RU2825827C1 - Novel pyrimidine derivative and composition containing same for preventing or treating neurodegenerative diseases and cancer - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel pyrimidine derivative, specifically to a compound of formula 1 or a pharmaceutically acceptable salt thereof, where each R₁' is independently selected from the group consisting of C₁-C₆alkoxy or haloC₁-C₆alkoxy; R₁'' is hydrogen or halogen; R₂ is a substituted or unsubstituted pyrazole, wherein said substituted pyrazole has, as a substitute, at least one radical selected from the group consisting of halogen, hydroxy, cyano, amino, amide, nitro, C₁-C₆alkylsulphonyl, acetyl, methyloxycarbonyl, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted C₃-C₆heterocycloalkyl, which refers to a cyclic saturated hydrocarbon bearing one heteroatom, such as O, as a ring member; phenyl, pyridinyl; wherein each substituted alkyl, substituted benzyl has at least one radical selected from the group consisting of halogen, hydroxy, cyano, amino, amide, nitro, C₁-C₆alkyl, C₁-C₆alkoxy, C₄-C₆heterocycloalkyl, which refers to a cyclic saturated hydrocarbon bearing at least one heteroatom, such as N or O, as a ring member; R₃ is halogen or halogenC₁-C₆alkyl; R₄ is any of structures from B-1 to B-20, from B-22 to B-29, specified in the claim, and Y is selected from a group consisting of O and S. Invention also relates to a pharmaceutical composition based on said compound.

EFFECT: obtaining alternative compounds for treating LRRK2-mediated neurodegenerative diseases and cancer.

4 cl, 3 tbl, 3 ex

Description

Field of technology

[1] The present invention relates to a novel pyrimidine derivative and a composition containing the same for the prevention or treatment of neurodegenerative disease and cancer.

Prior art

[2] A neurodegenerative disease is a brain disorder that occurs with age due to the accumulation of environmental and genetic factors and is an umbrella term for a range of different symptoms that result from the progressive degeneration and death of neurons in the central nervous system. Neurodegenerative diseases are characterized by damage to neurons and loss of neuronal structure or function, resulting in memory impairment. Representative examples of neurodegenerative diseases include Parkinson's disease, Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, prion disease, motor neuron disease, spinocerebellar ataxia, spinal muscular atrophy, Creutzfeldt-Jakob disease, and alcoholic dementia.

[3] Parkinson's disease, which is one of the representative neurodegenerative diseases along with Alzheimer's disease, is caused by a deficiency of the neurotransmitter dopamine due to the loss of dopaminergic neurons in the substantia nigra of the brainstem. A typical characteristic feature of Parkinson's disease is the formation of intracellular protein inclusions in neurons called Lewy bodies, followed by the appearance of obvious symptoms in the motor system such as hunched posture, tremor, rigidity, instability, etc., as well as in mental functions such as depression, anxiety, sleep disturbance, etc.

[4] The cause of Parkinson's disease is poorly understood, but is thought to involve the complex action of several factors, including environmental factors, genetic factors, aging, mitochondrial dysfunction, and defective clearance of waste proteins. Parkinson's disease occurs mostly sporadically, but inherited mutations in genes account for 5-10% of cases. Genes known to be involved in the etiology of Parkinson's disease include genes encoding proteins such as parkin, putative PTEN-inducible kinase 1 (PINK1; PTEN stands for phosphatase and tensin homolog with a deletion on chromosome 10), DJ-1, α-synuclein, and LRRK2 (leucine-rich repeat kinase 2).

[5] Among them, the G2019S mutation in the LRRK2 gene is the most common genetic cause with a dominant genotype. LRRK2, which is a member of the leucine-rich repeat kinase family, consists of 2527 amino acids with high interspecies similarity and exhibits both guanosine triphosphatase (GTPase) and serine-threonine kinase activities in a single protein. LRRK2 is expressed with high expression levels in dopaminergic neurons present in the cerebral cortex, substantia nigra, striatum, hippocampus, and cerebellum, which are associated with the etiology of Parkinson's disease. Increased LRRK2 activity affects the onset and progression of Parkinson's disease. Normally, LRRK2 overexpression in neuronal cells induces apoptosis, and mutant animals overexpressing LRRK2 exhibit dopaminergic neuron death, Lewy body formation, and movement disorder similar to Parkinson's disease. LRRK2 knockout animals have been reported to exhibit neurite outgrowth in the brain and inhibition of aging-dependent α-synuclein aggregation, which is closely associated with the onset of Parkinson's disease, indicating the possibility of treating Parkinson's disease by regulating LRRK2 activity. In addition, LRRK2 is known to be clinically associated with the transition from mild cognitive impairment to Alzheimer's disease. Thus, compounds and compositions effective in regulating LRRK2 activity may have therapeutic effects on neurodegenerative diseases. Therefore, selective inhibition of LRRK2 activity could be a useful target in the development of new drugs for the treatment of diseases.

[6] In addition to the above-mentioned neurodegenerative diseases, research has been conducted on the mechanism of inhibiting cancer cell growth and promoting cancer cell apoptosis by regulating LRRK2 in various cancer cell lines.

[7] Among other things, it has been reported that tissues affected by kidney cancer, thyroid cancer and liver cancer overexpress LRRK2, and hyperactivity of LRRK2 variants (especially, for example, with the G2019S mutation) increases the risk of breast cancer. In addition, a study was reported that patients with brain cancer in Korea who overexpressed LRRK2 survived for a very short period of time. Recently, Voronoi received approval to begin phase 1 clinical trials of an LRRK2 inhibitor as a therapeutic agent for the treatment of brain cancer. Therefore, selective inhibition of LRRK2 activity may be a target for the development of a wide range of drugs not only for the treatment of neurodegenerative diseases but also for the treatment of cancer.

[8] As for relevant documents relating to compositions comprising pyrimidine derivatives as active ingredients for the prevention or treatment of neurodegenerative diseases, mention may be made of Korean Patent No. 10-1566091, which discloses pyrazolaminopyrimidine derivatives as LRRK2 modulators, Korean Patent No. 10-2025451, which discloses 2-(phenyl or pyrid-3-yl)aminopyrimidine derivatives as LRRK2 kinase modulators for the treatment of Parkinson's disease, Korean Patent No. 10-1208198, which discloses a pharmaceutical composition comprising a compound having an inhibitory effect on LRRK2 kinase activity as an active ingredient for the treatment or prevention of Parkinson's disease, and Korean Patent No. 10-2019-0018676A, which discloses pyrimidin-2-ylamino-1H-pyrazoles as LRRK2 inhibitors for use in the treatment of neurodegenerative disorder. However, no reports prior to the present invention have described the pyrimidine derivatives of the present invention represented by chemical formula 1, their LRRK2 inhibitory activity, and their therapeutic potential for the treatment of neurodegenerative disease.

[9] The present invention was inspired by the intensive and thorough study conducted by the present inventors on LRRK, as a result of which it was found that the pyrimidine derivatives of the present invention represented by chemical formula 1 exhibit excellent LRRK2 inhibitory activity and effectively cross the blood-brain barrier (BBB).

Description of the invention

Technical problem

[10] One aspect of the present invention is to provide a novel pyrimidine and a composition containing the same for preventing or treating a neurodegenerative disease and cancer, and more particularly relates to a novel pyrimidine derivative that exhibits excellent properties in inhibiting LRRK2 activity and crossing the blood-brain barrier (BBB), and a composition containing the same for preventing or treating a neurodegenerative disease and cancer.

Solution to the problem

[11] The present invention relates to a compound represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[12] Chemical formula 1

[13]

[14] where

each R ₁ is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, amide, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and haloC ₁ -C ₆ alkoxy;

[15] R ₂ is a substituted or unsubstituted pyrazole,

[16] wherein the substituted pyrazole has as a substituent at least one radical selected from the group consisting of halogen, hydroxy, cyano, amino, amide, nitro, C ₁ -C ₆ alkylsulfonyl, acetyl, methyloxycarbonyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₂ heterocycloalkyl, substituted or unsubstituted C ₄ -C ₁₂ aryl and substituted or unsubstituted C ₄ -C ₁₂ heteroaryl,

[17] wherein each substituted alkyl, substituted benzyl, substituted _C3 - _C12 cycloalkyl, substituted _C4 - _C12 aryl and substituted _C4 - _C12 heteroaryl has as a substituent at least one radical selected from the group consisting of halogen, hydroxy, cyano, amino, amide, nitro, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C3 - _C12 heterocycloalkyl, _C4 - _C12 aryl- _C1 - _C6 alkoxy and -C(=O)O-( _C1 - _C6 )alkyl;

[18] R ₃ is halogen or halogenC ₁ -C ₆ alkyl;

[19] R ₄ is represented by any of the structures B-1 through B-29 below:

[20]

[21]

[22]

[23] where

R ₆ is selected from the group consisting of a hydrogen atom, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl sulfonate and C ₁ -C ₆ alkylamino;

[24] each R ₇ is independently selected from the group consisting of hydrogen, halogen, haloC ₁ -C ₆ alkyl, and C ₁ -C ₆ alkyl;

[25] each R ₈ is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, cyano, C ₁ -C ₆ dialkylamino, aminosulfonyl, C ₁ -C ₆ alkylsulfonamino, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyloxy and C ₁ -C ₆ alkoxy;

[26] R ₉ is selected from the group consisting of a hydrogen atom, halogen, hydroxy, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylacetyl, C ₁ -C ₆ alkyloxycarbonyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkoxy, morpholine, piperidine, pyrrolidine, oxetanyl, C ₁ -C ₆ alkyl-substituted piperidine, and acetate;

[27] R ₁₀ is selected from the group consisting of a hydrogen atom, C ₁ -C ₆ alkyl, phenyl, oxetanyl and acetate;

[28] R ₁₁ represents a hydrogen atom or combines with R ₁₀ to form a saturated or unsaturated C ₅ -C ₆ heterocycloalkyl;

[29] R ₁₂ represents a hydrogen atom or C ₁ -C ₆ alkyl;

[30] R ₁₃ represents a hydrogen atom, C ₁ -C ₆ alkylcarbonyl or C ₁ -C ₆ alkylacetyl;

[31] R ₁₄ represents a hydrogen atom, C ₁ -C ₆ alkyl, hydroxyC ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxyC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxycarbonylC ₁ -C ₆ alkyl or methylsulfonylC ₁ -C ₆ alkyl;

[32] Ak is C ₁ -C ₆ alkyl;

[33] each k is independently equal to 0, 1, or 2 (provided that all k cannot be equal to zero at the same time);

[34] I is equal to 1 or 2;

[35] m is 0, 1, 2, 3, or 4;

[36] n is 0 or 1;

[37] each W independently represents CH or N;

[38] Z represents O or SO ₂ ;

[39] X is C, CH or N; and

[40] Y is selected from the group consisting of O and S.

[41]

[42] Specific examples of a compound of chemical formula 1 include:

[43] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 1);

[44] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone (compound 2);

[45] 1-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-one (compound 3);

[46] (4-((5-chloro-4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 4);

[47] 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (compound 5);

[48] 2-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile (compound 6);

[49] 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile (compound 7);

[50] (4-((5-chloro-4-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 8);

[51] methyl-2-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl )acetate (compound 9);

[52] (4-((5-chloro-4-(1-(methylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 10);

[53] (4-((5-chloro-4-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 11);

[54] (4-((5-chloro-4-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 12);

[55] (4-((5-chloro-4-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 13);

[56] (4-((5-chloro-4-(1-phenyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 14);

[57] (4-((5-chloro-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 15);

[58] (4-((5-chloro-4-(1-(methoxymethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 16);

[59] (4-((5-chloro-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 17);

[60] (4-((5-chloro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 18);

[61] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone (compound 19);

[62] (4-((5-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 20);

[63] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide (compound 21);

[64] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyrrolidin-1-yl)methanone (compound 22);

[65] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-ethyl-3-methoxy-N-(2-methoxyethyl)benzamide (compound 23);

[66] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-hydroxy-2-methylpropan-2-yl)-3-methoxybenzamide (compound 24);

[67] N-(tert-butyl)-4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 25);

[68] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)-3-methoxybenzamide (compound 26);

[69] 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-methylbutanenitrile (compound 27);

[70] (4-((5-chloro-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 28);

[71] (3-methoxy-4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 29);

[72] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4,4-difluorocyclohexyl)-3-methoxybenzamide (compound 30);

[73] (3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone (compound 31);

[74] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-7-azaspiro[3.5 ]nonan-7-yl)methanone (compound 32);

[75] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1-oxa-6-azaspiro[3.3 ]heptan-6-yl)methanone (compound 33);

[76] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 34);

[77] (4-((5-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl) (2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone (compound 35);

[78] (3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 36);

[79] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 37);

[80] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 38);

[81] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(2-hydroxypropan-2-yl)piperidin-1-yl)methanone (compound 39);

[82] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-6-azaspiro[3.3 ]heptan-6-yl)methanone (compound 40);

[83] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4,4-difluoropiperidin-1-yl)methanone (compound 41);

[84] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2,2-dimethylmorpholino)methanone (compound 42);

[85] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidin-1-yl)methanone (compound 43);

[86] 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazin-1-yl)ethan-1-one (compound 44);

[87] (4-isopropylpiperazin-1-yl)(3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)methanone (compound 45);

[88] (2-fluoro-5-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 46);

[89] (3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-pyrimidin-2-yl)amino)phenyl)(4-phenylpiperazin-1-yl)methanone (compound 47);

[90] (2-fluoro-5-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(4- isopropylpiperazin-1-yl)methanone (compound 48);

[91] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone (compound 49);

[92] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(oxetan-3-yl)piperazin-1-yl)methanone (compound 50);

[93] ((1R,5S)-8-oxa-3-azabicpo[3.2.1]octan-3-yl)(4-((5-chloro-4-(1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone (compound 51);

[94] (4-((5-chloro-4-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 52);

[95] (4-((5-chloro-4-(1-propyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 53);

[96] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 54);

[97] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 55);

[98] (4-((5-chloro-4-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 56);

[99] (4-((5-chloro-4-(1-propyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 57);

[100] (4-((5-chloro-4-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 58);

[101] (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 59);

[102] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl) benzamide (compound 60);

[103] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 61);

[104] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 62);

[105] (4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 63) ;

[106] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 64);

[107] (2-fluoro-4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-pyrimidin-2-yl)amino)-5-methoxyphenyl)(morpholino) methanone (compound 65);

[108] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(tetrahydro-2H-pyran-4-yl )methanone (compound 66);

[109] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methyltetrahydro-2H-pyran-4-yl)methanone (compound 67);

[110] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methyltetrahydro-2H-pyran-4 -yl)methanone (compound 68);

[111] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone (compound 69);

[112] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(2-hydroxypropan-2- yl)piperidin-1-yl)methanone (compound 70);

[113] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone (compound 71);

[114] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(oxetan-3-yl) piperazin-1-yl)methanone (compound 72);

[115] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidin-1-yl)methanone (compound 73);

[116] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanthione (compound 74);

[117] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1-isopropylpiperidin-4-yl)methanone (compound 75);

[118] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methoxypiperidin-1-yl)methanone (compound 76);

[119] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-oxa-9-azaspiro[5.5]undecan-9-yl)methanone (compound 77);

[120] 1-(4-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazin-1-yl )ethan-1-one (compound 78);

[121] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(methylsulfonyl)piperidin-1- yl)methanone (compound 79);

[122] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(tetrahydro-2H-pyran-4- yl)benzamide (compound 80);

[123] N-(1-(2-(o-tolyl)quinolin-3-yl)ethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-amine (compound 81);

[124] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-cyclopropyl-3-methoxybenzamide (compound 82);

[125] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydroxyazetidin-1-yl)methanone (compound 83);

[126] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1,1-dioxidothiomorpholino)methanone (compound 84);

[127] (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 85);

[128] (8)-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-(hydroxymethyl) pyrrolidin-1-yl)methanone (compound 86);

[129] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(hexahydropyrrolo[1,2-a]pyrazine -2(1H)-yl)methanone (compound 87);

[130] (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1- yl)methanone (compound 88);

[131] ((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone (compound 89);

[132] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone (compound 90);

[133] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-((1R,4R)-4-hydroxycyclohexyl)-3 -methoxybenzamide (compound 91);

[134] (6-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(morpholino)methanone (compound 92);

[135] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-(dimethylamino)cyclohexyl)-3-methoxybenzamide ( compound 93);

[136] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(dimethylamino)piperidin-1- yl)methanone (compound 94);

[137] ((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone (compound 95);

[138] 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 96);

[139] (R)-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydroxypyrrolidin-1 -yl)methanone (compound 97);

[140] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(5-methylhexahydropyrrolo[3,4-c ]pyrrol-2(1H)-yl)methanone (compound 98);

[141] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-isopropylpiperidin-4-yl)-3-methoxybenzamide (compound 99);

[142] 2-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)hexahydropyrrolo[1,2-a] pyrazin-6(2H)-one (compound 100);

[143] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N,N-dimethylbenzamide (compound 101);

[144] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-methylpiperazine-1 -yl)methanione (compound 102);

[145] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanthione (compound 103);

[146] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-methylpiperazine-1 -yl)methanone (compound 104);

[147] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(morpholino)methanone (compound 105 );

[148] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanthione (compound 106);

[149] (5-chloro-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluorophenyl)(4-methylpiperazine-1 -yl)methanone (compound 107);

[150] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(4-methylpiperazin-1- yl)methanone (compound 108);

[151] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methylphenyl)(4-methylpiperazin-1-yl)methanone (compound 109);

[152] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-(dimethylamino) piperidin-1-yl)methanone (compound 110);

[153] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-(dimethylamino) piperidin-1-yl)methanone (compound 111);

[154] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-phenylbenzamide (compound 112);

[155] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorophenyl)-3-methoxybenzamide (compound 113) ;

[156] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluorophenyl)-3-methoxybenzamide (compound 114) ;

[157] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorophenyl)-3-methoxybenzamide (compound 115) ;

[158] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyanophenyl)-3-methoxybenzamide (compound 116) ;

[159] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanophenyl)-3-methoxybenzamide (compound 117) ;

[160] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenzamide (compound 118) ;

[161] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenzamide (compound 119) ;

[162] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorobenzyl)-3-methoxybenzamide (compound 120) ;

[163] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(o-tolyl)benzamide (compound 121 );

[164] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(m-tolyl)benzamide (compound 122 );

[165] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(p-tolyl)benzamide (compound 123 );

[166] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methylbenzyl)benzamide (compound 124 );

[167] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methylbenzyl)benzamide (compound 125 );

[168] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methylbenzyl)benzamide (compound 126);

[169] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-(dimethylamino)phenyl)-3-methoxybenzamide ( connection 127);

[170] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanobenzyl)-3-methoxybenzamide (compound 128) ;

[171] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-2- yl)-3-methoxybenzamide (compound 129);

[172] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-M-((tetrahydrofuran-3-yl) methyl)benzamide (compound 130);

[173] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyano-4-fluorophenyl)-3-methoxybenzamide (compound 131);

[174] N-(5-chloro-2-fluorophenyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (connection 132);

[175] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-(4-fluorophenyl)ethyl)-3-methoxybenzamide (compound 133);

[176] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,4-difluorobenzyl)-3-methoxybenzamide (compound 134);

[177] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3,5-difluorobenzyl)-3-methoxybenzamide (compound 135);

[178] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methylpyridin-4-yl) benzamide (compound 136);

[179] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxybenzamide (compound 137);

[180] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxybenzamide (compound 138);

[181] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N,N-diethyl-3-methoxybenzamide (compound 139);

[182] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyethyl)benzamide (compound 140 );

[183] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxy-N-methylbenzamide (compound 141);

[184] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxy-N-methylbenzamide (compound 142) ;

[185] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-N-(1-methylpiperidin- 4-yl)benzamide (compound 143);

[186] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methyl-1H-pyrazol- 4-yl)benzamide (compound 144);

[187] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-isopropyl-1H-pyrazol-4-yl) -3-methoxybenzamide (compound 145);

[188] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-chlorobenzyl)-3-methoxybenzamide (compound 146) ;

[189] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-chlorobenzyl)-3-methoxybenzamide (compound 147) ;

[190] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-chlorobenzyl)-3-methoxybenzamide (compound 148) ;

[191] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-chlorophenyl)-3-methoxybenzamide (compound 149) ;

[192] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-chlorophenyl)-3-methoxybenzamide (compound 150) ;

[193] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-chlorophenyl)-3-methoxybenzamide (compound 151) ;

[194] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxybenzyl)-3-methoxybenzamide (compound 152) ;

[195] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxybenzyl)-3-methoxybenzamide (compound 153) ;

[196] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)benzamide (compound 154 );

[197] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-2-ylmethyl)benzamide ( connection 155);

[198] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-3-ylmethyl)benzamide ( compound 156);

[199] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-4-ylmethyl)benzamide ( connection 157);

[200] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyphenyl)-3-methoxybenzamide (compound 158) ;

[201] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxyphenyl)-3-methoxybenzamide (compound 159) ;

[202] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxyphenyl)-3-methoxybenzamide (compound 160) ;

[203] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyphenyl)benzamide (compound 161 );

[204] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methoxyphenyl)benzamide (compound 162 );

[205] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxyphenyl)benzamide (compound 163 );

[206] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-1- yl)-3-methoxybenzamide (compound 164);

[207] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)-N-methylbenzamide (connection 165);

[208] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2,2,6,6- tetramethylpiperidin-4-yl)benzamide (compound 166);

[209] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,6-dimethylpiperidin-1-yl)-3 -methoxybenzamide (compound 167);

[210] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-((6-chloropyridin-3-yl)methyl)- 3-methoxybenzamide (compound 168);

[211] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-N-(2-(pyridin-2-yl)ethyl)benzamide (compound 169);

[212] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-(difluoromethoxy)phenyl)-3-methoxybenzamide ( connection 170);

[213] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-ethylphenyl)-3-methoxybenzamide (compound 171);

[214] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-ethylphenyl)-3-methoxybenzamide (compound 172);

[215] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-ethylphenyl)-3-methoxybenzamide (compound 173);

[216] N-benzyl-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (compound 174) ;

[217] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-N-(3-methylbenzyl) benzamide (compound 175);

[218] ethyl 3-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamido)propanoate (compound 176);

[219] N-benzyl-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxybenzamide (compound 177) ;

[220] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-isopropoxyphenyl)-3-methoxybenzamide (compound 178) ;

[221] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-phenylethyl)benzamide (compound 179 );

[222] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide (connection 180);

[223] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-(trifluoromethyl)phenyl)benzamide (connection 181);

[224] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-phenylpropyl)benzamide (compound 182 );

[225] N-(4-aminobenzyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 183) ;

[226] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluoro-5-methylphenyl)-3-methoxybenzamide (connection 184);

[227] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluoro-4-methylphenyl)-3-methoxybenzamide (connection 185);

[228] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluoro-2-methylphenyl)-3-methoxybenzamide (connection 186);

[229] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluoro-3-methylphenyl)-3-methoxybenzamide (compound 187);

[230] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluoro-2-methylphenyl)-3-methoxybenzamide (connection 188);

[231] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-sulfamoylbenzyl)benzamide (compound 189);

[232] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-(methylsulfonamido)phenyl)benzamide (compound 190);

[233] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-sulfamoylphenyl)benzamide (compound 191 );

[234] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-(methylsulfonyl)ethyl)benzamide (compound 192);

[235] methyl-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-valinate (compound 193) ;

[236] methyl-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-isoleucinate (compound 194) ;

[237] ethyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)glycinate (compound 195);

[238] N-(4-aminophenethyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 196) ;

[239] N-(3-(1H-imidazol-1-yl)propyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino )-3-methoxybenzamide (compound 197);

[240] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,2-dimethoxyethyl)-3-methoxybenzamide (compound 198);

[241] methyl-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-leucinate (compound 199) ;

[242] methyl-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-prolinate (compound 200) ;

[243] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxybenzyl)-N-methylbenzamide (connection 201);

[244] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-ethyl-3-methoxy-N-methylbenzamide (compound 202);

[245] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxybenzyl)benzamide (compound 203 );

[246] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxy-3,5- dimethylphenyl)benzamide (compound 204);

[247] N-(3-aminobenzyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 205) ;

[248] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-5- yl)-3-methoxybenzamide (compound 206);

[249] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-4- yl)-3-methoxybenzamide (compound 207);

[250] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-2- yl)-3-methoxy-N-methylbenzamide (compound 208);

[251] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-1- yl)-3-methoxy-N-methylbenzamide (compound 209);

[252] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(ethyl(methyl)ano) piperidin-1-yl)methanone (compound 210);

[253] N-(1-acetylindolin-5-yl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy -N-methylbenzamide (compound 211);

[254] N-(1-acetylindolin-5-yl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (connection 212);

[255] ethyl-3-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamido)-4,4,4 -trifluorobutanoate (compound 213);

[256] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-5- yl)-3-methoxy-N-methylbenzamide (compound 214);

[257] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-4- yl)-3-methoxy-N-methylbenzamide (compound 215);

[258] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(pyrrolidin-1-yl) piperidin-1-yl)methanone (compound 216) and

[259] [1,4'-bipiperidin]-1'-yl-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrinidin-2-yl)amino)- 3-methoxyphenyl)methanone (compound 217).

[260] In addition, the compound of the present invention represented by chemical formula 1 is prepared by the methods illustrated in the following reaction schemes 1 (amide coupling), 2 (Suzuki reaction) and 3 (Buchwald reaction).

[261] Reaction scheme 1

[262]

[263] Reaction scheme 2

[264]

[265] Reaction scheme 3

[266]

[267] By carrying out the reactions illustrated in reaction schemes 1, 2 and 3, a compound represented by chemical formula 1 is synthesized.

[268] In reaction schemes 1, 2 and 3

[269] X, m, R ₁ , R ₂ , R ₃ and R ₄ are as defined for chemical formula 1.

[270] Compounds A, B, D, and E used for reaction schemes 1, 2, and 3 can be purchased from Aldrich, Merck, TCI, and ACROS, respectively.

[271] A detailed description of the method for producing the compound of the present invention represented by chemical formula 1 will be given below.

[272] In the method for producing the compound of the present invention represented by chemical formula 1,

[273] The reaction conditions shown in Reaction Scheme 1 involve the reaction of compound A with compound B to form compound C.

[274] Reaction Scheme 1 is a step in which compound A and compound B are subjected to an amination reaction to give compound C. This reaction can be carried out without the participation of a base, but is usually carried out in the presence of a base suitable for the amination reaction, for example, an organic base such as pyridine, triethylamine, diethylisopropylamine, etc., in dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene, N,N-dimethylformamide, etc., which do not adversely influence the reaction. There is no particular limitation on the reaction temperature. However, the reaction can generally be carried out in the cold up to room temperature, and is preferably carried out at room temperature.

[275] Reaction Scheme 2 represents the step in which compound D is reacted with compound E to form compound F.

[276] As illustrated in Reaction Scheme 2, compound D is reacted with compound E in the presence of a metal catalyst to form compound F. Palladium is usually used as the metal catalyst in this reaction. Tetrakistriphenylphosphine palladium(0) (( _PPh3 ) _4Pd ), palladium(II) acetate (Pd(OAc) ₂ ), tris(dibenzylideneacetone)dipalladium(0) ( _Pd2dba3 ), bis(triphenylphosphine)palladium(II) chloride ( _PdCl2 ( _PPh3 ) ₂ ), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (Pd(dppf) _Cl2 ) can _be used. An example of a base used in this reaction may be potassium carbonate, KOtBu, cesium carbonate, potassium phosphate, sodium hydroxide, triethylamine, etc. This reaction is carried out in a solvent that does not have any adverse effect on this reaction, such as purified water, toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide, etc. There is no particular limitation on the reaction temperature. However, the reaction can generally be carried out at room temperature to higher temperatures, and is preferably carried out at higher temperatures.

[277] Reaction Scheme 3 is a step in which compound C, which is the product of Reaction Scheme 1, is reacted with compound F, which is the product of Reaction Scheme 2, in the presence of a metal catalyst to produce a compound of formula _1. In this reaction, a typical metal catalyst is palladium, examples of which are tetrakistriphenylphosphine palladium(0) (( _PPh3 ) _4Pd ), palladium(II) acetate (Pd(OAc) ₂ ), tris(dibenzylideneacetone)dipalladium(0) ( _Pd2dba3 ), bis(triphenylphosphine)palladium(II) chloride ( _PdCl2 ( _PPh3 ) ₂ ) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (Pd(dppf) _Cl2 ). In the presence of such a metal catalyst, this reaction can be carried out without a ligand, but generally, advantage is taken of a ligand useful for the Buchwald reaction such as triphenylphosphine (( _PPh3 ) ₄ ), 1,2-bis(diphenylphosphino)propane (DPPP), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) and so on. Examples of the base used in this reaction include potassium carbonate, KOtBu, cesium carbonate, potassium phosphate, sodium hydroxide and triethylamine. This reaction is carried out in a solvent which does not adversely affect the reaction, such as toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide, etc. There is no particular limitation on the reaction temperature. Generally, the reaction temperature is set in the range of room temperature to a higher temperature, and the reaction is preferably carried out at a higher temperature.

[278] Thus, the reaction according to one of the embodiments can be preferably carried out under Pd(OAc) ₂ /Cs ₂ CO ₃ /Xantphos reaction conditions or under ZnCl ₂ /trifluoroacetic acid reaction conditions, without limitation.

[279] Any solvent can be used in the present invention as long as the compounds A and B and the substances used in the reactions are dissolved therein. Examples of the solvent include: ether solvents such as dioxane, tetrahydrofuran (THF), ethyl ether, 1,2-dimethoxyethane, etc.; lower alcohols such as methanol, ethanol, propanol, and butanol; dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dichloroethane, and a combination thereof.

[280] In addition, the reaction temperature is not particularly limited, but may preferably be in the range of 0°C to 100°C, for example, room temperature. In addition, no particular limitation is imposed on the reaction time. For example, the reaction can be carried out for 2 hours to 20 hours, and in another embodiment, for 20 minutes to 8 hours.

[281] The following terms have the following meanings unless otherwise specified. Therefore, any undefined term has the meaning commonly understood in the art.

[282] The terms "cyclic" and "ring" refer to epicyclic or aromatic groups which may be substituted or unsubstituted and/or containing or not containing a heteroatom, and which may be monocyclic, bicyclic or polycyclic.

[283] The terms "halogen atom" and "halogen" are used in the traditional sense and refer to a substituent such as a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), or an iodine atom (I).

[284] The term "alkyl" as used herein refers to a linear or branched hydrocarbon, examples of which are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, pentyl, hexyl, and the like.

[285] The term "alkoxy" refers to a linear or branched saturated hydrocarbon linked through one terminal ether linkage. Examples include methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, 1-methylpropoxy, etc.

[286] The term "cycloalkyl" refers to a monofunctional cyclic saturated hydrocarbon. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.1]heptyl, spiro[4.5]decyl, spiro[5.5]undecyl, adamantyl, etc.

[287] The term "aryl" means an aromatic substituent comprising at least one ring having a pi-electron system for forming covalent bonds, such as phenyl, benzyl, naphthyl, anthryl, biphenyl, triphenyl, and the like.

[288] The term "arylalkyl" refers to an aryl derivative of an alkyl group, wherein "aryl" and "alkyl" are as defined above.

[289] The term "heterocycloalkyl" refers to a monofunctional cyclic saturated hydrocarbon bearing at least one heteroatom such as N, O or S as a ring member. There is a wide range of heterocycloalkyls according to the numbers and kinds of heteroatoms and the numbers of carbon atoms, examples of which include aziridinyl, pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinyl, oxopiperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dioxothiazepanyl, azocanyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, dioxanyl and dioxolanyl.

[290] The term "heteroaryl" refers to an aromatic ring compound bearing at least one heteroatom such as N, O or S. There is a wide range of heteroaryls according to the numbers and kinds of heteroatoms contained in the ring moieties and the numbers of carbon atoms, examples of which include pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, furanyl, quinolidinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, pyranyl, thiophenyl, thiazolyl, dibenzothiophenyl, dibenzofuranyl, dibenzoselenophenyl, thiophenyl, benzofuranyl, benzothiophenyl, benzoselenophenyl, carbazolyl, indolocarbazolyl, pyridylindolyl, pyrrolodipyridinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, oxazinyl, oxathiazinyl, oxadiazinyl, indolyl, benzimidazolyl, indazolyl, indoxazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, linyl, cinnolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, phthalazinyl, pteridinyl, xanthenyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzofuropyridinyl, furodipyridinyl, benzothienopyridinyl, thienodipyridinyl, benzoselenophenopyridinyl and selenophenodipyridinyl.

[291] Furthermore, the compound of the present invention may contain at least one asymmetric carbon atom and may exist in racemic form or in optically active form. All compounds and diastereomers fall within the scope of the present invention.

[292] As used herein, the term "pharmaceutically acceptable salt thereof" refers to a salt or complex of the compound of chemical formula 1 that retains the desired biological activity. Examples of the salt include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compound can also be administered in the form of a pharmaceutically acceptable quaternary salt. Among others, the salt includes chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate or carboxylate (e.g. benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamate, mandelate and diphenylacetate). It is intended that the compound of chemical formula 1 of the present invention encompasses any of the salt, hydrate, solvate and prodrug, which can be prepared using typical methods.

[293] The acid addition salts of the present invention can be prepared using typical methods. For example, a derivative of the compound of chemical formula 1 can be dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., and an organic acid or an inorganic acid can be added to form a precipitate, which can then be filtered and dried to obtain an acid addition salt. Alternatively, the solvent and excess acid are evaporated under reduced pressure, and the residue is crystallized in an organic solvent to obtain an acid addition salt.

[294] In addition, a pharmaceutically acceptable metal salt can be obtained using a base. An alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering off the undissolved salt, and then evaporating and drying the filtrate. Sodium, potassium, or calcium salts are pharmaceutically acceptable as metal salts. In addition, the corresponding silver salts can be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).

[295] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound represented by chemical formula 1 as an active ingredient for preventing or treating a neurodegenerative disease and cancer. All of the compounds represented by chemical formula 1 have LRRK2 inhibitory activity.

[296] A neurodegenerative disease refers to a disease that causes various symptoms because degenerative changes occur in the central nervous system due to gradual and progressive death of nerve cells, and it may be selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, prion disease, motor neuron disease, spinocerebellar ataxia, spinal muscular atrophy, Creutzfeldt-Jakob disease and alcoholic dementia, but not limited to these.

[297] In addition, the cancer may be selected from the group consisting of kidney cancer, thyroid cancer, breast cancer, liver cancer, and brain cancer, but is not limited thereto.

[298] The pharmaceutical composition of the present invention can be prepared in suitable dosage forms using a commonly used pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" refers to a composition that is physiologically acceptable when administered to humans and does not cause an allergic reaction or the like thereto, such as gastrointestinal upset, dizziness, etc. In addition, the composition can be prepared and used in the form of oral compositions such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions according to a general method.

[299] Carriers, excipients and diluents that can be incorporated into the composition may include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, arabic rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate and mineral oil. The compositions can be prepared using a generally used diluent or excipient such as a filler, stabilizer, binder, disintegrant, surfactant and so on. Solid compositions for oral administration include a tablet, a pill, a powder, a granule, a capsule and the like, and such solid compositions can be prepared by mixing at least one or more excipients such as starch, microcrystalline cellulose, sucrose or lactose, low-substituted hydroxypropyl cellulose, hypromellose and the like with the compound of the present invention. Furthermore, in addition to the usual excipients, lubricating agents such as magnesium stearate and talc can also be used. Liquid compositions for oral administration can correspond to suspensions, oral liquids, emulsions, syrups and the like, and can include various excipients such as a wetting agent, a sweetener, a flavoring agent, a preservative and the like, in addition to water and liquid paraffin which are usually used as the usual diluents. Compositions for parenteral administration include a sterile aqueous solution, a non-aqueous solution, a suspension, an emulsion, a lyophilized agent, and a suppository. In the case of a non-aqueous solution and a non-aqueous suspension, propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an injectable ester such as ethyl oleate, and the like can be used. As a base for a suppository, witepsol, macrogol, tween 61, cocoa butter, lauric fat, glycerin, gelatin, and the like can be used. In the case of preparation in the form of compositions for parenteral administration, the pyrimidine derivative, which is a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof, is sterilized and/or mixed with a preservative, stabilizer, wettable powder or emulsifier, adjuvant such as salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances in water to prepare a solution or suspension, and the resulting solution or the resulting suspension can be prepared as a unit dose in an ampoule or in a vial.

[300] The pharmaceutical composition containing the compound of chemical formula 1 disclosed in the present invention as an active ingredient can be administered to mammals such as rats, farm animals and humans by various routes. All routes of administration can be envisaged, and, for example, the pharmaceutical composition can be administered orally, rectally or by intravenous, intramuscular, subcutaneous, intrauterine, intradural or cerebrovascular injection. The dose can be varied according to the age, sex and body weight of the subject to be treated, the specific disease or specific pathology to be treated, the severity of the disease or pathology, the duration of administration, the route of administration, the degree of absorption of the drug, the rate of distribution and excretion, the types of other drugs used, the insight of the physicians prescribing the treatment, and so on. Determining the dose based on these factors is within the skill of those skilled in the art, and in general, the dose is in the range of 0.01 mg/kg/day to about 2000 mg/kg/day. A more preferred dose is 1 mg/kg/day to 500 mg/kg/day. The administration can be performed once a day or several times a day. The dose does not limit the scope of the present invention in any way.

[301] The pharmaceutical composition of the present invention can be used alone or in combination with surgery, hormonal therapy, chemotherapy and a biological response modulator for the prevention or treatment of neurodegenerative disease and cancer.

Beneficial effects of the invention

[302] The present invention relates to a novel pyrimidine derivative and a composition containing the same for preventing or treating a neurodegenerative disease and cancer. Due to the excellent inhibitory activity against LRRK2 and the ability to effectively cross the blood-brain barrier (BBB), the pyrimidine derivatives find preferable applications in pharmaceutical compositions for preventing and treating neurodegenerative diseases and cancer.

The best mode of carrying out the invention

[303] Embodiments of the present invention will now be described in detail. However, this invention may be embodied in many different forms and should not be construed as limited to the illustrated embodiments set forth in this specification. Rather, these illustrated embodiments are provided so that this description will be thorough and complete and will fully convey the scope of the invention to those skilled in the art.

[304] EXAMPLE 1. Synthesis and physicochemical characteristics of pyrimidine derivatives

[305] The synthetic procedures for compounds 1-217 of the present invention are given below.

[306] Compound 1. (4-((5-Chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone

[307] 1) Synthesis of (4-amino-3-methoxyphenyl)(morpholino)methanone

[308]

[309] In a 25 mL round-bottomed flask were placed 4-amino-3-methoxybenzoic acid (500 mg, 3 mmol), morpholine (0.31 mL, 3.6 mmol), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl) (747 mg, 3.9 mmol), HOBt (527 mg, 3.9 mmol) and DCM (dichloromethane) (10 mL), followed by DIPEA (1.05 mL, 6 mmol) at 0 °C. The mixture was then stirred at room temperature (rt) for 12 h. Ethyl acetate and saturated aqueous NaCl were added and the resulting organic layer was dried (Mg ₂ SO ₄ ), filtered and concentrated. The crude product was dissolved in DCM and isolated by column chromatography to give the title compound as a pale yellow solid (634 mg, 2.68 mmol) (yield 89.1%).

[310] ¹ H NMR (nuclear magnetic resonance; 300 MHz, chloroform-d) δ 6.94 (d, J=1.8 Hz, 1H), 6.85 (dd, J=7.9; 1.8 Hz, 1H), 6.70 (d, J=7.9 Hz, 1H), 3.87 (s, 3H). 3.56-3.75 (m, 8H).

[311] 2) Synthesis of 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine

[312]

[313] To a 5 mL microwave reactor vial were added 2,4,5-trichloropyrimidine (0.63 mL, 5.5 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (720 mg, 5.78 mmol), 2 M _Na2CO3 solution ( _5.5 mL, 11 mmol) and dioxane (9 mL) and degassed twice. After addition of Pd(dppf) _Cl2 (1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) (402 mg, 0.55 mmol), degassing was repeated once more. The mixture was stirred at 90 °C for 12 h and passed through a _celite filter. After addition of ethyl acetate and water, the resulting organic layer was dried ( _Mg2SO4 ), filtered and concentrated. The crude product was dissolved in DCM and isolated by column chromatography to give the title compound as a pale yellow solid (820 mg, 3.58 mmol) (yield 65%).

[314] ¹ H NMR (300 MHz, chloroform-d) δ 8.57 (s. 1H), 8.14 (s, 1H), 8.08 (s. 1H). 3.96 (s. 3H).

[315] 3) Synthesis of (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone

[316]

[317] (4-Amino-3-methoxyphenyl)(morpholino)methanone (120 mg, 0.525 mmol), 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine (118 mg, 0.5 mmol), xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (29 mg, 0.05 mmol), cesium carbonate (326 mg, 1 mmol) and dioxane (2 mL) were added to a 5 mL microwave reactor vial and the vial was degassed three times. Pd(OAc) ₂ (11 mg, 0.05 mmol) was then added and degassing was performed one more time. The mixture was stirred at 90 °C for 12 h. After addition of ethyl acetate and water, the resulting organic layer was dried ( _Mg2SO4 ), filtered and concentrated. The crude product was dissolved in DCM ( _{dichloromethane} ) and isolated by column chromatography to give the title compound as a white solid (163 mg; 0.38 mmol) (yield 76%).

[318] ^1H NMR (300 MHz, chloroform-d) δ 8.50 (d, J=8.8 Hz, 1H), 8.35-8.38 (m, 3H), 8.13 (s, 1H), 7.02-7.08 (m , 2H), 4.01(s, 3H), 3.96 (s, 3H), 3.60-3.80 (m, 8H).

[319] The following compounds were synthesized in a manner similar to that described for compound 1 in Example 1, and the chemical structures and NMR spectral data for the synthesized compounds are summarized in Table 1 below.

[320] (4-((5-Chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 1);

[321] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone (compound 2);

[322] 1-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-one (compound 3);

[323] (4-((5-chloro-4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 4);

[324]

[325] 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (compound 5);

[326] 2-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile (compound 6);

[327] 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile (compound 7);

[328] (4-((5-chloro-4-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 8);

[329] methyl-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetate (compound 9);

[330] (4-((5-chloro-4-(1-(methylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 10);

[331] (4-((5-chloro-4-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 11);

[332] (4-((5-chloro-4-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 12);

[333] (4-((5-chloro-4-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 13);

[334] (4-((5-chloro-4-(1-phenyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 14);

[335] (4-((5-chloro-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 15);

[336] (4-((5-chloro-4-(1-(methoxymethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 16);

[337] (4-((5-chloro-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 17);

[338] (4-((5-chloro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 18);

[339] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone (compound 19);

[340] (4-((5-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 20);

[341] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide (compound 21);

[342] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyrrolidin-1-yl)methanone (compound 22);

[343] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-ethyl-3-methoxy-N-(2-methoxyethyl)benzamide (compound 23);

[344] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-hydroxy-2-methylpropan-2-yl)-3-methoxybenzamide (compound 24);

[345] N-(tert-butyl)-4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 25);

[346] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)-3-methoxybenzamide (compound 26);

[347] 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-methylbutanenitrile (compound 27);

[348] (4-((5-chloro-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 28);

[349] (3-methoxy-4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 29);

[350] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4,4-difluorocyclohexyl)-3-methoxybenzamide (compound 30);

[351] (3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone (compound 31);

[352] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-7-azaspiro[3.5 ]nonan-7-yl)methanone (compound 32);

[353] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1-oxa-6-azaspiro[3.3 ]heptan-6-yl)methanone (compound 33);

[354] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 34);

[355] (4-((5-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl) (2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone (compound 35);

[356] (3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 36);

[357] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 37);

[358] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 38);

[359] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(2-hydroxypropan-2-yl)piperidin-1-yl)methanone (compound 39);

[360] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-6-azaspiro[3.3 ]heptan-6-yl)methanone (compound 40);

[361] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4,4-difluoropiperidin-1-yl)methanone (compound 41);

[362] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2,2-dimethylmorpholino)methanone (compound 42);

[363] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidin-1-yl)methanone (compound 43);

[364] 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazin-1-yl)ethan-1-one (compound 44);

[365] (4-isopropylpiperazin-1-yl)(3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)methanone (compound 45);

[366] (2-fluoro-5-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 46);

[367] (3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-pyrimidin-2-yl)amino)phenyl)(4-phenylpiperazin-1-yl)methanone (compound 47);

[368] (2-fluoro-5-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(4- isopropylpiperazin-1-yl)methanone (compound 48);

[369] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone (compound 49);

[370] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(oxetan-3-yl)piperazin-1-yl)methanone (compound 50);

[371] ((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(4-((5-chloro-4-(1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone (compound 51);

[372] (4-((5-chloro-4-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 52);

[373] (4-((5-chloro-4-(1-propyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 53);

[374] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 54);

[375] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 55);

[376] (4-((5-chloro-4-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 56);

[377] (4-((5-chloro-4-(1-propyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 57);

[378] (4-((5-chloro-4-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 58);

[379] (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 59);

[380] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl) benzamide (compound 60);

[381] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 61);

[382] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 62);

[383] (4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 63) ;

[384] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 64);

[385] (2-fluoro-4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-pyrimidin-2-yl)amino)-5-methoxyphenyl)(morpholino) methanone (compound 65);

[386] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(tetrahydro-2H-pyran-4-yl )methanone (compound 66);

[387] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methyltetrahydro-2H-pyran-4-yl)methanone (compound 67);

[388] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methyltetrahydro-2H-pyran-4 -yl)methanone (compound 68);

[389] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone (compound 69);

[390] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(2-hydroxypropan-2- yl)piperidin-1-yl)methanone (compound 70);

[391] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone (compound 71);

[392] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(oxetan-3-yl) piperazin-1-yl)methanone (compound 72);

[393] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidin-1-yl)methanone (compound 73);

[394] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanthione (compound 74);

[395] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1-isopropylpiperidin-4-yl)methanone (compound 75);

[396] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methoxypiperidin-1-yl)methanone (compound 76);

[397] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-oxa-9-azaspiro[5.5]undecan-9-yl)methanone (compound 77);

[398] 1-(4-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazin-1-yl )ethan-1-one (compound 78);

[399] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(methylsulfonyl)piperidin-1- yl)methanone (compound 79);

[400] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(tetrahydro-2H-pyran-4- yl)benzamide (compound 80);

[401] N-(1-(2-(o-tolyl)quinolin-3-yl)ethyl)-6,7-Dihydro-5H-pyrrolo[2,3-c1]pyrimidin-4-amine (compound 81);

[402] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-cyclopropyl-3-methoxybenzamide (compound 82);

[403] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydroxyazetidin-1-yl)methanone (compound 83);

[404] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1,1-dioxidothiomorpholino)methanone (compound 84);

[405] (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 85);

[406] (3)-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-(hydroxymethyl) pyrrolidin-1-yl)methanone (compound 86);

[407] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(hexahydropyrrolo[1,2-a]pyrazine -2(1H)-yl)methanone (compound 87);

[408] (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1- yl)methanone (compound 88);

[409] ((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone (compound 89);

[410] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone (compound 90);

[411] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-((1R,4R)-4-hydroxycyclohexyl)-3 -methoxybenzamide (compound 91);

[412] (6-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(morpholino)methanone (compound 92);

[413] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-(dimethylamino)cyclohexyl)-3-methoxybenzamide ( compound 93);

[414] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(dimethylamino)piperidin-1- yl)methanone (compound 94);

[415] ((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone (compound 95);

[416] 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 96);

[417] (R)-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydroxypyrrolidin-1 -yl)methanone (compound 97);

[418] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(5-methylhexahydropyrrolo[3,4-c ]pyrrol-2(1H)-yl)methanone (compound 98);

[419] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-isopropylpiperidin-4-yl)-3-methoxybenzamide (compound 99);

[420] 2-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)hexahydropyrrolo[1,2-a] pyrazin-6(2H)-one (compound 100);

[421] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N,N-dimethylbenzamide (compound 101);

[422] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-methylpiperazine-1 -yl)methanione (compound 102);

[423] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanthione (compound 103);

[424] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-methylpiperazine-1 -yl)methanone (compound 104);

[425] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(morpholino)methanone (compound 105 );

[426] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanthione (compound 106);

[427] (5-chloro-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluorophenyl)(4-methylpiperazine-1 -yl)methanone (compound 107);

[428] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(4-methylpiperazin-1- yl)methanone (compound 108);

[429] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methylphenyl)(4-methylpiperazin-1-yl)methanone (compound 109);

[430] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-(dimethylamino) piperidin-1-yl)methanone (compound 110);

[431] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-(dimethylamino) piperidin-1-yl)methanone (compound 111);

[432] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-phenylbenzamide (compound 112);

[433] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorophenyl)-3-methoxybenzamide (compound 113) ;

[434] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluorophenyl)-3-methoxybenzamide (compound 114) ;

[435] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorophenyl)-3-methoxybenzamide (compound 115) ;

[436] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyanophenyl)-3-methoxybenzamide (compound 116) ;

[437] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanophenyl)-3-methoxybenzamide (compound 117) ;

[438] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenzamide (compound 118) ;

[439] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenzamide (compound 119) ;

[440] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorobenzyl)-3-methoxybenzamide (compound 120) ;

[441] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(o-tolyl)benzamide (compound 121 );

[442] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(m-tolyl)benzamide (compound 122 );

[443] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(p-tolyl)benzamide (compound 123 );

[444] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methylbenzyl)benzamide (compound 124 );

[445] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methylbenzyl)benzamide (compound 125 );

[446] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methylbenzyl)benzamide (compound 126 );

[447] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-(dimethylamino)phenyl)-3-methoxybenzamide ( connection 127);

[448] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanobenzyl)-3-methoxybenzamide (compound 128) ;

[449] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-2- yl)-3-methoxybenzamide (compound 129);

[450] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-((tetrahydrofuran-3-yl)methyl )benzamide (compound 130);

[451] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyano-4-fluorophenyl)-3-methoxybenzamide (compound 131);

[452] N-(5-chloro-2-fluorophenyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (connection 132);

[453] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-(4-fluorophenyl)ethyl)-3-methoxybenzamide (compound 133);

[454] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,4-difluorobenzyl)-3-methoxybenzamide (compound 134);

[455] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3,5-difluorobenzyl)-3-methoxybenzamide (compound 135);

[456] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methylpyridin-4-yl) benzamide (compound 136);

[457] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxybenzamide (compound 137);

[458] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxybenzamide (compound 138);

[459] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N,N-diethyl-3-methoxybenzamide (compound 139);

[460] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyethyl)benzamide (compound 140 );

[461] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxy-N-methylbenzamide (compound 141);

[462] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxy-N-methylbenzamide (compound 142) ;

[463] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-N-(1-methylpiperidin- 4-yl)benzamide (compound 143);

[464] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methyl-1H-pyrazol- 4-yl)benzamide (compound 144);

[465] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-isopropyl-1H-pyrazol-4-yl) -3-methoxybenzamide (compound 145);

[466] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-chlorobenzyl)-3-methoxybenzamide (compound 146) ;

[467] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-chlorobenzyl)-3-methoxybenzamide (compound 147) ;

[468] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-chlorobenzyl)-3-methoxybenzamide (compound 148) ;

[469] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-chlorophenyl)-3-methoxybenzamide (compound 149) ;

[470] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-chlorophenyl)-3-methoxybenzamide (compound 150) ;

[471] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-chlorophenyl)-3-methoxybenzamide (compound 151) ;

[472] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxybenzyl)-3-methoxybenzamide (compound 152) ;

[473] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxybenzyl)-3-methoxybenzamide (compound 153) ;

[474] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)benzamide (compound 154 );

[475] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-2-ylmethyl)benzamide ( connection 155);

[476] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-3-ylmethyl)benzamide ( compound 156);

[477] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-4-ylmethyl)benzamide ( connection 157);

[478] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyphenyl)-3-methoxybenzamide (compound 158) ;

[479] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxyphenyl)-3-methoxybenzamide (compound 159) ;

[480] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxyphenyl)-3-methoxybenzamide (compound 160) ;

[481] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyphenyl)benzamide (compound 161 );

[482] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methoxyphenyl)benzamide (compound 162 );

[483] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxyphenyl)benzamide (compound 163 );

[484] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-1- yl)-3-methoxybenzamide (compound 164);

[485] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)-N-methylbenzamide (connection 165);

[486] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2,2,6,6- tetramethylpiperidin-4-yl)benzamide (compound 166);

[487] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,6-dimethylpiperidin-1-yl)-3 -methoxybenzamide (compound 167);

[488] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-((6-chloropyridin-3-yl)methyl)- 3-methoxybenzamide (compound 168);

[489] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-N-(2-(pyridin-2-yl)ethyl)benzamide (compound 169);

[490] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-(difluoromethoxy)phenyl)-3-methoxybenzamide ( connection 170);

[491] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-ethylphenyl)-3-methoxybenzamide (compound 171);

[492] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-ethylphenyl)-3-methoxybenzamide (compound 172);

[493] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-ethylphenyl)-3-methoxybenzamide (compound 173);

[494] N-benzyl-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (compound 174) ;

[495] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-N-(3-methylbenzyl) benzamide (compound 175);

[496] ethyl 3-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamido)propanoate (compound 176);

[497] N-benzyl-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxybenzamide (compound 177) ;

[498] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-isopropoxyphenyl)-3-methoxybenzamide (compound 178) ;

[499] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-phenylethyl)benzamide (compound 179 );

[500] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide (connection 180);

[501] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-(trifluoromethyl)phenyl)benzamide (connection 181);

[502] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-phenylpropyl)benzamide (compound 182 );

[503] N-(4-aminobenzyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 183) ;

[504] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluoro-5-methylphenyl)-3-methoxybenzamide (connection 184);

[505] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluoro-4-methylphenyl)-3-methoxybenzamide (connection 185);

[506] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluoro-2-methylphenyl)-3-methoxybenzamide (connection 186);

[507] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluoro-3-methylphenyl)-3-methoxybenzamide (compound 187);

[508] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluoro-2-methylphenyl)-3-methoxybenzamide (connection 188);

[509] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-sulfamoylbenzyl)benzamide (compound 189);

[510] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-(methylsulfonamido)phenyl)benzamide (compound 190);

[511] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-sulfamoylphenyl)benzamide (compound 191 );

[512] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-(methylsulfonyl)ethyl)benzamide (compound 192);

[513] methyl-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-1-valinate (compound 193) ;

[514] methyl-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-1-isoleucinate (compound 194) ;

[515] ethyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)glycinate (compound 195);

[516] N-(4-aminophenethyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 196) ;

[517] N-(3-(1H-imidazol-1-yl)propyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino )-3-methoxybenzamide (compound 197);

[518] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,2-dimethoxyethyl)-3-methoxybenzamide (compound 198);

[519] methyl-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-leucinate (compound 199) ;

[520] methyl-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-prolinate (compound 200) ;

[521] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxybenzyl)-N-methylbenzamide (connection 201);

[522] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-ethyl-3-methoxy-N-methylbenzamide (compound 202);

[523] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxybenzyl)benzamide (compound 203 );

[524] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxy-3,5- dimethylphenyl)benzamide (compound 204);

[525] N-(3-aminobenzyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 205) ;

[526] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-5- yl)-3-methoxybenzamide (compound 206);

[527] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-4- yl)-3-methoxybenzamide (compound 207);

[528] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-2- yl)-3-methoxy-N-methylbenzamide (compound 208);

[529] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-1- yl)-3-methoxy-N-methylbenzamide (compound 209);

[530] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(ethyl(methyl)amino) piperidin-1-yl)methanone (compound 210);

[531] N-(1-acetylindolin-5-yl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy -N-methylbenzamide (compound 211);

[532] N-(1-acetylindolin-5-yl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (connection 212);

[533] ethyl-3-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamido)-4,4,4 -trifluorobutanoate (compound 213);

[534] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-5- yl)-3-methoxy-N-methylbenzamide (compound 214);

[535] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-4- yl)-3-methoxy-N-methylbenzamide (compound 215);

[536] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(pyrrolidin-1-yl) piperidin-1-yl)methanone (compound 216) and

[537] [1,4'-bipiperidin]-1'-yl-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)- 3-methoxyphenyl)methanone (compound 217).

[539] Compound 1. (4-((5-Chloro-4-phenylpyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone

[540]

[541] 2,5-Dichloro-4-phenylpyrimidin-4-amine (206 mg, 0.94 mmol), (4-amino-3-methoxyphenyl)(morpholino)methanone (200 mg, 0.85 mmol), anhydrous 2-BuOH (1.8 mL), and trifluoroacetic acid (TFA; 0.2 mL) were added to a 5 mL microwave reactor vial and the vial contents were heated at 110 °C for 12 h. Upon completion of the reaction, methylene chloride (MC) and saturated aqueous NaHCO ₃ solution were added. The resulting organic layer was dried (Mg ₂ SO ₄ ), filtered, and concentrated. The crude product was dissolved in DCM and isolated by column chromatography to give the title compound as a white solid (110 mg) (yield 31%).

[542] ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.60 (d, J=6.0 Hz, 1H), 8.51(S, 1H), 8.02 (S, 1H), 7.90 (m, 2H), 7.55 (m, 3H), 7.08 (s, 1H), 7.02 (d, J=6.0 Hz, 1H), 3.97 (s, 3H), 3.72 (m, 8H), 3.11(d, J=6.0 Hz, 3H).

[543] Compound 2. (4-((5-Chloro-4-(pyridin-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone

[544]

[545] (4-((4,5-Dichloropyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (100 mg, 0.26 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (48.5 mg, 0.236 mmol), 2 M _Na2CO3 (0.35 mL, 0.7 mmol) and _dioxane (2 mL) were added to a 5 mL microwave reactor vial and the vial was degassed twice. Then Pd( _PPh3 ) ₄ (23 mg, 0.02 mmol) was added and degassing was performed once more. The mixture was stirred at 110 °C for 12 h. After filtration through a Celite filter, ethyl acetate and water were added. The resulting organic layer was _dried ( _Mg2SO4 ), filtered and concentrated. The crude product was dissolved in DCM and isolated by column chromatography to afford the title compound as a white solid (67.3 mg, 0.158 mmol) (yield 67%).

[546] ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.20 (s, 1H), 8.77 (s, 1H), 8.53 (s, 1H), 8.51(d, J=8.2 Hz, 1H), 8.38 (d, J=7.6 Hz, 1H), 8.04 (s, 1H), 7.59 (d, J=9.5 Hz, 1H), 7.08 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 3.97 (s, 3H), 3.60-3.79 (m, 8H).

[547] Compound 3. (4-((5-Chloro-4-(3-nitrophenyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone

[548]

Pd( _PPh3 ) ₄ ,

2 _{M Na2CO3}

Dioxane 110°C,

during the night

[549] To a 5 mL microwave reactor vial were added (4-((4,5-dichloropyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (100 mg, 0.26 mmol), 4,4,5,5-tetramethyl-2-(3-nitrophenyl)-1,3,2-dioxaborolane (58.8 mg, 0.236 mmol), 2 M _Na2CO3 solution ( _0.35 mL, 0.7 mmol) and dioxane (2 mL) and the vial was degassed twice. Then Pd( _PPh3 ) ₄ (23 mg, 0.02 mmol) was added and degassing was repeated once. The mixture was stirred at 110 °C for 12 h. After filtration through a Celite filter, ethyl acetate and water were added. The resulting organic layer was _dried ( _Mg2CO4 ), filtered and concentrated. The crude product was dissolved in DCM and isolated by column chromatography to afford the title compound as a white solid (65.3 mg, 0.139 mmol) (yield 59%).

[550] ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.81(t, J=2.3 Hz, 1H), 8.55 (s, 1H), 8.51(d, J=8.3 Hz, 1H), 8.38 (ddd, J=8.3; 2.3; 1.0 Hz, 1H), 8.27 (dt, J=8.0; 1.4 Hz, 1H), 8.03 (s, 1H), 7.71(t, J=8.0 Hz, 1H), 7.08 (d, J=1.8 Hz, 1H), 7.03 (del, J=8.3; 1.8 Hz, 1H), 3.97 (s, 3H), 3.60 -3.81 (m, 8H).

[551] EXAMPLE 2. Identification of LRRK2 inhibitory activity

[552] Representative compounds synthesized in Example 1 were evaluated for inhibitory activity against wild-type LRRK2 and LRRK2 mutant (G2019S), and the results are summarized in Tables 2 and 3. Briefly, a T7 phage strain harboring the wild-type kinase containing amino acid residues H970 to E2527 of human-derived LRRK2 (Accession No. NP_940980.3) or a T7 phage strain harboring the G2019S mutation was infected into E. coli BL21, which was then grown to logarithmic phase. After infection with the T7 phage strains (MOI = 0.4), the cells were cultured at 32°C for 90-150 min with shaking. E. coli lysates were then centrifuged (6,000 × g) and the supernatant was filtered through a 0.2 μm filter. Kinases were produced in human embryonic kidney 293 (HEK 293) cells by labeling DNA to produce DNA-labeled kinases for detection by quantitative polymerase chain reaction (qPCR). Affinity binding media for use in kinase assays were generated by treating streptavidin-coated magnetic beads with biotinylated small molecule ligands at room temperature for 30 min. The ligand-loaded beads were then blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce); containing 1% bovine serum albumin (BSA), 0.05% Tween 20, 1 mM dithiothreitol (DTT)) to remove unbound ligands and thus reduce non-specific phage binding. The resulting kinase, affinity binding ligand beads, and each compound (10, 50, or 100 nM; concentrations used are listed in Table 2 below) were then mixed with 1× binding buffer (20% SeaBlock, 0.17× PBS, 0.05% Tween 20, 6 mM DTT) to form a final volume of 0.02 ml in each well of 384-well polypropylene plates and incubated at room temperature with shaking. After one hour of incubation, affinity binding beads were washed with wash buffer (1×PBS, 0.05% Tween 20), resuspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity binding ligand) and incubated at room temperature for 30 min with shaking. Eluted samples were then quantified for wild-type and mutant LRRK2 (G2019S) by qPCR. Activities are expressed as percentages of control (%cnt). Compounds used in the activity assays were prepared as 40-fold concentrated solutions in 100% DMSO. These concentrated solutions were diluted directly during the assay procedures.

[553] The results of the assay are summarized in Tables 2 and 3 below. Table 2 includes data on the inhibitory activity of representative compounds of the present invention at a concentration of 100 nM against wild-type (WT) LRRK2 and the mutant form of LRRK2 (G2019S), while Table 3 includes data on the inhibitory activity of representative compounds at concentrations of 10 nM and 50 nM against wild-type LRRK2 (residual kinase activity: +++less than 10%; ++less than 30%; +less than 50%; - 50% or greater).

[557]

[558]

[559] As can be seen from Tables 2 and 3, the pyrimidine derivatives of the present invention were found to have inhibitory activity against LRRK2. The pyrimidine derivatives, which are compounds of chemical formula 1 wherein the substituent R ₄ is pyrazole and the substituent R ₅ is halogen or haloalkyl, at a concentration of 50 nM exhibited very high inhibitory activity against LRRK2 compared to other compounds.

[560] EXAMPLE 3. Penetration through the blood-brain barrier (BBB)

[561] Each test compound was administered orally at a dose of 10 mg/kg. Three hours later, the animals were sacrificed, blood samples were immediately collected from the heart, and centrifuged to obtain plasma samples. To remove residual blood, the heart was perfused with 20 ml of saline containing heparin (10 units/ml), and the brain was excised. The brain was homogenized with three volumes of PBS buffer. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) (Agilent, Santa Clara, CA, USA) was preferably used for quantitative analysis of the compounds in the obtained plasma and brain tissue samples. LC separation was performed using a mobile phase consisting of 80% acetonitrile and 20% water containing 0.1% formic acid. For each compound, the elution buffer was used for a total of 3 min at a flow rate of 0.3 ml/min. The content of each compound was quantified using the multiple reaction monitoring method (for reference compounds 4 and 5, the orally administered Parkinson's disease drugs DNL-151 and DNL-201 were used as LRRK2 protein inhibitors, respectively).

[562] Three hours after oral administration, it was measured that Compound 37, as a representative of the compounds of the present invention, had an effective concentration in the brain tissue that was 1.64 and 2.77 times higher than that of Comparative Compound 4 (DNL-151) and Comparative Compound 5 (DNL-201), respectively.

[563] The compound of the present invention has been shown to be effective for the treatment of neurodegenerative diseases, including Parkinson's disease, and cancer.

[564] From this result, it is evident that pyrimidine derivatives, which are compounds of chemical formula 1 wherein the substituent R ₄ is pyrazole and the substituent R ₅ is halogen or haloalkyl, may be very useful for the prevention or treatment of neurodegenerative diseases and cancers, since they effectively cross the blood-brain barrier and also inhibit the activity of LRRK2 protein.

[565] PREPARATION EXAMPLE 1. Preparation of powder composition

[566] Compound 37 of the present invention ((4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone) (2 g) and lactose (1 g) were mixed and loaded into a sealed bag to prepare a powder composition.

[567] PREPARATION EXAMPLE 2. Preparation of a composition in the form of a tablet

[568] Compound 37 of the present invention ((4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone) (100 mg), microcrystalline cellulose (100 mg), lactose hydrate (60 mg), low-substituted hydroxypropyl cellulose (20 mg) and magnesium stearate (2 mg) were mixed and compressed into a tablet using a standard tabletting method.

[569] PREPARATION EXAMPLE 3. Preparation of a capsule-shaped composition

[570] Compound 37 of the present invention ((4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone) (100 mg), microcrystalline cellulose (100 mg), lactose hydrate (60 mg), low-substituted hydroxypropyl cellulose (20 mg) and magnesium stearate (2 mg) were mixed and loaded into a gelatin capsule according to a standard method for preparing a capsule composition.

[571] PREPARATION EXAMPLE 4. Preparation of a composition in pill form

[572] Compound 37 of the present invention ((4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone) (90 mg), glutinous rice starch (5 mg) and purified water (5 mg) were mixed with a small amount of antihygroscopic additives including dextrin, maltodextrin, corn starch and microcrystalline cellulose (MCSS), and prepared into a pill dosage form (100 mg) according to a standard procedure.

[573] PREPARATION EXAMPLE 5. Preparation of injection composition

[574] Compound 37 of the present invention ((4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone) (10 mg) was mixed with an appropriate amount of sterile distilled water for injection and an appropriate amount of a pH adjusting agent per ampoule (2 ml) and prepared into an injection composition according to a standard method.

Claims (244)

1. A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: Where each R ₁ ' is independently selected from the group consisting of C ₁ -C ₆ alkoxy or haloC ₁ -C ₆ alkoxy; R ₁ '' represents hydrogen or halogen; R ₂ is a substituted or unsubstituted pyrazole, wherein said substituted pyrazole has as a substituent at least one radical selected from the group consisting of halogen, hydroxy, cyano, amino, amide, nitro, C ₁ -C ₆ alkylsulfonyl, acetyl, methyloxycarbonyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ heterocycloalkyl, which refers to a cyclic saturated hydrocarbon bearing one heteroatom, such as O, as a ring member; phenyl, pyridinyl; wherein each substituted alkyl, substituted benzyl has as a substituent at least one radical selected from the group consisting of halogen, hydroxy, cyano, amino, amide, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₄ -C ₆ heterocycloalkyl, which refers to a cyclic saturated hydrocarbon bearing at least one heteroatom, such as N or O, as a ring member; R ₃ is halogen or halogenC ₁ -C ₆ alkyl; R ₄ is represented by any of the structures B-1 through B-20, B-22 through B-29, given below: Where R ₆ is selected from the group consisting of a hydrogen atom, halogen, hydroxy, C ₁ -C ₆ hydroxyalkyl and C ₁ -C ₆ alkylamino; each R ₇ is independently selected from the group consisting of hydrogen, halogen, haloC ₁ -C ₆ alkyl and C ₁ -C ₆ alkyl; each R ₈ is independently selected from the group consisting of hydrogen, halogen, amino, hydroxy, cyano, C ₁ -C ₆ dialkylamino, aminosulfonyl, C ₁ -C ₆ alkylsulfonamino, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, halogenC ₁ -C ₆ alkyloxy and C ₁ -C ₆ alkoxy; R ₉ is selected from the group consisting of a hydrogen atom, hydroxy, hydroxyC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxycarbonyl, C ₁ -C ₆ alkylamino, morpholine; R ₁₀ is selected from the group consisting of a hydrogen atom, C ₁ -C ₆ alkyl, phenyl, oxetanyl and acetate; R ₁₁ represents a hydrogen atom or combines with R ₁₀ to form a saturated or unsaturated C ₅ -C ₆ heterocycloalkyl, which refers to a cyclic saturated hydrocarbon bearing one heteroatom, such as N, as a ring member; R ₁₂ represents a hydrogen atom or C ₁ -C ₆ alkyl; R ₁₃ represents a hydrogen atom, C ₁ -C ₆ alkylcarbonyl; R ₁₃ represents a hydrogen atom, C ₁ -C ₆ alkyl, hydroxyC ₁ -C 6 ₅ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl or methylsulfonyl-C ₁ -C ₆ alkyl; Ak is C ₁ -C ₆ alkyl; each k is independently equal to 0, 1, or 2 (provided that all k are not simultaneously equal to zero); l is equal to 1 or 2; m is 0, 1, 2, 3, or 4; n is 0 or 1; each W is independently CH or N; Z is O or _SO2 ; X is C, CH or N; and Y is selected from the group consisting of O and S. 2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, selected from the group consisting of: (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 1); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone (compound 2); 1-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-one (compound 3); (4-((5-chloro-4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 4); 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (compound 5); 2-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile (compound 6); 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile (compound 7); (4-((5-chloro-4-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 8); methyl 2-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetate (compound 9); (4-((5-chloro-4-(1-(methylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 10); (4-((5-chloro-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 15); (4-((5-chloro-4-(1-(methoxymethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 16); (4-((5-chloro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 18); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone (compound 19); (4-((5-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 20); 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide (compound 21); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyrrolidin-1-yl)methanone (compound 22); 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-ethyl-3-methoxy-N-(2-methoxyethyl)benzamide (compound 23); 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-hydroxy-2-methylpropan-2-yl)-3-methoxybenzamide (compound 24); N-(tert-butyl)-4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 25); 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)-3-methoxybenzamide (compound 26); 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-methylbutanenitrile (compound 27); (4-((5-chloro-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 28); (3-methoxy-4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 29); 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4,4-difluorocyclohexyl)-3-methoxybenzamide (compound 30); (3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone (compound 31); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone (compound 32); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1-oxa-6-azaspiro[3.3]heptan-6-yl)methanone (compound 33); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 34); (4-((5-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone (compound 35); (3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 36); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 37); 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 38); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(2-hydroxypropan-2-yl)piperidin-1-yl)methanone (compound 39); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone (compound 40); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4,4-difluoropiperidin-1-yl)methanone (compound 41); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2,2-dimethylmorpholino)methanone (compound 42); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidin-1-yl)methanone (compound 43); 1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazin-1-yl)ethan-1-one (compound 44); (4-isopropylpiperazin-1-yl)(3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)methanone (compound 45); (2-fluoro-5-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 46); (3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(4-phenylpiperazin-1-yl)methanone (compound 47); (2-fluoro-5-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(4-isopropylpiperazin-1-yl)methanone (compound 48); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone (compound 49); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(oxetan-3-yl)piperazin-1-yl)methanone (compound 50); ((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone (compound 51); (4-((5-chloro-4-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 52); (4-((5-chloro-4-(1-propyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 53); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 54); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 55); (4-((5-chloro-4-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 56); (4-((5-chloro-4-(1-propyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 57); (4-((5-chloro-4-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 58); (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 59); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 60); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 61); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 62); (4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 63); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 64); (2-fluoro-4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxyphenyl)(morpholino)methanone (compound 65); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(tetrahydro-2H-pyran-4-yl)methanone (compound 66); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methyltetrahydro-2H-pyran-4-yl)methanone (compound 67); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methyltetrahydro-2H-pyran-4-yl)methanone (compound 68); (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone (compound 69); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(2-hydroxypropan-2-yl)piperidin-1-yl)methanone (compound 70); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone (compound 71); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(oxetan-3-yl)piperazin-1-yl)methanone (compound 72); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidin-1-yl)methanone (compound 73); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanethione (compound 74); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1-isopropylpiperidin-4-yl)methanone (compound 75); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methoxypiperidin-1-yl)methanone (compound 76); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-oxa-9-azaspiro[5.5]undecan-9-yl)methanone (compound 77); 1-(4-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazin-1-yl)ethan-1-one (compound 78); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(methylsulfonyl)piperidin-1-yl)methanone (compound 79); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzamide (compound 80); N-(1-(2-(o-tolyl)quinolin-3-yl)ethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-amine (compound 81); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-cyclopropyl-3-methoxybenzamide (compound 82); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydroxyazetidin-1-yl)methanone (compound 83); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1,1-dioxidothiomorpholino)methanone (compound 84); (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 85); (S)-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone (compound 86); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanone (compound 87); (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 88); ((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone (compound 89); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone (compound 90); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-((1R,4R)-4-hydroxycyclohexyl)-3-methoxybenzamide (compound 91); (6-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(morpholino)methanone (compound 92); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-(dimethylamino)cyclohexyl)-3-methoxybenzamide (compound 93); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(dimethylamino)piperidin-1-yl)methanone (compound 94); ((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone (compound 95); 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 96); (R)-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydroxypyrrolidin-1-yl)methanone (compound 97); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (compound 98); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-isopropylpiperidin-4-yl)-3-methoxybenzamide (compound 99); 2-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (compound 100); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N,N-dimethylbenzamide (compound 101); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-methylpiperazin-1-yl)methanethione (compound 102); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanethione (compound 103); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 104); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(morpholino)methanone (compound 105); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-methoxyphenyl)(morpholino)methanethione (compound 106); (5-chloro-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluorophenyl)(4-methylpiperazin-1-yl)methanone (compound 107); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(4-methylpiperazin-1-yl)methanone (compound 108); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methylphenyl)(4-methylpiperazin-1-yl)methanone (compound 109); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-(dimethylamino)piperidin-1-yl)methanone (compound 110); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro5-methoxyphenyl)(4-(dimethylamino)piperidin-1-yl)methanone (compound 111); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-phenylbenzamide (compound 112); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorophenyl)-3-methoxybenzamide (compound 113); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluorophenyl)-3-methoxybenzamide (compound 114); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorophenyl)-3-methoxybenzamide (compound 115); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyanophenyl)-3-methoxybenzamide (compound 116); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanophenyl)-3-methoxybenzamide (compound 117); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenzamide (compound 118); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenzamide (compound 119); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorobenzyl)-3-methoxybenzamide (compound 120); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(o-tolyl)benzamide (compound 121); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(m-tolyl)benzamide (compound 122); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(p-tolyl)benzamide (compound 123); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methylbenzyl)benzamide (compound 124); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methylbenzyl)benzamide (compound 125); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methylbenzyl)benzamide (compound 126); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-(dimethylamino)phenyl)-3-methoxybenzamide (compound 127); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanobenzyl)-3-methoxybenzamide (compound 128); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-2-yl)-3-methoxybenzamide (compound 129); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-((tetrahydrofuran-3-yl)methyl)benzamide (compound 130); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyano-4-fluorophenyl)-3-methoxybenzamide (compound 131); N-(5-chloro-2-fluorophenyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 132); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-(4-fluorophenyl)ethyl)-3-methoxybenzamide (compound 133); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,4-difluorobenzyl)-3-methoxybenzamide (compound 134); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3,5-difluorobenzyl)-3-methoxybenzamide (compound 135); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methylpyridin-4-yl)benzamide (compound 136); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxybenzamide (compound 137); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxybenzamide (compound 138); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N,N-diethyl-3-methoxybenzamide (compound 139); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyethyl)benzamide (compound 140); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxy-N-methylbenzamide (compound 141); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxy-N-methylbenzamide (compound 142); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-N-(1-methylpiperidin-4-yl)benzamide (compound 143); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methyl-1H-pyrazol-4-yl)benzamide (compound 144); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-isopropyl-1H-pyrazol-4-yl)-3-methoxybenzamide (compound 145); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-chlorobenzyl)-3-methoxybenzamide (compound 146); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-chlorobenzyl)-3-methoxybenzamide (compound 147); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-chlorobenzyl)-3-methoxybenzamide (compound 148); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-chlorophenyl)-3-methoxybenzamide (compound 149); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-chlorophenyl)-3-methoxybenzamide (compound 150); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-chlorophenyl)-3-methoxybenzamide (compound 151); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxybenzyl)-3-methoxybenzamide (compound 152); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxybenzyl)-3-methoxybenzamide (compound 153); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)benzamide (compound 154); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-2-ylmethyl)benzamide (compound 155); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-3-ylmethyl)benzamide (compound 156); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-4-ylmethyl)benzamide (compound 157); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyphenyl)-3-methoxybenzamide (compound 158); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxyphenyl)-3-methoxybenzamide (compound 159); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxyphenyl)-3-methoxybenzamide (compound 160); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyphenyl)benzamide (compound 161); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methoxyphenyl)benzamide (compound 162); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxyphenyl)benzamide (compound 163); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-1-yl)-3-methoxybenzamide (compound 164); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)-N-methylbenzamide (compound 165); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)benzamide (compound 166); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,6-dimethylpiperidin-1-yl)-3-methoxybenzamide (compound 167); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-((6-chloropyridin-3-yl)methyl)-3-methoxybenzamide (compound 168); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-N-(2-(pyridin-2-yl)ethyl)benzamide (compound 169); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-(difluoromethoxy)phenyl)-3-methoxybenzamide (compound 170); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-ethylphenyl)-3-methoxybenzamide (compound 171); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-ethylphenyl)-3-methoxybenzamide (compound 172); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-ethylphenyl)-3-methoxybenzamide (compound 173); N-benzyl-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (compound 174); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-N-(3-methylbenzyl)benzamide (compound 175); ethyl 3-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamido)propanoate (compound 176); N-benzyl-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxybenzamide (compound 177); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-isopropoxyphenyl)-3-methoxybenzamide (compound 178); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-phenylethyl)benzamide (compound 179); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide (compound 180); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-(trifluoromethyl)phenyl)benzamide (compound 181); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-phenylpropyl)benzamide (compound 182); N-(4-aminobenzyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 183); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluoro-5-methylphenyl)-3-methoxybenzamide (compound 184); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluoro-4-methylphenyl)-3-methoxybenzamide (compound 185); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluoro-2-methylphenyl)-3-methoxybenzamide (compound 186); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluoro-3-methylphenyl)-3-methoxybenzamide (compound 187) 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluoro-2-methylphenyl)-3-methoxybenzamide (compound 188); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-sulfamoylbenzyl)benzamide (compound 189); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-(methylsulfonamido)phenyl)benzamide (compound 190); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-sulfamoylphenyl)benzamide (compound 191); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-(methylsulfonyl)ethyl)benzamide (compound 192); methyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-valinate (compound 193); methyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-isoleucinate (compound 194); ethyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)glycinate (compound 195); N-(4-aminophenethyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 196); N-(3-(1H-imidazol-1-yl)propyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 197); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,2-dimethoxyethyl)-3-methoxybenzamide (compound 198); methyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-leucinate (compound 199); methyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-prolinate (compound 200); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxybenzyl)-N-methylbenzamide (compound 201); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-ethyl-3-methoxy-N-methylbenzamide (compound 202); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxybenzyl)benzamide (compound 203); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxy-3,5-dimethylphenyl)benzamide (compound 204); N-(3-aminobenzyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 205); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-5-yl)-3-methoxybenzamide (compound 206); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-4-yl)-3-methoxybenzamide (compound 207); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-2-yl)-3-methoxy-N-methylbenzamide (compound 208); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-1-yl)-3-methoxy-N-methylbenzamide (compound 209); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(ethyl(methyl)amino)piperidin-1-yl)methanone (compound 210); N-(1-acetylindolin-5-yl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (compound 211); N-(1-acetylindolin-5-yl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 212); ethyl 3-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamido)-4,4,4-trifluorobutanoate (compound 213); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-5-yl)-3-methoxy-N-methylbenzamide (compound 214); 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-inden-4-yl)-3-methoxy-N-methylbenzamide (compound 215); (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone (compound 216) and [1,4'-bipiperidin]-1'-yl-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone (compound 217). 3. A pharmaceutical composition for preventing or treating a neurodegenerative disease, containing a compound represented by chemical formula 1 according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. The pharmaceutical composition according to claim 3, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic lateral sclerosis, prion disease, motor neuron disease, spinocerebellar ataxia, spinal muscular atrophy, Creutzfeldt-Jakob disease and alcoholic dementia.