Macrocyclic pyrimidine derivatives, their production method, and pharmaceutical compositions containing the same as an active ingredient for preventing or treating neurodegenerative diseases

Abstract

The present invention relates to a macrocyclic pyrimidine derivative, a method for producing the same, and a pharmaceutical composition for preventing or treating neurodegenerative diseases, which contains the same as an active ingredient. The macrocyclic pyrimidine derivative according to the present invention has excellent LRRK2 inhibitory activity and efficiently passes through the blood-brain barrier (BBB), and therefore can be effectively used as a pharmaceutical composition for preventing or treating neurodegenerative diseases.

Description

[Technical field]

[0001] The present invention relates to a macrocyclic pyrimidine derivative, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient for preventing or treating a neurodegenerative disease. [Background technology]

[0002] Neurodegenerative diseases are a type of brain disease that occurs with aging and are known to be caused by the accumulation of environmental and genetic factors. Neurodegenerative diseases are a general term for diseases in which degeneration occurs due to the steady and gradual death of nerve cells in the central nervous system, resulting in a variety of symptoms, and are characterized by cell destruction and loss of nerve structure and function, including memory impairment.

[0003] Representative examples include Parkinson's disease, Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, prion disease, motor neuron disease, spinocerebellar degeneration, spinal muscular atrophy, Creutzfeldt-Jakob disease, and alcoholic dementia.

[0004] Parkinson's disease, along with Alzheimer's disease, is one of the representative neurodegenerative diseases, and is caused by the loss of the neurotransmitter dopamine due to a deficiency of dopaminergic neurons in the substantia nigra of the brainstem. As a result, protein aggregates called Lewy bodies are formed in nerve cells, causing motor symptoms such as stooped posture, tremors, muscle rigidity, and instability, as well as mental symptoms such as depression, anxiety, and sleep disorders.

[0005] The cause of Parkinson's disease is unknown, but it is presumed to result from a combination of factors including environmental factors, genetic factors, aging, mitochondrial dysfunction, and abnormalities in the ability to process unnecessary proteins. Most cases of Parkinson's disease are accidental, but 5% to 10% are known to be hereditary diseases caused by gene mutations, and the causative genes are known to be parkin, PINK1, DJ-1, α-synuclein, and LRRK2 (leucine-rich repeat kinase 2).

[0006] Among these, the most frequently occurring dominant genotype is the G2019S mutation in the LRRK2 gene. LRRK2 is a type of protein belonging to the leucine-rich repeat kinase family, and consists of an amino acid sequence of 2,527 amino acids with high interspecies similarity. It combines GTPase activity and serine-threonine kinase activity in a single protein.

[0007] LRRK2 is reported to be highly expressed in dopaminergic neurons in the cerebral cortex, substantia nigra, striatum, hippocampus, and cerebellum, which are involved in the pathogenesis of Parkinson's disease, and increased activity of LRRK2 is known to affect the onset and progression of Parkinson's disease. It has been reported that when normal LRRK2 is overexpressed in neurons in LRRK2 hyperactive mutant animals, apoptosis is induced, resulting in apoptosis of dopaminergic neurons, Lewy bodies, and movement disorders similar to the symptoms of Parkinson's disease. In the case of LRRK2 knockout animals, neurite extension in the brain is inhibited, which is closely related to Parkinson's disease, and α-synuclein increases depending on age, and it has been confirmed in animal models that Parkinson's disease can be treated by inhibiting LRRK2. In addition, LRRK2 is known to be involved in the transmission of mild cognitive impairment associated with Alzheimer's disease, and therefore compounds and compositions that are effective in controlling LRRK2 activity may have a therapeutic effect on neurodegenerative diseases and the like. Therefore, selective inhibition of LRRK2 activity can be an effective target in the development of novel therapeutic agents for diseases.

[0008] In addition to the above neurodegenerative diseases, anticancer activity via inhibition of LRRK2 has been studied in various types of cancer as a mechanism for inhibiting cancer cell proliferation and promoting apoptosis. In particular, it has been reported that LRRK2 is overexpressed in kidney, thyroid, and liver cancer tissues, and it is known that LRRK2 overexpression due to LRRK2 mutations (especially G2019S type) increases the risk of breast cancer. Furthermore, some research results have reported that patients with LRRK2 overexpression in the tissues of domestic brain tumor patients have a significantly shorter survival time. In this regard, the initiation of the first phase of clinical trials using Boronoi as an LRRK2 inhibitor for the treatment of brain tumors was recently approved. Therefore, selective inhibition of LRRK2 activity can be a goal for the development of a wide range of novel drugs, including not only the treatment of neurodegenerative diseases but also anticancer drug treatment.

[0009] Meanwhile, in the prior art literature relating to compositions for preventing or treating neurodegenerative diseases, which contain pyrimidine derivatives as active ingredients, pyrimidin-2-ylamino-1H-pyrazole is disclosed as an LRRK2 inhibitor used in the treatment of neurodegenerative disorders (Patent Document 1). However, there have been no reports to date that mention the pyrimidine derivatives of formula 1 and the like of the present invention, the LRRK2 inhibitory activity of the derivatives, and the possibility of treating neurodegenerative diseases using the derivatives.

[0010] Therefore, through extensive research into LRRK2 derivatives, the inventors of the present invention have confirmed that the macrocyclic pyrimidine derivatives of the present invention, such as formula 1, have excellent LRRK2 inhibitory activity and efficiently pass through the blood-brain barrier (BBB), thereby completing the present invention. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] Korean Patent Publication No. 10-2019-0018676 Summary of the Invention [Problem to be solved by the invention]

[0012] One aspect of the present invention is to provide novel macrocyclic pyrimidine derivatives.

[0013] Another aspect of the present invention is to provide a novel pharmaceutical composition for the prevention or treatment of a neurodegenerative disease.

[0014] Another aspect of the present invention is to provide a novel health functional food for preventing or alleviating neurodegenerative diseases. [Means for solving the problem]

[0015] Thus, the present invention provides a compound of formula 1: [ka] [Formula 1] (In formula 1, A is O or N(R 2 ) and R 1 is hydrogen, halogen, or unsubstituted or halogen-substituted C 1~10 is alkyl, R 2 and R 3 and each independently represent hydrogen or unsubstituted C 1~10 is alkyl, p is 0 to 3; R 4 However, hydrogen, halogens, C 1~10 Alkyl or OR 4a R 4a is hydrogen, unsubstituted or halogen-substituted C 1~10 Alkyl, C 3~7 cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein n is 1 to 5), or a solvate, hydrate, or pharma- ceutically acceptable salt thereof.

[0016] In another aspect, the present invention provides a method for preparing a compound of formula 1, comprising: Reaction Scheme 1 below: [ka] [Reaction Scheme 1] (In reaction scheme 1, A, R 1 , R 3 , R 4 , p, and n are as defined in Equation 1), cyclizing a compound of formula 1A to produce a compound of formula 1.

[0017] In another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of a neurodegenerative disease, comprising a compound represented by formula 1 as described herein, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0018] In another aspect, the present invention provides a health functional food for preventing or alleviating a neurodegenerative disease, comprising a compound represented by formula 1 as described herein, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient. Effect of the Invention

[0019] Since the macrocyclic pyrimidine derivative according to the present invention has excellent LRRK2 inhibitory activity and efficiently crosses the blood-brain barrier (BBB), the macrocyclic pyrimidine derivative may be useful for use as a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present invention will be described in detail below.

[0021] It should be noted that the embodiments of the present invention can be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. Furthermore, the embodiments of the present invention are provided to more specifically explain the present invention to those skilled in the art who have ordinary knowledge in the related technical field.

[0022] In addition, in this specification, the expression "comprises" or "contains" a certain component does not exclude the inclusion of other components, unless otherwise specified, but means that other components may be further contained.

[0023] The terms "alkylene" or "alkyl" include straight or branched chain saturated hydrocarbon residues, unless otherwise specified. For example, "C 1~6 By "alkyl" is meant an alkyl group having a backbone of 1 to 6 carbons. More specifically, 1~6Alkyl may include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, etc. "Alkenyl" includes unsaturated hydrocarbons containing one or more carbon-carbon double bonds, ranging from 1 to 5, in the "alkyl" hydrocarbon chain.

[0024] The term "cycloalkyl" includes cyclic, fully saturated hydrocarbon residues, and "3- to 7-membered cycloalkyl" means a cycloalkyl having from 3 to 7 carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, bridged, fused, or spirocycloalkyls consisting of 2 or 3 rings may also be included.

[0025] The term "heterocycloalkyl", unless otherwise specified, includes a monovalent saturated moiety consisting of one to three rings containing one, two, three, or four heteroatoms selected from N, O, or S as ring atoms forming the ring. In this case, nitrogen (N) is included in the ring as NH to which a hydrogen is attached. When there are two or three rings, it can be a bridged heterocycloalkyl, a fused heterocycloalkyl, or a spiroheterocycloalkyl.

[0026] The term "heteroaryl", unless otherwise specified, can encompass a single ring or a two or three fused ring aromatic radical containing one or more aromatic rings containing one, two or three ring heteroatoms selected from N, O or S as ring atoms.

[0027] The term "substituted with halogen" means a state in which substitution is performed with one or more halogen atoms. The number of substituted halogen atoms is specifically in the range of 1 to 6, 1 to 5, or 1 to 4. For example, haloC 1~10 Alkyl is a C alkyl group in which 1 to 6 carbon atoms are substituted with halogen atoms. 1~10 It means alkyl.

[0028] The term "alkylcarbonyl" or "alkenylcarbonyl" means an alkyl or alkenyl substituted through a carbonyl group.

[0029] As used herein, "substituted" means unsubstituted, unless otherwise specified.

[0030] One aspect of the present invention is a compound of formula 1: [ka] [Formula 1] (In formula 1, A is O or N(R 2 ) and R 1 is hydrogen, halogen, or unsubstituted or halogen-substituted C 1~10 is alkyl, R 2 and R 3 and each independently represent hydrogen or unsubstituted C 1~10 is alkyl, p is 0 to 3; R 4 But halogen, C 1~10 Alkyl or OR 4a R 4a is hydrogen, unsubstituted or halogen-substituted C 1~10 Alkyl, C 3~7 cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein n is 1 to 5), or a solvate, hydrate, or pharma- ceutically acceptable salt thereof.

[0031] In the above formula 1, as another example, R 1 is halogen, or unsubstituted or substituted with 1 to 5 halogens 1~6 is alkyl, R 2 and R 3 and each independently represent hydrogen or C1~6 is alkyl, p is 0 to 2; R 4 But halogen, C 1~6 Alkyl or OR 4a R 4a is hydrogen, unsubstituted or halogen-substituted C 1~6 Alkyl, C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl; n is 1 to 5.

[0032] In formula 1, as another example, R 1 is halogen or unsubstituted or substituted with 1 to 3 halogens 1~3 is alkyl, R 2 and R 3 and each independently represent hydrogen or C 1~3 is alkyl, p is 0 to 2; R 4 But halogen, C 1~3 Alkyl or OR 4a R 4a is hydrogen, unsubstituted or halogen-substituted C 1~3 Alkyl, C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl; n is 1 to 5.

[0033] In formula 1, as another example, R 1 is -Cl, -F, or -CF3; R 2 and R 3 and each independently represent hydrogen or C 1~3 is alkyl, p is 0 to 2; R 4 But, -F, C 1~3 Alkyl or OR 4a R 4ais unsubstituted or substituted with 1 to 3 halogens 1~3 Alkyl, C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl having one O atom; n is 1 to 4.

[0034] In formula 1, as another example, R 1 is -CL, -F, or -CF3; R 2 and R 3 and are each independently hydrogen, methylethyl, or isopropyl; p is 0 to 2; R 4 are independently -F, ethyl, -CF3, methoxy, isopropoxy, -OCF3, cyclopropoxy, oxetan-3-yloxy; n is 2 to 4.

[0035] In another example, the compound according to formula 1 above is 1 5 -bromo-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one, 1 5 -bromo-2,5,11-triaza-1(2,4)-pyrimidina-3(1,3)-benzenecycloundecaphan-4-one, is excluded.

[0036] As another example, the compound represented by formula 1 is the compound: <1> 3 6 -Methoxy-5,9-dimethyl-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononaphan-4-one; 2,2,2-trifluoroacetate, <2> 1 5 -chloro-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one, <3> 15 -chloro-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one, <4> 1 5 -Chloro-3 6 -Methoxy-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one, <5> 1 5 -Chloro-3 6 -Methoxy-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one, <6> 1 5 -Chloro-3 6 -Methoxy-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <7> 1 5 -Fluoro-3 6 -Methoxy-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one, <8> 1 5 -Chloro-3 6 -Fluoro-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <9> 1 5 -Chloro-3 4 -Methoxy-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <10> 1 5 -Chloro-3 5 -Methoxy-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <11> 1 5 -Chloro-3 6-Methoxy-5-methyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <12> 1 5 -Chloro-3 6 -Methoxy-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <13> 1 5 -Chloro-3 6 -Ethyl-5-methyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <14> 1 5 -Chloro-3 5 -Methoxy-5-methyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <15> 1 5 -Chloro-3 4 -Methoxy-5-methyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <16> 1 5 -Chloro-3 6 -Methoxy-5-methyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <17> 1 5 -Chloro-3 5 -Methoxy-5-methyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <18> 1 5 -Chloro-3 4 -Methoxy-5-methyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <19> 15 -Chloro-3 6 -Ethyl-5-methyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <20> 1 5 -Chloro-3 6 -Methoxy-5,8-dimethyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <21> 1 5 -Chloro-5-ethyl-3 6 -Methoxy-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <22> 1 5 -Chloro-5-isopropyl-3 6 -Methoxy-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one, <23> 1 5 -Chloro-3 6 -Methoxy-5,9-dimethyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <24> 3 6 -Methoxy-5-methyl-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <25> 3 6 -Methoxy-5,8-dimethyl-1 5 -(Trifluoromethyl)-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <26> 3 6 -Methoxy-5-methyl-1 5-(Trifluoromethyl)-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <27> 1 5 -Chloro-3 6 -Methoxy-5,10-dimethyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <28> 3 5 -Fluoro-3 6 -Methoxy-5,9-dimethyl-1 5 -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one, <29> 3 6 -Methoxy-5,10-dimethyl-1 5 -(Trifluoromethyl)-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <30> 5,9-Dimethyl-3 6 -(trifluoromethoxy)-1 5 -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one, <31> 5,9-Dimethyl-1 5 ,3 6 -bis(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one, <32> 3 5 -Methoxy-5,9-dimethyl-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononaphan-4-one; 2,2,2-trifluoroacetate, <33> 3 6 -Methoxy-5-methyl-1 5-(Trifluoromethyl)-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <34> 3 5 -Fluoro-3 6 -Methoxy-5-methyl-1 5 -(trifluoromethyl)-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one, <35> 5-Methyl-3 6 -(trifluoromethoxy)-1 5 -(trifluoromethyl)-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one, <36> 3 5 -Fluoro-3 6 -Methoxy-5-methyl-1 5 -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <37> 3 5 -Methoxy-5-methyl-1 5 -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <38> 5-Methyl-3 6 -(oxetane-3-yloxy)-1 5 -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <39> 3 6 -Isopropoxy-5-methyl-1 5 -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <40> 1 5 -Chloro-5-methyl-3 6 -(trifluoromethoxy)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <41> 5-Methyl-36 -(trifluoromethoxy)-1 5 -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <42> 1 5 -Chloro-3 6 -Methoxy-5-methyl-9-oxa-2,5-diaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <43> 3 6 -Methoxy-5-methyl-1 5 -(trifluoromethyl)-9-oxa-2,5-diaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <44> 5-Methyl-3 6 -(trifluoromethoxy)-1 5 -(trifluoromethyl)-9-oxa-2,5-diaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <45> 3 5 -Fluoro-3 6 -Methoxy-5-methyl-1 5 -(trifluoromethyl)-9-oxa-2,5-diaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <46> 3 6 -Cyclopropoxy-5-methyl-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, and <47> 3 6 -Cyclopropoxy-5,9-dimethyl-1 5 -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, is selected from the group:

[0037] The compound represented by formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid, non-toxic organic acids such as aliphatic monocarboxylates and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, and alkanedioates, aromatic acids, and organic acids such as aliphatic and aromatic sulfonic acids, trifluoroacetate, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. These pharma- ceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-dioate, hexane-1,6-dioate, benzoate, Examples of the salts include chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0038] The acid addition salts according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, and acetonitrile, adding an organic or inorganic acid, and filtering and drying the resulting precipitate, or by distilling off the solvent and excess acid under reduced pressure, drying, and crystallizing in the organic solvent.

[0039] The term "hydrate" refers to a compound of the present invention, or a salt thereof, containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate of the compound of formula 1 of the present invention may contain a stoichiometric amount of water bound by non-covalent intermolecular forces, or may contain a non-stoichiometric amount of water. The hydrate may contain one or more equivalents of water, preferably 1 to 5 equivalents of water. Such a hydrate can be prepared by crystallizing the compound of formula 1 of the present invention, its isomer, or a pharma- ceutical acceptable salt thereof from water or a solvent containing water.

[0040] The term "solvate" refers to a compound of the invention, or a salt thereof, that contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvates include those that are volatile, non-toxic, and / or suitable for administration to humans.

[0041] In another embodiment of the present invention, As shown in reaction scheme 1 below: A method for preparing a compound of formula 1 is provided, comprising cyclizing a compound of formula 1A to prepare a compound of formula 1 (Step 4): [ka] [Reaction Scheme 1] (In reaction scheme 1, A, R 1 , R 3 , R 4 , p, and n are as defined in Equation 1).

[0042] This is the process in which the compound represented by formula 1A in Reaction Scheme 1 is reacted in the presence of a metal catalyst to cause a crystallization reaction, which is achieved via a substitution reaction of the chloro substituent of the pyrimidine ring with an amino group.

[0043] For this reaction, the metal catalyst is typically palladium, and examples of the metal catalyst that can be used include tetrakis(triphenylphosphine)palladium(0) ((PPh3)4Pd), palladium acetate (II), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3), bis(triphenylphosphine)palladium(II chloride (PdCl2(PPh3)2), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(0) chloride (Pd(dppf)Cl2). Although the reaction may be carried out without the use of a ligand, the reaction is generally carried out in the presence of a metal catalyst, such as triphenylphosphine ((PPh3)4), 1,2-bis(diphenylphosphino)propane (DPPP), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), Xantphos, and XPhos. The reaction is carried out using a ligand that is commonly used in the Buchwald reaction of the above. Examples of bases that can be used here include potassium carbonate, KOtBu, cesium carbonate, potassium phosphate, sodium hydroxide, triethylamine, etc., and the reaction is carried out using a solvent that does not adversely affect the reaction, such as toluene, tetrahydrofuran, dioxane, and N,N-dimethylformamide. The reaction conditions for the crystallization reaction may be either acidic or basic, and conditions known in the art may be applied.

[0044] After step 4, a reaction for forming a salt may be further included. The reaction conditions for forming the salt may be an organic acid or an inorganic acid as defined above, and conditions known in the art may be applied.

[0045] Formula 1A in Scheme 1 can also be prepared as in Scheme 2: [ka] [Reaction Scheme 2] (In reaction scheme 2, A, R 1 , R 3 , R 4 , p, and n are as defined in Formula 1; B is hydrogen).

[0046] The production method according to Reaction Scheme 2 will be described in detail below.

[0047] In step 1 of reaction scheme 2, a compound represented by formula 1F is subjected to a Buchwald-Hartwig amination reaction (where A is NR 2 (when A is O) or via an alkoxide substitution reaction (when A is O) with 1E to produce a compound of formula 1C. This reaction is preferably carried out in the presence of a palladium catalyst and a base, and the Buchwald-Hartwig amination reactor may be modified based on what is known in the art. In the alkoxide substitution reaction, a strong base such as a hydrogen compound may be required.

[0048] Step 2 is a hydrolysis reaction, which converts carbamate to a secondary amine under acidic conditions. The reaction is preferably carried out under acidic conditions, and the reaction conditions for hydrolysis may be those known in the art.

[0049] Step 3 is an amidation reaction in which Formula 1B is reacted with various benzoic acids 1C to produce Formula 1A. The reaction conditions for the amidation reaction may be those known in the art.

[0050] This production method is not limited to the embodiment of the present invention exemplified, and the solvent, reactants, temperature conditions, etc. can be changed based on general knowledge of organic chemistry.

[0051] In another embodiment of the present invention, Provided is a pharmaceutical composition for preventing or treating a neurodegenerative disease, comprising a compound represented by the above formula 1, a solvate thereof, a hydrate thereof, or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0052] The neurodegenerative disease may be Parkinson's disease, Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, prion disease, motor neuron disease, spinocerebellar degeneration, spinal muscular atrophy, Creutzfeldt-Jakob disease, or alcoholic dementia.

[0053] The above compounds may inhibit LRRK2 (leucine-rich repeat kinase 2) activity.

[0054] In the present invention, the expression "containing as an active ingredient" means containing as an ingredient that plays an important role in the prevention, alleviation, or treatment of neurodegenerative diseases, in which case the range of dosage can be changed depending on the severity of the disease and the preparation, and the number of doses can be changed depending on the age, weight, and constitution of the subject. In a specific embodiment of the present invention, the compound represented by formula 1 in the pharmaceutical composition of the present invention is contained in an amount of, for example, 0.001 mg / kg or more, 0.1 mg / kg or more, 10 mg / kg or more, 100 mg / kg or more, 250 mg / kg or more, or 0.1 g / kg or more. The upper limit of the amount of the compound represented by formula 1 contained in the pharmaceutical composition of the present invention can be selected and set within an appropriate range by a person skilled in the art. The upper limit of the amount may be selected within a range that can have activity without showing lethal toxicity, and may be, for example, 2000 mg / kg or less, or 1000 mg / kg or less.

[0055] Pharmaceutical compositions according to the present invention may comprise an effective amount of a compound of formula 1 alone, or may include one or more pharma- ceutically acceptable carriers, excipients, or diluents.

[0056] The pharma- ceutically acceptable carrier, excipient, or diluent refers to a substance that is physiologically acceptable and does not normally cause allergic reactions, such as gastrointestinal upset, dizziness, or similar reactions, when administered to humans. Examples of the carrier, excipient, and diluent include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. The composition may further include fillers, anticoagulants, lubricants, wetting agents, flavorings, emulsifiers, and preservatives.

[0057] The compound represented by formula 1 or its pharma- ceutically acceptable salt can be administered in various oral or parenteral dosage forms in clinical administration. When formulated, the compound is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which are prepared by mixing one or more compounds with at least one excipient such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, liquid preparations may contain various excipients such as wetting agents, sweeteners, flavorings, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0058] A pharmaceutical composition containing the compound represented by the above formula 1 or a pharma- ceutical acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration is carried out by subcutaneous injection, intravenous injection, intramuscular injection, or intrapleural injection.

[0059] In this case, to prepare a preparation for parenteral administration, the compound represented by the above formula 1 or a pharma- ceutically acceptable salt thereof is mixed with a stabilizer or buffer in water to form an aqueous solution or suspension. The aqueous solution or suspension may be prepared in a unit dosage form of an ampoule or vial. The composition may be sterilized and / or may contain auxiliary agents such as preservatives, stabilizers, dehydrating agents, or emulsifiers, salts for adjusting osmotic pressure, and / or buffers, and other medicamentously useful substances, and may be formulated by conventional mixing, sizing, or coating methods.

[0060] In the present invention, the term "prevention" means that the pharmaceutical composition or food composition of the present invention is administered, ingested, or applied to a subject not suffering from a neurodegenerative disease, thereby suppressing or inhibiting the symptoms of the neurodegenerative disease and preventing the onset of cancer symptoms in advance.

[0061] In the present invention, the term "treatment" means that the pharmaceutical composition of the present invention is administered to a subject suffering from a neurodegenerative disease, and includes not only complete cure of the symptoms of a neurodegenerative disease, but also partial cure, reduction, and alleviation of the symptoms of a neurodegenerative disease.

[0062] The pharmaceutical compositions of the present invention are administered in effective dosages.

[0063] In the present invention, the term "effective dose" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to the cure or palliative, and an effective dose can be determined based on the individual type and severity of the disease, age, sex, drug activity, drug sensitivity, time of administration, route of administration and excretion rate, duration of treatment, drugs currently in use, and other factors known in the medical art.

[0064] Furthermore, the compound represented by the above formula 1 may be in the form of not only a pharma- ceutically acceptable salt but also a solvate, hydrate, etc. that can be produced from a pharma- ceutically acceptable salt.

[0065] In another aspect of the invention, Provided is a health functional food for preventing or alleviating a neurodegenerative disease, comprising a compound represented by formula 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0066] In the present invention, the term "alleviation" is meant to include the reduction or improvement of symptoms of a neurodegenerative disease by administering, ingesting, or applying the pharmaceutical composition or food composition of the present invention to a subject suffering from a neurodegenerative disease.

[0067] In the present invention, the term "health functional food" can be used without distinction from "dietary supplements" and means a food manufactured or processed using raw materials or ingredients having useful functionality for the human body according to the Health Functional Food Law, and the term "functional" means intake for the purpose of obtaining a useful effect for health purposes such as adjusting nutrients for the structure and function of the human body or for physiological effects. The health functional food or dietary supplement of the present invention thus obtained is very useful because it can be consumed every day. In the case of a health functional food or dietary supplement in the form of a pill, granule, tablet, or capsule, it is usually added in the range of 0.1% by weight to 100% by weight, preferably 0.5% by weight to 80% by weight. In a specific example, the health functional food or dietary supplement of the present invention can be in the form of a pill, tablet, capsule, or drink.

[0068] The contents of the description regarding the pharmaceutical composition and food composition of the present invention are equally applicable unless inconsistent.

[0069] In another aspect, the present invention provides a method for preventing or treating a neurodegenerative disease, comprising administering to a subject in need thereof a compound of formula 1 as described herein, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0070] In another aspect, the present invention provides the use of a compound of formula 1 as described herein, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof in the prophylaxis or treatment of a neurodegenerative disease.

[0071] In the above-mentioned method or use, the detailed description of the pharmaceutical composition or health functional food described above can be applied. EXAMPLES

[0072] The present invention will be described in detail below with reference to examples and experimental examples.

[0073] It should be noted that the following examples and experimental examples are merely intended to more specifically illustrate one embodiment of the present invention, and the present invention is not limited thereto.

[0074] <Example 1> 3 6 -Methoxy-5-methyl-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; Formation of 2,2,2-trifluoroacetate

[0075] Step 1: [ka] To a stirred solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 eq.) in anhydrous tetrahydrofuran was added N-tert-butoxycarbonyl-N,N'-dimethyl-1,3-propanediamine (1.2 eq.) and triethylamine (1.2 eq.) at 0°C. The resulting solution was allowed to warm to room temperature and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the mixture was extracted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give the desired product.

[0076] Step 2: [ka] The BOC-containing 2-chloro-4-alkylamine-substituted pyrimidine was added to 6.0 M hydrogen chloride and stirred at 40° C. for 1 hour, after which the solvent was removed under reduced pressure to give the desired amine salt, which was used directly in the next reaction.

[0077] Step 3: [ka] The pyrimidine salt (1.0 equivalent) was dissolved in anhydrous dimethylformamide solvent, and 3-aminobenzoic acid (1.0 equivalent), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridium 3-oxide hexafluorophosphate (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridium 3-oxide hexafluorophosphate; hexafluorophosphate azabenzotriazole tetramethyluronium; HATU) (1.2 equivalents), and triethylamine (5.2 equivalents) were added and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water and ethyl acetate in an ice bath and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the mixture solvent was concentrated under reduced pressure and purified by column chromatography to obtain the desired product.

[0078] Step 4: [ka] According to the above reaction scheme, 3-amino-N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)(methyl)amino)propyl)-4-methoxy-N-methylbenzamide (86 mg) was dissolved in 1,4-dioxane (4.0 mL), and palladium(II) acetate (9.0 mg), Xantphos (46.2 mg), and potassium phosphate tribasic (84.7 mg) were added. The mixture was bubbled under nitrogen for 5 minutes. The mixture was then heated to 90° C. and stirred for 16 hours. After the reaction was completed, the mixture was diluted with ethyl acetate, the solid was removed by filtration through Celite, and the mixture was washed with brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the mixture solvent was concentrated under reduced pressure, and purified by column chromatography to give 3H2O4. 6 -Methoxy-5,9-dimethyl-1 5 To obtain 4-(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one (pale yellow oil, 57 mg, 72%).

[0079] Step 5: 3 6 -Methoxy-5-methyl-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; Formation of 2,2,2-trifluoroacetate To generate the salt form, the above compound (1.0 equiv.) was dissolved in dichloromethane and trifluoroacetate solution (1.5 equiv.) was added, and the mixture was then stirred at room temperature for 10-30 minutes. The solvent and excess trifluoroacetate were concentrated under reduced pressure and slowly evaporated to obtain the desired salt form of the above compound. 1H NMR (400 MHz, CD2Cl2) δ11.90 (bs, 1H), 10.84 (s, 1H), 8.28 (s, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.5, 2.1 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 3.93 (s, 3H), 3.35 - 3.30 (m, 3H), 3.23 (bs, 4H), 3.06 (s, 3H), 2.20 (bs, 2H).

[0080] Hereafter, the compound of Example 2 was prepared similarly to Example 1. For the examples obtained in the form of TFA salt, it was carried out up to step 5, for the non-salt form it was carried out up to step 4.

[0081] <Example 2> 1 5 - Preparation of chloro-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one 1 H NMR (400 MHz, DMSO-d6) δ9.28 (d, J = 3.6 Hz, 1H), 8.73 (s, 1H), 7.95 (d, J = 3.7 Hz, 1H), 7.52 (s, 1H), 7.25 (td, J = 7.5, 3.6 Hz, 1H), 7.21 (s, 1H), 7.05 (d, J = 4.9 Hz, 1H), 4.28 (t, J = 12.5 Hz, 1H), 3.76 - 3.64 (m, 1H), 3.53 (t, J = 12.9 Hz, 1H), 2.97 (d, J = 3.6 Hz, 3H), 2.91 - 2.81 (m, 1H).

[0082] <Example 3> 1 5 -Chloro-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one (1 5 -Chloro-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one) 1H NMR (400 MHz, DMSO-d6) δ9.52 (s, 1H), 9.32 (s, 1H), 8.28 (s, 1H), 7.95 (s, 1H), 7.45 (t, J = 5.9 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 3.26 (dt, J = 11.6, 6.2 Hz, 2H), 3.18 (q, J = 6.0 Hz, 2H), 1.79 (bs, 2H), 1.41 (bs, 2H).

[0083] <Example 4> 1 5 -Chloro-3 6 -Methoxy-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one 1 H NMR (400 MHz, DMSO-d6) δ9.25 (bs, 1H), 8.15 (bs, 1H), 7.95 (s, 1H), 7.72 (s, 1H), 7.51 (t, J = 6.1 Hz, 1H), 7.18 (dd, J = 8.3, 2.1 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 3.31 - 3.22 (m, 2H), 3.17 (dt, J = 6.4, 4.6 Hz, 2H), 1.85 - 1.71 (m, 2H), 1.43 - 1.33 (m, 2H).

[0084] <Example 5> 1 5 -Chloro-3 6 -Methoxy-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one 1H NMR (400 MHz, CD2Cl2) δ10.50 (s, 1H), 10.10 (bs, 1H), 8.89 (d, J = 2.1 Hz, 1H), 7.91 (s, 1H), 7.44 (dd, J = 8.5, 2.1 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.86 - 6.74 (m, 1H), 6.58 - 6.46 (m, 1H), 4.21 (q, J = 11.3 Hz, 1H), 3.93 (s, 3H), 3.82 - 3.64 (m, 2H), 3.30 - 3.10 (m, 1H).

[0085] <Example 6> 1 5 -Chloro-3 6 -Methoxy-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ10.76 (bs, 1H), 10.39 (s, 1H), 8.64 (d, J = 2.2 Hz, 1H), 7.89 (s, 1H), 7.38 (dd, J = 8.5, 2.1 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.61 (s, 1H), 4.53 - 4.38 (m, 1H), 4.01 - 3.87 (m, 1H), 3.90 (s, 3H), 3.76 (ddt, J = 13.5, 10.8, 3.1 Hz, 1H), 3.07 (s, 3H), 3.00 (ddd, J = 13.7, 11.0, 6.9 Hz, 1H).

[0086] <Example 7> 1 5 -Fluoro-3 6 -Methoxy-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one 1H NMR (400 MHz, DMSO) δ8.74 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 4.5 Hz, 1H), 7.84 (dd, J = 6.2, 3.5 Hz, 1H), 7.79 (s, 1H), 7.11 (dd, J = 8.3, 2.1 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.28 - 4.16 (m, 1H), 3.85 (s, 3H), 3.67 (tt, J = 12.5, 6.5 Hz, 1H), 3.52 (tt, J = 13.2, 2.9 Hz, 1H), 2.95 (s, 3H), 2.83 (ddd, J = 13.2, 10.7, 6.9 Hz, 1H).

[0087] <Example 8> 1 5 -Chloro-3 6 -Fluoro-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; Preparation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ11.07 (s, 1H), 8.93 (bs, 1H), 8.67 (dd, J = 7.2, 2.2 Hz, 1H), 8.00 (s, 1H), 7.41 (ddd, J = 8.5, 4.5, 2.2 Hz, 1H), 7.20 (dd, J = 10.3, 8.5 Hz, 1H), 6.74 (t, J = 5.2 Hz, 1H), 4.46 - 4.31 (m, 1H), 3.97 (tt, J = 12.8, 6.6 Hz, 1H), 3.82 - 3.67 (m, 1H), 3.13 (s, 3H), 3.12 - 3.04 (m, 1H).

[0088] <Example 9> 1 5 -Chloro-3 4 -Methoxy-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ11.36 (s, 1H), 8.19 (d, J = 2.6 Hz, 1H), 7.86 (s, 1H), 7.25 (dd, J = 8.9, 2.7 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 6.52 (s, 1H), 6.16 (bs, 1H), 4.25 (t, J = 12.4 Hz, 1H), 3.88 (tt, J = 12.6, 6.6 Hz, 1H), 3.79 (s, 3H), 3.64 (t, J = 12.6 Hz, 1H), 3.14 (s, 3H), 3.12 - 3.01 (m, 1H).

[0089] <Example 10> 1 5 -Chloro-3 5 -Methoxy-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ11.54 (s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 6.91 (dd, J = 2.4, 1.4 Hz, 1H), 6.86 (t, J = 2.1 Hz, 1H), 6.56 (s, 1H), 6.15 (bs, 1H), 4.44 (t, J = 12.5 Hz, 1H), 3.91 (tt, J = 12.6, 6.6 Hz, 1H), 3.80 (s, 3H), 3.75 (ddd, J = 14.0, 8.6, 3.4 Hz, 1H), 3.10 (s, 3H), 3.02 (ddd, J = 13.5, 10.9, 6.9 Hz, 1H).

[0090] <Example 11> 1 5 -Chloro-3 6 -Methoxy-5-methyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ12.51 (s, 1H), 10.90 (s, 1H), 10.85 (s, 1H), 10.37 (t, J = 1.7 Hz, 1H), 9.53 (t, J = 2.1 Hz, 1H), 9.47 (dd, J = 2.5, 1.2 Hz, 1H), 6.97 (bs, 1H), 6.58 (s, 3H), 6.06 (bs, 2H), 5.84 (bs, 2H), 5.74 (s, 3H), 4.83 (bs, 2H).

[0091] <Example 12> 1 5 -Chloro-3 6 -Methoxy-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ10.05 (s, 1H), 9.68 (bs, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.96 (s, 1H), 7.84 (t, J = 7.3 Hz, 1H), 7.49 (dd, J = 8.6, 2.1 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.91 (t, J = 5.9 Hz, 1H), 3.95 (s, 3H), 3.43 - 3.34 (m, 2H), 3.30 (q, J = 6.5 Hz, 2H), 2.19 (dq, J = 14.6, 7.6, 7.1 Hz, 2H).

[0092] <Example 13> 1 5 -Chloro-3 6 -Ethyl-5-methyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; Formation of 2,2,2-trifluoroacetate 1H NMR (400 MHz, CD2Cl2) δ11.35 (s, 1H), 7.78 (s, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.27 (dd, J = 7.9, 1.7 Hz, 1H), 6.85 - 6.80 (m, 1H), 5.09 (bs, 1H), 3.27 - 3.10 (m, 4H), 3.02 (s, 3H), 2.80 (q, J = 7.6 Hz, 2H), 2.10 (bs, J = 21.3 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).

[0093] <Example 14> 1 5 -Chloro-3 5 -Methoxy-5-methyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ12.09 (s, 1H), 7.79 (s, 1H), 7.42 (d, J = 1.8 Hz, 1H), 6.90 (t, J = 1.8 Hz, 1H), 6.82 (t, J = 2.2 Hz, 1H), 6.64 - 6.59 (m, 1H), 3.84 (s, 3H), 3.31 (bs, 2H), 3.29 - 3.18 (m, 2H), 3.04 (s, 3H), 2.83 (bs, 1H), 2.15 (bs, 2H).

[0094] <Example 15> 1 5 -Chloro-3 4 -Methoxy-5-methyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; Formation of 2,2,2-trifluoroacetate 1H NMR (400 MHz, CD2Cl2) δ11.27 (bs, 1H), 10.65 (s, 1H), 7.93 (s, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.28 (dd, J = 8.8, 2.6 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.73 (t, J = 5.8 Hz, 1H), 3.82 (s, 3H), 3.46 - 3.37 (m, 1H), 3.32 (ddd, J = 15.4, 10.0, 5.9 Hz, 1H), 3.15 (s, 3H), 3.07 (td, J = 13.5, 5.9 Hz, 2H), 2.48 - 2.28 (m, 1H), 1.84 (q, J = 11.8 Hz, 1H).

[0095] <Example 16> 1 5 -Chloro-3 6 -Methoxy-5-methyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ10.68 (s, 1H), 10.13 (bs, 1H), 7.78 (s, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 8.5, 2.1 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.57 (t, J = 7.0 Hz, 1H), 3.92 (s, 3H), 3.50 (q, J = 6.3 Hz, 2H), 3.43 - 3.35 (m, 2H), 3.02 (s, 3H), 1.88 - 1.77 (m, 2H), 1.69 (dt, J = 10.8, 5.9 Hz, 2H).

[0096] <Example 17> 1 5 -Chloro-3 5-Methoxy-5-methyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ10.71 (s, 1H), 9.97 (bs, 1H), 7.95 (s, 1H), 7.13 (t, J = 1.7 Hz, 1H), 6.93 (dd, J = 2.4, 1.3 Hz, 1H), 6.84 (t, J = 2.1 Hz, 1H), 6.57 (t, J = 7.0 Hz, 1H), 3.83 (s, 3H), 3.51 (q, J = 6.2 Hz, 2H), 3.45 (t, J = 7.9 Hz, 2H), 3.13 (s, 3H), 1.84 (q, J = 9.2, 8.5 Hz, 2H), 1.73 (q, J = 9.5, 7.9 Hz, 2H).

[0097] <Example 18> 1 5 -Chloro-3 4 -Methoxy-5-methyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ10.34 (s, 1H), 10.33 (bs, 1H), 7.90 (s, 1H), 7.25 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H), 6.99 (d, J = 9.4 Hz, 1H), 6.54 (t, J = 6.7 Hz, 1H), 3.83 (s, 3H), 3.68 (dt, J = 14.1, 7.0 Hz, 2H), 3.14 (s, 3H), 3.10 - 2.95 (m, 2H), 1.85 - 1.74 (m, 2H), 1.71 - 1.60 (m, 1H), 1.59 - 1.47 (m, 1H).

[0098] <Example 19> 1 5 -Chloro-3 6-Ethyl-5-methyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ10.70 (bs, 1H), 10.02 (s, 1H), 7.96 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 1.7 Hz, 1H), 7.35 (dd, J = 7.9, 1.8 Hz, 1H), 6.54 (t, J = 6.8 Hz, 1H), 3.51 - 3.44 (m, 2H), 3.42 - 3.32 (m, 2H), 3.13 (s, 3H), 2.74 (q, J = 7.5 Hz, 2H), 1.84 - 1.75 (m, 2H), 1.73 - 1.64 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H).

[0099] <Example 20> 1 5 -Chloro-3 6 -Methoxy-5,8-dimethyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (500 MHz, CD2Cl2) δ12.21 (bs, 1H), 9.64 (s, 1H), 8.47 (d, J = 2.2 Hz, 1H), 7.99 (s, 1H), 7.45 (dd, J = 8.5, 2.2 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 4.35 (ddd, J = 14.2, 11.7, 3.0 Hz, 1H), 4.18 (ddd, J = 13.3, 11.7, 3.1 Hz, 1H), 3.90 (s, 3H), 3.67 - 3.59 (m, 1H), 3.58 (s, 3H), 3.23 - 3.11 (m, 1H), 3.16 (s, 3H).

[0100] <Example 21> 1 5-Chloro-5-ethyl-3 6 -Methoxy-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (500 MHz, CD2Cl2) δ11.40 (bs, 1H), 9.75 (s, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.03 (s, 1H), 7.44 (dd, J = 8.5, 2.2 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.64 (t, J = 5.0 Hz, 1H), 4.44 - 4.31 (m, 1H), 4.01 - 3.92 (m, 1H), 3.90 (s, 3H), 3.85 - 3.79 (m, 1H), 3.79 - 3.72 (m, 1H), 3.40 (dq, J = 14.0, 7.0 Hz, 1H), 3.21 (ddd, J = 13.8, 11.0, 6.9 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H).

[0101] <Example 22> 1 5 -Chloro-5-isopropyl-3 6 -Methoxy-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one 1H NMR (400 MHz, CD2Cl2) δ9.45 (s, 1H), 8.58 (d, J = 2.2 Hz, 1H), 7.99 (s, 1H), 7.42 (dd, J = 8.6, 2.2 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.65 (s, 1H), 4.37 (p, J = 6.9 Hz, 1H), 4.28 - 4.15 (m, 1H), 3.92 (s, 3H), 3.99 - 3.87 (m, 1H), 3.82 (td, J = 10.9, 10.3, 3.8 Hz, 1H), 3.22 (ddd, J = 14.1, 11.0, 6.7 Hz, 1H), 1.44 (d, J = 7.2 Hz, 3H), 1.42 (d, J = 7.1 Hz, 3H).

[0102] <Example 23> 1 5 -Chloro-3 6 -Methoxy-5,9-dimethyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ10.35 (s, 1H), 9.19 (bs, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.84 (s, 1H), 7.36 (dd, J = 8.5, 2.1 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 3.93 (s, 3H), 3.57 (s, 3H), 3.26 (bs, 4H), 3.06 (s, 3H), 2.08 (bs, 2H).

[0103] <Example 24> 3 6 -Methoxy-5-methyl-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; Formation of 2,2,2-trifluoroacetate This compound was synthesized in the same manner as in Example 1, except that step 4 was carried out as follows. [ka]

[0104] According to the above reaction scheme, 3-Amino-N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-4-methoxy-N-methylbenzamide (335 mg) was dissolved in isopropyl alcohol, and then 4.0 M hydrogen chloride in 1,4-dioxane solution (0.22 ml) was added. The mixture was stirred at 95° C. for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, extracted with ethylene acetate, and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (white solid, 269 mg, 80%). 1 H NMR (400 MHz, CD2Cl2) δ11.03 (s, 1H), 8.17 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.5, 2.0 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.75 - 6.62 (m, 1H), 5.77 (bs, 1H), 3.95 (s, 3H), 3.45 - 3.24 (m, 4H), 3.04 (s, 3H), 2.15 (bs, J = 16.6 Hz, 2H).

[0105] <Example 25> 3 6 -Methoxy-5,8-dimethyl-1 5 -(Trifluoromethyl)-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; Formation of 2,2,2-trifluoroacetate 1H NMR (400 MHz, CD2Cl2) δ10.57 (s, 1H), 10.11 (bs, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.29 (s, 1H), 7.41 (dd, J = 8.4, 2.2 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 4.40 - 4.29 (m, 1H), 4.18 (t, J = 11.7 Hz, 1H), 3.91 (s, 3H), 3.62 (td, J = 12.5, 6.0 Hz, 1H), 3.28 (q, J = 1.9 Hz, 3H), 3.19 - 3.11 (m, 1H), 3.09 (s, 3H).

[0106] <Example 26> 3 6 -Methoxy-5-methyl-1 5 -(Trifluoromethyl)-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ10.59 (s, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.30 - 8.16 (m, 1H), 8.09 (bs, 1H), 7.42 (dd, J = 8.5, 2.1 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.58 - 6.39 (m, 1H), 4.55 - 4.35 (m, 1H), 3.91 (s, 3H), 3.88 - 3.75 (m, 2H), 3.08 (s, 3H), 3.02 (ddd, J = 13.7, 10.9, 7.0 Hz, 1H).

[0107] <Example 27> 1 5 -Chloro-3 6 -Methoxy-5,10-dimethyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; Formation of 2,2,2-trifluoroacetate 1H NMR (400 MHz, CD2Cl2) δ12.90 (bs, 1H), 9.08 (s, 1H), 7.85 (s, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.31 (dd, J = 8.5, 2.1 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 3.89 (s, 3H), 3.62 (t, J = 7.0 Hz, 2H), 3.59 (s, 3H), 3.44 (t, J = 6.2 Hz, 2H), 3.13 (s, 3H), 1.85 - 1.73 (m, 4H).

[0108] <Example 28> 3 5 -Fluoro-3 6 -Methoxy-5,9-dimethyl-1 5 Preparation of -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one 1 H NMR (400 MHz, DMSO) δ9.25 (s, 1H), 8.38 (s, 1H), 7.83 (t, J = 1.7 Hz, 1H), 7.00 (dd, J = 11.5, 1.9 Hz, 1H), 3.89 (d, J = 1.6 Hz, 3H), 3.17 (bs, 4H), 3.12 - 3.07 (m, 3H), 2.93 (s, 3H), 2.11 (bs, 2H).

[0109] <Example 29> 3 6 -Methoxy-5,10-dimethyl-1 5 -(Trifluoromethyl)-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; Formation of 2,2,2-trifluoroacetate 1H NMR (400 MHz, CD2Cl2) δ13.10 (bs, 1H), 10.39 (s, 1H), 8.30 (s, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.30 (dd, J = 8.5, 2.1 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 3.91 (s, 3H), 3.68 (t, J = 6.7 Hz, 2H), 3.40 - 3.35 (m, 2H), 3.30 (q, J = 1.8 Hz, 3H), 3.06 (s, 3H), 1.82 - 1.72 (m, 4H).

[0110] <Example 30> 5,9-Dimethyl-3 6 -(trifluoromethoxy)-1 5 Preparation of -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one 1 H NMR (400 MHz, DMSO) δ9.66 (s, 1H), 8.39 (s, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.44 (dq, J = 8.4, 1.6 Hz, 1H), 7.21 (dd, J = 8.4, 2.1 Hz, 1H), 3.12 (BS, 4H), 3.09 - 3.08 (M, 3H), 2.95 (S, 3H), 2.10 (BS, 2H).

[0111] <Example 31> 5,9-Dimethyl-1 5 ,3 6 - Preparation of bis(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one 1H NMR (400 MHz, DMSO) δ9.16 (s, 1H), 8.38 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 3.18 - 3.01 (m, 5H), 2.96 (s, 3H), 2.95 - 2.90 (m, 2H), 1.99 (bs, 2H).

[0112] <Example 32> 3 5 -Methoxy-5,9-dimethyl-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; Formation of 2,2,2-trifluoroacetate 1 H NMR (400 MHz, CD2Cl2) δ12.24 (bs, 1H), 12.05 (s, 1H), 8.25 (s, 1H), 7.42 (t, J = 1.7 Hz, 1H), 6.90 (dd, J = 2.3, 1.3 Hz, 1H), 6.82 (t, J = 2.1 Hz, 1H), 3.83 (s, 3H), 3.32 (d, J = 1.8 Hz, 3H), 3.20 (bs, 4H), 3.07 (s, 3H), 2.22 (bs, 2H).

[0113] <Example 33> 3 6 -Methoxy-5-methyl-1 5 -(Trifluoromethyl)-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; Formation of 2,2,2-trifluoroacetate 1H NMR (400 MHz, CD2Cl2) δ10.85 (s, 1H), 9.57 (bs, 1H), 8.13 (s, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 8.6, 2.1 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.48 (d, J = 7.0 Hz, 1H), 3.92 (s, 3H), 3.52 (q, J = 6.1 Hz, 2H), 3.41 - 3.36 (m, 2H), 3.05 (s, 3H), 1.88 - 1.76 (m, 2H), 1.69 (q, J = 5.4 Hz, 2H).

[0114] <Example 34> 3 5 -Fluoro-3 6 -Methoxy-5-methyl-1 5 Preparation of -(trifluoromethyl)-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one 1 H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 8.17 (d, J = 1.0 Hz, 1H), 7.43 (t, J = 1.6 Hz, 1H), 7.17 (t, J = 6.2 Hz, 1H), 7.00 (dd, J = 11.5, 1.9 Hz, 1H), 3.88 (d, J = 1.5 Hz, 3H), 3.33 - 3.26 (m, 4H), 2.90 (s, 3H), 1.72 - 1.63 (m, 2H), 1.55 - 1.47 (m, 2H).

[0115] <Example 35> 5-Methyl-3 6 -(trifluoromethoxy)-1 5 Preparation of -(trifluoromethyl)-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one 1H NMR (400 MHz, DMSO) δ9.64 (s, 1H), 8.23 ​​(d, J = 0.9 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.50 - 7.37 (m, 2H), 7.24 (dd, J = 8.5, 2.1 Hz, 1H), 3.31 - 3.18 (m, 4H), 2.93 (s, 3H), 1.67 (q, J = 8.3 Hz, 2H), 1.51 (q, J = 5.3, 4.6 Hz, 2H).

[0116] The structures of the compounds of Examples 1 to 35 according to the present invention are shown in Table 1.

[0117] [Table 1] TIFF2024546154000012.tif194170TIFF2024546154000013.tif198170

[0118] The compounds of Examples 36 to 41 were produced in the same manner as in Example 1.

[0119] <Example 36> 3 5 -Fluoro-3 6 -Methoxy-5-methyl-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one

[0120] <Example 37> 3 5 -Methoxy-5-methyl-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one

[0121] <Example 38> 5-Methyl-3 6 -(oxetane-3-yloxy)-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one

[0122] <Example 39> 3 6 -Isopropyl-5-methyl-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one

[0123] <Example 40> 1 5 -Chloro-5-methyl-3 6 -(Trifluoromethoxy)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one

[0124] <Example 41> 5-Methyl-3 6 -(trifluoromethoxy)-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one

[0125] <Example 42> 1 5 -Chloro-3 6 -Methoxy-5-methyl-9-oxa-2,5-diaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one

[0126] This compound was prepared similarly to Example 1, except for step 1.

[0127] Step 1: [ka] Anhydrous sodium hydride (60% dispersion in mineral oil, 79 mg, 3.3 mmol) was added to the suspension of Boc-containing alcohol (340 mg, 1.1 equiv.) and dissolved in anhydrous tetrahydrofuran at 0° C. After stirring for 5 min, 2,4,5-trichloropyrimidine (300 mg, 1.0 equiv.) was added slowly and the resulting solution was allowed to warm to room temperature and stirred for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the mixture was extracted with dichloromethane (50 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the desired product (430 mg, 78%).

[0128] Examples 43 to 45 were carried out in the same manner as in Example 42 to obtain the target compound.

[0129] <Example 43> 3 6 -Methoxy-5-methyl-1 5 -(Trifluoromethyl)-9-oxa-2,5-diaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one

[0130] <Example 44> 5-Methyl-3 6 -(trifluoromethoxy)-1 5 -(Trifluoromethyl)-9-oxa-2,5-diaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one

[0131] <Example 45> 3 5 -Fluoro-3 6 -Methoxy-5-methyl-1 5 -(Trifluoromethyl)-9-oxa-2,5-diaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one

[0132] Examples 46 and 47 were carried out in the same manner as in Example 1 to obtain the desired compounds.

[0133] <Example 46> 3 6 -Cyclopropoxy-5-methyl-1 5-(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one

[0134] <Example 47> 3 6 -Cyclopropoxy-5,9-dimethyl-1 5 -(Trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one

[0135] The compound structures and analytical data of Examples 36 to 47 are shown in Table 2.

[0136] [Table 2] TIFF2024546154000016.tif230170

[0137] <Experimental Example 1> Evaluation of LRRK2 inhibitory activity To evaluate the inhibitory activity of wild-type and G2019S mutant LRRK2 (leucine-rich repeat kinase 2), the "HotSpot" assay platform was used at Reaction Biology Corporation. The experimental method was as follows.

[0138] Specific kinase and substrate pairs were prepared in reaction buffer (20 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) along with the required cofactors. The compounds were transferred to the reaction and after 20 min, ATP (Sigma) and 33A mixture of P ATP (PerkinElmer) was added to a final concentration of 10 μM. Reactions were carried out at 25°C for 120 min and then dropped onto P81 ion exchange filter paper (Whatman). The filter paper was washed extensively with 0.75% phosphoric acid to remove unbound phosphate. After subtracting background values ​​obtained from standard reactions containing inactive enzyme, kinase activity data were expressed as a percentage of kinase activity remaining in the test sample relative to the solvent (dimethylsulfoxide) reaction. IC 50 Values ​​were obtained using Prism (GraphPad Software) and the results are shown in Table 3.

[0139] [Table 3]

[0140] According to Table 2, it was confirmed that the macrocyclic pyrimidine derivatives of the present invention have excellent inhibitory activity against wild-type and G2019S mutant LRRK2 proteins. Therefore, the compounds according to the present invention are expected to be effective in preventing or treating diseases associated with the excessive activation of wild-type LRRK2 protein or G2019S mutant LRRK2 protein.

[0141] <Experimental Example 2> Evaluation of blood-brain barrier (BBB) ​​permeability To evaluate the blood-brain barrier permeability, the following experiment was carried out.

[0142] Test substances were prepared at a dose of 5 mg / kg, and after oral administration, the animals were sacrificed 1 and 3 hours later, and blood was taken from the heart and centrifuged to obtain plasma samples. The remaining blood was removed from the body, and the brain was removed after cardiac perfusion with 20 ml of saline containing 10 U / ml of heparin. Three times the weight of PBS buffer was added to the brain tissue and homogenized. Quantitative analysis of the above prepared plasma and brain tissue was performed using LC-MS / MS (Agilent, Santa Clara, CA, USA). A mobile phase consisting of 20% water, 80% acetonitrile, and 0.1% formic acid was used for separation of substances in LC. The total run time for each substance was 3 minutes, and the flow rate was 0.3 ml / min. The results are shown in Table 4.

[0143] [Table 4]

[0144] As shown in Table 3, the average BBB penetration rate of the examples was about 30%, and in particular, the BBB penetration rate of Example 1 was as high as 68%. Therefore, the compound according to the present invention is expected to be effective in preventing or treating neurodegenerative diseases by efficiently passing through the BBB.

Claims

1. Formula 1: 【Chemistry 1】 [Formula 1] (In formula 1, A is O or N(R ２ ) and R １ is hydrogen, halogen, or unsubstituted or halogen-substituted C １～１０ is alkyl, R ２ and R ３ and each independently represent hydrogen or unsubstituted C １～１０ is alkyl, p is 0 to 3; R ４ But halogen, C １～１０ Alkyl or OR ４ａ R is independently selected from the group consisting of ４ａ is hydrogen, unsubstituted or halogen-substituted C １～１０ Alkyl, C ３～７ cycloalkyl or 3- to 7-membered heterocycloalkyl; n is 1 to 5), a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

2. R １ is halogen, or unsubstituted or substituted with 1 to 5 halogens C １～６ is alkyl, R ２ and R ３ and each independently represent hydrogen or C １～６ is alkyl, p is 0 to 2; R ４ But hydrogen, halogen, C １～６ Alkyl or OR ４ａ R is independently selected from the group consisting of ４ａ is unsubstituted or substituted with 1 to 5 halogens; １～６ Alkyl, C ３～６ cycloalkyl or 3- to 6-membered heterocycloalkyl; The compound according to claim 1, or a solvate, hydrate, or pharma- ceutically acceptable salt thereof, wherein n is 1 to 5.

3. R １ is halogen or C substituted with 1 to 3 halogens １～３ is alkyl, R ２ and R ３ and each independently represent hydrogen or C １～３ is alkyl, p is 0 to 2; R ４ But halogen, C １～３ Alkyl or OR ４ａ are independently selected from the group consisting of R ４ａ is unsubstituted or substituted with 1 to 3 halogens １～３ Alkyl, C ３～６ cycloalkyl or 3- to 6-membered heterocycloalkyl; The compound according to claim 1, or a solvate, hydrate, or pharma- ceutically acceptable salt thereof, wherein n is 1 to 5.

4. R １ is -Cl, -F, or -CF ３ and R ２ and R ３ and each independently represent hydrogen or C １～３ is alkyl, p is 0 to 2; R ４ But, -F, C １～３ Alkyl or OR ４ａ are independently selected from the group consisting of R ４ａ is unsubstituted or substituted with 1 to 3 halogens １～３ Alkyl, C ３～６ cycloalkyl or 3- to 6-membered heterocycloalkyl having one O atom; The compound according to claim 1, or a solvate, hydrate, or pharma- ceutically acceptable salt thereof, wherein n is 1 to 4.

5. R １ is -Cl, -F, or -CF ３ and R ２ and R ３ and are each independently hydrogen, methylethyl, or isopropyl; p is 0 to 2; R ４ are independently -F, ethyl, -CF ３ , methoxy, isopropoxy, -OCF ３ , cyclopropoxy, oxetan-3-yloxy; The compound according to claim 1, or a solvate, hydrate, or pharma- ceutically acceptable salt thereof, wherein n is 2 to 4.

6. The compound according to claim 1, its solvate, its hydrate, or its pharma- ceutically acceptable salt, wherein the compound represented by the above formula 1 is the following compound: <1>3 ６ -Methoxy-5,9-dimethyl-1 ５ -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononaphan-4-one; 2,2,2-trifluoroacetate, <2>1 ５ -chloro-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one, <3>1 ５ -chloro-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one, <4>1 ５ -Chloro-3 ６ -Methoxy-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one, <5>1 ５ -Chloro-3 ６ -Methoxy-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one, <6>1 ５ -Chloro-3 ６ -Methoxy-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <7>1 ５ -Fluoro-3 ６ -methoxy-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one, <8>1 ５ -Chloro-3 ６ -fluoro-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <9>1 ５ -Chloro-3 ４ -Methoxy-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <10>1 ５ -Chloro-3 ５ -Methoxy-5-methyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <11>1 ５ -Chloro-3 ６ -Methoxy-5-methyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <12>1 ５ -Chloro-3 ６ -Methoxy-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <13>1 ５ -Chloro-3 ６ -ethyl-5-methyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <14>1 ５ -Chloro-3 ５ -Methoxy-5-methyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <15>1 ５ -Chloro-3 ４ -Methoxy-5-methyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <16>1 ５ -Chloro-3 ６ -Methoxy-5-methyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <17>1 ５ -Chloro-3 ５ -Methoxy-5-methyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <18>1 ５ -Chloro-3 ４ -Methoxy-5-methyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <19>1 ５ -Chloro-3 ６ -ethyl-5-methyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <20>1 ５ -Chloro-3 ６ -Methoxy-5,8-dimethyl-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <21>1 ５ -Chloro-5-ethyl-3 ６ -Methoxy-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <22>1 ５ -Chloro-5-isopropyl-3 ６ -Methoxy-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one, <23>1 ５ -Chloro-3 ６ -Methoxy-5,9-dimethyl-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <24>3 ６ -Methoxy-5-methyl-1 ５ -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one; 2,2,2-trifluoroacetate, <25>3 ６ -Methoxy-5,8-dimethyl-1 ５ -(trifluoromethyl)-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <26>3 ６ -Methoxy-5-methyl-1 ５ -(trifluoromethyl)-2,5,8-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclooctaphan-4-one; 2,2,2-trifluoroacetate, <27>1 ５ -Chloro-3 ６ -Methoxy-5,10-dimethyl-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <28>3 ５ -Fluoro-3 ６ -Methoxy-5,9-dimethyl-1 ５ -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one, <29>3 ６ -Methoxy-5,10-dimethyl-1 ５ -(trifluoromethyl)-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <30> 5,9-dimethyl-3 ６ -(trifluoromethoxy)-1 ５ -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one, <31> 5,9-dimethyl-1 ５ , 3 ６ -bis(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononapan-4-one, <32>3 ５ -Methoxy-5,9-dimethyl-1 ５ -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononaphan-4-one; 2,2,2-trifluoroacetate, <33>3 ６ -Methoxy-5-methyl-1 ５ -(trifluoromethyl)-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one; 2,2,2-trifluoroacetate, <34>3 ５ -Fluoro-3 ６ -Methoxy-5-methyl-1 ５ -(trifluoromethyl)-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one, <35> 5-methyl-3 ６ -(trifluoromethoxy)-1 ５ -(trifluoromethyl)-2,5,10-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclodecaphan-4-one, <36>3 ５ -Fluoro-3 ６ -Methoxy-5-methyl-1 ５ -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <37>3 ５ -Methoxy-5-methyl-1 ５ -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <38> 5-methyl-3 ６ -(oxetane-3-yloxy)-1 ５ -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <39>3 ６ -isopropyl-5-methyl-1 ５ -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <40>1 ５ -Chloro-5-methyl-3 ６ -(trifluoromethoxy)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <41> 5-methyl-3 ６ -(trifluoromethoxy)-1 ５ -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <42>1 ５ -Chloro-3 ６ -methoxy-5-methyl-9-oxa-2,5-diaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <43>3 ６ -Methoxy-5-methyl-1 ５ -(trifluoromethyl)-9-oxa-2,5-diaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <44> 5-methyl-3 ６ -(trifluoromethoxy)-1 ５ -(trifluoromethyl)-9-oxa-2,5-diaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <45>3 ５ -Fluoro-3 ６ -Methoxy-5-methyl-1 ５ -(trifluoromethyl)-9-oxa-2,5-diaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, <46>3 ６ -Cyclopropoxy-5-methyl-1 ５ -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, and <47>3 ６ -Cyclopropoxy-5,9-dimethyl-1 ５ -(trifluoromethyl)-2,5,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclonaphan-4-one, A compound, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof, which is selected from the group consisting of:

7. A method for preparing a compound of formula 1, comprising the steps of: The following reaction scheme 1: 【Chemistry 2】 [Reaction Scheme 1] (In reaction scheme 1, A, R １ , R ３ , R ４ , p, and n are as defined in formula 1 of claim 1, cyclizing a compound of formula 1A to produce a compound of formula 1.

8. A pharmaceutical composition for preventing or treating a neurodegenerative disease, comprising a compound represented by formula 1 according to claim 1, its solvate, its hydrate, or a pharma- ceutical acceptable salt thereof as an active ingredient.

9. 9. The pharmaceutical composition of claim 8, wherein the neurodegenerative disease comprises Parkinson's disease, Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, prion disease, motor neuron disease, spinocerebellar degeneration, spinal muscular atrophy, Creutzfeldt-Jakob disease, or alcoholic dementia.

10. 9. The pharmaceutical composition of claim 8, wherein the compound inhibits LRRK2 (leucine-rich repeat kinase 2) activity.

11. A health functional food composition for preventing or alleviating a neurodegenerative disease, comprising the compound represented by formula 1 described in claim 1, its solvate, its hydrate, or a pharma- ceutically acceptable salt thereof as an active ingredient.

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