NOVEL PYRIMIDINE DERIVATIVE AND COMPOSITION CONTAINING THE SAME FOR PREVENTING OR TREATING NEURODEGENERATIVE DISEASES AND CANCER

Abstract

The present invention provides a novel pyrimidine derivative and a composition containing the same for preventing or treating neurodegenerative diseases and cancer. The pyrimidine derivative has excellent LRRK2 protein inhibitory activity and can efficiently pass through the blood-brain barrier (BBB), making it useful for pharmaceutical compositions for the prevention or treatment of neurodegenerative diseases and cancer.

Description

[Technical field]

[0001] The present invention relates to a novel pyrimidine derivative and a composition containing the same for preventing or treating neurodegenerative diseases and cancer. [Background technology]

[0002] Neurodegenerative diseases are brain diseases that occur with aging and are known to be caused by the accumulation of environmental and genetic factors. They are a collective term for diseases that induce various symptoms as degenerative changes occur due to the gradual death of nerve cells in the central nervous system, and are characterized by cell damage and loss of neural structure and function, including memory impairment. Representative examples 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 alcohol-related dementia.

[0003] Parkinson's disease, along with Alzheimer's disease, is one of the most well-known neurodegenerative diseases, and is caused by a lack of dopamine, a neurotransmitter, due to the loss of dopaminergic neurons in the substantia nigra of the brainstem. As a result, protein aggregates called Lewy bodies are formed in neurons, causing motor dysfunction such as forward-leaning posture, tremors, muscle rigidity, and instability, as well as mental symptoms such as depression, anxiety, and sleep disorders.

[0004] The cause of Parkinson's disease is not clearly known, but it is believed to develop due to the combined effects of various factors, such as environmental factors, genetic factors, aging, mitochondrial dysfunction, and abnormalities in the function of processing unnecessary proteins. Most Parkinson's disease occurs sporadically, but 5-10% are known to manifest as a genetic disease caused by gene mutations, and the causative genes known to be parkin, PINK1, DJ-1, α-synuclein, and LRRK2 (leucine-rich repeat kinase 2) are among them.

[0005] Among these, the G2019S mutation of the LRRK2 gene is dominant and occurs most frequently. LRRK2 is a protein belonging to the leucine-rich repeat kinase family, and is composed of a 2527 amino acid sequence with high interspecies similarity, and has both GTPase and serine-threonine kinase activities in one protein. LRRK2 has been reported to be highly expressed in dopamine neurons in the cerebral cortex, substantia nigra, striatum, hippocampus, cerebellum, etc., which are related to the pathogenesis of Parkinson's disease, and increased activity of LRRK2 is known to affect the onset and progression of Parkinson's disease. It has been confirmed that overexpression of normal LRRK2 in nerve cells induces apoptosis, and dopamine neuron death, Lewy bodies, and movement disorders similar to Parkinson's disease symptoms have been reported in LRRK2 hyperactive mutant animals. In LRRK2 knockout animals, neurite outgrowth and inhibition of aging-dependent α-synuclein increase closely associated with Parkinson's disease have been observed in the brain, and the possibility of treating Parkinson's disease by inhibiting LRRK2 has also been confirmed in animal models. LRRK2 is also known to be involved in the transfer of mild cognitive impairment associated with Alzheimer's disease, and compounds and compositions effective in regulating LRRK2 activity can provide therapeutic effects for neurodegenerative diseases, etc. Therefore, selective inhibition of LRRK2 activity can be a useful target for the development of new drugs for disease treatment.

[0006] In addition to the neurodegenerative diseases mentioned above, the anticancer activity of LRRK2 inhibition is being studied in various types of cancer because of its mechanism of suppressing cancer cell proliferation and promoting death.

[0007] In particular, it has been reported that LRRK2 is overexpressed in kidney cancer, thyroid cancer, and liver cancer tissues, and it is known that overactivation of LRRK2 due to LRRK2 mutations (especially G2019S type) increases the risk of breast cancer. In addition, research results have been reported showing that patients with overexpressed LRRK2 in Korean brain cancer tissues have a significantly shorter survival time. In relation to this, Voronoi recently entered the first clinical trial of an LRRK2 inhibitor as a brain cancer treatment and received approval. Therefore, selective inhibition of LRRK2 activity could be a target for the development of a wide range of new drugs, not only for the treatment of neurodegenerative diseases but also for anti-cancer treatment.

[0008] Meanwhile, as prior art documents related to compositions for preventing or treating neurodegenerative diseases containing pyrimidine derivatives as active ingredients, Patent Document 1: Korean Patent Registration No. 10-1566091 discloses a pyrazole aminopyrimidine derivative as an LRRK2 regulator, Patent Document 2: Korean Patent Registration No. 10-2025451 discloses a 2-(phenyl or pyrid-3-yl)aminopyrimidine derivative as a kinase LRRK2 regulator for the treatment of Parkinson's disease, Patent Document 3: Korean Patent Registration No. 10-1208198 discloses a pharmaceutical composition for treating or preventing Parkinson's disease containing a compound having LRRK2 kinase inhibitory activity as an active ingredient, and Patent Document 4: Korean Patent Publication No. 10-2019-0018676 discloses pyrimidin-2-ylamino-1H-pyrazole as an LRRK2 inhibitor for use in the treatment of neurodegenerative disorders. However, there have been no previous reports that mention the pyrimidine derivatives such as Formula 1 of the present invention and the LRRK2 inhibitory activity of the derivatives and the possibility of treating neurodegenerative diseases thereby.

[0009] Therefore, in the course of researching LRRK2 derivatives, the inventors have confirmed that a pyrimidine derivative such as the present invention's chemical formula 1 has excellent LRRK2 inhibitory activity and efficiently passes through the blood-brain barrier (BBB), thereby completing the present invention. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Korean Patent No. 10-1566091 [Patent Document 2] Korean Patent No. 10-2025451 [Patent Document 3] Korean Patent No. 10-1208198 [Patent Document 4] Korean Patent Publication No. 10-2019-0018676 Summary of the Invention [Problem to be solved by the invention]

[0011] An object of the present invention is to provide a novel pyrimidine derivative and a composition containing the same for preventing or treating neurodegenerative diseases and cancer, more specifically, to provide a novel pyrimidine derivative having excellent LRRK2 inhibitory activity and blood-brain barrier (BBB) ​​passing effect, and a composition containing the same for preventing or treating neurodegenerative diseases and cancer. [Means for solving the problem]

[0012] The present invention relates to a compound represented by the following chemical formula 1, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof, in particular:

[0013] [ka]

[0014] R1 is independently substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, amido, nitro, C1-C6 alkyl, C1-C6 alkoxy, or haloC1-C6 alkoxy;

[0015] R2 is substituted with a substituted or unsubstituted pyrazole substituent;

[0016] wherein the substituted pyrazole is selected from the group consisting of halogen, hydroxy, cyano, amino, amido, nitro, C1-C6 alkylsulfonyl, acetyl, methyloxycarbonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C3-C 12 Cycloalkyl, substituted or unsubstituted C3-C 12 Heterocycloalkyl, substituted or unsubstituted C4-C 12 Aryl, or substituted or unsubstituted C4-C 12 Heteroaryl is substituted with one or more substituents selected from the group consisting of

[0017] Further, the substituted alkyl, benzyl, C3-C 12 Cycloalkyl, C4-C 12 Aryl, C4-C 12 Heteroaryl is any of halogen, hydroxy, cyano, amino, amido, nitro, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 Heterocycloalkyl, C4-C 12 substituted by one or more substituents selected from the group consisting of aryl-C1-C6 alkoxy, or -C(=O)O-alkyl(C1-C6);

[0018] R3 is substituted with a halogen or haloC1-C6 alkyl substituent;

[0019] R4 can be expressed by the following B-1 to B-29,

[0020] [ka]

[0021] R6 is independently substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkylsulfonate, or C1-C6 alkylamino;

[0022] R7 is independently substituted with one or more substituents selected from the group consisting of hydrogen, halogen, haloC1-C6 alkyl, or C1-C6 alkyl;

[0023] R8 is independently substituted with one or more substituents selected from the group consisting of hydrogen, halogen, amino, hydroxy, cyano, C1-C6 dialkylamino, aminosulfonyl, C1-C6 alkylsulfonamino, C1-C6 alkyl, haloC1-C6 alkyl, haloC1-C6 alkyloxy, or C1-C6 alkoxy;

[0024] R9 is independently substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, hydroxyC1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacetyl, C1-C6 alkyloxycarbonyl, C1-C6 alkylamino, C1-C6 alkoxy, morpholine, piperidine, pyrrolidine, oxetanyl, piperidine substituted with C1-C6 alkyl, or acetate;

[0025] R 10 is independently substituted with one or more substituents selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, oxetanyl, or acetate;

[0026] R 11 is hydrogen or R 10 is bonded to a saturated or unsaturated C5-C6 heterocycloalkyl substituent;

[0027] R 12 is hydrogen or C1-C6 alkyl;

[0028] R 13 is hydrogen or C1-C6 alkylcarbonyl, or C1-C6 alkylacetyl;

[0029] R 14is hydrogen, C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxyC1-C6 alkyl, C1-C6 alkyloxycarbonylC1-C6 alkyl, or methylsulfonylC1-C6 alkyl;

[0030] Ak is C1-C6 alkyl;

[0031] k is independently 0, 1, or 2 (wherein k is not simultaneously 0);

[0032] l is 1 or 2;

[0033] m is 0, 1, 2, 3, or 4;

[0034] n is 0 or 1,

[0035] W is independently CH or N;

[0036] X is C, CH, or N;

[0037] Y is a substituent selected from the group consisting of O or S; and

[0038] Z is O or SO2;

[0039] The compound represented by Chemical Formula 1, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof, is characterized in that:

[0040] More specifically, the compound of the present invention represented by the above formula 1 is

[0041] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 1);

[0042] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone (compound 2);

[0043] 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);

[0044] (4-((5-chloro-4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 4);

[0045] 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (compound 5);

[0046] 2-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile (compound 6);

[0047] 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile (compound 7);

[0048] (4-((5-chloro-4-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 8);

[0049] Methyl 2-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetate (compound 9);

[0050] (4-((5-chloro-4-(1-(methylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 10);

[0051] (4-((5-chloro-4-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 11);

[0052] (4-((5-chloro-4-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 12);

[0053] (4-((5-chloro-4-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 13);

[0054] (4-((5-chloro-4-(1-phenyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 14);

[0055] (4-((5-chloro-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 15);

[0056] (4-((5-chloro-4-(1-(methoxymethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 16);

[0057] (4-((5-chloro-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 17);

[0058] (4-((5-chloro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 18);

[0059] (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);

[0060] (4-((5-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 20);

[0061] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide (compound 21);

[0062] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyrrolidin-1-yl)methanone (compound 22);

[0063] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-ethyl-3-methoxy-N-(2-methoxyethyl)benzamide (compound 23);

[0064] 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);

[0065] N-(tert-butyl)-4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 25);

[0066] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)-3-methoxybenzamide (compound 26);

[0067] 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-methylbutanenitrile (compound 27);

[0068] (4-((5-chloro-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 28);

[0069] (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);

[0070] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4,4-difluorocyclohexyl)-3-methoxybenzamide (compound 30);

[0071] (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);

[0072] (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);

[0073] (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);

[0074] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 34);

[0075] (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);

[0076] (3-Methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 36);

[0077] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 37);

[0078] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 38);

[0079] (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);

[0080] (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);

[0081] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4,4-difluoropiperidin-1-yl)methanone (compound 41);

[0082] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2,2-dimethylmorpholino)methanone (compound 42);

[0083] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidin-1-yl)methanone (compound 43);

[0084] 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);

[0085] (4-isopropylpiperazin-1-yl)(3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)methanone (compound 45);

[0086] (2-fluoro-5-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 46);

[0087] (3-Methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(4-phenylpiperazin-1-yl)methanone (compound 47);

[0088] (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);

[0089] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone (compound 49);

[0090] (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);

[0091] ((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);

[0092] (4-((5-chloro-4-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 52);

[0093] (4-((5-chloro-4-(1-propyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 53);

[0094] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 54);

[0095] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 55);

[0096] (4-((5-chloro-4-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 56);

[0097] (4-((5-chloro-4-(1-propyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 57);

[0098] (4-((5-chloro-4-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 58);

[0099] (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 59);

[0100] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 60);

[0101] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 61);

[0102] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 62);

[0103] (4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 63);

[0104] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 64);

[0105] (2-fluoro-4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxyphenyl)(morpholino)methanone (compound 65);

[0106] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(tetrahydro-2H-pyran-4-yl)methanone (compound 66);

[0107] (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);

[0108] (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);

[0109] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone (compound 69);

[0110] (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);

[0111] (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);

[0112] (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);

[0113] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidin-1-yl)methanone (compound 73);

[0114] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanethione (compound 74);

[0115] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1-isopropylpiperidin-4-yl)methanone (compound 75);

[0116] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methoxypiperidin-1-yl)methanone (compound 76);

[0117] (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);

[0118] 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);

[0119] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(methylsulfonyl)piperidin-1-yl)methanone (compound 79);

[0120] 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);

[0121] N-(1-(2-(o-tolyl)quinolin-3-yl)ethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-amine (compound 81);

[0122] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-cyclopropyl-3-methoxybenzamide (compound 82);

[0123] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydroxyazetidin-1-yl)methanone (compound 83);

[0124] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1,1-dioxidethiomorpholino)methanone (compound 84);

[0125] (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 85);

[0126] (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);

[0127] (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);

[0128] (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 88);

[0129] ((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);

[0130] (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);

[0131] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-((1r,4r)-4-hydroxycyclohexyl)-3-methoxybenzamide (compound 91);

[0132] (6-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(morpholino)methanone (compound 92);

[0133] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-(dimethylamino)cyclohexyl)-3-methoxybenzamide (compound 93);

[0134] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(dimethylamino)piperidin-1-yl)methanone (compound 94);

[0135] ((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);

[0136] 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 96);

[0137] (R)-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydroxypyrrolidin-1-yl)methanone (compound 97);

[0138] (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);

[0139] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-isopropylpiperidin-4-yl)-3-methoxybenzamide (compound 99);

[0140] 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);

[0141] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N,N-dimethylbenzamide (compound 101);

[0142] (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);

[0143] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanethione (compound 103);

[0144] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 104);

[0145] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(morpholino)methanone (compound 105);

[0146] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanethione (compound 106);

[0147] (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);

[0148] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(4-methylpiperazin-1-yl)methanone (compound 108);

[0149] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methylphenyl)(4-methylpiperazin-1-yl)methanone (compound 109);

[0150] (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);

[0151] (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);

[0152] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-phenylbenzamide (compound 112);

[0153] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorophenyl)-3-methoxybenzamide (compound 113);

[0154] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluorophenyl)-3-methoxybenzamide (compound 114);

[0155] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorophenyl)-3-methoxybenzamide (compound 115);

[0156] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyanophenyl)-3-methoxybenzamide (compound 116);

[0157] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanophenyl)-3-methoxybenzamide (compound 117);

[0158] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenzamide (compound 118);

[0159] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenzamide (compound 119);

[0160] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorobenzyl)-3-methoxybenzamide (compound 120);

[0161] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(o-tolyl)benzamide (compound 121);

[0162] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(m-tolyl)benzamide (compound 122);

[0163] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(p-tolyl)benzamide (compound 123);

[0164] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methylbenzyl)benzamide (compound 124);

[0165] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methylbenzyl)benzamide (compound 125);

[0166] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methylbenzyl)benzamide (compound 126);

[0167] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-(dimethylamino)phenyl)-3-methoxybenzamide (compound 127);

[0168] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanobenzyl)-3-methoxybenzamide (compound 128);

[0169] 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);

[0170] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-((tetrahydrofuran-3-yl)methyl)benzamide (compound 130);

[0171] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyano-4-fluorophenyl)-3-methoxybenzamide (compound 131);

[0172] N-(5-chloro-2-fluorophenyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 132);

[0173] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-(4-fluorophenyl)ethyl)-3-methoxybenzamide (compound 133);

[0174] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,4-difluorobenzyl)-3-methoxybenzamide (compound 134);

[0175] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3,5-difluorobenzyl)-3-methoxybenzamide (compound 135);

[0176] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methylpyridin-4-yl)benzamide (compound 136);

[0177] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxybenzamide (compound 137);

[0178] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxybenzamide (compound 138);

[0179] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N,N-diethyl-3-methoxybenzamide (compound 139);

[0180] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyethyl)benzamide (compound 140);

[0181] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxy-N-methylbenzamide (compound 141);

[0182] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxy-N-methylbenzamide (compound 142);

[0183] 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);

[0184] 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);

[0185] 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);

[0186] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-chlorobenzyl)-3-methoxybenzamide (compound 146);

[0187] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-chlorobenzyl)-3-methoxybenzamide (compound 147);

[0188] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-chlorobenzyl)-3-methoxybenzamide (compound 148);

[0189] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-chlorophenyl)-3-methoxybenzamide (compound 149);

[0190] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-chlorophenyl)-3-methoxybenzamide (compound 150);

[0191] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-chlorophenyl)-3-methoxybenzamide (compound 151);

[0192] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxybenzyl)-3-methoxybenzamide (compound 152);

[0193] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxybenzyl)-3-methoxybenzamide (compound 153);

[0194] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)benzamide (compound 154);

[0195] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-2-ylmethyl)benzamide (compound 155);

[0196] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-3-ylmethyl)benzamide (compound 156);

[0197] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-4-ylmethyl)benzamide (compound 157);

[0198] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyphenyl)-3-methoxybenzamide (compound 158);

[0199] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxyphenyl)-3-methoxybenzamide (compound 159);

[0200] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxyphenyl)-3-methoxybenzamide (compound 160);

[0201] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyphenyl)benzamide (compound 161);

[0202] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methoxyphenyl)benzamide (compound 162);

[0203] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxyphenyl)benzamide (compound 163);

[0204] 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);

[0205] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)-N-methylbenzamide (compound 165);

[0206] 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);

[0207] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,6-dimethylpiperidin-1-yl)-3-methoxybenzamide (compound 167);

[0208] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-((6-chloropyridin-3-yl)methyl)-3-methoxybenzamide (compound 168);

[0209] 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);

[0210] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-(difluoromethoxy)phenyl)-3-methoxybenzamide (compound 170);

[0211] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-ethylphenyl)-3-methoxybenzamide (compound 171);

[0212] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-ethylphenyl)-3-methoxybenzamide (compound 172);

[0213] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-ethylphenyl)-3-methoxybenzamide (compound 173);

[0214] N-benzyl-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (compound 174);

[0215] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-N-(3-methylbenzyl)benzamide (compound 175);

[0216] Ethyl 3-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamido)propanoate (compound 176);

[0217] N-benzyl-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxybenzamide (compound 177);

[0218] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-isopropoxyphenyl)-3-methoxybenzamide (compound 178);

[0219] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-phenylethyl)benzamide (compound 179);

[0220] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide (compound 180);

[0221] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-(trifluoromethyl)phenyl)benzamide (compound 181);

[0222] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-phenylpropyl)benzamide (compound 182);

[0223] N-(4-aminobenzyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 183);

[0224] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluoro-5-methylphenyl)-3-methoxybenzamide (compound 184);

[0225] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluoro-4-methylphenyl)-3-methoxybenzamide (compound 185);

[0226] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluoro-2-methylphenyl)-3-methoxybenzamide (compound 186);

[0227] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluoro-3-methylphenyl)-3-methoxybenzamide (compound 187);

[0228] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluoro-2-methylphenyl)-3-methoxybenzamide (compound 188);

[0229] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-sulfamoylbenzyl)benzamide (compound 189);

[0230] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-(methylsulfonamido)phenyl)benzamide (compound 190);

[0231] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-sulfamoylphenyl)benzamide (compound 191);

[0232] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-(methylsulfonyl)ethyl)benzamide (compound 192);

[0233] Methyl(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-valinate (compound 193);

[0234] Methyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-isoleucinate (compound 194);

[0235] Ethyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)glycinate (compound 195);

[0236] N-(4-aminophenethyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 196);

[0237] 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);

[0238] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,2-dimethoxyethyl)-3-methoxybenzamide (compound 198);

[0239] Methyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-leucinate (compound 199);

[0240] Methyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-prolinate (Compound 200);

[0241] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxybenzyl)-N-methylbenzamide (compound 201);

[0242] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-ethyl-3-methoxy-N-methylbenzamide (compound 202);

[0243] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxybenzyl)benzamide (compound 203);

[0244] 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);

[0245] N-(3-aminobenzyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 205);

[0246] 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);

[0247] 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);

[0248] 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);

[0249] 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);

[0250] (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);

[0251] 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);

[0252] N-(1-acetylindolin-5-yl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 212);

[0253] Ethyl 3-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamido)-4,4,4-trifluorobutanoate (compound 213);

[0254] 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);

[0255] 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);

[0256] (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

[0257] [1,4'-bipiperidin]-1'-yl(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone (Compound 217);

[0258] In addition, the compound represented by the above Chemical Formula 1 of the present invention can be prepared by the following Reaction Scheme 1 (amide coupling), Reaction Scheme 2 (Suzuki reaction), and Reaction Scheme 3 (Buchwald reaction).

[0259] [ka]

[0260] [ka]

[0261] [ka]

[0262] The compound represented by chemical formula 1 is produced by reactions 1, 2, and 3.

[0263] In the above reaction schemes 1, 2, and 3,

[0264] X, m, R1, R2, R3, and R4 are as defined in Chemical Formula 1 above;

[0265] Compounds A, B, D, and E in the above reaction schemes 1, 2, and 3 are purchased from Aldrich, Merck, TCI, and ACROS and used in the preparation.

[0266] The method for preparing the compound represented by Formula 1 according to the present invention will now be described in detail.

[0267] In the method for producing the compound represented by Chemical Formula 1 according to the present invention,

[0268] The reaction conditions of the above reaction formula 1 are a step of producing compound C by reacting a compound represented by compound A with compound B.

[0269] The above reaction formula 1 is a step of preparing compound C by a general amination reaction between a compound represented by compound A and compound B. This reaction can be carried out without using a base, but is generally carried out in the presence of an organic amine such as pyridine, triethylamine, or diethylisopropylamine, which is a base that can be used in amidation reactions, using dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene, N,N-dimethylformamide, etc., which do not adversely affect the reaction. The reaction temperature is not particularly limited, but can generally be carried out at cold to room temperature, and is preferably carried out at room temperature.

[0270] The reaction conditions of the above reaction formula 2 are a step of preparing compound F by reacting a compound represented by compound D with compound E.

[0271] The above reaction formula 2 is a step of preparing compound F by reacting a compound represented by compound D with compound E under a metal catalyst. In this reaction, palladium is typically used as the metal catalyst, and tetrakistriphenylphosphinepalladium(0) ((PPh3)4Pd), palladium acetate(II) (Pd(OAc)2), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3), bis(triphenylphosphine)palladium(II) chloride (PdCl2(PPh3)2) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(0) chloride (Pd(dppf)Cl2) can be used. Here, usable bases include potassium carbonate, KOtBu, cesium carbonate, potassium phosphate, sodium hydroxide, triethylamine, etc., and the reaction is carried out using a solvent such as purified water, toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide, etc. that does not adversely affect the reaction. The reaction temperature is not particularly limited, but in general, the reaction can be carried out at room temperature or under heating, and is preferably carried out under heating.

[0272] The above reaction formula 3 is a step of preparing compound 1 by reacting a compound represented by compound C, which is the result of reaction formula 1, with compound F, which is the result of reaction formula 2, under a metal catalyst. In this reaction, the metal catalyst is typically palladium, and tetrakistriphenylphosphinepalladium(0) ((PPh3)4Pd), palladium acetate(II) (Pd(OAc)2), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3), bis(triphenylphosphine)palladium(II) chloride (PdCl2(PPh3)2) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(0) chloride (Pd(dppf)Cl2), etc., can be used. This reaction can be carried out without using a ligand, but generally, the reaction is carried out using ligands used in the Buchwald reaction under metal catalysis, such as triphenylphosphine ((PPh3)4), 1,2-bis(diphenylphosphino)propane (DPPP), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), Xantphos, and XPhos. At this time, bases that can be used include potassium carbonate, KOtBu, cesium carbonate, potassium phosphate, sodium hydroxide, and triethylamine, and the reaction is carried out using a solvent that does not adversely affect the reaction, such as toluene, tetrahydrofuran, dioxane, and N,N-dimethylformamide. The reaction temperature is not particularly limited, but generally, the reaction can be carried out at room temperature or under heating, and is preferably carried out under heating.

[0273] In this case, any of these are included in the present invention, and as an example of reaction conditions, the reaction can be preferably carried out under Pd(OAc)2 / Cs2CO3 / Xantphos reaction conditions, ZnCl2 / trifluoroacetic acid reaction conditions, or the like.

[0274] In this case, the solvent that can be used in the reaction may be any solvent that can dissolve the compounds represented by Compound A and B and the substances used in the reaction. Examples of the solvent that can be used include ether solvents including dioxane, tetrahydrofuran (THF), ethyl ether, 1,2-dimethoxyethane, etc.; lower alcohols including methanol, ethanol, propanol, and butanol; dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, and mixtures thereof.

[0275] The reaction temperature is not particularly limited, but may be preferably 0° C. to 100° C., for example, room temperature. The reaction time is not particularly limited, but may be set to, for example, 2 hours to 20 hours, and as another example, when heated, the reaction may be carried out for 20 minutes to 8 hours.

[0276] Additionally, in the present invention, the following terms have the following meanings unless otherwise specified: Any term not defined has its art-understood meaning.

[0277] The terms "cyclic" and "ring" refer to a substituted or aromatic group which may be substituted or unsubstituted and / or contain or not contain heteroatoms and may be monocyclic, bicyclic or polycyclic.

[0278] The terms "halo" and "halogen" are used in the conventional sense to refer to a fluoro (F), chloro (Cl), bromo (Br) or iodo (I) substituent.

[0279] The term "alkyl" refers to a single-bonded straight or branched chain hydrocarbon radical, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, pentyl, and hexyl.

[0280] The term "alkoxy" refers to a single bonded straight or branched chain saturated hydrocarbon attached oxygen radical, such as methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, 1-methylpropoxy, and the like.

[0281] The term "cycloalkyl" refers to a cyclic, single-bonded, saturated hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.1]heptyl, spiro[4.5]decyl, spiro[5.5]undecyl, adamantyl, and the like.

[0282] The term "aryl" refers to an aromatic substituent having at least one ring with a shared pi electron system, such as, for example, phenyl, benzyl, naphthyl, anthryl, biphenyl, triphenyl, and the like.

[0283] The term "arylalkyl" refers to an aryl group substituted with an alkyl group, wherein the aryl and alkyl are as disclosed above.

[0284] The term "heterocycloalkyl" refers to a cyclic, single-bonded, saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S, and includes, depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms, aziridinyl, pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinyl, oxopiperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dioxothiazepanyl, azocanyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, dioxanyl, dioxolanyl, and the like.

[0285] The term "heteroaryl" refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S, and depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms, can be selected from pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, furanyl, quinolizinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, pyranyl, thiophenyl, thiazolyl, dibenzothiophenyl, dibenzofuranyl, dibenzoselenophene, thiophene, benzofuran, benzothiophenyl, benzoselenophenyl, carbazolyl, indolocarbazolyl, pyridylindolyl, pyrrolodipyridinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, cyclohexyl ... Zolyl, oxatriazolyl, dioxazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, oxazinyl, oxathiazinyl, oxadiazinyl, indolyl, benzimidazolyl, indazolyl, indoxazinyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxanyl, naphthyridinyl, phthalazinyl, phteridinyl, xanthenyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzofuropyridinyl, furodipyridinyl, benzothienopyridinyl, thienodipyridinyl, benzoselenophenopyridinyl and selenophenodipyridinyl.

[0286] It should be noted that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms, and all such compounds and partial stereoisomers are included within the scope of the present invention.

[0287] In the present invention, the pharma- ceutically acceptable salt refers to a salt or complex of Formula 1 that retains the desired biological activity. Examples of such salts 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 poly-galacturonic acid. The compounds may also be administered as pharma- ceutically acceptable quaternary salts known to those skilled in the art, including, in particular, chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandelloate, and diphenylacetate). In addition to pharma-ceutically acceptable salts, the compounds of formula 1 of the present invention may include all salts, hydrates, solvates, and prodrugs that can be prepared by conventional methods.

[0288] The acid addition salt according to the present invention can be prepared by a conventional method. For example, the derivative of Chemical Formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., and an organic or inorganic acid is added to produce a precipitate, which is then filtered and dried. Alternatively, the solvent and excess acid can be distilled under reduced pressure, dried, and crystallized in an organic solvent.

[0289] Pharmaceutically acceptable metal salts can also be prepared using bases. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving the compound in a solution of an excess of alkali metal hydroxide or alkaline earth metal hydroxide, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are prepared as metal salts suitable for pharmaceutical use. The corresponding salts can also be obtained by reacting alkali metal or alkaline earth metal salts with a suitable silver salt (e.g., silver nitrate).

[0290] In yet another aspect, the present invention relates to a pharmaceutical composition for preventing or treating neurodegenerative diseases and cancer, comprising a compound represented by Chemical Formula 1 as an active ingredient, wherein the compound represented by Chemical Formula 1 has an activity of inhibiting all LRRK2.

[0291] The neurodegenerative disease refers to a disease in which degenerative changes due to the gradual death of nerve cells in the central nervous system appear, causing various symptoms, and 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 alcohol related dementia, but is not particularly limited thereto.

[0292] Furthermore, the cancer may be selected from the group consisting of kidney cancer, thyroid cancer, breast cancer, liver cancer, and brain cancer, but is not particularly limited thereto.

[0293] The pharmaceutical composition according to the present invention can be formulated in a suitable form together with a commonly used pharma- ceutically acceptable carrier. The term "pharmaceutical acceptable" means that it is physiologically acceptable and does not usually cause allergic reactions or similar reactions such as gastrointestinal disorders and dizziness when administered to humans. In addition, the compositions can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, external preparations, suppositories, and sterile injection solutions by a conventional method.

[0294] The carrier, excipient and diluent that may be included in the composition may include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate and mineral oil. When formulated, it is prepared using a diluent or excipient such as a filler, stabilizer, binder, disintegrant, surfactant, etc. that is commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are prepared by mixing the compound of the present invention with at least one excipient, such as starch, microcrystalline cellulose, sucrose or lactose, low-substituted hydroxypropyl cellulose, hypromellose, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, resistant solutions, emulsions, syrups, etc., and may contain various excipients such as wetting agents, sweeteners, flavorings, preservatives, etc. in addition to water and liquid paraffin, which are commonly used simple diluents. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspension solvents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin, etc. In order to prepare a dosage form for parenteral administration, the pyrimidine derivative compound of the above formula 1 or a pharma- ceutically acceptable salt thereof is sterilized or mixed with auxiliary agents such as preservatives, stabilizers, hydrating agents or emulsifying agents, salts for adjusting osmotic pressure or buffers, and other therapeutically useful substances in water to prepare a solution or suspension, which can be prepared into a unit-dosage form in ampoules or vials.

[0295] The pharmaceutical composition containing the compound of formula 1 disclosed in the present invention as an active ingredient may be administered to mammals such as rodents, livestock, and humans by various routes. Any manner of administration may be envisaged, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine, intradural or intracerebrovascular injection. The dosage will vary depending on the age, sex, and weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the administration time, the administration route, the absorption, distribution and excretion rate of the drug, the type of other drugs used, and the prescriber's judgment. Determination of the dosage based on such factors is within the level of one of ordinary skill in the art, and generally, the dosage ranges from 0.01 mg / kg / day to about 2000 mg / kg / day. More preferably, the dosage is from 1 mg / kg / day to 500 mg / kg / day. The dosage may be administered once a day or in several divided doses. The dosage is not intended to limit the scope of the present invention in any respect.

[0296] In addition, the pharmaceutical compositions of the present invention can be used alone or in combination with methods using surgery, hormonal therapy, chemotherapy, and biological response modifiers to prevent or treat neurodegenerative diseases and cancer. Effect of the Invention

[0297] The present invention relates to a novel pyrimidine derivative and a composition for preventing or treating neurodegenerative diseases and cancer, comprising the same. The pyrimidine derivative has excellent LRRK2 inhibitory activity and efficiently crosses the blood-brain barrier (BBB), and can be usefully used as a pharmaceutical composition for preventing or treating neurodegenerative diseases and cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0298] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the following embodiments are provided so that the present disclosure will be thorough and complete, and will fully convey the concept of the present invention to those skilled in the art.

[0299] <Example 1. Synthesis of pyrimidine derivatives and confirmation of physicochemical properties>

[0300] The synthesis process of the compounds 1 to 217 of the present invention is as follows.

[0301] Compound 1. (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone

[0302] 1) Synthesis of (4-amino-3-methoxyphenyl)(morpholino)methanone

[0303] [ka]

[0304] In a 25mL round-bottom flask, 500mg (3mmol) of 4-amino-3-methoxybenzoic acid, 0.31mL (3.6mmol) of morpholine, 747mg (3.9mmol) of EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl), 527mg (3.9mmol) of HOBt (hydroxybenzotriazole), and 10mL of DCM (dichloromethane) were added, and 1.05mL (6mmol) of DIPEA (diisopropylethylamine) was added at 0℃, and the mixture was stirred at room temperature for 12 hours. The organic layer was extracted by adding ethyl acetate, saturated aqueous NaCl solution, and water, and then dried (Mg2SO4), filtered, and concentrated to obtain a crude product, which was dissolved in DCM and separated by column chromatography to obtain 634mg (2.68mmol, 89.1% yield) of the title compound as a pale yellow solid.

[0305] 1 H NMR (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).

[0306] 2) Synthesis of 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine

[0307] [ka]

[0308] In a 5mL microwave vial, 0.63mL (5.5mmol) of 2,4,5-trichloropyrimidine, 720mg (5.78mmol) of (1-methyl-1H-pyrazol-4-yl)boronic acid, 5.5mL (11mmol) of 2M Na2CO3 solution, and 9mL of dioxane were added, degassed twice, and 402mg (0.55mmol) of Pd(dppf)Cl2(1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)) was added, degassed once more, and then stirred at 90°C for 12 hours. After filtering through Celite filter, the organic layer was extracted with ethyl acetate and water, dried (Mg2SO4), filtered, and concentrated to obtain a crude product, which was dissolved in DCM and separated by column chromatography to obtain 820mg (3.58mmol, 65% yield) of the title compound as a pale yellow solid.

[0309] 1 H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 3.96 (s, 3H).

[0310] 3) Synthesis of (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone

[0311] [ka]

[0312] In a 5mL microwave vial, 120mg (0.525mmol) of (4-amino-3-methoxyphenyl)(morpholino)methanone, 118mg (0.5mmol) of 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine, 29mg (0.05mmol) of xantphos,4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, 326mg (1mmol) of cesium carbonate, and 2mL of dioxane were added, and the mixture was degassed three times. Then, 211mg (0.05mmol) of Pd(OAc) was added, and the mixture was degassed once more. The mixture was then stirred at 90°C for 12 hours. The organic layer was extracted with ethyl acetate and water, dried (Mg2SO4), filtered, and concentrated to obtain a crude product, which was dissolved in DCM (dichloromethane) and separated by column chromatography to obtain 163 mg (0.38 mmol, 76% yield) of the title compound as a white solid.

[0313] 1 H 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).

[0314] The following compounds were prepared using the reaction for preparing Compound 1 in Example 1. The chemical structures and NMR spectrum data of the prepared compounds are summarized in Table 1 below.

[0315] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 1);

[0316] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone (compound 2);

[0317] 1-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)a

[0318] (amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-one (compound 3);

[0319] (4-((5-chloro-4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 4);

[0320] 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (compound 5);

[0321] 2-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile (compound 6);

[0322] 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile (compound 7);

[0323] (4-((5-chloro-4-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 8);

[0324] Methyl 2-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetate (compound 9);

[0325] (4-((5-chloro-4-(1-(methylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 10);

[0326] (4-((5-chloro-4-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 11);

[0327] (4-((5-chloro-4-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 12);

[0328] (4-((5-chloro-4-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 13);

[0329] (4-((5-chloro-4-(1-phenyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 14);

[0330] (4-((5-chloro-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 15);

[0331] (4-((5-chloro-4-(1-(methoxymethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 16);

[0332] (4-((5-chloro-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 17);

[0333] (4-((5-chloro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 18);

[0334] (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);

[0335] (4-((5-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 20);

[0336] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide (compound 21);

[0337] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyrrolidin-1-yl)methanone (compound 22);

[0338] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-ethyl-3-methoxy-N-(2-methoxyethyl)benzamide (compound 23);

[0339] 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);

[0340] N-(tert-butyl)-4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 25);

[0341] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)-3-methoxybenzamide (compound 26);

[0342] 3-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-methylbutanenitrile (compound 27);

[0343] (4-((5-chloro-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 28);

[0344] (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);

[0345] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4,4-difluorocyclohexyl)-3-methoxybenzamide (compound 30);

[0346] (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);

[0347] (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);

[0348] (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);

[0349] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 34);

[0350] (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);

[0351] (3-Methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 36);

[0352] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 37);

[0353] 4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 38);

[0354] (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);

[0355] (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);

[0356] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4,4-difluoropiperidin-1-yl)methanone (compound 41);

[0357] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(2,2-dimethylmorpholino)methanone (compound 42);

[0358] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidin-1-yl)methanone (compound 43);

[0359] 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);

[0360] (4-isopropylpiperazin-1-yl)(3-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)methanone (compound 45);

[0361] (2-fluoro-5-methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(morpholino)methanone (compound 46);

[0362] (3-Methoxy-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)(4-phenylpiperazin-1-yl)methanone (compound 47);

[0363] (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);

[0364] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone (compound 49);

[0365] (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);

[0366] ((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);

[0367] (4-((5-chloro-4-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 52);

[0368] (4-((5-chloro-4-(1-propyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 53);

[0369] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 54);

[0370] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(pyridin-4-yl)methanone (compound 55);

[0371] (4-((5-chloro-4-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 56);

[0372] (4-((5-chloro-4-(1-propyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 57);

[0373] (4-((5-chloro-4-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 58);

[0374] (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 59);

[0375] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 60);

[0376] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 61);

[0377] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 62);

[0378] (4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 63);

[0379] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 64);

[0380] (2-fluoro-4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxyphenyl)(morpholino)methanone (compound 65);

[0381] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(tetrahydro-2H-pyran-4-yl)methanone (compound 66);

[0382] (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);

[0383] (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);

[0384] (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone (compound 69);

[0385] (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);

[0386] (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);

[0387] (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);

[0388] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-morpholinoazetidin-1-yl)methanone (compound 73);

[0389] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanethione (compound 74);

[0390] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1-isopropylpiperidin-4-yl)methanone (compound 75);

[0391] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methoxypiperidin-1-yl)methanone (compound 76);

[0392] (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);

[0393] 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);

[0394] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(methylsulfonyl)piperidin-1-yl)methanone (compound 79);

[0395] 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);

[0396] N-(1-(2-(o-tolyl)quinolin-3-yl)ethyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-amine (compound 81);

[0397] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-cyclopropyl-3-methoxybenzamide (compound 82);

[0398] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydroxyazetidin-1-yl)methanone (compound 83);

[0399] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1,1-dioxidethiomorpholino)methanone (compound 84);

[0400] (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 85);

[0401] (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);

[0402] (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);

[0403] (4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazin-1-yl)methanone (compound 88);

[0404] ((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);

[0405] (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);

[0406] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-((1r,4r)-4-hydroxycyclohexyl)-3-methoxybenzamide (compound 91);

[0407] (6-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(morpholino)methanone (compound 92);

[0408] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-(dimethylamino)cyclohexyl)-3-methoxybenzamide (compound 93);

[0409] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(dimethylamino)piperidin-1-yl)methanone (compound 94);

[0410] ((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);

[0411] 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (compound 96);

[0412] (R)-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydroxypyrrolidin-1-yl)methanone (compound 97);

[0413] (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);

[0414] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-isopropylpiperidin-4-yl)-3-methoxybenzamide (compound 99);

[0415] 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);

[0416] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N,N-dimethylbenzamide (compound 101);

[0417] (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);

[0418] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanethione (compound 103);

[0419] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (compound 104);

[0420] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(morpholino)methanone (compound 105);

[0421] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanethione (compound 106);

[0422] (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);

[0423] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(4-methylpiperazin-1-yl)methanone (compound 108);

[0424] (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methylphenyl)(4-methylpiperazin-1-yl)methanone (compound 109);

[0425] (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);

[0426] (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);

[0427] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-phenylbenzamide (compound 112);

[0428] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorophenyl)-3-methoxybenzamide (compound 113);

[0429] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluorophenyl)-3-methoxybenzamide (compound 114);

[0430] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorophenyl)-3-methoxybenzamide (compound 115);

[0431] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyanophenyl)-3-methoxybenzamide (compound 116);

[0432] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanophenyl)-3-methoxybenzamide (compound 117);

[0433] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenzamide (compound 118);

[0434] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenzamide (compound 119);

[0435] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorobenzyl)-3-methoxybenzamide (compound 120);

[0436] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(o-tolyl)benzamide (compound 121);

[0437] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(m-tolyl)benzamide (compound 122);

[0438] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(p-tolyl)benzamide (compound 123);

[0439] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methylbenzyl)benzamide (compound 124);

[0440] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methylbenzyl)benzamide (compound 125);

[0441] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methylbenzyl)benzamide (compound 126);

[0442] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-(dimethylamino)phenyl)-3-methoxybenzamide (compound 127);

[0443] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanobenzyl)-3-methoxybenzamide (compound 128);

[0444] 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);

[0445] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-((tetrahydrofuran-3-yl)methyl)benzamide (compound 130);

[0446] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyano-4-fluorophenyl)-3-methoxybenzamide (compound 131);

[0447] N-(5-chloro-2-fluorophenyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 132);

[0448] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-(4-fluorophenyl)ethyl)-3-methoxybenzamide (compound 133);

[0449] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,4-difluorobenzyl)-3-methoxybenzamide (compound 134);

[0450] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3,5-difluorobenzyl)-3-methoxybenzamide (compound 135);

[0451] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methylpyridin-4-yl)benzamide (compound 136);

[0452] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxybenzamide (compound 137);

[0453] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxybenzamide (compound 138);

[0454] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N,N-diethyl-3-methoxybenzamide (compound 139);

[0455] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyethyl)benzamide (compound 140);

[0456] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxy-N-methylbenzamide (compound 141);

[0457] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxy-N-methylbenzamide (compound 142);

[0458] 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);

[0459] 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);

[0460] 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);

[0461] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-chlorobenzyl)-3-methoxybenzamide (compound 146);

[0462] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-chlorobenzyl)-3-methoxybenzamide (compound 147);

[0463] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-chlorobenzyl)-3-methoxybenzamide (compound 148);

[0464] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-chlorophenyl)-3-methoxybenzamide (compound 149);

[0465] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-chlorophenyl)-3-methoxybenzamide (compound 150);

[0466] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-chlorophenyl)-3-methoxybenzamide (compound 151);

[0467] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxybenzyl)-3-methoxybenzamide (compound 152);

[0468] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxybenzyl)-3-methoxybenzamide (compound 153);

[0469] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)benzamide (compound 154);

[0470] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-2-ylmethyl)benzamide (compound 155);

[0471] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-3-ylmethyl)benzamide (compound 156);

[0472] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(pyridin-4-ylmethyl)benzamide (compound 157);

[0473] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyphenyl)-3-methoxybenzamide (compound 158);

[0474] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxyphenyl)-3-methoxybenzamide (compound 159);

[0475] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxyphenyl)-3-methoxybenzamide (compound 160);

[0476] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyphenyl)benzamide (compound 161);

[0477] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methoxyphenyl)benzamide (compound 162);

[0478] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxyphenyl)benzamide (compound 163);

[0479] 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);

[0480] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)-N-methylbenzamide (compound 165);

[0481] 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);

[0482] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,6-dimethylpiperidin-1-yl)-3-methoxybenzamide (compound 167);

[0483] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-((6-chloropyridin-3-yl)methyl)-3-methoxybenzamide (compound 168);

[0484] 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);

[0485] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-(difluoromethoxy)phenyl)-3-methoxybenzamide (compound 170);

[0486] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-ethylphenyl)-3-methoxybenzamide (compound 171);

[0487] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-ethylphenyl)-3-methoxybenzamide (compound 172);

[0488] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-ethylphenyl)-3-methoxybenzamide (compound 173);

[0489] N-benzyl-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (compound 174);

[0490] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-N-(3-methylbenzyl)benzamide (compound 175);

[0491] Ethyl 3-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamido)propanoate (compound 176);

[0492] N-benzyl-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-isopropyl-3-methoxybenzamide (compound 177);

[0493] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-isopropoxyphenyl)-3-methoxybenzamide (compound 178);

[0494] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-phenylethyl)benzamide (compound 179);

[0495] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide (compound 180);

[0496] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-(trifluoromethyl)phenyl)benzamide (compound 181);

[0497] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-phenylpropyl)benzamide (compound 182);

[0498] N-(4-aminobenzyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 183);

[0499] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluoro-5-methylphenyl)-3-methoxybenzamide (compound 184);

[0500] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluoro-4-methylphenyl)-3-methoxybenzamide (compound 185);

[0501] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluoro-2-methylphenyl)-3-methoxybenzamide (compound 186);

[0502] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluoro-3-methylphenyl)-3-methoxybenzamide (compound 187);

[0503] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluoro-2-methylphenyl)-3-methoxybenzamide (compound 188);

[0504] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-sulfamoylbenzyl)benzamide (compound 189);

[0505] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-(methylsulfonamido)phenyl)benzamide (compound 190);

[0506] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-sulfamoylphenyl)benzamide (compound 191);

[0507] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-(methylsulfonyl)ethyl)benzamide (compound 192);

[0508] Methyl(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-valinate (compound 193);

[0509] Methyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-isoleucinate (compound 194);

[0510] Ethyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)glycinate (compound 195);

[0511] N-(4-aminophenethyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 196);

[0512] 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);

[0513] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,2-dimethoxyethyl)-3-methoxybenzamide (compound 198);

[0514] Methyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-leucinate (compound 199);

[0515] Methyl (4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)-L-prolinate (Compound 200);

[0516] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxybenzyl)-N-methylbenzamide (compound 201);

[0517] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-ethyl-3-methoxy-N-methylbenzamide (compound 202);

[0518] 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxybenzyl)benzamide (compound 203);

[0519] 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);

[0520] N-(3-aminobenzyl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 205);

[0521] 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);

[0522] 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);

[0523] 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);

[0524] 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);

[0525] (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);

[0526] 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);

[0527] N-(1-acetylindolin-5-yl)-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamide (compound 212);

[0528] Ethyl 3-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzamido)-4,4,4-trifluorobutanoate (compound 213);

[0529] 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);

[0530] 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);

[0531] (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

[0532] [1,4'-bipiperidin]-1'-yl(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)methanone (compound 217);

[0533] [Table 1-1]

[0534] [Table 1-2]

[0535] [Table 1-3]

[0536] [Table 1-4]

[0537] [Table 1-5]

[0538] [Table 1-6]

[0539] [Table 1-7]

[0540] [Table 1-8]

[0541]

Table 1-9

[0542]

Table 1-10

[0543]

Table 1-11

[0544]

Table 1-12

[0545]

Table 1-13

[0546]

Table 1-14

[0547]

Table 1-15

[0548]

Table 1-16

[0549]

Table 1-17

[0550]

Table 1-18

[0551]

Table 1-19

[0552]

Table 1-20

[0553]

Table 1-21

[0554]

Table 1-22

[0555]

Table 1-23

[0556]

Table 1-24

[0557]

Table 1-25

[0558]

Table 1-26

[0559]

Table 1-27

[0560]

Table 1-28

[0561] [Table 1-29]

[0562] [Table 1-30]

[0563] [Table 1-31]

[0564] [Table 1-32]

[0565] [Table 1-33]

[0566] [Table 1-34]

[0567] [Table 1-35]

[0568] [Table 1-36]

[0569] Comparative compound 1. (4-((5-chloro-4-phenylpyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone

[0570] [ka]

[0571] 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 TFA (0.2 mL) were placed in a 5 mL microwave vial and heated at 110°C for 12 hours. After the reaction, the pressure was reduced, and MC and saturated aqueous NaHCO3 were added for extraction. The organic layer was dried (Mg2SO4), filtered, and concentrated to obtain a crude product, which was dissolved in DCM and separated by column chromatography to obtain the title compound (110 mg, 31% yield) as a white solid.

[0572] 1H NMR(300 MHz, CDCl3) δ 8.60 (d, J = 6.0 Hz, 1H), 8.51 (s, 1H), 8.02(s, 1H), 7.90 (m, 2H), 7.55 (m, 3 H), 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)

[0573] Comparative compound 2. (4-((5-chloro-4-(pyridin-3-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone

[0574] [ka]

[0575] In a 5mL microwave vial, 100mg (0.26mmol) of (4-((4,5-dichloropyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone, 48.5mg (0.236mmol), 0.35mL (0.7mmol) of 2M Na2CO3 solution, and 2mL of dioxane were added and degassed twice, and 423mg (0.02mmol) of Pd(PPh3) was added and degassed once more, and then stirred at 110°C for 12 hours. After filtering through Celite, the organic layer was extracted with ethyl acetate and water, dried (Mg2SO4), filtered, and concentrated to obtain a crude product, which was dissolved in DCM and separated by column chromatography to obtain 67.3mg (0.158mmol, 67% yield) of the title compound as a white solid.

[0576] 1H NMR (300 MHz, CDCl3) 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)

[0577] Comparative compound 3. (4-((5-chloro-4-(3-nitrophenyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone

[0578] [ka]

[0579] In a 5mL microwave vial, 100mg (0.26mmol) of (4-((4,5-dichloropyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone, 58.8mg (0.236mmol), 0.35mL (0.7mmol) of 2M Na2CO3 solution, and 2mL of dioxane were added and degassed twice, and 423mg (0.02mmol) of Pd(PPh3) was added and degassed once more, and then stirred at 110°C for 12 hours. After filtering through Celite, the organic layer was extracted with ethyl acetate and water, dried (Mg2SO4), filtered, and concentrated to obtain a crude product, which was dissolved in DCM and separated by column chromatography to obtain 65.3mg (0.139mmol, 59% yield) of the title compound as a white solid.

[0580] 1H NMR (300 MHz, CDCl3) 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 (dd, J = 8.3, 1.8 Hz, 1H), 3.97 (s, 3H), 3.60 - 3.81 (m, 8H)

[0581] <Example 2. Confirmation of LRRK2 inhibitory activity>

[0582] The representative compounds of the present invention synthesized in Example 1 were used to confirm the inhibitory activity against LRRK2 wild type and LRRK2 (G2019S) mutant type, and the results are shown in Tables 2 and 3. Specifically, T7 phage strains to which the wild type kinase or the G2019S mutant kinase of human LRRK2 (Accession no. NP_940980.3) composed of the amino acid sequence from amino acid H970 to E2527 was attached were simultaneously grown in a host E. coli derived from the BL21 strain, and the E. coli was grown to log-phase and infected with T7 phage (multiplicity of infection=0.4), followed by shaking culture at 32° C. for about 90 to 150 minutes. E. coli lysates were then centrifuged (6,000 x g) and filtered through a 0.2 μm filter, after which kinases were produced in HEK-293 cells and DNA was attached, resulting in DNA-tagged kinases for qPCR detection. Affinity resins for kinase assays were prepared as streptavidin-coated magnetic beads that were treated with biotinylated small molecule ligands for 30 min at room temperature, after which the liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and reduce nonspecific phage binding. Then, kinase and ligand-affinity beads prepared in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6mM DTT) and compounds (10, 50 or 100 nM; concentrations used are specified in Table 2 below) were mixed in a polypropylene 384-well plate to a final volume of 0.02 ml and incubated with shaking at room temperature.After 1 hour of reaction, the affinity beads were washed with washing buffer (1x PBS, 0.05% Tween 20) and resuspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5μM non-biotinylated affinity ligand) and incubated with shaking at room temperature for 30 minutes. The kinase concentrations of LRRK2 wild type and LRRK2 (G2019S) mutant in the eluted samples were then measured by qPCR, and activity values ​​were expressed as % of ctrl compared to the control group. Compounds commonly used in activity evaluation were used in 100% DMSO, with 40x stocks made and directly diluted during the analysis.

[0583] The evaluation results are shown in Tables 2 and 3 below. Table 2 confirms the inhibitory activity of a representative compound of the present invention at a concentration of 100 nM against wild-type LRRK2 and LRRK2 (G2019S) mutant type, and Table 3 confirms the inhibitory activity of a representative compound of the present invention at concentrations of 10 nM and 50 nM against wild-type LRRK2. (+++ less than 10% activity; ++ less than 30% activity; + less than 50% activity; -50% or more activity)

[0584] [Table 2]

[0585] [Table 3-1]

[0586] [Table 3-2]

[0587] Referring to Tables 2 and 3, it can be confirmed that the pyrimidine derivatives of the present invention are substances having LRRK2 inhibitory activity. In particular, it can be confirmed that the compound in which R4 substituted with a pyrimidine group in the structural formula of Chemical Formula 1 is a pyrazole group and R5 is a halogen or haloalkyl has a significantly superior LRRK2 protein inhibitory activity at a concentration of 50 nM compared to compounds having other substitutions.

[0588] Example 3: Blood-brain barrier (BBB) ​​permeability confirmation

[0589] After oral administration of the test substance at a dose of 10 mg / kg, the animals were sacrificed at 3 hours, and blood was collected from the heart immediately after the administration and centrifuged to prepare plasma samples. To remove blood remaining in the body, the heart was perfused with 20 ml of saline containing 10 U / ml heparin, and the brain was then removed. The brain tissue was homogenized by adding PBS buffer in an amount three times the weight of the brain tissue. LC-MS / MS (Agilent, Santa Clara, CA, USA) was used for quantitative analysis of the prepared plasma and brain tissue. Separation of the substances in LC used a mobile phase consisting of 80% acetonitrile and 20% water with 0.1% formic acid. The total run time per substance was 3 minutes, and the flow rate was 0.3 ml / min. Quantitation of each substance was performed using a multiple reaction detection method (comparative compound-4 and comparative compound-5 were LRRK2 protein inhibitors, and oral Parkinson's treatment drugs DNL-151 and DNL-201 were used, respectively).

[0590] Compound 37, a representative example of the present invention, showed effective drug concentrations in brain tissue 3 hours after oral administration that were 1.64 and 2.77 times higher than those of comparative compound-4 (DNL-151) and comparative compound-5 (DNL-201), respectively.

[0591] It has proven effective in treating neurodegenerative diseases, including Parkinson's disease, and cancer.

[0592] From these results, it can be seen that the compound of the present invention, in which R4 substituted with a pyrimidine group in the structural formula of Chemical Formula 1 is a pyrazole group and R5 is a halogen or haloalkyl, has an excellent blood-brain barrier passing effect in addition to an LRRK2 protein inhibitory effect, and can be very useful for the prevention or treatment of neurodegenerative diseases and cancer.

[0593] <Formulation Example 1. Production of Powder>

[0594] The compound of the present invention 37 ((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 filled into an airtight cloth to prepare a powder.

[0595] <Formulation Example 2. Tablet Production>

[0596] 100 mg of the 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 of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropylcellulose, and 2 mg of magnesium stearate were mixed and compressed into tablets by a conventional tablet manufacturing method.

[0597] <Formulation Example 3. Production of Capsules>

[0598] 100 mg of the present compound 37 ((4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone), 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropylcellulose and 2 mg of magnesium stearate were mixed, and the above ingredients were mixed according to a conventional capsule preparation method, and charged into a gelatin capsule to prepare a capsule.

[0599] <Formulation Example 4. Manufacturing of pills>

[0600] 90 mg of the compound 37 of the present invention ((4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone), 5 mg of glutinous rice starch, 5 mg of purified water, and a small amount of dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as additives to inhibit hygroscopicity were mixed and then made into 100 mg pills by a conventional method.

[0601] <Formulation Example 5. Manufacture of injections>

[0602] 10 mg of the present compound 37 ((4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone), an appropriate amount of sterile distilled water for injection, and an appropriate amount of a pH adjuster were mixed, and then the above-mentioned ingredient content was prepared per ampoule (2 ml) according to a conventional injection manufacturing method.

Claims

1. A compound represented by the following chemical formula 1, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 R １ ' is independently １ -C ６ Alkoxy or haloC １ -C ６ is an alkoxy; R １ " is hydrogen or halogen; R ２ is a substituted or unsubstituted pyrazole substituent, wherein the substituted pyrazole substituents are halogen, hydroxy, cyano, amino, amido, nitro, C １ -C ６ Alkyl sulfonyl, 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 ６ -C １２ Aryl, or substituted or unsubstituted C ４ -C １２ and heteroaryl, wherein the substituted alkyl, benzyl, C ３ -C １２ Cycloalkyl, C ６ -C １２ Aryl, C ４ -C １２ Heteroaryl is halogen, hydroxy, cyano, amino, amido, nitro, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １２ Heterocycloalkyl, C ６ -C １２ Aryl-C １ -C ６ Alkoxy, or -C(=O)O-alkyl(C １ -C ６ ) is substituted with one or more substituents selected from the group consisting of; R ３ is halogen or haloC １ -C ６ is an alkyl substituent; R ４ can be displayed as B-1 to B-29 below. 【Chemistry 2】 R ６ are independently hydrogen, halogen, hydroxy, C １ -C ６ Alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Alkyl sulfonate, or C １ -C ６ one or more substituents selected from the group consisting of alkylamino; R ７ are independently hydrogen, halogen, haloC １ -C ６ Alkyl, or C １ -C ６ one or more substituents selected from the group consisting of alkyl; R ８ are independently hydrogen, halogen, amino, hydroxy, cyano, C １ -C ６ Dialkylamino, aminosulfonyl, C １ -C ６ Alkyl sulfone amino, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, haloC １ -C ６ Alkyloxy or C １ -C ６ one or more substituents selected from the group consisting of alkoxy; R ９ are independently hydrogen, 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 one or more substituents selected from the group consisting of alkyl-substituted piperidine and acetate; R １０ are independently hydrogen, C １ -C ６ one or more substituents selected from the group consisting of alkyl, phenyl, oxetanyl, or acetate; R １１ is hydrogen or R １０ Saturated or unsaturated C bonded to ５ -C ６ is a heterocycloalkyl substituent; R １２ is hydrogen or C １ -C ６ is alkyl; R １３ is hydrogen or C １ -C ６ Alkylcarbonyl, or C １ -C ６ alkylacetyl; R １４ is hydrogen, C １ -C ６ Alkyl, Hydroxy C １ -C ６ Alkyl, C １ -C ６ Alkoxy C １ -C ６ Alkyl, C １ -C ６ Alkyloxycarbonyl C １ -C ６ Alkyl or methylsulfonyl C １ -C ６ is alkyl; Ak is C １ -C ６ is alkyl; k is independently 0, 1, or 2 (wherein k is not simultaneously 0); l is 1 or 2; m is 0, 1, 2, 3, or 4; n is 0 or 1; W is independently CH or N; X is C, CH, or N; Y is a substituent selected from the group consisting of O or S; and Z is O or SO ２ is; A compound represented by Chemical Formula 1, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof.

2. The compound: (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-5-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-5-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-fluoro-5-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); Selected from the group consisting of or a pharma- ceutically acceptable salt thereof.

3. The compound represented by the formula 1 of claim 1, its optical isomer, or its pharma- ceutically acceptable salt as an active ingredient. A pharmaceutical composition for preventing or treating a neurodegenerative disease, comprising:

4. The neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic axonal sclerosis, prion disease, motor neuron disease, spinocerebellar ataxia, spinal muscular atrophy, Creutzfeldt-Jakob disease, and alcoholic dementia. The pharmaceutical composition for preventing or treating a neurodegenerative disease according to claim 3.

5. The compound represented by the formula 1 of claim 1, its optical isomer, or its pharma- ceutically acceptable salt as an active ingredient. A pharmaceutical composition for preventing or treating cancer, comprising:

6. The cancer disease is selected from the group consisting of kidney cancer, thyroid cancer, breast cancer, liver cancer, and brain cancer. The pharmaceutical composition for preventing or treating cancer according to claim 5 .

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