the unsaturated bonds in the ring are reduced by hydrogen, may include oxonium pyrenes (e.g., 1,2-oxonium pyrenes, 1,3-oxonium pyrenes, 1,4-oxonium pyrenes). Dihydronitrogenopeptide, tetrahydronitrogenopeptide, oxonitrocycloheptan (e.g., 1,2-oxonitrocycloheptan, 1,3-oxonitrocycloheptan, 1,4-oxonitrocycloheptan), 1,4-oxonitrocycloheptan-2-one (e.g., 1,4-), dihydrogenopeptide (3,4-dihydrogen-2H-1,4-oxonitrogenopeptide), succinyl, and succinyl-3-one.

[0023] Specific examples of unsaturated 7- to 12-membered bicyclic heterocycles and their oxides and dioxides containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms as heteroatoms constituting the ring, and heterocycles in which some or all of the unsaturated bonds in the ring are reduced by hydrogen, may include benzothiazoles (e.g., benzo[d]thiazole).

[0024] Specific examples of unsaturated 3- to 8-membered monocyclic hydrocarbons and their oxides and dioxides, as well as heterocycles in which some or all of the unsaturated bonds in the ring are reduced by hydrogen, may include benzene, cyclohexene, and cyclohexane.

[0025] When ring B is pyrimidine, it is preferable that ring C is selected from the group consisting of: the following unsaturated rings and their oxides and dioxides (excluding pyrimidine-2,4-diones and dihydropyrimidine-2,4-diones), and those in which some or all of the unsaturated bonds in these rings are reduced by hydrogen: Pyridine despair , Pyrimidine Indole, Pyrrolopyridine Indazole, Benzimidazole, Pyrazolopyridine, Imidazolidine, Imidazolium , Imidazolidinedazole , Triazopyridine, Pyrazolopyrimidine, Imidazorprine, Triazoropyrimidine, Quinoline, Isoquinoline, Oral-Nystatin Quinazoline, Quinine porphyrin, Benzodioxane, , Oxygen and nitrogen phosphate benzothiazole, and benzene.

[0026] Regarding ring C in the compound [I] of the present invention, when ring B is benzene, naphthalene, pyridine, pyrazole or thiazolyl At this time, the cyclic C-type pyrimidine-2,4-dione or dihydropyrimidine-2,4-dione is preferred. Cyclic B-type benzene or pyridine is also preferred.

[0027] R1-series halogens, C1-6 alkyl groups to be halogenated as desired, -O-C1-6 alkyl groups to be halogenated as desired, -CN or -SF5, and preferably halogens, C1-6 alkyl groups to be halogenated as desired, or -O-C1-6 alkyl groups to be halogenated as desired, and even more preferably fluorine, methyl, trifluoromethyl, or -O-trifluoromethyl.

[0028] R2-based halogens, C1-6 alkyl or -O-C1-6 alkyl, and preferably fluorine, methyl or -O-methyl.

[0029] R3 halogens, C1-6 alkyl groups to be halogenated as desired, or C1-6 alkyl-O-, -O-C1-6 alkyl groups to be halogenated as desired, -C1-6 alkyl-OH, -OH, -CN, -CONH2 or -NH2, preferably C1-6 alkyl groups to be halogenated as desired, -O-C1-6 alkyl groups, -OH, -CONH2 or -NH2, and most preferably methyl, trifluoromethyl, -O-methyl, -OH, -CONH2 or -NH2.

[0030] L-series bonds, C1-6 alkyl groups, -O- or -S-, preferably bonds or -O-, and most preferably -O-.

[0031] The k-system can be 0, 1, or 2, and when the k-system is 2, each R1 independently represents the same or different substituents. 0 or 1 is preferred, and 0 is even more preferred.

[0032] The m-system can be 0, 1, or 2, and when the m-system is 2, each R2 independently represents the same or different substituents. 0 or 1 is preferred, and 0 is even more preferred.

[0033] The n-system can be 0, 1, or 2, and when the n-system is 2, each R3 independently represents the same or different substituents. 0 or 1 is preferred.

[0034] The options presented regarding the preferred aspects of the above substituents and the compound of the present invention [I] include all combinations thereof, provided that they are not contradictory combinations.

[0035] Preferred aspects of compound [I] of the present invention are shown below. (1-1) In equation I, the D system ; A-ring benzene or pyridine; Cyclic β-pyrimidines; Ring C is selected from the group consisting of: the following unsaturated rings and their oxides and dioxides (excluding pyrimidine-2,4-diones and dihydropyrimidine-2,4-diones), and those in which some or all of the unsaturated bonds in these rings are reduced by hydrogen: Pyridine despair , Pyrimidine Indole, Pyrrolopyridine Indazole, Benzimidazole, Pyrazolopyridine, Imidazolidine, Imidazolium , Imidazolidinedazole , Triazopyridine, Pyrazolopyrimidine, Imidazorprine, Triazoropyrimidine, Quinoline, Isoquinoline, Oral-Nystatin Quinazoline, Quinine porphyrin, Benzodioxane, , Oxygen and nitrogen phosphate benzothiazole, and benzene; R1-series halogens, C1-6 alkyl groups to be halogenated as needed, -O-C1-6 alkyl groups or -CN groups to be halogenated as needed; R2-O-C1-6 alkyl; R3 halogens, C1-6 alkyl groups to be halogenated as needed, or -O-C1-6 alkyl groups, -O-C1-6 alkyl groups to be halogenated as needed, -C1-6 alkyl groups -OH, -OH, -CN, -CONH2 or -NH2; L-series-O-; k-system 0, 1, or 2, and when k-system 2, each R1 independently represents the same or different substituents; m is either 0 or 1; and The n-system can be 0, 1, or 2, and when the n-system is 2, each R3 independently represents the same or different substituents. (1-2) In formula I, ring C is selected from the group consisting of: the following unsaturated rings and their oxides, and those in which some or all of the unsaturated bonds in such rings are reduced by hydrogen: Pyridine despair , Pyrrolopyridine Indazole, Pyrazolopyridine, Imidazolidine, Imidazolium , Imidazolidinedazole , Pyrazolopyrimidine, Triazoropyrimidine, Quinoline, Isoquinoline, Oral-Nystatin Quinine porphyrin, and benzene; R1 series halogens or C1-6 alkyl groups that may be halogenated as needed; The R3 series consists of C1-6 alkyl groups that need to be halogenated, -O-C1-6 alkyl groups, -OH, -CONH2, or -NH2 that need to be halogenated. L-series-O-; k and n are either 0 or 1; and m series 0. (1-3) In formula I, ring C is selected from the group consisting of: the following unsaturated rings and their oxides, and those in which some or all of the unsaturated bonds in such rings are reduced by hydrogen: Pyridine despair , Pyrazolopyridine, and Imidazolidine; R3 series -OH or -NH2; L-series-O-; k and m are related to 0; and n is either 0 or 1. (1-4) A compound selected from the group consisting of the following compounds: Or its salt. (1-5) A compound selected from the group consisting of the following compounds: Or its salt.

[0036] Other preferred aspects of the compound [I] of the present invention are shown below. (2-1) In equation I, the D system Or, depending on the need, C1-6 alkyl groups that can be halogenated; A-ring benzene or pyridine; Ring B series pyridine, pyrazole, benzene, or naphthalene; Cyclic C-type pyrimidine-2,4-dione or dihydropyrimidine-2,4-dione; R1-series halogens, C1-6 alkyl groups to be halogenated as needed, -O-C1-6 alkyl groups to be halogenated as needed, -CN or -SF5; R2-series halogens, C1-6 alkyl groups, or -O-C1-6 alkyl groups; R3 series C1-6 alkyl; L-series bonds, C1-6 alkyl groups, -O- or -S-; k-system 0, 1, or 2, and when k-system 2, each R1 independently represents the same or different substituents; m-system 0, 1, or 2, and when m-system 2, each R2 independently represents the same or different substituents; and The n-system can be 0, 1, or 2, and when the n-system is 2, each R3 independently represents the same or different substituents. (2-2) In formula I, cyclic A-type benzene; BO-type benzene, pyridine, or terpinen ; Cyclic C-system dihydropyrimidine-2,4-dione; R1 series halogens; L-series-O-; k is either 0 or 1; and m and n are related to 0. (2-3) A compound selected from the group consisting of the following compounds: ; Or its salt. (2-4) A compound: Or its salt.

[0037] In this specification, the options and preferred embodiments of different features of the compounds, methods and compositions of the present invention, as presented, include all possible combinations of such options and preferred embodiments, provided that they are consistent combinations.

[0038] The method for manufacturing compound [I] of the present invention is explained below. Compound [I] of the present invention can be manufactured based on the manufacturing method described below for examples. The manufacturing methods described below are examples, and the method for manufacturing compound [I] is not limited thereto.

[0039] In the following reaction formulas, when alkylation, hydrolysis, amination, esterification, acetylation, etherification, nucleophilic substitution, addition, oxidation, reduction, etc., are carried out, these reactions are themselves carried out by known methods. Examples of such methods include those described in the following: Experimental Chemistry (5th edition, edited by the Chemical Society of Japan, Maruzen Co., Ltd.); Organic Functional Group Preparations, 2nd edition, Academic Press, Inc., 1989; Comprehensive organic Transformations, VCH Publishers, Inc., 1989; and PGM Wuts and TW Greene, Greene's Protective Groups in organic Synthesis (4th edition, 2006), etc.

[0040] Reaction 1-1 Where Y and Y' represent the detached basis, and the other symbols have the same definitions as above.

[0041] According to the reaction represented by reaction formula 1-1, the compound [I] of the present invention can be produced. Specifically, the cyclic pinacol ester ((BPin)2) of boric acid can be added to compound [IIa] to obtain compound [IIa'], and then compound [IIa'] can be combined with compound [IIIa] by Suzuki cross-coupling to produce compound [I].

[0042] Examples of "dissociative radicals" used in the above reactions include halogens, C1-18 alkyl sulfonyl groups, C1-8 alkyl sulfonyloxy groups, aryl sulfonyloxy groups, aralkyl sulfonyloxy groups, trihalomethane sulfonyloxy groups, dihydrothio groups, and toluene thiooxy groups. Halogens are preferred examples of dissociative radicals in the reactions.

[0043] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0044] Examples of "C1-18 alkyl sulfonyl" include C1-18 straight-chain or branched alkyl sulfonyl, and specific examples include methanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl, butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl, etc.

[0045] Examples of "lower alkane sulfonyloxy" include C1-6 straight-chain or branched alkane sulfonyloxy, and specific examples include methane sulfonyloxy, ethane sulfonyloxy, 1-propane sulfonyloxy, 2-propane sulfonyloxy, 1-butane sulfonyloxy, 3-butane sulfonyloxy, 1-pentane sulfonyloxy, 1-hexane sulfonyloxy, etc.

[0046] Examples of "aromatic sulfonyloxy groups" include naphthalenesulfonyloxy and benzenesulfonyloxy groups, which may have 1 to 3 substituents selected from the group consisting of halogens, nitro groups, C1-6 straight-chain or branched alkoxy groups on a benzene ring, and C1-6 straight-chain or branched alkyl groups. Specific examples of these "benzenesulfonyloxy groups that may have substituents" include benzenesulfonyloxy, 4-methylbenzenesulfonyloxy, 2-methylbenzenesulfonyloxy, 4-nitrobenzenesulfonyloxy, 4-methoxybenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, 3-chlorobenzenesulfonyloxy, etc. Specific examples of "naphthalenesulfonyloxy groups" include α-naphthalenesulfonyloxy, β-naphthalenesulfonyloxy, etc.

[0047] Examples of "aranesulfonyloxy" include naphthyl-substituted C1-6 straight-chain or branched alkanesulfonyloxy and phenyl-substituted C1-6 straight-chain or branched alkanesulfonyloxy, which may have 1 to 3 substituents selected from the group consisting of halogens, nitro groups, C1-6 straight-chain or branched alkoxy groups on a benzene ring, and C1-6 straight-chain or branched alkyl groups. Specific examples of such "phenyl-substituted alkanesulfonyloxy" include phenylmethanesulfonyloxy, 2-phenylethanesulfonyloxy, 4-phenylbutanesulfonyloxy, 4-tolylmethanesulfonyloxy, 2-tolylmethanesulfonyloxy, (4-nitrophenyl)methanesulfonyloxy, (4-methoxyphenyl)methanesulfonyloxy, (3-chlorophenyl)methanesulfonyloxy, etc. Examples of "naphthyl-substituted alkane sulfonyloxy" include α-naphthylmethanesulfonyloxy, β-naphthylmethanesulfonyloxy, etc.

[0048] A specific example of the "trihaloalkane sulfonyloxy" group is trifluoromethane sulfonyloxy.

[0049] Specific examples of "dihydrosulfide" include dimethyl dihydrosulfide, diethyl dihydrosulfide, dipropyl dihydrosulfide, di(2-cyanoethyl) dihydrosulfide, di(2-nitroethyl) dihydrosulfide, di(aminoethyl) dihydrosulfide, di(2-methylaminoethyl) dihydrosulfide, di(2-dimethylaminoethyl) dihydrosulfide, di(2-hydroxyethyl) dihydrosulfide, di(3-hydroxypropyl) dihydrosulfide, di(2-methoxyethyl) dihydrosulfide, di(2-aminomethoxyethyl) dihydrosulfide, di(2-carboxyethyl) dihydrosulfide, di(2-methoxycarbonylethyl) dihydrosulfide, diphenyl dihydrosulfide, etc.

[0050] There are no particular limitations on the "palladium compound" used in this reaction, and examples include tetravalent palladium catalysts, such as sodium hexachloropalladium(IV) tetrahydrate and potassium hexachloropalladium(IV); divalent palladium catalysts, such as [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (Pd(dppf)Cl2·CH2Cl2), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd Palladium (G3), palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) acetoacetone, palladium(II) dichlorobis(benzonitrile), palladium(II) dichlorobis(acetonitrile), palladium(II) dichlorobis(triphenylphosphine), palladium(II) dichlorotetramine, palladium(II) dichloro(cyclooctyl-1,5-diene), palladium(II) trifluoroacetate; and zero-valent palladium catalysts, such as tris(dibenzylacetone)dipalladium(O) (Pd2(dba)3), tris(dibenzylacetone)dipalladium(O)-chloroform complex, and tetra(triphenylphosphine)palladium(O) (Pd(PPh3)4). These palladium compounds are used alone or as mixtures of two or more thereof.

[0051] In this reaction, there is no particular limitation on the amount of palladium used relative to 1 mol of compound [IIa], and it is generally in the range of 0.000001 to 20 mol. More preferably, the amount of palladium used relative to 1 mol of compound [IIa] is in the range of 0.0001 to 5 mol.

[0052] Examples of "bases" used in this reaction include inorganic bases, organic bases, etc. Examples of "inorganic bases" include alkali metal hydroxides (e.g., sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxides (e.g., magnesium hydroxide and calcium hydroxide), alkali metal carbonates (e.g., sodium carbonate and potassium carbonate), alkaline earth metal carbonates (e.g., magnesium carbonate and calcium carbonate), alkali metal bicarbonates (e.g., sodium bicarbonate and potassium bicarbonate), alkali metal phosphates (e.g., sodium phosphate and potassium phosphate), and alkaline earth metal phosphates (e.g., sodium phosphate and potassium phosphate). Examples of "organic bases" include trialkylamines (e.g., trimethylamine, triethylamine, and diisopropylethylamine), dialkylamines (e.g., diethylamine, diisopropylamine), methylpyridine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). These bases are used alone or as a mixture of two or more of them.

[0053] Regarding the "boronic acid" or "boronic ester" used in this reaction, those that are produced, isolated, and purified can be used alone. For example, in the presence of palladium compounds, dipinalol diborane can react with precursor halogenated compounds, and the reaction product can be used for Suzuki cross-coupling without separation and purification.

[0054] The "solvent" used in this reaction can be any solvent that is inert in the reaction, and examples include water, ether (such as diethyl ether), etc. The solvents used include: 1,2-dimethoxyethane, diethylene glycol dimethyl ether, hydrocarbons (e.g., hexane), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, or carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, or xylene), lower alcohols (e.g., methanol, ethanol, or isopropanol), polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), trimethylamine hexamethylphosphate, or acetonitrile), ketones (e.g., acetone or methyl ethyl ketone), and esters (e.g., methyl acetate or ethyl acetate). One of these solvents may be used alone, or a mixture of two or more may be used.

[0055] Other reaction conditions (reaction temperature, reaction time, etc.) can be appropriately determined based on the known Suzuki cross-coupling reaction.

[0056] Reaction 1-2 The Y-series is a detached base, and the other symbols have the same definitions as above.

[0057] According to the reactions represented by reaction formulas 1-2, the compound [I] of the present invention can be produced. Specifically, compound [IIa] can be combined with compound [IIIb] by Suzuki cross-coupling to produce compound [I].

[0058] The palladium compounds, bases, solvents, etc. that can be used in reactions 1-2 are the same as those that can be used in reaction 1-1.

[0059] Reaction 1-3 The Y-series is a detached base, and the other symbols have the same definitions as above.

[0060] Compound [I] of the present invention can be produced according to the reactions represented by reaction formulas 1-3. Specifically, compound [IIa] can be linked to compound [IIIc] by Suzuki cross-coupling to produce compound [I].

[0061] The palladium compounds, bases, solvents, etc. that can be used in reactions 1-3 are the same as those that can be used in reaction 1-1.

[0062] Reaction 2-1 The symbols have the same definition as described above.

[0063] According to the reaction represented by reaction formula 2-1, compound [Ia], which is included in compound [I] of the present invention, can be produced. Specifically, compound [VI] is added to the amino group of compound [IIb], and then the chlorine of the product is released for cyclization, thereby producing compound [Ia].

[0064] Examples of "bases" used in this reaction include inorganic 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), and sodium hexamethyldisilamide (NaHMDS). Examples of "organic bases" include trialkylamines (e.g., trimethylamine, triethylamine), Hünig's base (N,N-diisopropylethylamine), pyridine, and N-methylphosphonoline.

[0065] The "solvent" used in this reaction can be any solvent that is inert in the reaction, and examples include water, ether (such as diethyl ether), etc. The solvents used include: 1,2-dimethoxyethane, diethylene glycol dimethyl ether, hydrocarbons (e.g., hexane), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, or carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, or xylene), lower alcohols (e.g., methanol, ethanol, or isopropanol), polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), trimethylamine hexamethylphosphate, or acetonitrile), ketones (e.g., acetone or methyl ethyl ketone), and esters (e.g., methyl acetate or ethyl acetate). One of these solvents may be used alone, or a mixture of two or more may be used.

[0066] Other reaction conditions (reaction temperature, reaction time, etc.) can be appropriately determined based on commonly known condensation reactions. For example, the reaction temperature can range from room temperature to the reflux temperature of the solvent, and the reaction time can range from 10 minutes to 10 hours.

[0067] Reaction 2-2 The symbols have the same definition as described above.

[0068] According to the reaction represented by reaction formula 2-2, compound [Ib], which is included in compound [I] of the present invention, can be produced. Specifically, compound [III] (acrylic acid) is 1,4-added to the amino group of compound [IIb], and then the amino group of the product is converted into a urea derivative and cyclized (intramolecular acetylation) using urea, thereby producing compound [Ib].

[0069] The "solvent" used in this reaction can be any solvent that is inert in the reaction, and examples include water, ether (such as diethyl ether), etc. Hydrogenated hydrocarbons (e.g., tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether or ethylene glycol dimethyl ether), hydrocarbons (e.g., hexane), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane or carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene or xylene), lower alcohols (e.g., methanol, ethanol or isopropanol), polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), hexamethyltrimethylamine phosphate or acetonitrile), ketones (e.g., acetone or methyl ethyl ketone), esters (e.g., methyl acetate or ethyl acetate). One of these solvents may be used alone, or a mixture of two or more may be used.

[0070] Examples of "acids" used in this reaction include inorganic 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.

[0071] Other reaction conditions (reaction temperature, reaction time, etc.) can be appropriately determined based on commonly known 1,4-addition and amination reactions.

[0072] Reaction 3-1 Where Y is a deionized group, L1 is a -O-, -S-, or C1-6 alkyl group, and other symbols have the same definition as above.

[0073] According to the reaction represented by reaction formula 3-1, compound [Ic] included in compound [I] of the present invention can be produced. Specifically, compound [Ic] can be produced by releasing the deionization group Y of compound [V] and being replaced by compound [IV].

[0074] Examples of "base" used in this reaction include 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 hydroxide (NaH), and hexamethyldisilamide sodium (NaHMDS). Examples of "organic bases" include trialkylamines (e.g., trimethylamine, triethylamine), Hünig's base (N,N-diisopropylethylamine), pyridine, and N-methylphospholine.

[0075] The "solvent" used in this reaction can be any solvent that is inert in the reaction, and examples include water, ether (such as diethyl ether), etc. The solvents used include: 1,2-dimethoxyethane, diethylene glycol dimethyl ether, hydrocarbons (e.g., hexane), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, or carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, or xylene), lower alcohols (e.g., methanol, ethanol, or isopropanol), polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), trimethylamine hexamethylphosphate, or acetonitrile), ketones (e.g., acetone or methyl ethyl ketone), and esters (e.g., methyl acetate or ethyl acetate). One of these solvents may be used alone, or a mixture of two or more may be used.

[0076] Other reaction conditions (reaction temperature, reaction time, etc.) can be appropriately determined based on commonly known condensation reactions. For example, the reaction temperature can range from room temperature to 100°C, and the reaction time can range from 1 hour to 10 hours.

[0077] In each of the above reaction equations, the reaction products can be used in the next reaction as a reaction solution or as crude products, but they can also be separated from the reaction mixture by conventional methods and easily purified by conventional separation techniques. Examples of conventional separation techniques include recrystallization, distillation, and chromatography.

[0078] Each of the starting material compound, intermediate compound, and target compound in the above steps, as well as the compound [I] of the present invention, includes geometric isomers, stereoisomers, optical isomers, and tautomers. The corresponding isomers can be separated by conventional optical resolution methods. They can also be manufactured from starting material compounds with suitable optical activity.

[0079] The compound [I] of the present invention can be manufactured by the synthetic method shown in the above reaction formula or by a similar method.

[0080] Unless otherwise specified, the raw material compounds used to manufacture the compound [I] of the present invention may be commercial compounds or may be produced by known or similar methods.

[0081] The starting material compound and target compound in each of the above steps can be used in the form of a suitable salt. Examples of such salts include those similar to those given below as examples of salts of the compound [I] of the present invention.

[0082] When the compounds or commercial products obtained in each step are in their free form, they can be converted into the target salt using known methods.

[0083] The compounds of the present invention [I] also include embodiments in which they are pharmaceutically acceptable salts, and in some cases, depending on the type of substituent, these compounds may also form acid addition salts or salts formed with bases. Examples of “acids” herein 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, lactic acid, etc. Examples of “bases” include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; organic bases such as methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tri(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, methylpyridine, and choline; and ammonium salts, etc. This compound can also form salts with amino acids such as lysine, arginine, aspartic acid, glutamic acid, etc.

[0084] The present invention also covers various hydrates, solvates and polymorphs of the compound [I] and its salts.

[0085] The compounds [I] of the present invention also include compounds in which one or more isotopic atoms have been substituted by one or more atoms. Examples of isotopic atoms include deuterium (2H), tritium (3H), 13C, 15N, 18O, etc.

[0086] The compounds of the present invention [I] include pharmaceutically acceptable precursors. Examples of substituents that can be modified to form precursors include reactive functional groups, such as -OH, -COOH, amines, etc. The modifying groups of such functional groups are suitably selected from the "substituents" section of this specification.

[0087] The compound [I] of the present invention, or its salt, may be in the form of a pharmaceutically acceptable eutectic or eutectic salt. Eutectic or eutectic salt, as used herein, refers to a crystalline substance composed of two or more separate solids, each having different physical properties (e.g., structure, melting point, heat of fusion, etc.), at room temperature. Eutectic or eutectic salts can be suitably prepared by well-known co-crystallization methods.

[0088] The compounds [I] of the present invention and their salts have excellent effects in the treatment, prevention and / or diagnosis of diseases involving epileptic seizures or convulsive seizures. The term "epileptic seizure" applies to any of the following seizure types: focal seizures (also known as partial seizures) with motor onset (including automatisms, atonic seizures, intergenerational seizures, epileptic spasms, hyperkinetic seizures, myoclonic seizures, and tonic seizures) and non-motor onset (including autonomic epilepsy, behavioral inhibition seizures, cognitive impairment seizures, emotional seizures, and sensory seizures); and focal to bilateral tonic intergenerational seizures (secondary spread of partial seizures); including motor seizures (including tonic intergenerational seizures, intergenerational 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, and myoclonic absence seizures). Generalized seizures including myoclonic seizures and eyelid myoclonic seizures; and seizures of unknown origin including motor seizures (including tonic-clonic seizures and epileptic spasms) and non-motor seizures (including behavioral inhibition seizures). Examples of diseases involving seizures or convulsions include DeWitt syndrome, Lennox syndrome, West syndrome (nodding epilepsy), Ōtahara syndrome, Tazawa syndrome, acquired epileptic aphasia, Rasmussen syndrome, Ecardi syndrome, Panagiotopoulos syndrome, Kuyevenikov syndrome, Tasinari syndrome, Gschwynd syndrome, hemiphagic epilepsy syndrome, medial temporal lobe epilepsy, epilepsy with structural / metabolic causes (post-stroke epilepsy, post-traumatic epilepsy, infectious epilepsy, epilepsy associated with cerebrovascular disorders, epilepsy associated with brain tumors, epilepsy associated with neurodegenerative diseases, epilepsy associated with autoimmune disorders, etc.), and congenital malformations, congenital metabolic disorders (e.g., phenylketonuria, mitochondrial diseases, lysosomal diseases, Steger-Weber syndrome, etc.), and congenital genetic abnormalities (Rett syndrome, Angelman syndrome, 5P syndrome, 4P syndrome, Down syndrome, etc.). The compound [I] of the present invention, or its salts, is also effective in treating, preventing, and / or diagnosing multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile epilepsy, and status epilepticus. In the present invention, multidrug-resistant seizures and refractory seizures are defined as seizures that cannot be controlled due to the ineffectiveness or inadequacy of one or more antiepileptic drugs, regardless of the type of seizure as described above. Furthermore, the compounds [I] of the present invention and their salts, when used as active ingredients in pharmaceuticals, possess excellent characteristics, such as few side effects, tolerability, and stability (storage stability, metabolic stability, etc.). The group of compounds of the present invention also functions as prophylactic and / or therapeutic agents for refractory epileptic seizures in which conventional drug therapy has failed.

[0089] Next, a pharmaceutical preparation containing the compound [I] of the present invention or its salt as an active ingredient (hereinafter also referred to as "pharmaceutical composition") is explained.

[0090] Pharmaceutical formulations are obtained by formulating the compound of the invention [I] or a salt thereof in the form of conventional pharmaceutical formulations, and are prepared using the compound of the invention [I] or a salt thereof and a pharmaceutically acceptable carrier. Examples of carriers include commonly used diluents or excipients, such as fillers, swelling agents, binders, wetting agents, disintegrants, surfactants, lubricants, etc.

[0091] Depending on the therapeutic purpose, such pharmaceutical preparations can be selected from various forms, including tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions, etc.).

[0092] When formulations are made into tablets, a wide range of known carriers can be used, and examples include excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorbents such as sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as colloidal silica; and lubricants such as magnesium stearate, polyethylene glycol, etc.

[0093] In addition, tablets can be formulated as needed with common coatings, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, two-tablet or multi-tablet tablets.

[0094] When formulations are made into pills, a wide range of known carriers can be used, and examples include excipients such as glucose; binders such as gum arabic powder; and disintegrants such as laminarin.

[0095] When formulating a preparation into a liquid, emulsion, or suspension, widely known diluents can be used, examples of which include water. Common solubilizers and buffers may also be included, as well as, as needed, colorants, preservatives, flavorings, sweeteners, and other pharmaceuticals.

[0096] When formulating a preparation into suppositories, a wide range of known carriers can be used, and examples include cocoa butter, etc.

[0097] When the formulation is an injectable, the liquid, emulsion, or suspension is preferably sterilized, and even more preferably isotonic with blood. Sufficient amounts of sodium chloride may be included in the injectable, and may also include another drug, sedative, etc.

[0098] The amount of compound [I] or its salt contained in the pharmaceutical preparation is not particularly limited and can be appropriately selected from a wide range, but generally the compound [I] or its salt of the present invention is preferably contained in an amount of 1% to 70% of the pharmaceutical preparation.

[0099] There are no particular limitations on the method of administering the pharmaceutical preparations of the present invention, and administration can be carried out by means suitable to the dosage form, the patient's age and sex, disease state, and other conditions. For example, if it is in the form of tablets, pills, liquids, suspensions, emulsions, granules, or capsules, it can be administered orally. If it is an injectable preparation, it can be administered intravenously alone or mixed with a common replacement fluid (such as glucose or amino acids) for intravenous administration, or it can be administered intramuscularly, intradermally, subcutaneously, or intraperitoneally as needed. In the case of suppositories, it can be administered rectally.

[0100] The dosage of a drug preparation can be selected based on the method of administration, the patient's age and sex, the severity of the disease, and other conditions, but it is usually administered in one or more doses at a rate of 0.01 mg to 100 mg per kg of body weight per day, or preferably 0.1 mg to 50 mg.

[0101] The dosage is affected by various conditions, and in some cases, a dosage below the above range may be sufficient, while in other cases, a dosage above the above range may be required.

[0102] The compound [I] of the present invention, or a salt thereof, can be used in combination with various therapeutic or preventative agents for diseases in which the compound [I] is considered effective. Such combinations can be administered simultaneously, separately, continuously, or at suitable intervals. Simultaneously administered formulations can be prepared alone or in combination.

[0103] One embodiment of the present invention provides a pharmaceutical composition comprising the compound of the present invention [I] or a salt thereof together with a pharmaceutically acceptable carrier and / or excipient.

[0104] Another embodiment provides a therapeutic, preventive, and / or diagnostic agent for seizures or convulsive episodes (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile epilepsy, and status epilepticus), the agent containing the compound of the present invention [I] or a salt thereof, together with a pharmaceutically acceptable carrier and / or excipient.

[0105] Another embodiment provides a therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile epilepsy, and status epilepticus), the pharmaceutical composition containing the compound of the present invention [I] or a salt thereof, together with a pharmaceutically acceptable carrier and / or excipient.

[0106] Another embodiment provides a method for treating, preventing, and / or diagnosing seizures involving epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile epilepsy, and status epilepticus), the method comprising administering an effective amount of the compound of the invention [I] or a salt thereof to a human in need.

[0107] Another embodiment provides the compound [I] of the present invention or a salt thereof, the compound or a salt thereof for the treatment, prevention and / or diagnosis of seizures involving epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile epilepsy and status epilepticus).

[0108] Another embodiment provides the use of the compound [I] of the present invention or a salt thereof in the manufacture of a medicament for treating, preventing and / or diagnosing seizures involving epileptic seizures or convulsive seizures (including multidrug-resistant seizures, refractory seizures, acute symptomatic seizures, febrile epilepsy and status epilepticus). [Example] The present invention will be further explained in detail below by way of the following experimental examples, reference examples and examples, but these do not limit the present invention and these can be modified to the extent that they do not depart from the scope of the present invention. The following abbreviations are used in this instruction manual.

[0109] abbreviation word REX Reference Example Number EX Instance number STR Structural formula (in which the label "chirality" indicates the absolute configuration of the structure) RProp Manufacturing method (the number indicates that the compound was manufactured using the same raw materials in the same manner as the reference example compound having that number as the reference example number) Prop Manufacturing method (the number indicates that the compound was manufactured using the same raw materials in the same manner as the example compound having that number as the example number). data Physical property data (NMR1: δ (ppm) in 1H-NMR in dimethyl sulfoxide-d6; NMR2: δ (ppm) in 1H-NMR in CDCl3; MS: mass spectrometry) 9-BBN 9-Borobicyclo[3.3.1]nonane AcOEt Ethyl acetate AcOH Acetic acid AcOK Potassium acetate AcONa Sodium acetate BBr3 Boron tribromide n-BuLi n-Butyllithium tBu3P·HBF4 tert-butylphosphine tetrafluoroborate (BPin)2 Bis(pinacol)diboron CDI 1,1'-Carbonyldiimidazole m-CPBA m-chloroperoxybenzoic acid Cs2CO3 cesium carbonate DBU 1,8-Dazabicyclo[5.4.0]-7-undecene DCC Dicyclohexylcarbodiimide DCE 1,2-Dichloroethane DCM dichloromethane DEAD Diethyl azodicarbonate DHP 3,4-Dihydro-2H-piperanan DIBAL Diisobutylaluminum hydride DIBOC Dibutyl dicarbonate (di-tertiary butyl ester) DIPEA Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP 4-(dimethylamino)pyridine DME Dimethoxyethane DMF N,N-Dimethylformamide DMSO Dimethicone DPPA Diphenylphosphine azide Et2O Diethyl ether EtOH ethanol HCl hydrochloric acid Hexane n-Hexane HOBt 1-Hydroxybenzotriazole IPA 2-Propanol IPE diisopropyl ether K2CO3 Potassium carbonate K3PO4 Tripotassium phosphate KHCO3 Potassium bicarbonate KOH potassium hydroxide KOtBu Potassium butoxide (tertiary grade) LAH Lithium aluminum hydride LDA Lithium diisopropylamide LHMDS Hexamethyldisilylaminolithium LiOH Lithium hydroxide MeCN Acetonitrile MEK 2-Butanone MeOH methanol NaBH4 Sodium borohydride Na2CO3 Sodium carbonate NaH Sodium hydride NaHCO3 Sodium bicarbonate NaOH Sodium hydroxide NaOtBu Sodium butanol NBS N-bromosuccinimide NCS N-chlorosuccinimide NMP N-methylpyrrolidone Pd2(dba)3 Tris(dibenzylacetone)dipalladium(0) PdCl2(dppf)DCM [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct Pd(OAc)2 Palladium(II) acetate Pd(PPh3)4 Tetra(triphenylphosphine)palladium(0) Pd / C Carbon carrying palladium Pt / C Carbon carrying platinum PEG polyethylene glycol PPTS p-Pyridonium p-toluenesulfonate TBAF Tetra-n-Butylammonium fluoride TCDI 1,1'-Thiocarbonyldiimidazole TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TPP Triphenylphosphine WSC 3-Ethyl-1-(3-dimethylaminopropyl)carbodiimide ZCl benzyl chloroformate XPhos Pd G3 (2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate

[0110] In the following examples, "room temperature" generally indicates a temperature from about 10°C to about 35°C. Unless otherwise stated, ratios indicated for mixed solvents are volume ratios. Unless otherwise stated, percentages are expressed as weight %. 1H NMR (proton nuclear magnetic resonance spectrum) was measured using Fourier transform NMR (either Bruker AVANCE III 400 (400 MHz) or Bruker AVANCE III HD (500 MHz)). In silicone column chromatography, when the reaction is indicated as alkaline, an aminopropylsilane-bonded silicone is used. The absolute configuration of the compound was determined by known X-ray crystallographic analysis methods (e.g., Shigeru Oba and Shigenobu Yano, "Basic Course for Chemists 12, X-ray Crystal Structure Analysis" (1st edition, 1999)), or estimated from the experimental rules of Shi's 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 containing 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 solution, and the resulting crystals were collected by filtration and washed with water to obtain the target compound (27.7 g).

[0112] Reference Example 2 Synthesis of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrimidine The mixture contained 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. The mixture of 10 mL was heated to reflux under a nitrogen atmosphere for 10 hours. Water and AcOEt were added to the reaction solution, and the mixture was filtered through diatomaceous earth. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, and then concentrated. The residue was suspended in IPE, insoluble substances were filtered off, the filtrate was concentrated, and the resulting solid was washed with hexane to obtain the target compound (646 mg).

[0113] Reference Example 18 3-Methoxy-6-(2-(methylthio)pyrimidin-5-yl) tadalafil Synthesis Containing 3-chloro-6-methoxy (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-di A mixture of 20 mL of acetylene and 2 mL of water was heated to reflux under a nitrogen atmosphere for 1.5 hours. The reaction solution 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 3-Methoxy-6-(2-(methylsulfonylurea)pyrimidin-5-yl)pyrazinyl Synthesis The product containing 3-methoxy-6-(2-(methylthio)pyrimidin-5-yl) A mixture of 242.6 mg of m-CPBA (77% water content), 627.9 mg of water, and 20 mL of DCM was stirred at 0°C for 1 hour and then stirred overnight at room temperature. The reaction solution was poured into ice and a saturated aqueous solution of NaHCO3, and the product was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and then 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)pyrimidin-5-yl)pyridine-2-amine The mixture contained 2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine (1.96 g), 2-amino-5-bromopyridine (1.037 g), K3PO4 (3.86 g), PdCl2(dppf)DCM (273.3 mg), and 1,4 ... A mixture of hexane (30 mL) and water (3 mL) was heated to reflux under nitrogen atmosphere for 6 hours. Water was added to the reaction solution, and the product was then extracted with AcOEt. The organic layer was dried with anhydrous sodium sulfate and then concentrated. The residue was purified by alkaline silica gel chromatography (hexane / AcOEt) to obtain the target compound (1.175 g).

[0116] Reference Example 22 Synthesis of 5-(2-(methylsulfinyl)pyrimidin-5-yl)pyridine-2-amine A mixture containing 1.175 g of 5-(2-(methylthio)pyrimidin-5-yl)pyridine-2-amine, 2.43 g of Oxone (registered trademark), 30 mL of THF, and 10 mL of water was stirred at 0°C for 10 minutes under nitrogen atmosphere and then stirred at room temperature for 2.75 hours. The reaction solution was poured into ice and a saturated aqueous solution of NaHCO3, and the product was extracted with DCM. The organic layer was dried with anhydrous sodium sulfate and then 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 containing 5-bromo-2-chloropyrimidine (2.30 g), 1-dodecylthiol (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 with anhydrous sodium sulfate, and then 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)pyrimidin-5-yl)pyridine-2-amine The mixture contained 5-bromo-2-(dodecylthio)pyrimidine (1.008 g), 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridine (811.6 mg), K3PO4 (1.82 g), PdCl2(dppf)DCM (107.7 mg), and 1,4-dioxane-2-ylpyridine. A mixture of hexane (20 mL) and water (2 mL) was heated to reflux under nitrogen atmosphere for 2.25 hours. Water was added to the reaction solution, and the product was then extracted with AcOEt. The organic layer was dried with anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel chromatography (hexane / AcOEt) to obtain the target compound (1.01 g).

[0119] Reference Example 25 Synthesis of 5-(2-(dodecylsulfinyl)pyrimidin-5-yl)pyridine-2-amine A mixture containing 5-(2-(dodecylthio)pyrimidin-5-yl)pyridine-2-amine (1.010 g), Oxone (registered trademark) (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 solution was poured into a solution containing ice water, saturated NaHCO3 aqueous solution, and DCM, and extracted with DCM. The organic layer was dried with anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel chromatography (hexane / AcOEt) to obtain the target compound (163 mg).

[0120] Reference Example 26 3-(benzyloxy)-6-(2-phenoxypyrimidin-5-yl)-tetrazol Synthesis The mixture contained 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. The mixture (20 mL) was heated to reflux under nitrogen atmosphere for 3 hours. 3-(benzyloxy)-6-chlorodiphenyltrimethylammonium chloride was then added. PdCl2(dppf)DCM (0.370 g), K3PO4 (3.85 g), and water (5 mL) were added to the reaction solution and heated to reflux for 2 hours. Water and AcOEt were added to the reaction solution, and the mixture was filtered through diatomaceous earth. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, and then concentrated. The residue was purified by silica column chromatography (DCM / AcOEt), and the resulting solid was washed with AcOEt to obtain the target compound (2.54 g).

[0121] Reference Example 35 4-(2-phenoxypyrimidin-5-yl)-2-(tetrahydro-2H-piperan-2-yl)tadalafil Synthesis of 3(2H)-ketones The mixture contained 1.496 g of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine and 4-bromo-2-(tetrahydro-2H-piperan-2-yl)pyrimidine. -3(2H)-ketone (1.00 g), PdCl2(dppf)DCM (0.063 g), K3PO4 (1.229 g), 1,4-di- A mixture of hexane (10 mL) and water (3 mL) was stirred overnight at 100°C. Water was added to the reaction solution 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 60% NaH (0.933 g) was added to a 20 mL solution of DMF containing 4.20 g of 5-bromo-1H-pyrazolo[3,4-b]pyridine at 0°C with stirring. After 20 minutes, triisopropylchlorosilane (4.99 mL) was added and the mixture was stirred for 30 minutes. The reaction solution was poured into ice water and the precipitated solid was collected by filtration. The solid was dissolved in AcOEt and dried over anhydrous magnesium sulfate, and then 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-dioxaneborane-2-yl)pyrimidine A mixture containing 5-bromo-4-methoxy-2-phenoxypyrimidine (15.00 g), (BPin)2 (14.9 g), AcOK (10.5 g), PdCl2(dppf)DCM (2.18 g), and DMSO (60 mL) was stirred at 100°C for 3 hours under a nitrogen atmosphere. The reaction solution was poured into ice water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt) to obtain the target compound (9.61 g).

[0124] Reference Example 40 Synthesis of 2-(dodecylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine A mixture containing 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 solution was poured into ice water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (1.90 g).

[0125] Reference Example 41 Synthesis of 6-(2-(dodecylthio)pyrimidin-5-yl)imidazo[1,2-a]pyridine The following ingredients were added: 2-(dodecylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine (3.00 g), 6-bromoimidazolo(1,2-a)pyridine (1.53 g), PdCl2(dppf)DCM (0.301 g), K3PO4 (3.13 g), and 1,4-dioxaneborane-2-ylpyrimidine. A mixture of 20 mL of acetic acid and 10 mL of water was stirred at 95°C for 1 hour. The reaction solution was poured into ice water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt) to obtain the target compound (2.05 g).

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

[0127] Reference Example 43 Synthesis of 5-nitro-2-phenoxypyrimidine A mixture containing 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 solution, and the resulting crystals were collected by filtration and washed with water to obtain the target compound (6.55 g).

[0128] Reference Example 44 Synthesis of 2-phenoxypyrimidine-5-amine 5-Nitro-2-phenoxypyrimidine (7.45 g) and Pd / C (3 g) containing 10% water were suspended in EtOH (100 mL) and stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, 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-phenoxypyrimidin-5-yl)urea A THF (10 mL) solution containing 1.00 g of 2-phenoxypyrimidine-5-amine was stirred at room temperature, and 0.713 mL of 3-chloropropyl isocyanate was added. The mixture was stirred overnight. The precipitated solid was collected by filtration and washed with THF to obtain the target compound (756 mg).

[0130] Reference Example 46 Synthesis of 2-(3-fluoromethoxyphenoxy)-5-nitropyrimidine A mixture containing 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 then 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% water-containing 10% Pd / C (3 g) were suspended in EtOH (100 mL) and stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth 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-(triisopropylsiloxy)piperidin-1-yl)pyrimidine A mixture containing 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 for 3 hours under a nitrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (250 mg).

[0133] Reference Example 56 Synthesis of (R)-1-(2-phenoxypyrimidin-5-yl)-4-(triisopropylsilyloxy)piperidin-2-one The mixture contained 5-iodo-2-phenoxypyrimidine (500 mg), (R)-4-(triisopropylsiloxy)piperidin-2-one (501 mg), copper iodide (I) (5.68 μl), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.053 mL), K3PO4 (712 mg), and 1,4-di... The mixture of 6 mL was stirred at 95°C for 3 hours under nitrogen atmosphere. The reaction solution was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by silica 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 containing 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 solution was poured into ice water, and the precipitate was collected by filtration and washed with water to obtain the target compound (80.7 g).

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

[0136] Reference Example 60 Synthesis of 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione A solution of toluene (50 mL) containing 4-bromoaniline (7.66 g) and acrylic acid (3.05 mL) was stirred overnight at 80°C. The reaction solution was concentrated by adding urea (5.35 g) and acetic acid (20 mL), and the mixture was heated to 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-dioxane-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture containing 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 then 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 HBr (12.5 mL) was added to a solution of AcOH (25 mL) containing 1-[4-(3-methoxyphenoxy)phenyl]dihydropyrimidine-2,4(1H,3H)-dione (3.86 g) under ice-cooling, and the mixture was stirred for 3 hours. Water (100 mL) was added to the reaction solution, the mixture was stirred, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried, and then purified by silica gel column chromatography (DCM / MeOH). The resulting 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 containing 3-fluoroiodobenzene (0.587 mL), 3-aminophenol (818 mg), K3PO4 (2.12 g), pyridinecarboxylic acid (123 mg), copper iodide (I) (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 then extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (865 mg).

[0140] Reference Example 83 Synthesis of 5-nitro-2-phenoxypyridine Sodium phenoxide (12.3 g) was added to a DMF (80 mL) solution containing 2-chloro-5-nitropyridine (16.0 g), and the solution was ice-cooled and stirred overnight at room temperature. 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-phenoxypyridine-3-amine A mixture containing 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 diatomaceous earth, 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 1-(6-chlorothiazolinone) Synthesis of 3-yl)pyrimidine-2,4(1H,3H)-dione Containing 3,6-dichlorodiphenyl A mixture of 10.00 g of uracil (8.28 g) and 100 mL of DMSO was stirred overnight at 70°C. 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] 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 prepared in the same manner as those of Reference Examples 1, 2, 18, 19, 21 to 26, 35, 38 to 47, 50, 56, 58 to 61, 76, 77, 83, 84, and 111. The structural formulas and physicochemical data of the compounds of Reference Examples 1 to 111 are shown in Tables 1-1 and 1-11.

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

[0145] [Example] Example 1 3-Methoxy-6-(2-phenoxypyrimidin-5-yl)-D-t Synthesis The mixture contains 5.00 g of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrimidine and 3-chloro-6-methoxypyridine. (3.64 g), PdCl2(dppf)DCM (0.137 g), K3PO4 (7.12 g), 1,4-dioxanone A mixture of 50 mL of organic compound and 25 mL of water was heated to reflux under nitrogen atmosphere for 2 hours. The reaction solution was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt) to obtain the target compound (4.42 g).

[0146] Example 4 3-(2-(3-fluorophenoxy)pyrimidin-5-yl)-6-methoxypyridyl Synthesis The mixture contained 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. The mixture (20 mL) was heated to reflux under nitrogen atmosphere for 2 hours. 3-Chloro-6-methoxydimethylamine was then added. 1.00 g of PdCl2(dppf)DCM (0.282 g), 2.94 g of K3PO4, and 5 mL of water were added to the reaction solution, and the mixture was heated to reflux overnight under nitrogen atmosphere. Water and AcOEt were added to the reaction solution, and the mixture was filtered through diatomaceous earth. The product was extracted with AcOEt. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, and then concentrated. The precipitated crystals were washed with EtOH to obtain the target compound (947 mg).

[0147] Example 6 Synthesis of 5-(6-methoxypyridin-3-yl)-2-phenoxypyrimidine The mixture contained 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), and 1,4-dioxane. A mixture of 10 mL of organic compound and 5 mL of water was heated to reflux under nitrogen atmosphere for 2 hours. The reaction solution was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (DCM / AcOEt), and the resulting solid was washed with EtOH to obtain the target compound (821 mg).

[0148] Example 7 Synthesis of 2-phenoxy-5-(pyridin-3-yl)pyrimidine The mixture contained 5-bromo-2-phenoxypyrimidine (1.0 g), 3-pyridineboronic acid (0.734 g), PdCl2 (dppf), DCM (0.163 g), K3PO4 (1.691 g), and 1,4-dioxane. A mixture of 10 mL of acetic acid and 5 mL of water was heated to reflux under a nitrogen atmosphere for 2 hours. The reaction solution 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 then 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 1-oxide of 3-(2-phenoxypyrimidin-5-yl)pyridine A mixture containing 2-phenoxy-5-(pyridin-3-yl)pyrimidine (749 mg), m-CPBA (1,616 mg) containing 77% water, and DCM (15 mL) was stirred overnight at room temperature. Dimethyl sulfide (309 μl) was added to the reaction solution and stirred for a period of time, followed by the addition of a saturated aqueous solution of NaHCO3, 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 6-(2-(3-fluorophenoxy)pyrimidin-5-yl)tadalafil Synthesis of 3-amines The product contains 581 mg of 2-(3-fluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrimidine and 3-amino-6-chloropyridine. (202 mg), K3PO4 (1.11 g), PdCl2 (dppf), DCM (68 mg), 1,4-dioxanone A mixture of hexane (20 mL) and water (2 mL) was heated to reflux under nitrogen atmosphere for 2 hours. The reaction solution was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, and then 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 6-(2-phenoxypyrimidin-5-yl)tadalafil Synthesis of 3-amines Containing 3-amino-6-chlorodiphenyltriol (205 mg), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrimidine (526 mg), K3PO4 (1.11 g), PdCl2(dppf)DCM (65.2 mg), 1,4-dioxane-2-yl)pyrimidine (205 mg), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrimidine (205 mg), K3PO4 ... A mixture of hexane (10 mL) and water (2 mL) was heated to reflux under nitrogen atmosphere for 5.5 hours. The reaction solution was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, and then 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-phenoxypyrimidin-5-yl)pyridine-2-amine The mixture contained 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrimidine (386 mg), 2-amino-5-bromopyridine (209 mg), K3PO4 (1.0 g), PdCl2(dppf)DCM (43.7 mg), and 1,4-dioxane-2-yl)pyrimidine. A mixture of hexane (20 mL) and water (2 mL) was heated to reflux under nitrogen atmosphere for 2.75 hours. The reaction solution 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 then 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 3-(2-phenoxypyrimidin-5-yl)-6-(trifluoromethyl)-3-yl Synthesis Containing 3-chloro-6-(trifluoromethyl) (209 mg), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine (373 mg), K3PO4 (780 mg), PdCl2(dppf)DCM (29.3 mg), 1,4-dioxaneborane-2-yl)pyrimidine ... A mixture of 20 mL of acetylene and 2 mL of water was heated to reflux under a nitrogen atmosphere for 5 hours. The reaction solution 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 then 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 1-oxide of 3-(2-(2-fluorophenoxy)pyrimidin-5-yl)pyridine A mixture containing 3-(2-(2-fluorophenoxy)pyrimidin-5-yl)pyridine (998 mg), m-CPBA (1,255 mg) containing 77% water, and DCM (15 mL) was stirred overnight at room temperature. Dimethyl sulfide and a saturated aqueous solution of NaHCO3 were added to the reaction solution, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (AcOEt / MeOH), and the resulting solid was washed with EtOH to obtain the target compound (383 mg).

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

[0156] Example 69 2-(6-(2-phenoxypyrimidin-5-yl)tadalafil Synthesis of 3-yl)prop-2-ol Ethyl 6-(2-phenoxypyrimidin-5-yl) 200 mg of 3-carboxylate was suspended in 3 mL of THF, and then 1.6 mL of THF containing 0.96 M methylmagnesium bromide was added under ice-cooling. The mixture was stirred overnight at room temperature. The reaction solution 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 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 (45 mg).

[0157] Example 72 (6-(2-phenoxypyrimidin-5-yl)ta Synthesis of 3-yl)methanol Ethyl 6-(2-phenoxypyrimidin-5-yl) tadalafil was subjected to ice cooling. 3-Carboxylate (400 mg) was added to a mixture containing calcium chloride (551 mg), NaBH4 (117 mg), THF (2 mL), and EtOH (2 mL), and the mixture was stirred for 30 minutes. An aqueous solution of citric acid was added to the reaction solution, and the product was then extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (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)pyrimidin-5-yl)pyridine-2-amine A mixture containing 5-(2-(methylsulfinyl)pyrimidin-5-yl)pyridine-2-amine (100 mg), 2,5-difluorophenol (130 mg), K₂CO₃ (236 mg), and DMF (7 mL) was stirred at 80°C for 3.5 hours under a nitrogen atmosphere. Water was added to the reaction solution, and the product was then extracted with AcOEt. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by alkaline 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)pyrimidin-5-yl)pyridine-2-amine A mixture containing 5-(2-(dodecylsulfinyl)pyrimidin-5-yl)pyridine-2-amine (163 mg), m-cresol (0.10 mL), K₂CO₃ (483 mg), and DMF (10 mL) was stirred at 80°C for 4 hours under a nitrogen atmosphere. Water was added to the reaction solution, and the product was then extracted with AcOEt. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by alkaline silica gel chromatography (hexane / AcOEt), and the resulting solid was washed with IPE to obtain the target compound (50 mg).

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

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

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

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

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

[0165] Example 118 Synthesis of 4-(2-phenoxypyrimidin-5-yl)quinoline The mixture contained 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine (500 mg), 4-bromoquinoline (419 mg), K3PO4 (712 mg), PdCl2 (dppf) DCM (13.70 mg), and 1,4-dioxaneborane-2-yl) A mixture of hexane (5 mL) and water (2.5 mL) was heated to reflux under a nitrogen atmosphere for 1.5 hours. Water was added to the reaction solution, 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-phenoxypyrimidin-5-yl)imidazo[1,2-a]pyridine The mixture contained 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine (400 mg), 6-bromo-imidazo[1,2-a]pyridine (291 mg), PdCl2(dppf)DCM (110 mg), K3PO4 (570 mg), and 1,4-dioxaneborane-2-ylpyrimidine. A mixture of 4 mL of acetylene (AcOEt) and 2 mL of water was stirred at 100°C for 3 hours under a nitrogen atmosphere. AcOEt and water were added to the reaction solution, and the mixture was filtered through diatomaceous earth. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by alkaline silica column chromatography (DCM / AcOEt) to obtain the target compound (318 mg).

[0167] Example 123 6-(2-phenoxypyrimidin-5-yl)imidazo[1,2-b]tadalafil Synthesis The mixture contained 400 mg of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrimidine and 6-chloro-imidazo[1,2-b]pyridine. (227 mg), PdCl2(dppf)DCM (110 mg), K3PO4 (570 mg), 1,4-didiphenyl ether (DPE) A mixture of hexane (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 solution, and the mixture was then filtered through diatomaceous earth. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (329 mg).

[0168] Example 137 Synthesis of 6-(2-phenoxypyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridine The mixture contained 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-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), and 1,4-dioxaneborane-2-ylpyrimidine. A mixture of 4 mL of acetic acid and 2 mL of water was stirred at 90°C for 3 hours under a nitrogen atmosphere. AcOEt and water were added to the reaction solution, and the mixture was then filtered through diatomaceous earth. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was dissolved in THF (5 mL), and 1N-TBAF (1.34 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by alkaline silica column chromatography (DCM / AcOEt) to obtain the target compound (325 mg).

[0169] Example 139 Synthesis of 4-(2-phenoxypyrimidin-5-yl)-1,8-naphthylidine The mixture contained 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine (300 mg), 4-chloro-[1,8]-naphthyl (199 mg), K3PO4 (427 mg), PdCl2(dppf)DCM (6.56 mg), and 1,4-dioxaneborane-2-yl) A mixture of 4 mL of acetic acid and 2 mL of water was heated to reflux under a nitrogen atmosphere for 3 hours. Water was added to the reaction solution, 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)pyrimidin-5-yl)imidazo[1,2-a]pyridine A mixture containing 300 mg of 6-(2-(dodecylsulfonylurea)pyrimidin-5-yl)imidazo[1,2-a]pyridine, 0.089 mL of 1-chloro-3-hydroxybenzene, 193 mg of K₂CO₃, and 3 mL of DMF was stirred at 80°C for 5 hours. The reaction solution 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 then concentrated. The residue was purified by alkaline column chromatography (DCM / AcOEt) to obtain the target compound (194 mg).

[0171] Example 172 Synthesis of 5-(2-phenoxypyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridine-2(3H)-one The mixture contained 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine (560 mg), 5-bromo-1H,2H,3H-pyrrolo[3,2-b]pyridin-2-one (200 mg), PdCl2(dppf)DCM (38.3 mg), K3PO4 (399 mg), and 1,4-dioxane-2-ylpyrimidine (200 mg). A mixture of 4 mL of acetic acid and 2 mL of water was stirred at 90°C for 5 hours under a nitrogen atmosphere. AcOEt and water were added to the reaction solution, and the mixture was then filtered through diatomaceous earth. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by alkaline silica column chromatography (DCM / AcOEt) to obtain the target compound (98 mg).

[0172] Example 173 Synthesis of 6-(2-phenoxypyrimidin-5-yl)-[1,2,3]triazolo[1,5-a]pyridine The mixture contained 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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), and 1,4-dioxacyclopentaborane-2-yl)pyrimidine. A mixture of α (4 mL) and water (2 mL) was stirred at 90°C for 5 hours. AcOEt and water were added to the reaction solution, and the mixture was then filtered through diatomaceous earth. The filtrate was separated, and the organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by alkaline silica column chromatography (DCM / AcOEt) to obtain the target compound (250 mg).

[0173] Example 198 Synthesis of 5-methyl-6-(2-phenoxypyrimidin-5-yl)imidazo[1,2-a]pyridine hydrochloride The mixture contained 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine (330 mg), 6-bromo-5-methyl-imidazo[1,2-a]pyridine (257 mg), PdCl2 (dppf), DCM (45.2 mg), K3PO4 (470 mg), and 1,4-dioxaneborane-2-yl)pyrimidine. A mixture of EtOH (4 mL) and water (2 mL) was stirred at 90°C for 5 hours. AcOEt and water were added to the reaction solution, and the mixture was then filtered through diatomaceous earth. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by alkaline silica column chromatography (DCM / AcOEt). The resulting oily material was dissolved in EtOH, to which 3 mL of 1N-HCl EtOH solution was added, the mixture was stirred, and then the reaction solution was concentrated. The precipitated crystals were recrystallized from EtOH / AcOEt to obtain the target compound (349 mg).

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

[0175] Example 221 Synthesis of 1-(2-(3-fluorophenoxy)pyrimidin-5-yl)tetrahydropyrimidin-2(1H)-one 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 solution, and the precipitated crystals were collected by filtration 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 solution, and the product was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (AcOEt / MeOH), and the resulting solid was washed with EtOH to obtain the target compound (460 mg).

[0176] Example 223 Synthesis of 2-phenoxy-5-(piperidin-1-yl)pyrimidine A mixture containing 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 solution, and the mixture was then filtered through diatomaceous earth. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel chromatography (hexane / AcOEt) to obtain the target compound (53 mg).

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

[0178] Example 229 Synthesis of 4-(2-phenoxypyrimidin-5-yl)urarin-3-one The mixture contained 5-iodo-2-phenoxypyrimidine (500 mg), 3-ketophosphoroline (254 mg), copper iodide (I) (31.9 mg), K3PO4 (712 mg), (1R,2R)-N,N-dimethyl-1,2-cyclohexanediamine (0.053 mL), and 1,4-dioxanediamine. The mixture of 6 mL was stirred at 90°C for 4 hours. The reaction solution was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (368 mg).

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

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

[0181] Example 257 Synthesis of 5-(2-phenoxypyrimidin-5-yl)-1H-benzo[d]imidazolium oxalate The mixture contained 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine (400 mg), 5-bromo-1H-benzo[d]imidazole (291 mg), PdCl2(dppf)DCM (110 mg), K3PO4 (570 mg), and 1,4 ... A mixture of hexane (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 solution, and the mixture was then filtered through diatomaceous earth. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt). The resulting oily material was dissolved in ethanol, and an ethanol solution (1 mL) containing oxalic acid (80 mg) was added. The precipitate was collected by filtration and dried to obtain the target compound (250 mg).

[0182] Example 262 Synthesis of 5-(2-phenoxypyrimidin-5-yl)-1H-indole The mixture contains 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrimidine (400 mg), 5-bromo-1-(triisopropylsilyl)-1H-indole (520 mg), PdCl2(dppf)DCM (110 mg), K3PO4 (570 mg), and 1,4 ... 1-bromo-1-(dioxaneborane-2-yl A mixture of hexane (4 mL) and water (2 mL) was stirred at 80°C for 3 hours under a nitrogen atmosphere. AcOEt and water were added to the reaction solution, and the mixture was then filtered through diatomaceous earth. The filtrate was separated, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was dissolved in THF (10 mL), to which TBAF (1.342 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and then 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 containing 4-(3-fluorophenoxy)aniline (5.00 g), acrylic acid (2.53 mL), and toluene (40 mL) was stirred overnight at 80°C. The reaction solution was concentrated, and urea (4.43 g) and AcOH (20 mL) were added. The mixture was then heated to reflux for 3 hours. Water was added, and the precipitate was collected by filtration. The precipitate was purified by silica gel column chromatography (DCM / MeOH) to obtain the target compound (2.33 g).

[0184] Example 305 Synthesis of 1-(4-(3-fluorobenzyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture containing m-fluorobenzyl chloride (0.11 mL), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-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 to reflux under nitrogen atmosphere for 2 hours. The reaction solution was poured into ice water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel 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 60% NaH (32.0 mg) was added to a DMF (5 mL) solution containing 1-(4-(3-fluorophenoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg), and stirred at 0°C for 30 minutes. Iodomethane (0.046 mL) was added while stirring at 0°C, and then stirred overnight at room temperature. The reaction solution was poured into ice water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by alkaline 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 containing 1-[4-(3-hydroxy)phenyl]dihydropyrimidine-2,4(1H,3H)-dione (337 mg), sodium difluorochloroacetate (344 mg), K₂CO₃ (234 mg), and DMF (1.7 mL) was stirred at 90°C for 4 hours. Sodium difluorochloroacetate (344 mg) was added, and the mixture was stirred for another 2 hours. Concentrated hydrochloric acid was added to the reaction solution, and the product was extracted with AcOEt. The product 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), crystallized by the addition of EtOH, and washed with EtOH to obtain the target compound (79 mg).

[0187] Example 321 Synthesis of 1-[4-(6-fluoropyridin-2-yloxy)phenyl]dihydropyrimidine-2,4(1H,3H)-dione A mixture containing 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 solution, and the precipitated solid was collected by filtration. The solid was purified by silica gel column chromatography (DCM / MeOH), and the resulting solid was washed with EtOH to obtain the target compound (244 mg).

[0188] Example 322 Synthesis of 1-(4-phenoxyphenyl)pyrimidine-2,4(1H,3H)-dione A mixture containing 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 solution was poured into water, and the product was extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel 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 containing monobromophenyl (0.158 mL), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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 to reflux under a nitrogen atmosphere for 12 hours. AcOEt and anhydrous magnesium sulfate were added to the reaction solution, and the mixture was then filtered through diatomaceous earth. The filtrate was concentrated, the residue was purified by silica gel chromatography (DCM / MeOH), and 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 containing 4-phenoxyaniline (0.50 g), toluene (5 mL), and crotonic acid (0.34 mL) was heated to reflux for 13 hours. Crotonic acid (0.34 mL) was added, and the mixture was heated to reflux for another 6 hours. The reaction solution was concentrated, and acetic acid (5 mL) and urea (0.324 g) were added, and the mixture was heated to reflux for 17 hours. Concentrated hydrochloric acid (0.23 mL) was added to the reaction solution, and the mixture was heated to reflux for 30 minutes. Water was added to the reaction solution, and the product was extracted with AcOEt. The product was washed with water, saturated NaHCO3 aqueous solution, and brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was crystallized by adding EtOH (3 mL) and IPE (3 mL). The solid was collected by filtration and washed with IPE to obtain the target compound (272 mg).

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

[0192] Example 343 Synthesis of 6-ethyl-1-(4-phenoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture containing 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 solution and the mixture was heated to reflux for 3 hours. Water and AcOEt were added to the reaction solution and separated. The organic layer was washed with a saturated aqueous solution of NaHCO3 and brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH) and crystallized by adding EtOH (2 mL). The solid was collected by filtration and washed with EtOH and IPE to obtain the target compound (204 mg).

[0193] Example 344 Synthesis of 1-[4-(3,5-difluoromethoxy)phenyl]dihydropyrimidine-2,4(1H,3H)-dione A mixture containing 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 another 1.5 hours. Water (15 mL) was added to the reaction solution, and the precipitated solid was collected by filtration and washed with water and EtOH to obtain the target compound (35 mg).

[0194] Example 346 1-(6-phenoxy-2-ethylhexyl) Synthesis of 3-yl)pyrimidine-2,4(1H,3H)-dione The mixture contained phenol (1.017 mL) and 1-(6-chlorophenoxyacetic acid). A mixture of 2.00 g (-3-yl)pyrimidine-2,4(1H,3H)-dione, 4.35 g (Cs₂CO₃), and 20 mL (DMSO) was stirred overnight at 130°C. An aqueous solution of citric acid was added to the reaction solution, and the product was then 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 1-(6-phenoxy-2-ethylhexyl) Synthesis of 3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(6-phenoxy-tadalafil) 577 mg of 3-yl)pyrimidine-2,4(1H,3H)-dione was dissolved in DMF (10 mL), and 50% Pd / C (500 mg) containing 10% water was added. The mixture was stirred at 50°C for 6 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, 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 to 10, 12 to 23, 25 to 29, 31 to 35, 37, 39 to 59, 61, 62, 64 to 68, 70, 71, 73 to 83, 85 to 87, 89, 90, 93, 95 to 105, 107 to 113, 115 to 117, 120 to 122, 124 to 136, 138, 140 to 162, 164 to 171, 174 to 197, 199 to 219, 222, 224, 225, 227, 228, 230 to 238, 241 to 256, 258 to 261, 263 to 301, 303, 304, 306, 307, 309 to 313, 315 to 3 Compounds 20, 323 to 326, 329 to 336, 338 to 342, 345, and 348 to 350 are manufactured in the same manner as those in Examples 1, 4, 6, 7, 11, 24, 30, 36, 38, 60, 63, 69, 72, 84, 88, 91, 92, 94, 106, 114, 118, 119, 123, 137, 139, 163, 172, 173, 198, 220, 221, 223, 226, 229, 239, 240, 257, 262, 302, 305, 308, 314, 321, 322, 327, 328, 337, 343, 344, 346, and 347. The structural formulas and physicochemical data of the compounds in Examples 1 to 350 are shown in Tables 2-1 to 2-37.

[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] [Experimental Examples] The following presents the pharmacological test results of typical compounds of the present invention and explains the pharmacological effects of these compounds, but the present invention is not limited to these test examples.

[0199] [Experimental Example 1] Model of Acoustic Epileptic Seizures The animal models used in this experiment were phenotypic models of partial seizures (including secondary generalized seizures) and generalized tonic-clonic seizures, and had high clinical predictability. This experiment was conducted based on the report by De Sarro et al. (Br J Pharmacol. [British Journal of Pharmacology] February 1988; 93(2): 247-56, Anticonvulsant effects of some calcium entry blockers in DBA / 2 mice, De Sarro GB, Meldrum BS, Nisticó G.). In this experimental 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 administered orally at a dose of 30 mg / kg to male and female DBA / 2 mice (Japan SLC, Inc., 3 weeks old, 8 mice per group). One hour after oral administration of the test compound, each mouse was placed in a 30 cm high, 23 cm diameter transparent acrylic cylinder and allowed 30 seconds for adaptation. They were then exposed to auditory stimulation (12.6 kHz, 100–110 dB) for 1 minute or until a tonic seizure occurred. The following scale was used to assess seizure response: 0: no seizure, 1: running, 2: interictal seizure, 3: tonic seizure, and 4: respiratory arrest. The maximum response was recorded as the seizure severity score. The attack suppression rate for each compound administration group was calculated using the following formula. [Mathematical Operations 1] The results are shown in Tables 3-1 to 3-3. Here, a seizure suppression rate of 90% or higher is denoted as "A", a seizure suppression rate of 70% or higher but less than 90% is denoted as "B", and a seizure suppression rate of 50% or higher but less than 70% is denoted as "C". [Table 3-1] [Table 3-2] [Table 3-3]

[0200] [Experimental Example 2] Rotating Bar Test This experiment was conducted to evaluate the effects of the compound on motor coordination. In this experimental example, the example compounds shown in Table 4 below were used as the test compounds. Male ICR mice (SLC Corporation, Japan, 5-6 weeks old, 8 mice per group) were trained to remain on a rotating bar (Muromachi Kikai Co., Ltd.) at a fixed speed (15 rpm) for 2 minutes. The test compound was suspended in 5% gum arabic / distilled water (w / v) and administered orally at a dose of 30 mg / kg. One hour after oral administration, the mice were placed back on the bar, and the speed was increased from 4 rpm to 40 rpm over 5 minutes. The time before falling off the bar was recorded for 200 seconds. The time before falling off the compound-administered group was calculated as a relative value to the mean time before falling off the solvent-administered group. The results are shown in Tables 4-1 and 4-2. Here, coordination barriers of 25% or less are denoted as "A", and coordination barriers of more than 25% but not exceeding 50% are denoted as "B". [Table 4-1] [Table 4-2]

[0201] [Experimental Example 3] Model of Maximum Electroconvulsive Outbreak (MES) This experiment was conducted to evaluate the anticonvulsant activity of the compound. The mouse model used in this experiment was a phenotypic model of generalized tonic-clonic seizures and secondary generalized partial seizures. This experiment was conducted based on the report by AJ Hill et al. (Br J Pharmacol. [British Journal of Pharmacology] December 2012; 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 administered orally at a dose of 30 mg / kg to male ICR mice (SLC Corporation, Japan, 5-6 weeks old, 8 mice per group). One hour after oral administration of the test compound, the mice were stimulated using an electroconvulsive device (UGO BASILE SRL Corporation) with an electric current (30 mA, 100 Hz, 0.2 s) applied via auricular electrodes. The incidence of tonic hind limb extension seizures was then recorded. In the above experiments, it was confirmed that in the solvent application group, tonic hindlimb extension seizures were induced in all cases, but in the test compound application group, the seizures were suppressed.

[0202] [Experimental Example 4] Subcutaneous pentylenetetrazol (scPTZ) model This experiment was conducted in Experiment Example 3 to evaluate the anticonvulsant activity of the compound. Unlike the phenotype in Experiment Example 3, the animal model used in this experiment was a phenotype model of generalized absence seizures and myoclonic seizures. The test compound was suspended in 5% gum arabic / distilled water (w / v) and administered orally at a dose of 30 mg / kg to male ICR mice (SLC Corporation, Japan, 5 to 6 weeks old, 10 mice per group). One hour later, 85 mg / kg of pentylenetetrazol dissolved in saline was administered subcutaneously, and the occurrence and duration of clonic seizures were assessed. In the above experiments, it was confirmed that clonic seizures were induced in all cases in the solvent administration group, but the seizures were suppressed in the test compound administration group.

[0203] Therefore, since the compounds of the present invention exhibit anticonvulsant activity in all cases across various animal models used to evaluate antiepileptic drugs, they can be used as antiepileptic drugs (compounds) with a broad therapeutic spectrum for the prevention and / or treatment of seizures or convulsive episodes (including multidrug-resistant seizures, refractory seizures, acute symptom seizures, febrile epilepsy, and status epilepticus). Furthermore, the compounds of the present invention can be used as diagnostic compounds for diseases involving seizures or convulsive episodes (including multidrug-resistant seizures, refractory seizures, acute symptom seizures, febrile epilepsy, and status epilepticus).

[0204] none

[0205] none

Claims

1. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive episodes, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is selected from the group consisting of:

2. A therapeutic, preventive and / or diagnostic pharmaceutical composition as described in claim 1, wherein the compound is selected from the group consisting of:

3. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is...

4. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is...

5. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is...

6. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is...

7. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is [missing information].

8. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is...

9. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is...

10. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is...

11. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is...

12. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is...

13. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is...

14. A therapeutic, preventive, and / or diagnostic pharmaceutical composition for the treatment of seizures or convulsive seizures, comprising a compound or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the compound is...

Images