KR102342803B1 - Novel pyrimidine derivatives and composition for preventing or treating neurodegenerative disease and cancer comprising thereof - Google Patents

Abstract

The present invention relates to a novel pyrimidine derivative and a composition for preventing or treating neurodegenerative diseases and cancer comprising the same, wherein the pyrimidine derivative has excellent LRRK2 protein inhibitory activity and efficiently passes through the blood-brain barrier (BBB) Thus, it can be usefully used as a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases and cancer.

Description

Novel pyrimidine derivatives and compositions for preventing or treating neurodegenerative diseases and cancer comprising the same

The present invention relates to a novel pyrimidine derivative and a composition for preventing or treating neurodegenerative diseases and cancer comprising the same.

Neurodegenerative disease (neurodegenerative disease) is a brain disease that occurs with aging is known to occur due to the accumulation of environmental and genetic factors. It is a collective term for a disease that causes various symptoms as degenerative changes due to gradual and steady death occur in nerve cells of the central nervous system, and is characterized by loss of neural structure and function, including cell damage and memory impairment. Representative examples include Parkinson's disease, Alzheimer's disease, Huntington's disease, Pick's disease, Amyotrophic lateral sclerosis, Prion disease, motor neuron Motor neuron disease, Spinocerebellar ataxia, Spinal muscular atrophy, Creutzfeldt-Jakob disease, and Alcohol related dementia.

Parkinson's disease is one of the representative neurodegenerative diseases along with Alzheimer's disease. As a result, protein aggregates called Lewy bodies are formed in nerve cells, and mental symptoms such as depression, anxiety, and sleep disorders appear along with motor dysfunction such as slouching posture, tremors, rigidity, and instability.

Although the cause of Parkinson's disease is not known with certainty, it is believed to be caused by the complex action of several factors, such as environmental factors, genetic factors, aging, mitochondrial dysfunction, and abnormalities in the ability to process unnecessary proteins. Most Parkinson's disease occurs sporadically, but 5-10% are known to be hereditary diseases caused by mutations in genes. , LRRK2 (leucine-rich repeat kinase 2) and the like have been known.

Among them, the G2019S mutation of the LRRK2 gene appears most frequently as a dominant genotype. It has both GTP hydrolase (GTPase) and serine-threonine kinase (Serine-threonine) activity in the protein. High expression of LRRK2 has been reported in dopaminergic neurons present in the cerebral cortex, substantia nigra, striatum, hippocampus, and cerebellum of the brain involved in the pathogenesis of Parkinson's disease. is known When normal LRRK2 is overexpressed in neurons, it has been confirmed that apoptosis is induced, and dopaminergic neuronal apoptosis, Lewy bodies, and movement disorders similar to Parkinson's disease symptoms have been reported in LRRK2 overactive mutant animals. In the case of LRRK2 knock-out animals, neurite outgrowth in the brain and inhibition of aging-dependent increase in α-synuclein closely related to Parkinson's disease have been observed. . In addition, LRRK2 is also known to be involved in the transfer of mild cognitive impairment associated with Alzheimer's disease, and compounds and compositions effective for regulating LRRK2 activity may provide therapeutic effects for neurodegenerative diseases and the like. Therefore, selective inhibition of LRRK2 activity could be a beneficial target for drug development for disease treatment.

In addition to the above neurodegenerative diseases, anticancer activity through LRRK2 inhibition is being studied in various cancer types as a mechanism for inhibiting proliferation and promoting apoptosis of cancer cells.

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 mutation (especially G2019S type) increases the risk of breast cancer. In addition, research results have been reported that the survival period of patients with LRRK2 overexpression in the tissues of domestic brain cancer patients is significantly shorter. In this regard, Voronoi recently received approval to enter phase 1 clinical trials for an LRRK2 inhibitor as a treatment for brain cancer. Therefore, selective inhibition of LRRK2 activity can be a target for the development of a wide range of new drugs, not only for the treatment of neurodegenerative diseases, but also for the treatment of cancer.

On the other hand, as a prior literature related to a composition for preventing or treating neurodegenerative diseases comprising a pyrimidine derivative as an active ingredient, Korean Patent No. 10-1566091 discloses a pyrazole aminopyrimidine derivative as an LRRK2 modulator, Korea Registered Patent No. 10-2025451 discloses a 2-(phenyl or pyrid-3-yl) aminopyrimidine derivative as a kinase LRRK2 modulator for the treatment of Parkinson's disease, and Korean Patent No. 10-1208198, LRRK2 phosphorylation Disclosed is a pharmaceutical composition for treating or preventing Parkinson's disease containing a compound having enzyme inhibitory activity as an active ingredient. -2-ylamino-1H-pyrazole has been disclosed. However, there is no previous report stating that the pyrimidine derivatives of the present invention represented by Formula 1 and the LRRK2 inhibitory activity of the derivatives and possible treatment of neurodegenerative diseases therefrom.

Accordingly, the present inventors completed the present invention by confirming that, in the process of researching the LRRK2 derivative, the pyrimidine derivative such as Formula 1 of the present invention has excellent LRRK2 inhibitory activity and efficiently passes through the blood-brain barrier (BBB). did

Korea Patent No. 10-1566091, pyrazole aminopyrimidine derivatives as LRRK2 modulators, registered on October 29, 2015. Korean Patent No. 10-2025451, a 2-(phenyl or pyrid-3-yl) aminopyrimidine derivative as a kinase LRRK2 modulator for the treatment of Parkinson's disease, September 19, 2019, registered. Korean Patent No. 10-1208198, a pharmaceutical composition for treating or preventing Parkinson's disease containing a compound having LRRK2 kinase inhibitory activity as an active ingredient, registered on November 28, 2012. Korean Patent Application Laid-Open No. 10-2019-0018676, pyrimidin-2-ylamino-1H-pyrazole as an LRRK2 inhibitor for use in the treatment of neurodegenerative disorders, registered on February 25, 2019.

Choi, H. G. et al., Brain Penetrant LRRK2 Inhibitor, ACS Med Chem Lett., 3(8), 658-662, 2012. Bae, Y. H. et al., Brain injury induces HIF-1α-dependent transcriptional activation of LRRK2 that exacerbates brain damage, Cell Death Dis., 9(11), 1125, 2018. Estrada, A. A. et al., Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors, J Med Chem., 55(22), 9416-9433, 2012. Wakabayashi, K. et al., The Lewy body in Parkinson's disease and related neurodegenerative disorders, Mol Neurobiol., 47(2), 495-508, 2013. Abdel-Magid, A. F., LRRK2 Kinase Inhibitors as Possible Therapy for Parkinson's Disease and Other Neurodegenerative Disorders, ACS Med Chem Lett., 10(6), 846-847, 2019. Looyenga, Brendan D., et al. "Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas." Proceedings of the National Academy of Sciences 108.4 (2011): 1439-1444. Ho, Dong Hwan, et al. "Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21 WAF1/CIP1 expression." Molecular brain 8.1 (2015): 1-15. Agalliu, Ilir, et al. "Higher frequency of certain cancers in LRRK2 G2019S mutation carriers with Parkinson disease: a pooled analysis." JAMA neurology 72.1 (2015): 58-65. https://voronoi.io/en/science/pipeline/vrn01-lrrk2-%eb%87%8c%ec%a2%85%ec%96%91/ Kim Tae-hwan, "Voronoi, approval of phase 1 clinical trial for brain cancer treatment… The first step in commercialization of 'VN10072'", Chosun Biz, 2019.08.14., https://biz.chosun.com/site/data/html_dir/2019/08/14 /2019081401566.html

An object of the present invention is to provide a novel pyrimidine derivative and a composition for preventing or treating neurodegenerative diseases and cancer containing the same, and more specifically, a novel pyrimidine derivative excellent in LRRK2 inhibitory activity and blood-brain barrier (BBB) passage An object of the present invention is to provide a composition for preventing or treating a pyrimidine derivative and a neurodegenerative disease and cancer containing the same.

The present invention relates to the provision of a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

[Formula 1]

R ₁ is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, amide, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or halo C ₁ -C ₆ alkoxy substituted with one or more substituents;

R ₂ is substituted with a substituted or unsubstituted pyrazole substituent,

wherein said substituted pyrazole is halogen, hydroxy, cyano, amino, amide, nitro, C ₁ -C ₆ alkylsulfonyl, acetyl, methyloxycarbonyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₂ heterocycloalkyl, substituted or unsubstituted C ₄ -C ₁₂ aryl, or substituted or unsubstituted substituted with one or more substituents selected from the group consisting of C ₄ -C _{12 heteroaryl,}

again wherein said substituted alkyl, benzyl, C ₃ -C ₁₂ cycloalkyl, C ₄ -C ₁₂ aryl, C ₄ -C ₁₂ heteroaryl is halogen, hydroxy, cyano, amino, amide, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₂ heterocycloalkyl, C ₄ -C ₁₂ aryl-C ₁ -C ₆ alkoxy, or —C(=O)O-alkyl(C ₁ -C ₆ ) substituted with one or more substituents selected from the group consisting of;

R ₃ is substituted with halogen or halo C ₁ -C ₆ alkyl substituent;

R ₄ may be represented by the following B-1 to B-29,

R ₆ is independently selected from the group consisting of hydrogen, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkylsulfonate, or C ₁ -C ₆ alkylamino substituted with one or more substituents;

R ₇ is independently substituted with one or more substituents selected from the group consisting of hydrogen, halogen, halo C ₁ -C ₆ alkyl, or C ₁ -C _{6 alkyl;}

R ₈ is independently hydrogen, halogen, amino, hydroxy, cyano, C ₁ -C ₆ dialkylamino, aminosulfonyl, C ₁ -C ₆ alkylsulfonamino, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyloxy, or C ₁ -C ₆ alkoxy substituted with one or more substituents;

R ₉ is 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 1} selected from the group consisting of -C ₆ alkylamino, C ₁ -C ₆ alkoxy, morpholine, piperidine, pyrrolidine, oxetanyl, piperidine substituted with C 1 -C _{6 alkyl, or acetate} substituted with one or more substituents;

R ₁₀ is independently substituted with one or more substituents selected from the group consisting of hydrogen, C ₁ -C _{6 alkyl, phenyl, oxetanyl, or acetate;}

R ₁₁ is combined with hydrogen or R ₁₀ and is substituted with a saturated or unsaturated C ₅ -C _{6 heterocycloalkyl substituent;}

R ₁₂ is hydrogen or C ₁ -C ₆ 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 alkyl;

Ak is C ₁ -C ₆ 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 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 ;

A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that

When the compound of Formula 1 is more specifically illustrated in the present invention,

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

(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidine- 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)(morphopoly no)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)(mor polyno)methanone (compound 8);

methyl 2-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazole-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-(pyridin-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 11);

(4-((5-chloro-4-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 12);

(4-((5-chloro-4-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 13);

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

(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-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 17);

(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-methylpiperazine) -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-methoxy Phenyl)(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-methoxy ethyl)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)(morphopoly no)methanone (Compound 28);

(3-methoxy-4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-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-isopropylpiperazine-1 -yl)methanone (Compound 34);

(4-((5-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy Phenyl)(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)pyridin-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-methylpiperidine-4 -yl)benzamide (Compound 38);

(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(2-hydroxypropane -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-difluoropyr peridin-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-morpholinoazetidine- 1-yl)methanone (Compound 43);

1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazine-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-phenyl piperazin-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)(morphopoly no)methanone (Compound 49);

(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(oxetane-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)methane on (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-methylpiperidine- 4-yl)benzamide (Compound 60);

(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazine-1- I) methanone (Compound 61);

(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazine-1 -yl)methanone (Compound 62);

(4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 63);

(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazine- 1-yl)methanone (Compound 64);

(2-fluoro-4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxy Phenyl)(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-hydroxy propan-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-aza spiro[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-(oxetane-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-morpholinoazetidine -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-isopropylpiperidine -4-yl)methanone (Compound 75);

(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methoxypiperidine- 1-yl)methanone (Compound 76);

(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-oxa-9-aza spiro[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)piperazine- 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-hydroxyazetidine- 1-yl)methanone (Compound 83);

(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1,1-dioxido Thiomorpholino)methanone (Compound 84);

(4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpipe Razin-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-isopropyl piperazin-1-yl)methanone (Compound 88);

((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(4-((5-chloro-4-(1-isopropyl-1H-pyrazole-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-aza spiro[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)p peridin-1-yl)methanone (Compound 94);

((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(4-((5-chloro-4-(1-isopropyl-1H-pyrazole-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-methylpi peridin-4-yl)benzamide (Compound 96);

(R)-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydro Roxypyrrolidin-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-methylpiperazine-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)(morphopoly no) methanethione (Compound 106);

(5-chloro-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluorophenyl)(4-methyl piperazin-1-yl)methanone (Compound 107);

(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(4-methyl piperazin-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-methoxybenz amide (Compound 113);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluorophenyl)-3-methoxybenz amide (Compound 114);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorophenyl)-3-methoxybenz amide (Compound 115);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyanophenyl)-3-methoxybenz amide (Compound 116);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanophenyl)-3-methoxybenz amide (Compound 117);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenz amide (Compound 118);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenz amide (Compound 119);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorobenzyl)-3-methoxybenz amide (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-methyl Toxybenzamide (Compound 127);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanobenzyl)-3-methoxybenz amide (Compound 128);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-indene-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-methoxybenz amide (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)benz amide (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-methyl piperidin-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-pyra zol-4-yl)benzamide (Compound 144);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-isopropyl-1H-pyrazole-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-methoxybenz amide (Compound 152);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxybenzyl)-3-methoxybenz amide (Compound 153);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)benz amide (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-methoxybenz amide (Compound 158);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxyphenyl)-3-methoxybenz amide (Compound 159);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxyphenyl)-3-methoxybenz amide (Compound 160);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyphenyl)benz amide (Compound 161);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methoxyphenyl)benz amide (Compound 162);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxyphenyl)benz amide (Compound 163);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-indene-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-methyl benzyl)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-methoxy benzamide (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)benz amide (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)benz amide (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-methoxybenz amide (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-methyl Toxybenzamide (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)benz amide (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-indene-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-indene-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-indene-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-indene-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-indene-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-indene-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-(pyrrolidine- 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); is selected from the group consisting of

In addition, the compound represented by Chemical Formula 1 of the present invention is prepared by the following scheme 1 (amide coupling), scheme 2 (suzuki reaction), and scheme 3 (buchwald reaction).

[Scheme 1]

[Scheme 2]

[Scheme 3]

A compound represented by Formula 1 is prepared by the reaction of Schemes 1, 2, and 3.

In Schemes 1, 2, and 3 above,

X, m, R ₁ , R ₂ , R ₃ , R ₄ are as defined in Formula 1 above,

Compound A, Compound B, Compound D, and Compound E of Schemes 1, 2, and 3 were purchased from Aldrich, Merck, TCI, and ACROS and used in their preparation.

Hereinafter, a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.

In the method for preparing a compound represented by Formula 1 according to the present invention,

The reaction condition of Scheme 1 is a step of preparing compound C by reacting the compound represented by compound A with compound B.

Scheme 1 is a step for preparing compound C by a general amidation reaction between the compound represented by the compound A and the compound B. Although this reaction can be carried out without using a base, dichloromethane that does not adversely affect the reaction in the presence of organic amines such as pyridine, triethylamine, and isopropylamine, which are bases that can be used in the amidation reaction in general , chloroform, tetrahydrofuran, diethyl ether, toluene, N,N,-dimethylformamide and the like to carry out 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.

The reaction condition of Scheme 2 is a step of preparing compound F by reacting the compound represented by compound D with compound E.

Scheme 2 is a step of preparing compound F by reacting the compound represented by compound D with compound E under a metal-catalyst. For this reaction the metal-catalyst is typically palladium, tetrakistriphenylphosphine palladium(0)((PPh ₃ ) ₄ Pd), palladium acetate(II)(Pd(OAc) ₂ ), tris(dibenzyl) Rideneacetone)dipalladium(0)(Pd ₂ dba ₃ ), bis(triphenylphosphine)palladium(II) chloride (PdCl ₂ (PPh ₃ ) ₂ ) and [1,1′-bis(diphenylphosphino) ) ferrocene] palladium (0) chloride (Pd(dppf)Cl ₂ ) and the like can be used. Bases that can be used at this time include potassium carbonate, KOtBu, cesium carbonate, potassium phosphate, sodium hydroxide, triethylamine, etc., purified water that does not adversely affect the reaction, toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide The reaction is performed using a solvent such as The reaction temperature is not particularly limited, but in general, the reaction can be carried out at room temperature or under heating, and preferably, it is carried out under heating.

Scheme 3 is a step of preparing Compound 1 by reacting the compound represented by Compound C, which is the product of Scheme 1, and Compound F, the product of Scheme 2, under a metal-catalyst. For this reaction the metal-catalyst is typically palladium, tetrakistriphenylphosphine palladium(0)((PPh ₃ ) ₄ Pd), palladium acetate(II)(Pd(OAc) ₂ ), tris(dibenzyl) Rideneacetone)dipalladium(0)(Pd ₂ dba ₃ ), bis(triphenylphosphine)palladium(II) chloride (PdCl ₂ (PPh ₃ ) ₂ ) and [1,1′-bis(diphenylphosphino) ) ferrocene] palladium (0) chloride (Pd(dppf)Cl ₂ ) and the like can be used. Although this reaction can be carried out without using a ligand, triphenylphosphine ((PPh ₃ ) ₄ ), 1,2-bis(diphenylphosphino)propane, which are ligands generally used in the Buchwald reaction under a metal-catalyst (DPPP), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP), xantphos (Xantphos), the reaction is carried out using the X-Phos (XPhos). The base that can be used at this time is potassium carbonate, KOtBu, cesium carbonate, potassium phosphate, sodium hydroxide, triethylamine, etc., and toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide, etc. The reaction is carried out using a solvent. The reaction temperature is not particularly limited, but in general, the reaction can be carried out at room temperature or under heating, and preferably, it is carried out under heating.

In this case, it is included in the present invention without limitation, and as an example of the reaction conditions, the reaction may be preferably carried out under Pd(OAc) ₂ / Cs ₂ CO ₃ / Xantphos reaction conditions, ZnCl ₂ / Trifluoroacetic acid reaction conditions, and the like.

In this case, the solvent that can be used for the reaction may be used without limitation as long as it is a solvent capable of dissolving the compounds represented by compounds A and B and the materials used for the reaction, for example, dioxane, tetrahydrofuran (THF), ethyl ether, ether solvents including 1,2-dimethoxyethane and the like; lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane and mixtures thereof can be used.

In addition, the reaction temperature is not particularly limited, but may preferably be carried out at 0° C. to 100° C., for example, at room temperature. Further, the reaction time is not particularly limited, but, for example, may be set to 2 to 20 hours, and as another example, may be reacted over 20 minutes to 8 hours when heated.

In addition, the following terms in the present invention have the following meanings unless otherwise indicated. Any terms not defined have the meanings understood in the art.

The terms "cyclic" and "ring" are substituted or unsubstituted and/or contain or contain heteroatoms, substituted or aromatic, which may be monocyclic, bicyclic or polycyclic. refers to the

The terms “halo” and “halogen” are used in their conventional sense to refer to a fluoro (F), chloro (Cl), bromo (Br) or iodo (I) substituent.

The term “alkyl” refers to a single-bonded straight-chain or branched hydrocarbon group. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, pentyl and hexyl.

The term “alkoxy” refers to an oxygen group to which a single-bonded straight-chain or branched saturated hydrocarbon is bound. Examples include methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, 1-methylpropoxy and the like.

The term “cycloalkyl” refers to a saturated hydrocarbon group of a single cyclic bond. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.1]heptyl, spiro[4.5]decyl, spiro[5.5]undecyl, and adamantyl. have.

The term “aryl” refers to an aromatic substituent having at least one ring having a shared pi electron system, for example, phenyl, benzyl, naphthyl, anthryl, biphenyl, triphenyl, and the like.

The term “arylalkyl” refers to an aryl group substituted with an alkyl group, and aryl and alkyl are as described above.

The term “heterocycloalkyl” refers to a saturated hydrocarbon group of a single cyclic bond containing one or more heteroatoms such as N, O, or S, and may vary depending on the number and type of heteroatoms included in the ring, and the number of carbon atoms. Lidinyl, pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinyl, oxopiperazinyl, morpholinyl, thiomorpholinyl, azepanil, diazepanil, oxazepanil, thia zepanyl, dioxothiazepanyl, azocanyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, dioxanyl, dioxolanyl, and the like.

The term “heteroaryl” refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S, and pyridyl, pyrrolyl, pyridyl, pyrrolyl, pyridyl, Rollidinyl, pyridinyl, furanyl, quinolidinyl, 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, oxatriazolyl, dioxazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, oxazinyl, oxathiazinyl, Oxadiazinyl, indolyl, benzimidazolyl, indazolyl, indoxazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, quinoxalinyl , naphthyridinyl, phthalazinyl, pteridinyl, xanthenyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzofuropyridinyl, furodipyridinyl, benzothienopyridinyl, thi nodipyridinyl, benzoselenophenopyridinyl and selenophenodipyridinyl; and the like.

Furthermore, the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of this invention.

In the present invention, the pharmaceutically acceptable salt means a salt or complex of Formula 1 having desirable biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, and the like. , benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and salts formed with organic acids such as poly-galacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, in particular chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carbohydrate. Voxylates (e.g., benzoates, succinates, acetates, glycorates, maleates, malates, fumarates, citrates, tartrates, ascorbates, cinnamoates, mandeloates and diphenylacetate). The compound of Formula 1 of the present invention may include all salts, hydrates, solvates and prodrugs that can be prepared by conventional methods as well as pharmaceutically acceptable salts.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc. and adding an organic or inorganic acid It can be prepared by filtration and drying, or by distilling the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).

In another aspect, the present invention relates to a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases and cancer comprising the compound represented by Formula 1 as an active ingredient, wherein the compound represented by Formula 1 inhibits both LRRK2 have activity.

The neurodegenerative disease refers to a disease that causes various symptoms while degenerative changes due to gradual and steady death appear in nerve cells of the central nervous system, Parkinson's disease, Alzheimer's disease, Huntington's disease disease, Pick's disease, Amyotrophic lateral sclerosis, Prion disease, Motor neuron disease, Spinocerebellar ataxia, Spinal muscular atrophy), Creutzfeldt-Jakob disease, and alcoholic dementia may be selected from the group consisting of, but not particularly limited thereto.

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

The pharmaceutical composition according to the present invention may be formulated in a suitable form together with a commonly used pharmaceutically acceptable carrier. “Pharmaceutically acceptable” refers to a composition that is physiologically acceptable and does not normally cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when administered to humans. In addition, the composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods.

Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate and mineral oil may be included, but are not limited thereto. In the case of formulation, it is prepared using commonly used diluents or excipients such as fillers, stabilizers, binders, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient, for example, starch, microcrystalline cellulose, sucrose or lactose, to the compound of the present invention; It is prepared by mixing low-substituted hydroxypropyl cellulose, hypromellose, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used. In order to formulate a formulation for parenteral administration, the pyrimidine derivative compound of Formula 1 or a pharmaceutically acceptable salt thereof is sterilized or an adjuvant such as a preservative, a stabilizer, a wetting agent or an emulsification accelerator, a salt or a buffer for regulating osmotic pressure, and It may be mixed with other therapeutically useful substances in water to prepare a solution or suspension, which may be prepared in ampoules or vial unit dosage form.

The pharmaceutical composition comprising the compound of Formula 1 disclosed in the present invention as an active ingredient may be administered to mammals such as mice, livestock, and humans by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection. The dosage may be determined by the age, sex, weight, specific disease or pathology to be treated, the severity of the disease or pathology, administration time, administration route, absorption, distribution and excretion rate of the drug, the type of other drugs used, and the prescriber's It will depend on judgment, etc. Dosage determination based on these factors is within the level of one of ordinary skill in the art, and generally dosages range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day. Administration may be administered once a day, or divided into several administrations. The above dosage does not limit the scope of the present invention in any way.

In addition, the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, chemotherapy and biological response modifiers for the prevention or treatment of neurodegenerative diseases and cancer.

The present invention relates to a novel pyrimidine derivative and a composition for preventing or treating neurodegenerative diseases and cancer comprising the same, wherein the pyrimidine derivative has excellent LRRK2 inhibitory activity and efficiently passes through the blood-brain barrier (BBB). It can be usefully used as a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases and cancer.

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, it is provided so that this disclosure will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

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

The synthesis process of compounds 1 to 297 of the present invention is as follows.

Compound 1. (4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methane On

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

In a 25 mL round-bottom flask, 500 mg (3 mmol) of 4-amino-3-methoxybenzoic acid, 0.31 mL (3.6 mmol) of morpholine, 747 mg (3.9 mmol) of EDCI (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl), 527 mg (3.9 mmol) of HOBt (hydroxybenzotriazole) and 10 mL of DCM (dichloromethane) were added, and 1.05 mL (6 mmol) of DIPEA (diisopropylethylamine) was added at 0 °C, followed by stirring at room temperature for 12 hours. The organic layer extracted by adding ethyl acetate, saturated aqueous NaCl solution and water was dried (Mg ₂ SO ₄ ), filtered and concentrated. The crude product was dissolved in DCM and separated by column chromatography. The title compound 634 mg (2.68 mmol, 89.1% yield) was obtained as a pale yellow solid.

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).

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

2,4,5-trichloropyrimidine 0.63 mL (5.5 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid 720mg (5.78 mmol), 5.5 mL of _{2M Na 2} CO _{3 solution (} 11 mmol), 9mL of dioxane, degassed twice, and then Pd(dppf)Cl ₂ (1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)) 402mg (0.55 mmol) was added, and then 1 time After further degassing, the mixture is stirred at 90 °C for 12 hours. After Celite filter, ethyl acetate and water were added, and the extracted organic layer was dried (Mg ₂ SO ₄ ), filtered and concentrated. The crude product was dissolved in DCM and separated by column chromatography to obtain 820 mg (3.58 mmol, 65% yield) of the title compound. It was obtained as a pale yellow solid.

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

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

(4-amino-3-methoxyphenyl) (morpholino)methanone 120mg (0.525 mmol), 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine 118mg (0.5 mmol), xantphos (xantphos, 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) 29mg (0.05 mmol), cesium carbonate 326mg (1 mmol), 2 mL of dioxane, and then degassed 3 times . After that, 11 mg (0.05 mmol) of Pd(OAc) _{2 was added and degassed once more.} After that, the mixture was stirred at 90°C for 12 hours. The organic layer extracted with ethyl acetate and water was dried (Mg ₂ SO ₄ ), filtered and concentrated. The crude product was dissolved in DCM (dichloromethan) and separated by column chromatography to obtain 163 mg (0.38 mmol, 76% yield) of the title compound. obtained as a white solid.

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).

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

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

(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidine- 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)a

mino)-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)(mor polyno)methanone (compound 8);

methyl 2-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazole-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-(pyridin-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 11);

(4-((5-chloro-4-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 12);

(4-((5-chloro-4-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 13);

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

(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-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 17);

(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-methylpiperazine) -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-methoxy Phenyl)(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-methoxy ethyl)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)(morphopoly no)methanone (Compound 28);

(3-methoxy-4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-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-isopropylpiperazine-1 -yl)methanone (Compound 34);

(4-((5-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy Phenyl)(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)pyridin-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-methylpiperidine-4 -yl)benzamide (Compound 38);

(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(2-hydroxypropane -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-difluoropyr peridin-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-morpholinoazetidine- 1-yl)methanone (Compound 43);

1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazine-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-phenyl piperazin-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)(morphopoly no)methanone (Compound 49);

(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(oxetane-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)methane on (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-methylpiperidine- 4-yl)benzamide (Compound 60);

(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazine-1- I) methanone (Compound 61);

(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazine-1 -yl)methanone (Compound 62);

(4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 63);

(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazine- 1-yl)methanone (Compound 64);

(2-fluoro-4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxy Phenyl)(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-hydroxy propan-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-aza spiro[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-(oxetane-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-morpholinoazetidine -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-isopropylpiperidine -4-yl)methanone (Compound 75);

(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methoxypiperidine- 1-yl)methanone (Compound 76);

(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-oxa-9-aza spiro[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)piperazine- 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-hydroxyazetidine- 1-yl)methanone (Compound 83);

(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1,1-dioxido Thiomorpholino)methanone (Compound 84);

(4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpipe Razin-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-isopropyl piperazin-1-yl)methanone (Compound 88);

((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(4-((5-chloro-4-(1-isopropyl-1H-pyrazole-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-aza spiro[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)p peridin-1-yl)methanone (Compound 94);

((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(4-((5-chloro-4-(1-isopropyl-1H-pyrazole-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-methylpi peridin-4-yl)benzamide (Compound 96);

(R)-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydro Roxypyrrolidin-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-methylpiperazine-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)(morphopoly no) methanethione (Compound 106);

(5-chloro-4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-2-fluorophenyl)(4-methyl piperazin-1-yl)methanone (Compound 107);

(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(4-methyl piperazin-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-methoxybenz amide (Compound 113);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluorophenyl)-3-methoxybenz amide (Compound 114);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorophenyl)-3-methoxybenz amide (Compound 115);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyanophenyl)-3-methoxybenz amide (Compound 116);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanophenyl)-3-methoxybenz amide (Compound 117);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenz amide (Compound 118);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenz amide (Compound 119);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorobenzyl)-3-methoxybenz amide (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-methyl Toxybenzamide (Compound 127);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanobenzyl)-3-methoxybenz amide (Compound 128);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-indene-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-methoxybenz amide (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)benz amide (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-methyl piperidin-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-pyra zol-4-yl)benzamide (Compound 144);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-isopropyl-1H-pyrazole-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-methoxybenz amide (Compound 152);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxybenzyl)-3-methoxybenz amide (Compound 153);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)benz amide (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-methoxybenz amide (Compound 158);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxyphenyl)-3-methoxybenz amide (Compound 159);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxyphenyl)-3-methoxybenz amide (Compound 160);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyphenyl)benz amide (Compound 161);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methoxyphenyl)benz amide (Compound 162);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxyphenyl)benz amide (Compound 163);

4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-indene-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-methyl benzyl)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-methoxy benzamide (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)benz amide (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)benz amide (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-methoxybenz amide (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-methyl Toxybenzamide (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)benz amide (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-indene-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-indene-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-indene-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-indene-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-indene-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-indene-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-(pyrrolidine- 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);

compound number chemical structure NMR spectral data 2

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.62 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 8.21 - 8.24 (m, 2H), 7.07 (s, 1H), 7.06 (m, 1H), 4.51 - 4.55 (m, 2H), 3.96 (s, 3H), 3.89 (s, 3H), 3.53 - 3.60 (m, 4H), 2.89 - 2.93 (m, 2H), 2.45 - 2.53 (m, 5H), 1.78 - 1.82 (m, 2H), 1.35 - 1.38 (m, 2H). 3

¹ H NMR (300 MHz, Chloroform- d ) δ 9.14 (d, J = 0.7 Hz, 1H), 8.49 - 8.55 (m, 2H), 8.45 (s, 1H), 7.94 (s, 1H), 7.02 - 7.10 (m, 2H), 3.97 (s, 3H), 3.50 - 3.85 (s, 8H), 2.79 (s, 3H). 4

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.54 (d, J = 6.0 Hz, 1H), 8.40 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 7.86 (s, 1H) , 7.06 (s, 1H), 7.04 (d, J = 6.0 Hz, 1H), 4.33 - 4.37 (m, 2H), 4.07 - 4.11 (m, 2H), 3.96 (s, 3H), 3.60 - 3.81 (m , 8H). 5

¹ H NMR (300 MHz, Methanol-d ⁴ ) d 8.73 (s, 1H), 8.55 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 7.13 (dd, J = 4.5, 2.7 Hz, 2H), 4.57 (t, J = 6.4 Hz, 2H), 4.00 (s, 3H), 3.71 (s, 7H), 3.12 (t, J = 6.4 Hz, 2H), 2.63 ( p, J = 1.9 Hz, 4H), 2.05 (s, 1H). 6

¹ H NMR (300 MHz, Chloroform- d ) δ 8.51 (d, J = 9.2 Hz, 2H), 8.45 (s, 1H), 8.41 (s, 1H), 7.89 (s, 1H), 6.98 - 7.13 (m) , 2H), 5.18 (s, 2H), 3.97 (s, 3H), 3.50 - 3.85 (m, 8H). 7

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.75 (s, 1H), 8.55 (s, 1H), 8.32 (d, J = 6.3 Hz, 2H), 8.26 (d, J = 8.1 Hz, 1H) , 7.09 (d, J = 8.9 Hz, 2H), 3.90 (s, 3H), 3.57 (d, J = 31.2 Hz, 9H), 3.17 (d, J = 6.6 Hz, 2H), 1.55 (d, J = 6.7 Hz, 3H). 8

¹ H NMR (400 MHz, Chloroform- d ) δ 8.54 (d, J = 8.1 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 3.0 Hz, 2H), 7.85 ( s, 1H), 7.03 (d, J = 9.8 Hz, 2H), 4.30 (t, J = 6.4 Hz, 2H), 3.94 (s, 3H), 3.79 - 3.59 (m, 12H), 2.85 (t, J) = 6.4 Hz, 2H), 2.49 (t, J = 4.6 Hz, 4H). 9

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.53 (d, J = 8.0 Hz, 1H), 8.46 (s, 1H), 8.43 (s, 1H), 8.39 (s, 1H), 7.97 (s, NH) , 7.06 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 5.02 (s, 2H), 3.96 (s, 3H), 3.82 (s, 3H), 3.60 - 3.81 (m, 8H). 10

¹ H NMR (300 MHz, Chloroform- d ) δ 8.92 (d, J = 0.7 Hz, 1H), 8.61 (d, J = 0.7 Hz, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.44 ( s, 1H), 7.92 (s, 1H), 7.00 - 7.13 (m, 2H), 3.96 (s, 3H), 3.55 - 3.83 (m, 8H), 3.44 (s, 3H). 11

¹ H NMR (300 MHz, Chloroform- d ) δ 9.47 (d, J = 0.8 Hz, 1H), 8.55 - 8.63 (m, 2H), 8.45 - 8.50 (m, 1H), 8.42 (s, 1H), 8.05 (dt, J = 8.3, 1.0 Hz, 1H), 7.83 - 7.94 (m, 2H), 7.23 - 7.30 (m, 1H), 7.04 - 7.10 (m, 2H), 3.97 (s, 3H), 3.61 - 3.79 (m, 8H). 12

¹ H NMR (400 MHz, Chloroform- d ) δ 9.10 (s, 1H), 8.88 (s, 1H), 8.63 (s, 2H), 8.56 (d, J = 8.1 Hz, 1H), 8.45 (s, 1H) ), 8.14 (dt, J = 8.6, 1.7 Hz, 1H), 7.92 (s, 1H), 7.49 (t, J = 6.4 Hz, 1H), 7.04 - 7.10 (m, 2H), 3.98 (s, 3H) , 3.56 - 3.82 (m, 8H). 13

¹ H NMR (400 MHz, Chloroform- d ) δ 8.93 (s, 1H), 8.75 (s, 2H), 8.59 (s, 1H), 8.53 (d, J = 8.3 Hz, 1H), 8.42 (s, 1H) ), 7.90 (s, 1H), 7.68 - 7.80 (m, 2H), 7.02 - 7.10 (m, 2H), 3.96 (s, 3H), 3.54 - 3.82 (m, 8H). 14

¹ H NMR (300 MHz, Chloroform- d ) δ 8.84 (d, J = 0.7 Hz, 1H), 8.55 - 8.60 (m, 2H), 8.42 (s, 1H), 7.90 (s, 1H), 7.74 - 7.81 (m, 2H), 7.48 - 7.56 (m, 2H), 7.32 - 7.41 (m, 1H), 7.03 - 7.10 (m, 2H), 3.97 (s, 3H), 3.61 - 3.79 (m, 8H). 15

¹ H NMR (300 MHz, Chloroform- d ) δ 8.74 (s, 1H), 8.49 - 8.55 (m, 2H), 8.45 (s, 1H), 7.91 (s, 1H), 7.07 - 7.49 (t, 1H) , 7.02 - 7.10 (m, 2H), 3.97 (s, 3H), 3.59 - 3.80 (m, 8H). 16

¹ H NMR (400 MHz, Chloroform- d ) δ 8.55 (d, J = 8.1 Hz, 1H), 8.52 (d, J = 3.6 Hz, 1H), 8.36 - 8.48 (m, 2H), 7.88 (s, 1H) ), 7.02 - 7.10 (m, 2H), 5.48 (s, 2H), 3.96 (s, 3H), 3.54 - 3.83 (m, 8H), 3.40 (s, 3H). 17

¹ H NMR (300 MHz, Chloroform- d ) δ 8.51 (d, J = 8.3 Hz, 1H), 8.41 (d, J = 0.7 Hz, 1H), 8.35 (s, 1H), 8.28 (d, J = 0.7) Hz, 1H), 7.88 (s, 1H), 7.22 - 7.30 (m, 2H), 7.05 (d, J = 1.8 Hz, 1H), 7.00 (dd, J = 8.3, 1.8 Hz, 1H), 6.87 - 6.95 (m, 2H), 5.32 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.59 - 3.78 (m, 8H). 18

¹ H NMR (300 MHz, Chloroform- d ) δ 8.57 (d, J = 8.8 Hz, 1H), 8.49 (s, 2H), 8.39 (s, 1H), 7.88 (s, 1H), 7.03 - 7.09 (m) , 2H), 3.96 (s, 3H), 3.54 - 3.85 (m, 8H). 19

¹ H NMR (300 MHz, Methanol-d ⁴ ) δ 8.58 - 8.48 (m, 2H), 8.42 (d, J = 4.3 Hz, 1H), 8.31 (d, J = 0.7 Hz, 1H), 7.10 (tt, J = 4.0, 1.9 Hz, 2H), 3.99 (d, J = 3.6 Hz, 6H), 3.92 (s, 1H), 3.42 (s, 4H), 3.19 (d, J = 32.8 Hz, 9H), 2.91 ( s, 3H), 2.05 (s, 2H), 1.78 - 1.54 (m, 2H). 20

¹ H NMR (400 MHz, Chloroform- d ) δ 8.56 (d, J = 8.2 Hz, 1H), 8.44 - 8.31 (m, 3H), 7.88 (s, 1H), 7.11 - 7.01 (m, 2H), 4.59 (p, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.72 (s, 9H), 1.68 (s, 9H), 1.59 (d, J = 6.7 Hz, 6H). 21

¹ H NMR (400 MHz, Chloroform- d ) δ 8.43 (s, 1H), 8.09 (d, J = 7.7 Hz, 2H), 7.11 (d, J = 21.2 Hz, 2H), 3.91 (s, 3H), 3.67 (s, 2H), 3.37 (d, J = 19.5 Hz, 2H), 3.15 (s, 2H). 22

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.53 (d, J = 8.0 Hz, 1H), 8.37 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 7.86 (s, NH) , 7.20 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.66 (t, J = 6.0 Hz, 2H), 3.55 (t, J = 6.0 Hz, 2H), 1.95 - 1.99 (m, 2H), 1.86 - 1.90 (m, 2H). 23

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.50 (d, J = 9.0 Hz, 1H), 8.36 (s, 2H), 8.31 (s, 1H), 7.90 (s, NH), 7.08 (s, 1H) , 7.04 (d, J = 9.0 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.59 - 3.63 (m, 6H), 3.37 (s, 3H), 1.25 (s, 3H). 24

¹ H NMR (300 MHz, Chloroform- d ) δ 8.51 (d, J = 8.4 Hz, 1H), 8.35 - 8.28 (m, 2H), 8.26 (s, 1H), 7.86 (s, 1H), 7.40 (d) , J = 1.9 Hz, 1H), 6.30 (s, 1H), 5.02 (t, J = 6.0 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.70 (d, J = 5.2 Hz) , 2H), 1.43 (s, 6H). 25

¹ H NMR (300 MHz, Chloroform- d ) δ 8.51 (d, J = 8.4 Hz, 1H), 8.35 - 8.28 (m, 2H), 8.26 (s, 1H), 7.86 (s, 1H), 7.40 (d) , J = 1.9 Hz, 1H), 6.30 (s, 1H), 5.02 (t, J = 6.0 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.70 (d, J = 5.2 Hz) , 2H), 1.43 (s, 6H). 26

¹ H NMR (400 MHz, Chloroform- d ) δ 8.54 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 1.9 Hz, 2H), 8.32 (s, 1H), 8.03 (s, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.40 - 7.34 (m, 1H), 6.68 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.50 (d, J = 5.9 Hz) , 2H), 1.32 (s, 6H) 27

¹ H NMR (300 MHz, Chloroform- d ) δ 8.55 (d, J = 8.1 Hz, 1H), 8.50 - 8.42 (m, 2H), 8.39 (s, 1H), 7.87 (s, 1H), 7.09 - 7.01 (m, 2H), 3.96 (s, 3H), 3.70 (s, 8H), 3.07 (s, 2H), 1.84 (s, 6H). 28

¹ H NMR (300 MHz, Chloroform- d ) δ 8.51 8.59 (m, 1H), 8.40 (d, J = 0.7 Hz, 1H), 8.37 (d, J = 0.7 Hz, 1H), 8.35 (s, 1H) , 7.85 (s, 1H), 7.00 7.07 (m, 2H), 4.36 (t, J = 5.1 Hz, 2H), 3.94 (s, 3H), 3.79 (t, J = 5.1 Hz, 2H), 3.60 3.75 ( m, 8H), 3.35 (s, 3H). 29

¹ H NMR (300 MHz, Chloroform-d) δ 8.67 (s, 1H), 8.58 (d, J = 8.2 Hz, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 8.05 (s, 1H) ), 7.01 - 7.11 (m, 2H), 4.35 - 4.50 (m, 1H), 4.10 - 4.20 (m, 2H), 3.97 (s, 3H), 3.50 - 3.80 (m, 10H), 2.09 - 2.21 (m) , 4H). 30

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.64 (s, 1H), 8.55 (s, 1H), 8.31 (d, J = 9.1 Hz, 2H), 8.23 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.58 (dd, J = 8.4, 1.9 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 3.98 - 4.06 (m, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 1.58 - 2.13 (m, 8H). 31

¹ H NMR (300 MHz, Chloroform-d) δ 8.64 (s, 1H), 8.53 (d, J = 8.7 Hz, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H) ), 7.04 (dd, J = 8.7, 1.8 Hz, 1H), 7.02 (d, J = 1.8 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 2.35 - 3.05 (m, 13H) , 2.29 (s, 3H), 1.82 - 1.97 (m, 2H), 1.40 - 1.61 (m, 2H). 32

¹ H NMR (300 MHz, Chloroform-d) δ 8.53 (d, J = 8.8 Hz, 1H), 8.36 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 7.84 (s, 1H) ), 7.03 (dd, J = 8.8, 1.8 Hz, 1H), 7.01 (s, J = 1.8 Hz, 1H), 4.45 - 4.52 (m, 4H), 4.00 (s, 3H), 3.94 (s, 3H) , 3.44 - 3.62 (m, 4H), 1.84 - 1.96 (m, 4H). 33

¹ H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 7.90 (s, 1H) ), 7.31 (d, J = 1.8 Hz, 1H), 7.22 (dd, J = 8.4, 1.8 Hz, 1H), 4.34 - 4.62 (m, 6H), 4.01 (s, 3H), 3.96 (s, 3H) , 2.86 (t, J = 7.9 Hz, 2H). 34

¹ H NMR (300 MHz, Chloroform-d) δ 8.54 (d, J = 8.7 Hz, 1H), 8.37 (d, J = 1.1 Hz, 2H), 8.31 (s, 1H), 7.85 (s, 1H), 7.02 - 7.10 (m, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 3.54 - 3.85 (m, 4H), 2.75 (p, J = 6.5 Hz, 1H), 2.45 - 2.68 (m, 4H), 1.07 (d, J = 6.5 Hz, 6H). 35

¹ H NMR (300 MHz, Chloroform-d) δ 8.54 (d, J = 8.7 Hz, 1H), 8.42 - 8.35 (m, 3H), 7.85 (s, 1H), 7.02 (dq, J = 3.8, 1.8 Hz) , 2H), 4.49 (s, 4H), 4.45 - 4.37 (m, 1H), 4.20 - 4.11 (m, 2H), 3.95 (s, 3H), 3.63 - 3.48 (m, 6H), 2.23 - 2.11 (m) , 4H), 1.91 (s, 4H). 36

¹ H NMR (300 MHz, Chloroform-d) δ 8.66 (s, 1H), 8.57 (d, J = 8.1 Hz, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 8.03 (s, 1H) ), 7.07 (d, J = 1.8 Hz, 1H), 7.06 (dd, J = 8.1, 1.8 Hz, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.60 - 3.79 (m, 8H) . 37

¹ H NMR (300 MHz, Chloroform- d ) δ 8.57 (d, J = 8.1 Hz, 1H), 8.33 - 8.41 (m, 3H), 7.85 (s, 1H), 7.02 - 7.09 (m, 2H), 4.59 (m, J = 6.7 Hz, 1H), 3.96 (s, 3H), 3.62-3.79 (m, 8H), 1.59 (d, J = 6.7 Hz, 6H). 38

¹ H NMR (300 MHz, Chloroform-d) δ 8.55 (dd, J = 8.5, 1.2 Hz, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 7.89 (s) , 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.30 (dd, J = 8.4, 1.9 Hz, 1H), 6.04 (s, 1H), 4.00 (s, 3H), 3.97 (s, 1H) , 2.77 - 2.90 (m, 2H), 2.31 (s, 3H), 1.98 - 2.25 (m, 5H), 1.53 - 1.69 (m, 2H). 39

¹ H NMR (300 MHz, Chloroform-d) δ 8.50 (d, J = 8.7 Hz, 1H), 8.34 (s, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 7.83 (s, 1H) ), 7.04 (dd, J = 8.7, 1.8 Hz, 1H), 7.02 (d, J = 1.8 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 2.58 - 3.06 (m, 2H) , 1.74 - 2.06 (m, 3H), 1.22 - 1.64 (m, 4H), 1.19 (s, 6H). 40

¹ H NMR (400 MHz, Chloroform-d) δ 8.56 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 4.5 Hz, 2H), 8.31 (s, 1H), 7.91 (s, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 8.4, 1.8 Hz, 1H), 4.82 (s, 4H), 4.28 - 4.61 (m, 4H), 4.01 (s, 3H), 3.96 (s, 3H). 41

¹ H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 7.84 (s, 1H) ), 7.05 (d, J = 8.4 Hz, 2H), 3.98 (s, 3H), 3.94 (s, 3H), 3.63 - 3.86 (m, 4H), 1.87 - 2.22 (m, 4H). 42

¹ H NMR (300 MHz, Chloroform-d) δ 8.55 (d, J = 8.7 Hz, 1H), 8.38 - 8.34 (m, 2H), 8.30 (s, 1H), 7.85 (s, 1H), 7.04 (dd , J = 1.8 Hz, 1H), 7.03 (d, J = 1.8 Hz, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 3.35 - 3.82 (m, 6H), 1.24 (s, 6H) . 43

¹ H NMR (300 MHz, Chloroform-d) δ 8.56 (d, J = 8.4 Hz, 1H), 8.36 - 8.39 (m, 2H), 8.32 (s, 1H), 7.91 (s, 1H), 7.35 (d , J = 1.8 Hz, 1H), 7.24 (dd, J = 8.4, 1.8 Hz, 1H), 4.18 - 4.41 (m, 3H), 4.04 - 4.13 (m, 1H), 4.01 (s, 3H), 3.97 ( s, 3H), 3.72 - 3.79 (m, 4H), 3.16 - 3.26 (m, 1H), 2.35 - 2.45 (m, 4H). 44

¹ H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 8.6 Hz, 1H), 8.34 (s, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 7.85 (s, 1H) ), 7.04 (t, J = 3.2 Hz, 2H), 3.98 (s, 3H), 3.94 (s, 3H), 3.41 - 3.82 (m, 8H), 2.12 (s, 3H). 45

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.66 (s, 1H), 8.55 (d, J = 9.0 Hz, 1H), 8.19 (s, 1H), 8.04 (s, 1H), 8.03 (s, 1H) , 7.08 (s, 1H), 7.05 (d, J = 9.0 Hz, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 3.94 - 3.99 (m, 4H), 2.74 (m, 1H), 2.52 - 2.58 (m, 4H), 1.07 (d, J = 6.0 Hz, 6H). 46

¹ H NMR (300 MHz, Chloroform-d) δ 8.69 (s, 1H), 8.47 (d, J = 11.9 Hz, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 8.04 (s, 1H) ), 6.96 (d, J = 5.9 Hz, 1H), 4.01 (s, 3H), 3.96 (s, 3H), 3.41 - 3.86 (m, 8H). 47

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.65 (s, 1H), 8.57 (d, J = 9.0 Hz, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 8.02 (s, 1H) , 7.45 - 7.48 (m, 2H), 7.08 - 7.12 (m, 2H), 6.91 - 6.95 (m, 3H), 3.98 (s, 3H), 3.92 (s, 3H), 3.78 - 3.86 (m, 4H) , 3.17 - 3.25 (m, 4H). 48

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.68 (s, 1H), 8.46 (d, J = 12.0 Hz, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 8.04 (s, 1H) , 6.94 (d, J = 6.0 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 3H). 49

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.46 (d, J = 12.0 Hz, 1H), 8.40 (s, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 7.90 (s, NH) , 6.94 (d, J = 6.0 Hz, 1H), 4.59 (m, 1H), 3.94 (s, 3H), 3.80 (s, 4H), 3.67 - 3.71 (m, 2H), 3.43 - 3.47 (m, 2H) ), 1.60 (d, J = 9.0 Hz, 6H). 50

¹ H NMR (300 MHz, Chloroform-d) δ 8.54 (d, J = 8.7 Hz, 1H), 8.33 - 8.39 (m, 2H), 8.30 (s, 1H), 7.84 (s, 1H), 7.01 - 7.08 (m, 2H), 4.65 (dt, J = 16.8, 6.4 Hz, 4H), 4.00 (s, 3H), 3.95 (s, 3H), 3.60 - 3.82 (m, 4H), 3.52 (p, J = 6.4) Hz, 1H), 2.28 - 2.42 (m, 4H). 51

¹ H NMR (300 MHz, Chloroform-d) δ 8.52 (d, J = 8.7 Hz, 1H), 8.37 - 8.32 (m, 2H), 8.28 (s, 1H), 7.83 (s, 1H), 6.98 - 7.05 (m, 2H), 4.18 - 4.49 (m, 2H), 3.98 (s, 3H), 3.94 (s, 3H), 2.99 - 3.79 (m, 4H), 1.68 - 1.99 (m, 4H). 52

¹ H NMR (300 MHz, Chloroform-d) δ 8.78 - 8.83 (m, 2H), 8.67 (d, J = 8.5 Hz, 1H), 8.41 (s, 1H), 8.38 (d, J = 0.7 Hz, 1H) ), 8.34 (d, J = 0.7 Hz, 1H), 8.09 (s, 1H), 7.55 - 7.60 (m, 3H), 7.41 (dd, J = 8.5, 1.9 Hz, 1H), 4.27 (q, J = 7.3 Hz, 2H), 4.03 (s, 3H), 1.57 (t, J = 7.3 Hz, 3H). 53

¹ H NMR (300 MHz, Chloroform-d) δ 8.77 - 8.85 (m, 2H), 8.67 (d, J = 8.5 Hz, 1H), 8.41 (s, 1H), 8.38 (s, 1H), 8.32 (s) , 1H), 8.09 (s, 1H), 7.54 - 7.61 (m, 3H), 7.40 (dd, J = 8.5, 1.9 Hz, 1H), 4.17 (t, J = 7.1 Hz, 2H), 4.02 (s, 3H), 1.97 (h, J = 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). 54

¹ H NMR (300 MHz, Chloroform- d ) δ 8.78 - 8.85 (m, 2H), 8.68 (d, J = 8.5 Hz, 1H), 8.40 (d, J = 6.2 Hz, 2H), 8.36 (s, 1H) ), 8.09 (s, 1H), 7.55 - 7.60 (m, 3H), 7.40 (dd, J = 8.5, 1.9 Hz, 1H), 4.59 (m, J = 6.6 Hz, 1H), 4.03 (s, 3H) , 1.59 (d, J = 6.7 Hz, 6H). 55

¹ H NMR (400 MHz, Chloroform-d) δ 8.81 (d, J = 5.0 Hz, 2H), 8.67 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 18.9 Hz, 2H), 8.32 ( s, 1H), 8.10 (s, 1H), 7.58 (d, J = 5.0 Hz, 2H), 7.57 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 4.03 (s, 3H), 4.01 (s, 3H). 56

¹ H NMR (300 MHz, Chloroform-d) δ 8.56 (d, J = 8.3 Hz, 1H), 8.33 - 8.40 (m, 3H), 7.86 (s, 1H), 7.02 - 7.08 (m, 2H), 4.27 (q, J = 7.3 Hz, 2H), 3.96 (s, 3H), 3.60 - 3.81 (m, 8H), 1.57 (t, J = 7.3 Hz, 3H). 57

¹ H NMR (300 MHz, Chloroform-d) δ 8.56 (d, J = 8.6 Hz, 1H), 8.36 - 8.40 (m, 2H), 8.32 (s, 1H), 7.85 (s, 1H), 7.03 - 7.10 (m, 2H), 4.17 (t, J = 7.2 Hz, 2H), 3.96 (s, 2H), 3.63 - 3.77 (m, 8H), 1.97 (m, J = 7.2 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). 58

¹ H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 8.2 Hz, 1H), 8.38 (s, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 7.85 (s, 1H) ), 7.06 (d, J = 8.2 Hz, 1H), 7.05 (dd, J = 8.2, 1.8 Hz, 1H) 3.96 (s, 3H), 3.60 - 3.81 (m, 8H), 1.20 - 1.26 (m, 2H) ), 1.06 - 1.14 (m, 2H). 59

¹ H NMR (300 MHz, Chloroform-d) δ 8.60 (d, J = 8.2 Hz, 1H), 8.46 (d, J = 0.7 Hz, 1H), 8.43 (d, J = 0.7 Hz, 1H), 8.39 ( s, 1H), 7.88 (s, 1H), 7.09 (d, J = 1.8 Hz, 1H), 7.05 (dd, J = 8.2, 1.8 Hz, 1H), 3.98 (s, 3H), 3.64 - 3.80 (m , 8H), 1.69 (s, 9H). 60

¹ H NMR (300 MHz, Chloroform- d ) δ 8.59 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 7.90 (s, 1H) ), 7.47 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 8.4, 1.9 Hz, 1H), 5.97 (d, J = 8.0 Hz, 1H), 4.52 - 4.66 (m, 1H), 4.00 (s, 3H), 2.78 - 2.93 (m, 2H), 2.33 (s, 3H), 2.13 - 2.26 (m, 3H), 2.00 - 2.14 (m, 3H), 1.59 (d, J = 6.7 Hz, 6H) ). 61

¹ H NMR (300 MHz, Chloroform- d ) δ 8.54 (d, J = 8.8 Hz, 1H), 8.36 (s, 2H), 8.30 (s, 1H), 7.85 (s, 1H), 7.06 (dd, J =8.8, 1.9 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 3.55 - 3.80 (m, 4H), 2.55 - 2.38 (m, 4H), 2.34 (s, 3H). 62

¹ H NMR (300 MHz, Chloroform- d ) δ 8.55 (d, J = 8.7 Hz, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 7.85 (s, 1H) ), 7.05 (d, J = 1.9 Hz, 1H), 7.04 (dd, J =8.7, 1.9 Hz, 1H), 4.50 - 4.65 (m, 1H), 3.95 (s, 3H), 3.50 - 3.85 (m, 4H), 2.37 - 2.52 (m, 4H), 2.34 (s, 3H), 1.59 (d, J = 6.7 Hz, 6H). 63

¹ H NMR (300 MHz, Chloroform- d ) δ 8.66 (s, 1H), 8.59 (d, J = 8.2 Hz, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H) ), 7.07 (d, J = 1.9 Hz, 1H), 7.05 (dd, J =8.2, 1.9 Hz, 1H), 4.57 (m, J = 6.7 Hz, 1H), 3.97 (s, 3H), 3.60 - 3.80 (m, 8H), 1.58 (d, J = 6.7 Hz, 6H). 64

¹ H NMR (400 MHz, Chloroform- d ) δ 8.56 (d, J = 8.2 Hz, 1H), 8.40 (s, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 7.85 (s, 1H) ), 7.06 (d, , J = 1.8 Hz, 1H), 7.05 (dd, , J = 8.2, 1.8 Hz, 1H), 4.53 - 4.65 (m, 1H), 3.96 (s, 3H), 3.88 - 3.48 ( m, 4H), 2.69 - 2.79 (m, 1H), 2.45 - 2.65 (m, 4H), 1.59 (d, J = 6.7 Hz, 6H), 1.07 (d, J = 6.5 Hz, 6H). 65

¹ H NMR (300 MHz, Chloroform- d ) δ 8.67 (s, 1H), 8.48 (d, J = 12.1 Hz, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 8.08 (s, 1H) ), 6.95 (d, J = 5.9 Hz, 1H), 4.50 - 4.65 (m, 1H), 3.94 (s, 3H), 3.75 - 3.85 (m, 4H), 3.60 - 3.70 (m, 2H), 3.40 - 3.50 (m, 2H), 1.58 (d, J = 6.7 Hz, 6H). 66

¹ H NMR (300 MHz, Chloroform- d ) δ 8.67 (d, J = 8.6 Hz, 1H), 8.41 (s, 1H), 8.40 (s, 1H), 8.37 (s, 1H), 8.02 (s, 1H) ), 7.65 (dd, J = 8.6, 1.8 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 4.52 - 4.67 (m, 1H), 4.03 - 4.12 (m, 2H), 4.00 (s, 3H), 3.47 - 3.65 (m, 3H), 1.67 - 2.02 (m, 5H), 1.60 (d, J = 6.7 Hz, 6H). 67

¹ H NMR (300 MHz, Chloroform- d ) δ 8.57 (d, J = 8.6 Hz, 1H), 8.39 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 7.97 (s, 1H) ), 7.63 (dd, J = 8.6, 1.9 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.73 - 3.82 (m, 2H) , 3.47 - 3.57 (m, 2H), 2.32 - 2.43 (m, 2H), 1.65 - 1.77 (m, 2H), 1.54 (s, 3H). 68

¹ H NMR (400 MHz, Chloroform- d ) δ 8.59 (d, J = 8.4 Hz, 1H), 8.41 (s, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 7.97 (s, 1H) ), 7.63 (dd, J = 8.4, 2.0 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 4.53 - 4.66 (m, 1H), 3.99 (s, 3H), 3.72 - 3.83 (m, 2H), 3.48 - 3.59 (m, 2H), 2.33 - 2.43 (m, 2H), 1.67 - 1.77 (m, 2H), 1.60 (d, J = 6.6 Hz, 6H), 1.54 (s, 3H). 69

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.42 (d, J = 12.0 Hz, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.88 (s, NH) , 6.92 (d, J = 6.0 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.78 - 3.82 (m, 4H), 3.66 - 3.70 (m, 2H), 3.42 - 3.46 (m) , 2H). 70

¹ H NMR (300 MHz, CDCl3) δ 8.53 (d, J = 8.7 Hz, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 8.33 (s, 1H), 7.83 (s, 1H), 7.00 - 7.06 (m, 2H), 4.56 (m, 1H), 3.93 (s, 3H), 2.83 (br s, 2H), 1.58 - 1.96 (m, 3H), 1.51 - 1.57 (m, 8H), 1.22 - 1.43 (m, 3H), 1.19 (s, 6H). 71

¹ H NMR (300 MHz, CDCl3) δ 8.54 (d, J = 8.7 Hz, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 6.98 - 7.04 (m, 2H), 4.57 (m, 1H), 4.47 (s, 4H), 3.93 (s, 3H), 3.54 (s, 4H), 1.84 - 1.97 (m, 4H), 1.57 (d, J = 6.7 Hz, 6H). 72

¹ H NMR (300 MHz, CDCl ₃ ) d 7.92(s, 1H), 7.36-7.53(m, 7H), 7.30(s, 1H), 6.54(s, 1H), 4.83(t, J = 6.6 Hz, 1H), 4.54 (s, 1H), 4.10 to 4.17 (m, 1H), 3.59 to 3.67 (m, 2H), 2.74 to 2.86 (m, 2H), 1.37 (d, J = 6.6 Hz, 3H). 73

¹ H NMR (300 MHz, CDCl3) δ 8.56 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 8.4, 1.8 Hz, 1H), 4.57 (m, 1H), 4.00 - 4.40 (m, 4H), 3.96 (s, 3H), 3.74 (t, J = 4.6 Hz, 4H), 3.19 (m, 1H), 2.38 - 2.40 (m, 4H), 1.58 (d, J = 6.7 Hz, 6H). 74

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.51 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 7.82 (s, 1H) , 7.01 (d, J = 1.9 Hz, 1H), 6.89 (dd, J = 8.4, 1.9 Hz, 1H), 4.58 (m, 1H), 4.44 (s, 2H), 3.95 (s, 3H), 3.86 - 3.90 (m, 2H), 3.62 - 3.80 (m, 4H), 1.58 (d, J = 6.6 Hz, 6H). 75

¹ H NMR (300 MHz, Chloroform- d ) δ 8.64 (d, J = 8.5 Hz, 1H), 8.40 (s, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 8.00 (s, 1H) ), 7.63 (dd, J = 8.5, 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 4.59 (m, 1H), 3.98 (s, 3H), 2.94 - 3.05 (m, 2H) , 2.73 (m, 1H), 2.30 - 2.44 (m, 2H), 1.82 - 1.99 (m, 4H), 1.59 (d, J = 6.7 Hz, 6H), 1.10 (d, J = 6.6 Hz, 6H). 76

¹ H NMR (300 MHz, Chloroform- d ) δ 8.53 (d, J = 8.7 Hz, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.87 (s, 1H) ), 6.98 - 7.08 (m, 2H), 4.58 (m, 1H), 3.74 - 4.06 (m, 5H), 3.29 - 3.53 (m, 6H), 1.80 - 1.99 (m, 2H), 1.52 - 1.71 (m) , 2H), 1.58 (d, J = 6.6 Hz, 6H). 77

¹ H NMR (300 MHz, Chloroform- d ) δ 8.54 (d, J = 8.7 Hz, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.86 (s, 1H) ), 7.01 - 7.06 (m, 2H), 4.58 (m, 1H), 3.94 (s, 3H), 3.48 - 3.76 (m, 8H), 1.49 - 1.68 (m, 8H), 1.58 (d, J = 6.6 Hz, 6H). 78

¹ H NMR (300 MHz, Chloroform- d ) δ 8.58 (d, J = 8.1 Hz, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 7.89 (s, 1H) ), 7.02 - 7.08 (m, 2H), 4.58 (m, 1H), 3.96 (s, 3H), 3.59 - 3.76 (m, 6H), 3.47 - 3.56 (m, 2H), 2.14 (s, 3H), 1.58 (d, J = 6.6 Hz, 6H). 79

¹ H NMR (300 MHz, Chloroform- d ) δ 8.56 (d, J = 8.7 Hz, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.88 (s, 1H) ), 7.00 - 7.06 (m, 2H), 4.57 (m, 1H), 4.30 - 4.68 (m, 2H) 3.95 (s, 3H), 3.10 (m, 1H), 2.91 - 3.04 (m, 2H), 2.88 (s, 3H), 2.12 - 2.26 (m, 2H), 1.74 - 1.94 (m, 2H), 1.58 (d, J = 6.7 Hz, 6H). 80

¹ H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 7.89 (s, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 8.4, 1.9 Hz, 1H), 6.07 (d, J = 7.8 Hz, 1H), 4.58 (m, 1H), 4.20 (m, 1H) ), 3.98 - 4.03 (m, 5H), 3.50 - 3.59 (m, 2H), 1.97 - 2.05 (m, 2H), 1.57 - 1.59 (m, 8H). 81

¹ H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 7.87 (s, 1H), 7.17 - 7.20 (m, 2H), 4.58 (m, 1H), 3.95 (s, 3H), 3.63 - 3.90 (m, 3H), 3.42 (m, 1H), 2.71 (m, 1H), 2.31 (s, 3H), 2.23 (s, 4H), 1.74 - 2.02 (m, 3H), 1.58 (d, J = 6.7 Hz, 6H). 82

¹ H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 7.89 (s, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 1H), 6.26 (br s, 1H), 4.58 (m, 1H), 3.98 (s, 3H), 2.91 (m, 1H), 1.59 (d, J = 6.7 Hz, 6H), 0.85 - 0.91 (m, 2H), 0.59 - 0.67 (m, 2H). 83

¹ H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 8.5 Hz, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.20 (dd, J = 8.5, 1.8 Hz, 1H), 4.73 (br s, 1H), 4.57 (m, 3H), 4.02 - 4.32 (m, 2H), 3.96 (s, 3H), 2.95 (m, 1H), 1.59 (d, J = 6.7 Hz, 6H). 84

¹ H NMR (300 MHz, Chloroform- d ) δ 8.60 (dd, J = 8.8, 2.2 Hz, 1H), 8.37 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 7.89 (s) , 1H), 6.98 - 7.11 (m, 2H), 4.57 (m, 1H), 4.06 - 4.22 (m, 4H), 3.96 (s, 3H), 2.97 - 3.21 (m, 4H), 1.57 (d, J) = 6.7 Hz, 6H). 85

¹ H NMR (300 MHz, Chloroform- d ) δ 8.57 (d, J = 8.6 Hz, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 7.85 (s, 1H) ), 7.01 - 7.08 (m, 2H), 3.95 (s, 3H), 3.58 - 3.83 (m, 4H), 2.41 - 2.54 (m, 4H), 2.36 (s, 3H), 1.67 (s, 9H). 86

¹ H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 8.2 Hz, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 7.88 (s, 1H), 7.14 - 7.21 (m, 2H), 5.03 (br s, 1H), 4.58 (m, 1H), 4.44 (m, 1H), 3.96 (s, 3H), 3.65 - 3.89 (m, 3H), 3.57 (m) , 1H), 2.18 (m, 1H), 1.88 (m, 1H), 1.64 - 1.81 (m, 3H), 1.59 (d, J = 6.7 Hz, 6H). 87

¹ H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 8.7 Hz, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 7.85 (s, 1H), 7.01 - 7.08 (m, 2H), 4.53 - 4.55 (m, 2H), 3.95 (s, 3H), 3.09 - 3.15 (m, 3H), 2.14 - 2.23 (m, 2H), 1.95 - 2.01 (m, 2H) ), 1.75 - 1.90 (m, 3H), 1.58 (d, J = 6.7 Hz, 6H), 1.42 (m, 1H). 88

¹ H NMR (300 MHz, Chloroform- d ) δ 8.56 (d, J = 8.1 Hz, 1H), 8.43 (d, J = 0.7 Hz, 1H), 8.41 (d, J = 0.7 Hz, 1H), 8.36 ( s, 1H), 7.84 (s, 1H), 7.01 - 7.07 (m, 2H), 3.95 (s, 3H), 3.57 - 3.86 (m, 4H), 2.76 (m, 1H), 2.48 - 2.64 (m, 4H), 1.66 (s, 9H), 1.08 (d, J = 6.5 Hz, 6H). 89

¹ H NMR (300 MHz, Chloroform- d ) δ 8.54 (d, J = 8.7 Hz, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.86 (s, 1H) ), 6.99 - 7.04 (m, 2H), 4.58 (m, 1H), 4.22 - 4.47 (m, 2H), 3.95 (s, 3H), 3.07 - 3.78 (m, 3H), 1.67 - 2.06 (m, 4H) ), 1.58 (d, J = 6.7 Hz, 6H). 90

¹ H NMR (300 MHz, Chloroform- d ) δ 8.57 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.91 (s, 1H) ), 7.31 (d, J = 1.8 Hz, 1H), 7.19 (dd, J = 8.4, 1.8 Hz, 1H), 4.74 - 4.88 (m, 4H), 4.58 (m, 1H), 4.27 - 4.56 (m, 4H), 3.96 (s, 3H), 1.58 (d, J = 6.7 Hz, 6H). 91

¹ H NMR (300 MHz, Chloroform- d ) δ 8.56 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.91 (s, 1H) ), 7.46 (d, J = 1.9 Hz, 1H), 7.26 (dd, J = 8.4, 1.9 Hz, 1H), 5.94 (d, J = 7.9 Hz, 1H), 4.58 (m, 1H), 3.98 (s) , 3H), 3.96 (m, 1H), 3.67 (m, 1H), 2.09 - 2.19 (m, 2H), 1.98 - 2.09 (m, 2H), 1.74 (br s, 1H), 1.59 (d, J = 6.7 Hz, 6H), 1.41 - 1.53 (m, 2H), 1.27 - 1.41 (m, 2H). 92

¹ H NMR (300 MHz, Chloroform- d ) δ 9.03 (br s, 1H), 8.46 - 8.53 (m, 3H), 8.38 (d, J = 0.7 Hz, 1H), 8.36 (d, J = 0.7 Hz, 1H), 7.82 (dd, J = 8.7, 2.3 Hz, 1H), 4.59 (m, 1H), 3.60 - 3.80 (m, 8H), 1.59 (d, J = 6.7 Hz, 6H). 93

¹ H NMR (300 MHz, Chloroform- d ) δ 8.58 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 7.90 (s, 1H) ), 7.48 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 8.4, 1.8 Hz, 1H), 6.32 (s, 1H), 4.61 (m, 1H), 4.27 (s, 1H), 4.00 (s, 3H), 2.45 (s, 6H), 2.38 (m, 1H), 1.88 - 2.05 (m, 2H), 1.64 - 1.87 (m, 6H), 1.60 (d, J = 6.7 Hz, 6H). 94

¹ H NMR (300 MHz, Chloroform- d ) δ 8.55 (d, J = 8.7 Hz, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.84 (s, 1H) ), 6.99 - 7.10 (m, 2H), 4.58 (m, 1H), 4.18 - 4.53 (m, 2H), 3.95 (s, 3H), 2.83 - 3.03 (m, 2H), 2.46 (m, 1H), 2.34 (s, 6H), 1.83 - 1.98 (m, 2H), 1.59 (d, J = 6.7 Hz, 6H), 1.41 - 1.58 (m, 2H). 95

¹ H NMR (300 MHz, Chloroform- d ) δ 8.56 (d, J = 8.2 Hz, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 7.88 (s, 1H) ), 7.16 (d, J = 1.7 Hz, 1H), 7.12 (dd, J = 8.2, 1.7 Hz, 1H), 4.67 (m, 1H), 4.58 (m, 1H), 4.20 (m, 1H), 3.96 (s, 3H), 3.74 - 3.90 (m, 2H), 3.59 - 3.73 (m, 2H), 1.86 - 2.09 (m, 4H), 1.58 (d, J = 6.7 Hz, 6H). 96

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.59 (d, J = 8.4 Hz, 1H), 8.42 (s, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 7.89 (s, 1H) , 7.46 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 1.9 Hz, 1H), 6.00 (d, J = 8.0 Hz, 1H), 3.99 - 4.05 (m, 4H), 2.86 (d, J = 11.8 Hz, 2H), 2.33 (s, 3H), 2.13 - 2.28 (m, 3H), 2.04 (s, 3H), 1.67 (s, 9H). 97

MS m/z : 458.2 [M+1] 98

¹ H NMR (300 MHz, CDCl ₃ ) d 7.92(s, 1H), 7.36-7.53(m, 7H), 7.30(s, 1H), 6.54(s, 1H), 4.83(t, J = 6.6 Hz, 1H), 4.54 (s, 1H), 4.10 to 4.17 (m, 1H), 3.59 to 3.67 (m, 2H), 2.74 to 2.86 (m, 2H), 1.37 (d, J = 6.6 Hz, 3H). 99

1H NMR (300 MHz, CDCl3) δ 8.58 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 7.90 (s, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.29 (m, 1H), 5.99 (d, J = 8.0 Hz, 1H), 4.59 (m, 1H), 3.99 - 4.02 (m, 4H), 2.84 - 2.93 ( m, 2H), 2.80 (m, 1H), 2.37 (t, J = 11.3 Hz, 2H), 2.07 - 2.11 (m, 2H), 1.58 - 1.64 (m, 8H), 1.09 (d, J = 6.5 Hz) , 6H). 100

¹ H NMR (300 MHz, Chloroform- d ) δ 8.57 (d, J = 8.3 Hz, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.90 (s, 1H) ), 7.00 - 7.08 (m, 2H), 4.57 (m, 1H), 4.18 - 4.45 (m, 2H), 4.07 (m, 1H), 3.95 (s, 3H), 3.62 (m, 1H), 2.77 - 3.03 (m, 2H), 2.63 (m, 1H), 2.37 - 2.48 (m, 2H), 2.21 (m, 1H), 1.57 (d, J = 6.7 Hz, 6H). 101

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.54 (d, J = 8.7 Hz, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 7.84 (s, 1H) , 7.05 - 7.08 (m, 2H), 4.58 (m, 1H), 3.95 (s, 3H), 3.09 (s, 6H), 1.58 (d, J = 6.6 Hz, 6H). 102

¹ H NMR (300 MHz, Chloroform- d ) δ 8.42 (d, J = 12.5 Hz, 1H), 8.38 - 8.39 (m, 2H), 8.36 (d, J = 0.7 Hz, 1H), 7.87 (s, 1H) ), 6.98 (d, J = 6.4 Hz, 1H), 4.59 (m, 1H), 4.32 - 4.66 (m, 2H), 3.94 (s, 3H), 3.65 - 3.92 (m, 2H), 2.57 - 2.91 ( m, 4H), 2.48 (s, 3H), 1.59 (d, J = 6.7 Hz, 6H). 103

¹ H NMR (300 MHz, Chloroform- d ) δ 8.51 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 7.82 (s, 1H) ), 7.00 (d, J = 1.9 Hz, 1H), 6.91 (dd, J = 8.4, 1.9 Hz, 1H), 4.57 (m, 1H), 4.33 - 4.64 (m, 2H). 3.95 (s, 3H), 3.73 - 3.87 (m, 2H), 2.62 - 2.81 (m, 2H), 2.46 - 2.60 (m, 2H), 2.42 (s, 3H), 1.59 (d, J = 6.7 Hz, 6H). 104

¹ H NMR (400 MHz, Chloroform- d ) δ 8.43 (d, J = 12.2 Hz, 1H), 8.37 (s, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 7.86 (s, 1H) ), 6.89 (d, J = 5.9 Hz, 1H), 4.57 (m, 1H), 3.91 (s, 3H), 3.76 - 3.85 (m, 2H), 3.43 (d, J = 6.0 Hz, 2H), 2.49 (t, J = 5.1 Hz, 2H), 2.39 (d, J = 5.0 Hz, 2H), 2.32 (s, 3H), 1.57 (d, J = 6.7 Hz, 6H). 105

¹ H NMR (300 MHz, CDCl3) δ 8.67 (d, J = 9.1 Hz, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 8.36 (s, 1H), 7.67 (s, 1H), 7.28 - 7.33 (m, 2H), 6.63 (t, J = 72.9 Hz, 1H), 4.59 (m, 1H), 3.50 - 3.75 (m, 8H), 1.59 (d, J = 6.7 Hz, 6H). 106

¹ H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 8.38 - 8.43 (m, 2H), 8.34 (d, J = 12.2 Hz, 1H), 7.00 (d, J = 6.4 Hz, 1H), 4.60 (p, J = 6.7 Hz, 1H), 4.45 (q, J = 4.9 Hz, 2H), 3.95 (s, 3H), 3.89 (t, J = 4.9 Hz, 2H), 3.71 - 3.83 (m, 2H) ), 3.53 - 3.70 (m, 2H), 1.59 (d, J = 6.7 Hz, 6H). 107

¹ H NMR (300 MHz, Chloroform- d ) δ 8.49 (dd, J = 8.8, 1.4 Hz, 1H), 8.40 (s, 1H), 8.36 (d, J = 0.7 Hz, 1H), 8.34 (d, J) = 0.7 Hz, 1H), 7.68 (s, 1H), 7.33 (dd, J = 8.8, 7.2 Hz, 1H), 4.58 (m, 1H), 3.78 - 3.90 (m, 2H), 3.35 - 3.48 (m, 2H), 2.48 - 2.58 (m, 2H), 2.39 - 2.47 (m, 2H), 2.35 (s, 3H), 1.58 (d, J = 6.7 Hz, 6H). 108

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.64 - 8.71 (m, 1H), 8.39 (s, 1H), 8.37 (d, J = 0.7 Hz, 1H), 8.35 (d, J = 0.7 Hz, 1H) , 7.63 (s, 1H), 7.30 - 7.33 (m, 2H), 6.63 (t, J = 73.0 Hz, 1H), 4.59 (m, 1H), 3.73 - 3.90 (m, 4H), 2.41 - 2.60 (m) , 4H), 2.39 (s, 3H), 1.59 (d, J = 6.7 Hz, 6H). 109

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 8.24 (m, 1H), 8.12 (m, 1H), 7.32 (m, 1H), 7.03 (br s, 1H), 4.57 (m, 1H), 3.60 - 3.79 (m, 4H), 2.45 - 2.50 (m, 4H), 2.36 (s, 6H), 1.57 (d, J = 6.7 Hz, 6H). 110

¹ H NMR (500 MHz, Chloroform- d ) δ 8.45 (d, J = 12.3 Hz, 1H), 8.38 (d, J = 0.7 Hz, 1H), 8.38 (s, 1H), 8.35 (d, J = 0.7 Hz, 1H), 7.89 (d, J = 1.4 Hz, 1H), 6.90 (d, J = 5.9 Hz, 1H), 4.88 (m, 1H), 4.58 (m, 1H), 3.93 (s, 3H), 3.86 (m, 1H), 2.99 - 3.18 (m, 2H), 2.80 (m, 1H), 2.62 (s, 6H), 2.19 (m, 1H), 2.10 (m, 1H), 1.62 - 1.74 (m, 2H), 1.58 (d, J = 6.7 Hz, 6H). 111

¹ H NMR (500 MHz, Chloroform- d ) δ 8.45 (d, J = 12.3 Hz, 1H), 8.38 (d, J = 0.7 Hz, 1H), 8.38 (s, 1H), 8.35 (d, J = 0.7 Hz, 1H), 7.89 (d, J = 1.4 Hz, 1H), 6.90 (d, J = 5.9 Hz, 1H), 4.88 (m, 1H), 4.58 (m, 1H), 3.93 (s, 3H), 3.86 (m, 1H), 2.99 - 3.18 (m, 2H), 2.80 (m, 1H), 2.62 (s, 6H), 2.19 (m, 1H), 2.10 (m, 1H), 1.62 - 1.74 (m, 2H), 1.58 (d, J = 6.7 Hz, 6H). 112

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.60 (d, J = 8.5 Hz, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 8.38 (s, 1H), 8.24 (s, 1H) , 7.88 (s, 1H), 7.64 - 7.71 (m, 2H), 7.56 (d, J = 1.9 Hz, 1H), 7.35 - 7.47 (m, 3H), 7.15 (m, 1H), 4.60 (m. 1H) ), 4.02 (s, 3H), 1.60 (d, J = 6.7 Hz, 6H). 113

¹ H NMR (300 MHz, MeOD) δ 8.62 (d, J = 8.5 Hz, 1H), 8.57 (d, J = 0.7 Hz, 1H), 8.45 (s, 1H), 8.36 (d, J = 0.7 Hz, 1H), 7.74 (m, 1H), 7.68 (dd, J = 8.5, 2.0 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.17 - 7.28 (m, 3H), 4.66 (m, 1H) ), 4.04 (s, 3H), 1.57 (d, J = 6.7 Hz, 6H). 114

¹ H NMR (300 MHz, MeOD) δ 8.61 (d, J = 8.5 Hz, 1H), 8.56 (d, J = 0.7 Hz, 1H), 8.44 (s, 1H), 8.34 (d, J = 0.7 Hz, 1H), 7.62 - 7.70 (m, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.5, 2.0, 1H), 7.35 (m, 1H), 6.86 (m, 1H) , 4.65 (m, 1H), 4.04 (s, 3H), 1.57 (d, J = 6.7 Hz, 6H). 115

¹ H NMR (300 MHz, MeOD) δ 8.60 (d, J = 8.5 Hz, 1H), 8.57 (d, J = 0.8 Hz, 1H), 8.44 (s, 1H), 8.35 (d, J = 0.8 Hz, 1H), 7.62 - 7.73 (m, 3H), 7.60 (d, J = 2.0 Hz, 1H), 7.07 - 7.13 (m, 2H), 4.65 (m, 1H), 4.04 (s, 3H), 1.57 (d) , J = 6.7 Hz, 6H). 116

¹ H NMR (300 MHz, MeOD) δ 8.35 - 8.42 (m, 2H), 8.17 - 8.22 (m, 2H), 8.10 (d, J = 1.9 Hz, 1H), 7.97 (s, 1H), 7.89 (m , 1H), 7.35 - 7.50 (m, 4H), 4.58 (m, 1H), 3.92 (s, 3H), 2.99 (s, 3H), 2.86 (s, 3H), 1.54 (d, J = 6.7 Hz, 6H). 117

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.64 (d, J = 8.5 Hz, 1H), 8.36 - 8.46 (m, 3H), 8.13 (d, J = 19.7 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H), 7.63 - 7.72 (m, 2H), 7.54 (d, J = 1.9 Hz, 1H), 7.45 (m, 1H), 4.60 (m, 1H), 4.02 (s, 3H), 1.60 ( d, J = 6.7 Hz, 6H). 118

¹ H NMR (300 MHz, MeOD) δ 8.31 - 8.40 (m, 2H), 8.10 - 8.20 (m, 2H), 7.34 - 7.48 (m, 3H), 7.26 (m, 1H), 7.01 - 7.16 (m, 2H), 4.46 - 4.64 (m, 3H), 3.84 (d, J = 2.2 Hz, 3H), 1.50 (dd, J = 6.8, 2.2 Hz, 6H). 119

¹ H NMR (300 MHz, MeOD) δ 8.48 - 8.54 (m, 2H), 8.37 (s, 1H), 8.30 (s, 1H), 7.48 - 7.57 (m, 2H), 7.34 (m, 1H), 7.18 (m, 1H), 7.11 m, 1H), 6.98 (m, 1H), 4.55 - 4.68 (m, 3H), 3.97 (s, 3H), 1.55 (d, J = 6.7 Hz, 6H). 120

¹ H NMR (300 MHz, MeOD) δ 8.50 - 8.59 (m, 2H), 8.42 (s, 1H), 8.33 (s, 1H), 7.50 - 7.59 (m, 2H), 7.34 - 7.45 (m, 2H) , 7.06 (t, J = 8.8 Hz, 2H), 4.65 (m, 1H), 4.56 (s, 2H), 4.00 (s, 3H), 1.56 (d, J = 6.7 Hz, 6H). 121

¹ H NMR (300 MHz, MeOD) δ 8.57 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 0.7 Hz, 1H), 8.37 (s, 1H), 8.31 (d, J = 0.7 Hz, 1H), 7.65 (dd, J = 8.5, 2.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.16 - 7.37 (m, 4H), 4.63 (m, 1H), 4.00 (s, 3H) ), 2.32 (s, 3H), 1.55 (d, J = 6.7 Hz, 6H). 122

¹ H NMR (300 MHz, MeOD) δ 8.48 - 8.54 (m, 2H), 8.33 (s, 1H), 8.28 (d, J = 0.7 Hz, 1H), 7.58 (dd, J = 8.5, 2.0 Hz, 1H) ), 7.45 - 7.54 (m, 3H), 7.22 (t, J = 7.8 Hz, 1H), 6.96 (m, 1H), 4.61 (m, 1H), 3.98 (s, 3H), 2.35 (d, J = 0.8 Hz, 3H), 1.55 (d, J = 6.7 Hz, 6H). 123

¹ H NMR (300 MHz, MeOD) δ 8.32 - 8.37 (m, 2H), 8.15 (d, J = 0.7 Hz, 1H), 8.14 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.5, 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.12 (m, 1H), 7.08 - 7.11 (m , 1H), 4.53 (m, 1H), 3.86 (s, 3H), 2.29 (s, 3H), 1.50 (d, J = 6.7 Hz, 6H). 124

¹ H NMR (300 MHz, MeOD) δ 8.50 - 8.52 (m, 2H), 8.36 (s, 1H), 8.30 (d, J = 0.7 Hz, 1H), 7.49 - 7.57 (m, 2H), 7.28 - 7.30 (m, 1H), 7.13 - 7.20 (m, 3H), 4.56 - 4.68 (m, 3H), 3.97 (s, 3H), 2.38 (s, 3H), 1.55 (d, J = 6.7 Hz, 6H). 125

¹ H NMR (300 MHz, MeOD) δ 8.49 - 8.59 (m, 2H), 8.42 (s, 1H), 8.34 (d, J = 0.7 Hz, 1H), 7.51 - 7.60 (m, 2H), 7.04 - 7.26 (m, 4H), 4.54 - 4.73 (m, 4H), 4.01 (s, 3H), 2.35 (d, J = 0.8 Hz, 3H), 1.57 (d, J = 6.7 Hz, 6H). 126

¹ H NMR (300 MHz, MeOD) δ 8.36 - 8.44 (m, 2H), 8.21 (d, J = 1.1 Hz, 2H), 7.38 - 7.48 (m, 2H), 7.20 - 7.28 (m, 2H), 7.08 - 7.16 (m, 2H), 4.48 - 4.62 (m, 3H), 3.88 (s, 3H), 2.30 (s, 3H), 1.51 (d, J = 6.7 Hz, 6H). 127

¹ H NMR (300 MHz, MeOD) δ 8.54 - 8.60 (m, 2H), 8.42 (s, 1H), 8.34 (d, J = 0.7 Hz, 1H), 7.56 - 7.65 (m, 2H), 7.46 - 7.52 (m, 2H), 6.81 (d, J = 9.1 Hz, 2H), 4.65 (m, 1H), 4.03 (s, 3H), 2.93 (s, 6H), 1.57 (d, J = 6.7 Hz, 6H) . 128

¹ H NMR (300 MHz, MeOD) δ 8.47 - 8.52 (m, 2H), 8.33 (s, 1H), 8.27 (d, J = 0.7 Hz, 1H), 7.66 - 7.72 (m, 2H), 7.47 - 7.56 (m, 4H), 4.54 - 4.69 (m, 3H), 3.95 (s, 3H), 1.54 (d, J = 6.7 Hz, 6H). 129

¹ H NMR (400 MHz, MeOD) δ 8.60 - 8.50 (m, 2H), 8.43 (s, 1H), 8.33 (s, 1H), 7.58 - 7.51 (m, 2H), 7.27 - 7.19 (m, 2H) , 7.19 - 7.13 (m, 2H), 4.65 (p, J = 6.7 Hz, 1H), 4.01 (s, 3H), 3.39 - 3.33 (m, 2H), 3.03 (dd, J = 15.8, 6.9 Hz, 2H) ), 1.56 (d, J = 6.7 Hz, 6H). 130

¹ H NMR (300 MHz, MeOD) δ 8.45 - 8.50 (m, 2H), 8.32 (s, 1H), 8.27 (d, J = 0.7 Hz, 1H), 7.44 - 7.46 (m, 2H), 4.61 (m) , 1H), 3.96 (s, 3H), 3.70 - 3.93 (m, 3H), 3.62 (m, 1H), 3.38 - 3.42 (m, 2H), 2.60 (m, 1H), 2.08 (m, 1H), 1.72 (m, 1H), 1.55 (d, J = 6.7 Hz, 6H) 131

¹ H NMR (300 MHz, MeOD) δ 8.61 (d, J = 8.5 Hz, 1H), 8.57 (d, J = 0.7 Hz, 1H), 8.44 (s, 1H), 8.34 (d, J = 0.7 Hz, 1H), 8.18 (m, 1H), 8.00 (m, 1H), 7.59 - 7.69 (m, 2H), 7.36 (t, J = 9.0 Hz, 1H), 4.65 (m, 1H), 4.05 (s, 3H) ), 1.57 (d, J = 6.7 Hz, 6H). 132

¹ H NMR (300 MHz, MeOD) δ 8.60 (d, J = 8.5 Hz, 1H), 8.56 (d, J = 0.7 Hz, 1H), 8.42 (s, 1H), 8.34 (d, J = 0.7 Hz, 1H), 7.93 (m, 1H), 7.57 - 7.68 (m, 2H), 7.17 - 7.27 (m, 2H), 4.65 (m, 1H), 4.03 (s, 3H), 1.57 (d, J = 6.7 Hz) , 6H). 133

¹ H NMR (300 MHz, MeOD) δ 8.41 - 8.49 (m, 2H), 8.31 (s, 1H), 8.27 (d, J = 0.7 Hz, 1H), 7.51 (m, 1H), 7.40 - 7.46 (m , 3H), 7.01 - 7.10 (m, 2H), 5.25 (q, J = 7.1 Hz, 1H), 4.60 (m, 1H), 3.93 (s, 3H), 1.57 (d, J = 7.1 Hz, 3H) , 1.54 (d, J = 6.7 Hz, 6H). 134

¹ H NMR (300 MHz, MeOD) δ 8.46 - 8.48 (m, 2H), 8.30 (s, 1H), 8.26 (d, J = 0.7 Hz, 1H), 7.37 - 7.53 (m, 3H), 6.88 - 7.02 (m, 2H), 4.56 - 4.65 (m, 3H), 3.93 (s, 3H), 1.54 (d, J = 6.7 Hz, 6H). 135

¹ H NMR (300 MHz, MeOD) δ 8.55 - 8.57 (m, 2H), 8.41 (s, 1H), 8.33 (d, J = 0.7 Hz, 1H), 7.51 - 7.60 (m, 2H), 6.93 - 7.01 (m, 2H), 6.83 (m, 1H), 4.56 - 4.70 (m, 3H), 4.00 (s, 3H), 1.56 (d, J = 6.7 Hz, 6H). 136

¹ H NMR (300 MHz, Chloroform- d ) δ 8.81 (d, J = 8.7 Hz, 1H), 8.75 (dd, J = 4.5, 1.4 Hz, 1H), 8.47 (dd, J = 8.4, 1.4 Hz, 1H) ), 8.44 (s, 1H), 8.42 (d, J = 0.7 Hz, 1H), 8.39 (d, J = 0.7 Hz, 1H), 8.24 (s, 1H), 8.05 (dd, J = 8.6, 1.9 Hz) , 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.47 (dd, J = 8.4, 4.5 Hz, 1H), 4.61 (m, 1H), 4.05 (s, 3H), 2.80 (s, 3H) , 1.60 (d, J = 6.7 Hz, 6H). 137

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.34 - 8.40 (m, 2H), 8.18 (s, 1H), 8.18 (s, 1H), 7.37 - 7.44 (m, 2H), 4.56 (m, 1H) ), 4.22 (m, 1H), 3.90 (s, 3H), 1.52 (d, J = 6.7 Hz, 6H), 1.27 (d, J = 6.6 Hz, 6H). 138

¹ H NMR (500 MHz, Methanol- d ₄ ) δ 8.43 (s, 1H), 8.41 (d, J = 8.3 Hz, 1H), 8.25 (s, 1H), 7.41 - 7.45 (m, 2H), 4.59 ( m, 1H), 3.92 (s, 3H), 3.74 (t, J = 5.9 Hz, 2H), 3.52 (t, J = 5.9 Hz, 2H), 1.54 (d, J = 6.7 Hz, 6H). 139

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.52 (d, J = 0.7 Hz, 1H), 8.48 (d, J = 8.7 Hz, 1H), 8.37 (s, 1H), 8.30 (d, J = 0.7 Hz, 1H), 7.00 - 7.06 (m, 2H), 4.63 (m, 1H), 3.96 (s, 3H), 3.34 - 3.62 (m, 4H), 1.55 (d, J = 6.7 Hz, 6H), 1.16 - 1.31 (m, 6H). 140

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.34 - 8.40 (m, 2H), 8.18 (s, 2H), 7.36 - 7.41 (m, 2H), 4.57 (m, 1H), 3.89 (s, 3H) ), 3.55 - 3.59 (m, 4H), 3.40 (s, 3H), 1.53 (d, J = 6.7 Hz, 6H). 141

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.47 (d, J = 0.7 Hz, 1H), 8.44 (d, J = 8.2 Hz, 1H), 8.30 (s, 1H), 8.26 (d, J = 0.7 Hz, 1H), 7.13 (s, 1H), 7.09 (dd, J = 8.2, 1.8 Hz, 1H), 4.61 (m, 1H), 3.94 (s, 3H), 3.47 - 3.88 (m, 4H), 3.13 (s, 3H), 1.53 (d, J = 6.7 Hz, 6H). 142

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.37 - 8.50 (m, 2H), 8.28 (s, 1H), 8.25 (s, 1H), 6.93 - 7.09 (m, 2H), 4.60 (m, 1H) ), 3.93 (s, 3H), 2.92 (s, 3H), 1.53 (d, J = 6.7 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H). 143

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.46 - 8.52 (m, 2H), 8.34 (s, 1H), 8.29 (s, 1H), 7.02 - 7.09 (m, 2H), 4.63 (m, 1H) ), 3.96 (s, 3H), 3.73 (m, 1H), 2.94 - 3.13 (m, 2H), 2.96 (s, 1H), 2.35 (s, 3H), 1.73 - 2.09 (m, 6H), 1.56 ( d, J = 6.7 Hz, 6H). 144

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.30 (d, J = 0.7 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 0.7 Hz, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.59 (s, 1H), 7.30 - 7.40 (m, 2H), 4.52 (m, 1H), 3.83 (s, 6H), 1.50 (d, J = 6.7 Hz, 6H). 145

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.41 - 8.46 (m, 2H), 8.25 (s, 1H), 8.22 (d, J = 0.7 Hz, 1H), 8.04 (d, J = 0.8 Hz, 1H), 7.67 (d, J = 0.8 Hz, 1H), 7.51 (dd, J = 8.5, 2.0 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 4.58 (m, 1H), 4.50 ( m, 1H), 3.93 (s, 3H), 1.53 (d, J = 10.1 Hz, 6H), 1.50 (d, J = 6.7 Hz, 6H). 146

¹ H NMR (300 MHz, Chloroform- d ) δ 8.54 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 8.34 (s, 2H), 7.96 (s, 1H), 7.49 (s, 1H) ), 7.23 - 7.38 (m, 5H), 6.62 (s, 1H), 4.61 (d, J = 6.0 Hz, 2H), 4.56 (m, 1H), 3.96 (s, 3H), 1.57 (d, J = 6.6 Hz, 6H). 147

¹ H NMR (300 MHz, Chloroform- d ) δ 8.54 (d, J = 8.5 Hz, 1H), 8.35 (s, 1H), 8.33 (s, 2H), 7.94 (s, 1H), 7.49 (d, J) = 1.9 Hz, 1H), 7.30 - 7.37 (m, 2H), 7.17 - 7.27 (m, 3H), 6.71 (t, J = 6.0 Hz, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.56 (m, 1H), 3.95 (s, 3H), 1.57 (d, J = 6.7 Hz, 6H). 148

¹ H NMR (300 MHz, Chloroform- d ) δ 8.55 (d, J = 8.5 Hz, 1H), 8.36 (s, 1H), 8.34 (s, 2H), 7.94 (s, 1H), 7.43 - 7.51 (m) , 2H), 7.30 - 7.40 (m, 2H), 7.19 - 7.28 (m, 2H), 6.75 (t, J = 6.0 Hz, 1H), 4.72 (d, J = 6.0 Hz, 2H), 4.57 (m, 1H), 3.95 (s, 3H), 1.57 (d, J = 6.7 Hz, 6H). 149

¹ H NMR (300 MHz, Chloroform- d ) δ 8.67 (d, J = 8.5 Hz, 1H), 8.58 (dd, J = 8.3, 1.5 Hz, 1H), 8.49 (s, 1H), 8.43 (s, 1H) ), 8.42 (s, 1H), 8.40 (s, 1H), 8.19 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.5, 2.0 Hz, 1H), 7.43 (dd, J = 8.0, 1.5 Hz, 1H), 7.35 (m, 1H), 7.07 (m, 1H), 4.60 (m, 1H), 4.04 (s, 3H), 1.60 (d, J = 6.7 Hz, 6H). 150

¹ H NMR (300 MHz, Chloroform- d ) δ 8.57 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 0.7 Hz, 1H), 8.37 (d, J = 0.7 Hz, 1H), 8.34 ( s, 1H), 8.07 (s, 1H), 8.04 (s, 1H), 7.81 (t, J = 2.0 Hz, 1H), 7.53 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.50 (d , J = 1.9 Hz, 1H), 7.41 (dd, J = 8.4, 1.9 Hz, 1H), 7.28 (m, 1H), 7.11 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 4.59 (m, 1H), 3.97 (s, 3H), 1.59 (d, J = 6.7 Hz, 6H). 151

¹ H NMR (300 MHz, Chloroform- d ) δ 8.59 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.37 (s, 1H), 8.36 (s, 1H), 8.04 (s, 1H) ), 8.01 (s, 1H), 7.60 - 7.66 (m, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.4, 2.0 Hz, 1H), 7.30 - 7.37 (m, 2H), 4.59 (m, 1H), 3.98 (s, 3H), 1.59 (d, J = 6.7 Hz, 6H). 152

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.31 (s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.25 - 8.31 (m, 2H), 7.56 - 7.65 (m, 2H), 7.11 (t, J = 8.0 Hz, 1H), 6.72 - 6.77 (m, 2H), 6.62 (ddd , J = 8.1, 2.4, 1.1 Hz, 1H), 4.67 (m, 1H), 4.42 (d, J = 5.9 Hz, 2H), 3.94 (s, 3H), 1.48 (d, J = 6.6 Hz, 6H) . 153

¹ H NMR (300 MHz, Chloroform- d ) δ 8.48 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.29 (s, 1H), 7.88 (s, 1H) ), 7.44 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 8.4, 1.8 Hz, 1H), 7.13 - 7.20 (m, 2H), 6.78 - 6.87 (m, 2H), 6.74 (t, J = 5.5 Hz, 1H), 4.55 (m, 1H), 4.52 (d, J = 6.0 Hz, 2H), 3.87 (s, 3H), 1.55 (d, J = 6.7 Hz, 6H). 154

¹ H NMR (400 MHz, MeOD) δ 8.59 - 8.53 (m, 2H), 8.45 (s, 1H), 8.35 (s, 1H), 7.59 - 7.53 (m, 2H), 7.31 - 7.21 (m, 2H) , 6.98 (d, J = 8.1 Hz, 1H), 6.92 (td, J = 7.5, 1.1 Hz, 1H), 4.65 (p, J = 6.7 Hz, 1H), 4.59 (s, 2H), 4.02 (s, 3H), 3.89 (s, 3H), 1.56 (d, J = 6.7 Hz, 6H). 155

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.50 (ddd, J = 5.0, 1.8, 0.9 Hz, 1H), 8.46 (d, J = 9 Hz, 1H), 8.44 (s, 1H), 8.27 ( s, 1H), 8.24 (s, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.52 (dd, J = 8.5, 2.0 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H) ), 7.44 (dt, J = 7.9, 1.0 Hz, 1H), 7.31 (ddd, J = 7.6, 5.0, 1.2 Hz, 1H), 4.69 (s, 2H), 4.59 (m, 1H), 3.92 (s, 3H), 1.53 (d, J = 6.7 Hz, 6H). 156

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.54 - 8.58 (m, 1H), 8.41 (dd, J = 4.9, 1.6 Hz, 1H), 8.26 - 8.31 (m, 2H), 8.10 (s, 1H) ), 8.05 (s, 1H), 7.30 - 7.42 (m, 3H), 4.56 (s, 2H), 4.50 (m, 1H), 3.79 (s, 3H), 1.48 (d, J = 6.7 Hz, 6H) . 157

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.43 - 8.49 (m, 2H), 8.35 (d, J = 8.6 Hz, 1H), 8.32 (s, 1H) 8.12 (s, 1H), 8.10 (s) , 1H), 7.35 - 7.45 (m, 4H), 4.58 (s, 2H), 4.52 (m, 1H), 3.83 (s, 3H), 1.49 (d, J = 6.7 Hz, 6H). 158

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.96 (s, 0.5H), 8.72 - 8.14 (m, 5H), 7.87 (dd, J = 8.6, 1.9 Hz, 0.5H), 7.77 - 7.26 (m) , 4H), 7.06 - 6.72 (m, 1H), 4.83 - 4.52 (m, 1H), 4.05 - 3.70 (m, 3H), 1.54 - 1.38 (m, 6H). 159

¹ H NMR (400 MHz, MeOD) δ 8.65 (d, J = 8.6 Hz, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 7.84 (dd, J = 8.6) , 1.9 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.68 - 6.45 (m, 3H), 4.66 (p, J = 6.7 Hz, 1H) ), 4.03 (s, 3H), 1.57 (d, J = 6.7 Hz, 6H). 160

¹ H NMR (300 MHz, MeOD) δ 8.65 - 8.58 (m, 2H), 8.46 (s, 1H), 8.37 (d, J = 0.7 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.48 (d , J = 8.8 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 4.67 (p, J = 6.7 Hz, 1H), 4.06 (s, 3H), 1.59 (d, J = 6.7 Hz, 6H) ). 161

¹ H NMR (300 MHz, MeOD) δ 8.63 (d, J = 9.0 Hz, 1H), 8.58 (d, J = 0.7 Hz, 1H), 8.46 (s, 1H), 8.37 (d, J = 0.7 Hz, 1H), 8.00 (dd, J = 7.9, 1.6 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.18 (ddd, J = 8.3, 7.4, 1.6 Hz, 1H), 7.08 (dd, J = 8.3, 1.5 Hz, 1H), 6.99 (td, J = 7.6, 1.5 Hz, 1H), 4.67 (p, J = 6.7 Hz, 1H), 4.05 (s, 3H), 3.94 (s, 3H), 1.57 (d, J = 6.7 Hz, 6H). 162

¹ H NMR (300 MHz, MeOD) δ 8.66 - 8.55 (m, 2H), 8.45 (s, 1H), 8.36 (s, 1H), 7.66 (dd, J = 8.5, 2.0 Hz, 1H), 7.61 (d , J = 2.0 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.29 - 7.22 (m, 2H), 6.77 - 6.66 (m, 1H), 4.66 (p, J = 6.7 Hz, 1H), 4.05 ( s, 3H), 3.82 (s, 3H), 1.57 (d, J = 6.7 Hz, 6H). 163

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (d, J = 8.4 Hz, 1H), 8.44 - 8.40 (m, 2H), 8.38 (s, 1H), 8.18 (s, 1H), 7.78 (s, 1H), 7.60 - 7.52 (m, 3H), 7.43 (dd, J = 8.5, 1.9 Hz, 1H), 6.92 (d, J = 9.0 Hz, 2H), 4.60 (p, J = 6.7 Hz, 1H), 4.01 (s, 3H), 3.82 (s, 3H), 1.60 (d, J = 6.7 Hz, 6H). 164

¹ H NMR (400 MHz, MeOD) δ 8.60 -8.55 (m, 2H), 8.47 (s, 1H), 8.37 (s, 1H), 7.63 -7.55 (m, 2H), 7.38 - 7.19 (m, 4H) , 5.70 (t, J = 7.9 Hz, 1H), 4.67 (hept, J = 6.5 Hz, 1H), 4.04 (s, 3H), 3.19 - 3.04 (m, 1H), 3.04 - 2.86 (m, 1H), 2.70 - 2.55 (m, 1H), 2.14 - 1.94 (m, 1H), 1.58 (d, J = 6.7 Hz, 6H). 165

¹ H NMR (400 MHz, CDCl3) δ 8.25 - 8.17 (m, 3H), 7.54 (d, J = 1.6 Hz, 1H), 7.37 (dd, J = 7.3, 1.8 Hz, 1H), 7.32 - 7.26 (m) , 3H), 6.99 - 6.89 (m, 2H), 6.67 (t, J = 5.9 Hz, 1H), 4.65 (d, J = 5.8 Hz, 2H), 4.52 (h, J = 6.6 Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.44 (s, 3H), 1.54 (d, J = 6.7 Hz, 6H). 166

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.56 (d, J = 8.4 Hz, 1H), 8.32 - 8.37 (m, 3H), 7.88 (s, 1H), 7.47 (d, J = 1.9 Hz, 1H) , 7.29 (dd, J = 8.4, 2.0 Hz, 1H), 6.02 (d, J = 7.8 Hz, 1H), 4.40 - 4.65 (m, 2H), 3.97 (s, 3H), 2.03 (dd, J = 12.6) , 3.7 Hz, 2H), 1.58 (d, J = 6.7 Hz, 6H), 1.35 (s, 6H), 1.24 (s, 9H). 167

¹ H NMR (300 MHz, MeOD) δ 8.60 (t, J = 4.1 Hz, 2H), 8.48 (s, 1H), 8.38 (s, 1H), 7.54 (d, J = 9.5 Hz, 2H), 4.68 ( m, 1H), 4.05 (s, 3H), 2.65 - 2.69 (s, 3H), 1.73 - 1.77 (m, 3H), 1.60 (s, 3H), 1.58 (s, 3H), 1.13 (d, J = 6.2 Hz, 6H). 168

¹ H NMR (300 MHz, MeOD) δ 8.48 - 8.50 (m, 2H), 8.38 (dd, J = 2.5, 0.7 Hz, 1H), 8.34 (s, 1H), 8.28 (d, J = 0.7 Hz, 1H) ), 7.83 (dd, J = 8.4, 2.5 Hz, 1H), 7.46 - 7.52 (m, 2H), 7.43 (dd, J = 8.4, 0.7 Hz, 1H), 4.55 - 4.67 (m, 3H), 3.95 ( s, 3H), 1.55 (d, J = 6.7 Hz, 6H). 169

¹ H NMR (300 MHz, MeOD) δ 8.22 - 8.55 (m, 5H), 7.70 (m, 1H), 7.34 - 7.42 (m, 2H), 6.80 - 6.90 (m, 2H), 4.61 (m, 1H) , 3.86 - 3.98 (m, 5H), 3.03 - 3.22 (m, 5H), 1.53 (d, J = 6.7 Hz, 6H). 170

¹ H NMR (300 MHz, MeOD) δ 8.31 - 8.40 (m, 2H), 8.11 - 8.19 (m, 2H), 7.64 (t, J = 2.2 Hz, 1H), 7.25 - 7.55 (m, 4H), 6.85 (m, 1H), 4.54 (m, 1H), 3.88 (s, 3H), 1.51 (d, J = 6.7 Hz, 6H). 171

¹ H NMR (300 MHz, MeOD) δ 8.59 (d, J = 8.5 Hz, 1H), 8.56 (d, J = 0.7 Hz, 1H), 8.43 (s, 1H), 8.34 (d, J = 0.7 Hz, 1H), 7.65 (dd, J = 8.5, 2.0 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.49 - 7.57 (m, 2H), 7.27 (t, J = 7.8 Hz, 1H), 7.00 (dt, J = 7.9, 1.2 Hz, 1H), 4.65 (m, 1H), 4.04 (s, 3H), 2.67 (q, J = 7.6 Hz, 2H), 1.57 (d, J = 6.7 Hz, 6H) ), 1.27 (t, J = 7.6 Hz, 3H). 172

¹ H NMR (300 MHz, MeOD) δ 8.58 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 0.7 Hz, 1H), 8.37 (s, 1H), 8.32 (d, J = 0.7 Hz, 1H), 7.66 (dd, J = 8.5, 2.0 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.22 - 7.37 (m, 4H), 4.60 (m, 1H), 4.00 (s, 3H) ), 2.71 (q, J = 7.6 Hz, 2H), 1.56 (d, J = 6.7 Hz, 6H), 1.18 - 1.26 (m, 3H). 173

¹ H NMR (300 MHz, MeOD) δ 8.45 (dd, J = 9.1, 2.0 Hz, 2H), 8.20 - 8.29 (m, 2H), 7.44 - 7.60 (m, 4H), 7.16 (dd, J = 8.5, 2.4 Hz, 2H), 4.58 (m, 1H), 3.94 (s, 3H), 2.54 - 2.68 (m, 2H), 1.48 - 1.58 (m, 6H), 1.20 - 1.25 (m, 3H). 174

¹ H NMR (300 MHz, MeOD) δ 8.40 - 8.50 (m, 2H), 8.36 (s, 1H), 8.29 (s, 1H), 7.35 (dd, J = 20.3, 6.5 Hz, 5H), 7.12 (dd , J = 8.3, 1.7 Hz, 2H), 4.55 - 4.80 (m, 3H), 3.87 (d, J = 55.9 Hz, 3H), 3.02 (s, 3H), 1.54 (d, J = 6.7 Hz, 6H) . 175

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.42 - 8.54 (m, 2H), 8.36 (s, 1H), 8.29 (s, 1H), 7.27 (t, J = 7.5 Hz, 1H), 6.98 - 7.22 (m, 5H), 4.68 (s, 2H), 4.62 (m, 1H), 3.72 (d, J = 55.0 Hz, 3H), 3.01 (s, 3H), 2.35 (s, 3H), 1.54 (d) , J = 6.7 Hz, 6H). 176

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.30 8.37 (m, 2H), 8.16 (s, 1H), 8.15 (s, 1H), 7.31 7.37 (m, 2H), 4.56 (m, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.63 (t, J = 6.9 Hz, 2H), 2.80 (s, 3H), 2.66 (t, J = 6.9 Hz, 2H), 1.52 (d, J = 6.7 Hz, 6H), 1.26 (t, J = 7.1 Hz, 3H). 177

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.60 (s, 1H), 8.52 (s, 1H), 8.20 - 8.32 (m, 3H), 7.29 - 7.39 (m, 4H), 7.23 (m, 1H) ), 7.04 - 7.13 (m, 2H), 4.66 (m, 1H), 4.59 (s, 2H), 4.19 (s, 1H), 3.88 (s, 3H), 1.47 (d, J = 6.6 Hz, 6H) , 1.12 (d, J = 6.3 Hz, 6H). 178

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.39 - 8.43 (m, 2H), 8.21 (s, 1H), 8.20 (s, 1H), 7.50 (dd, J = 8.5, 2.0 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.38 (m, 1H), 7.18 - 7.22 (m, 2H), 6.66 (m, 1H), 4.51 - 4.63 (m, 2H), 3.90 (s, 3H) , 1.52 (d, J = 6.7 Hz, 6H), 1.32 (d, J = 6.1 Hz, 6H). 179

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.47 - 8.51 (m, 2H), 8.34 (s, 1H), 8.29 (s, 1H), 7.53 (dd, J = 8.5, 2.0 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.40 - 7.45 (m, 2H), 7.29 - 7.37 (m, 2H), 7.23 (m, 1H), 4.61 (m, 1H), 3.94 (s, 3H) , 1.59 (d, J = 7.1 Hz, 3H), 1.55 (d, J = 6.7 Hz, 6H). 180

¹ H NMR (500 MHz, Methanol- d ₄ ) δ 8.39 - 8.43 (m, 2H), 8.22 (s, 1H), 8.20 (s, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.90 ( dt, J = 8.1, 1.3 Hz, 1H), 7.46 - 7.53 (m, 2H), 7.45 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 4.57 (m, 1H) ), 3.92 (s, 3H), 1.53 (d, J = 6.7 Hz, 6H). 181

¹ H NMR (500 MHz, Methanol- d ₄ ) δ 8.56 (d, J = 8.5 Hz, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.60 - 7.65 (m, 3H), 7.57 (d, J = 1.9 Hz, 1H), 4.61\3 (m, 1H), 4.01 (s, 3H), 1.56 (d) , J = 6.7 Hz, 6H). 182

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.45 - 8.51 (m, 2H), 8.32 (s, 1H), 8.28 (s, 1H), 7.52 (dd, J = 8.5, 1.9 Hz, 1H), 7.38 - 7.46 (m, 3H), 7.29 - 7.37 (m, 2H), 7.23 (m, 1H), 5.00 (m, 1H), 4.60 (m, 1H), 3.92 (s, 3H), 1.86 - 2.02 ( m, 3H), 1.54 (d, J = 6.7 Hz, 6H), 1.00 (t, J = 7.3 Hz, 3H). 183

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.33 - 8.41 (m, 2H), 8.16 - 8.21 (m, 2H), 7.34 - 7.44 (m, 2H), 7.08 - 7.17 (m, 2H), 6.65 - 6.75 (m, 2H), 4.55 (m, 1H), 4.43 (s, 2H), 3.86 (s, 3H), 1.51 (d, J = 6.7 Hz, 6H). 184

¹ H NMR (300 MHz, MeOD) δ 8.45 (d, J = 8.5 Hz, 1H), 8.42 (d, J = 0.7 Hz, 1H), 8.24 (s, 1H), 8.22 (d, J = 0.7 Hz, 1H), 7.44 - 7.60 (m, 3H), 6.97 - 7.09 (m, 2H), 4.58 (m, 1H), 3.93 (s, 3H), 2.32 (d, J = 0.9 Hz, 3H), 1.53 (d , J = 6.7 Hz, 6H). 185

¹ H NMR (300 MHz, MeOD) δ 8.60 (d, J = 8.5 Hz, 1H), 8.56 (s, 1H), 8.43 (d, J = 0.7 Hz, 1H), 8.34 (s, 1H), 7.50 - 7.68 (m, 3H), 6.99 - 7.09 (m, 2H), 4.65 (m, 1H), 4.03 (s, 3H), 2.37 (s, 3H), 1.56 (dd, J = 6.7, 0.7 Hz, 6H) . 186

¹ H NMR (300 MHz, MeOD) δ 8.64 (d, J = 8.5 Hz, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.32 (dd, J = 8.7) , 5.4 Hz, 1H), 6.92 - 7.11 (m, 2H), 4.61 - 4.72 (m, 2H), 4.05 (s, 3H), 2.31 (s, 3H), 1.57 (d, J = 6.7 Hz, 6H) . 187

¹ H NMR (300 MHz, MeOD) δ 8.54 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 0.7 Hz, 1H), 8.37 (s, 1H), 8.30 (d, J = 0.7 Hz, 1H), 7.52 - 7.62 (m, 3H), 7.32 (dd, J = 8.3, 2.1 Hz, 1H), 7.11 - 7.22 (m, 1H), 4.63 (m, 1H), 4.01 (s, 3H), 2.23 (d, J = 1.8 Hz, 3H), 1.56 (d, J = 6.7 Hz, 6H). 188

¹ H NMR (300 MHz, MeOD) δ 8.64 (d, J = 8.5 Hz, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 7.70 (dd, J = 8.5 , 1.9 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.16 - 7.29 (m, 2H), 7.02 (t, J = 9.0 Hz, 1H), 4.65 (q, J = 6.7 Hz, 2H) ), 4.05 (s, 3H), 2.21 (d, J = 2.2 Hz, 3H), 1.57 (d, J = 6.7 Hz, 6H). 189

¹ H NMR (300 MHz, MeOD) δ 8.53 - 8.62 (m, 2H), 8.47 (d, J = 7.5 Hz, 1H), 8.30 (m, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.48 - 7.62 (m, 4H), 4.66 (d, J = 3.2 Hz, 2H), 4.60 (d, J = 6.6 Hz, 1H), 4.02 (s, 3H), 1.57 (d, J = 6.7 Hz, 6H) ). 190

¹ H NMR (300 MHz, MeOD) δ 8.43 - 8.48 (m, 2H), 8.27 (s, 1H), 8.24 (d, J = 0.7 Hz, 1H), 7.76 (t, J = 2.1 Hz, 1H), 7.54 (dd, J = 8.5, 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.42 (ddd, J = 8.1, 2.0, 1.0 Hz, 1H), 7.30 (t, J = 8.1 Hz) , 1H), 7.01 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 4.60 (m, 1H), 3.94 (s, 3H), 3.02 (s, 3H), 1.54 (d, J = 6.7 Hz, 6H). 191

¹ H NMR (300 MHz, MeOD) δ 8.64 (d, J = 8.5 Hz, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.37 (d, J = 1.5 Hz, 2H), 7.92 ( ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.64 - 7.73 (m, 3H), 7.55 (t, J = 8.0 Hz, 1H), 4.65 (m, 1H), 4.07 (s, 3H), 1.57 (d, J = 6.7 Hz, 6H). 192

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.55 (d, J = 8.4 Hz, 1H), 8.35 - 8.46 (m, 3H), 8.18 (s, 1H), 7.45 (d, J = 1.9 Hz, 1H) , 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 7.00 (t, J = 6.0 Hz, 1H), 4.55 - 4.67 (m, 1H), 3.94 - 4.07 (m, 6H), 3.38 (t, J = 5.8 Hz, 2H), 3.01 (s, 4H), 1.59 (d, J = 6.7 Hz, 6H). 193

¹ H NMR (300 MHz, Chloroform- d ) δ 8.58 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 0.7 Hz, 1H), 8.35 (s, 1H), 8.34 (d, J = 0.7 Hz, 1H), 7.96 (s, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.4, 1.9 Hz, 1H), 6.65 (d, J = 8.6 Hz, 1H), 4.77 (dd, J = 8.6, 5.0 Hz, 1H), 4.57 (m, 1H), 3.97 (s, 3H), 3.78 (s, 3H), 2.28 (m, 1H), 1.58 (d, J = 6.7 Hz) , 6H), 1.01 (dd, J = 6.9, 5.8 Hz, 6H). 194

¹ H NMR (300 MHz, Chloroform- d ) δ 8.57 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 8.33 (s, 1H), 7.94 (s, 1H) ), 7.46 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.4, 1.9 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 4.80 (dd, J = 8.4, 5.0 Hz) , 1H), 4.57 (m, 1H), 3.95 (s, 3H), 3.77 (s, 3H), 2.01 (m, 1H), 1.57 (d, J = 6.7 Hz, 6H), 1.52 (m, 1H) , 1.23 (m, 1H), 0.96 (t, J = 7.2 Hz, 6H). 195

¹ H NMR (300 MHz, Chloroform- d ) δ 8.51 (d, J = 8.4 Hz, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 8.33 (s, 1H), 7.97 (s, 1H) ), 7.44 (d, J = 1.9 Hz, 1H), 7.39 (dd, J = 8.4, 1.9 Hz, 1H), 6.85 (t, J = 5.2 Hz, 1H), 4.59 (m, 1H), 4.20 - 4.31 (m, 4H), 3.94 (s, 3H), 1.58 (d, J = 6.7 Hz, 6H), 1.31 (t, J = 7.1 Hz, 3H). 196

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.54 (d, J = 0.7 Hz, 1H), 8.50 (m, 1H), 8.39 (s, 1H), 8.32 (d, J = 0.7 Hz, 1H) , 7.44 (d, J = 7.4 Hz, 2H), 6.99 - 7.05 (m, 2H), 6.66 - 6.73 (m, 2H), 4.64 (m, 1H), 3.98 (s, 3H), 3.49 - 3.58 (m) , 2H), 2.80 (t, J = 7.4 Hz, 2H), 1.56 (d, J = 6.7 Hz, 6H). 197

¹ H NMR (300 MHz, Chloroform- d ) δ 8.50 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 8.30 (s, 1H), 8.29 (s, 1H), 7.85 (s, 1H) ), 7.59 (s, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.37 (dd, J = 8.5, 1.8 Hz, 1H), 7.22 (s, 1H), 7.00 (d, J = 12.5 Hz) , 2H), 4.54 (m, 1H), 4.04 (t, J = 6.8 Hz, 2H), 3.90 (s, 3H), 3.43 (q, J = 6.4 Hz, 2H), 2.04 - 2.16 (m, 2H) , 1.55 (d, J = 6.7 Hz, 6H). 198

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.34 - 8.40 (m, 2H), 8.18 (s, 1H), 8.18 (s, 1H), 7.37 - 7.44 (m, 2H), 4.56 (m, 1H) ), 4.22 (m, 1H), 3.90 (s, 3H), 1.52 (d, J = 6.7 Hz, 6H), 1.27 (d, J = 6.6 Hz, 6H). 199

¹ H NMR (300 MHz, Chloroform- d ) δ 8.54 (d, J = 8.5 Hz, 1H), 8.36 (s, 1H), 8.33 (s, 1H), 8.33 (s, 1H), 7.92 (s, 1H) ), 7.44 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.5, 1.9 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 4.85 (m, 1H), 4.57 (m) , 1H), 3.93 (s, 3H), 3.77 (s, 3H), 1.64 - 1.83 (m, 3H), 1.57 (d, J = 6.7 Hz, 6H), 0.98 (dd, J = 6.0, 4.0 Hz, 6H). 200

¹ H NMR (300 MHz, Chloroform- d ) δ 8.50 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 8.34 (s, 1H), 7.91 (s, 1H) ), 7.18 - 7.27 (m, 2H), 4.66 (m, 1H), 4.58 (m, 1H), 3.92 (s, 3H), 3.76 (s, 3H), 3.72 (m, 2H), 2.31 (m, 1H), 1.84 - 2.09 (m, 4H), 1.57 (d, J = 6.7 Hz, 6H). 201

¹ H NMR (300 MHz, MeOD) δ 8.39 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.52 (dd, J = 8.1) , 1.9 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.7 Hz, 2H), 6.93 - 6.87 (m, 2H), 4.66 - 4.52 (m, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 3.44 (s, 3H), 1.51 (d, J = 6.7 Hz, 6H). 202

¹ H NMR (300 MHz, MeOD) δ 8.60 - 8.46 (m, 2H), 8.42 (s, 1H), 8.33 (s, 1H), 7.07 (d, J = 6.2 Hz, 2H), 4.65 (p, J) = 6.7 Hz, 1H), 3.98 (s, 3H), 3.70 - 3.36 (m, 2H), 3.07 (s, 3H), 1.23 (m, 3H). 203

¹ H NMR (400 MHz, MeOD) δ 8.53 (d, J = 7.5 Hz, 2H), 8.40 (s, 1H), 8.32 (s, 1H), 7.58 - 7.46 (m, 2H), 7.30 (d, J) = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.64 (hept, J = 6.8 Hz, 1H), 4.52 (s, 2H), 3.99 (s, 3H), 3.77 (s, 3H) ), 1.56 (d, J = 6.6 Hz, 6H). 204

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.47 (s, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 7.53 (dd, J = 8.5, 1.9 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.30 (s, 2H), 4.56 (s, 1H), 3.96 (s, 3H), 3.70 (s, 3H), 2.26 (s, 6H), 1.54 (d, J = 6.7 Hz, 6H). 205

¹ H NMR (300 MHz, Methanol- d ₄ ) δ 8.32 (dd, J = 4.6, 3.9 Hz, 2H), 8.14 (s, 1H), 8.11 (s, 1H), 7.39 (m, 1H), 7.36 ( m, 1H), 7.06 (t, J = 7.7 Hz, 1H), 6.74 (t, J = 2.0 Hz, 1H), 6.69 (m, 1H), 6.62 (m, 1H), 4.51 (m, 1H), 4.46 (s, 2H), 3.81 (s, 3H), 1.49 (d, J = 6.7 Hz, 6H). 206

¹ H NMR (300 MHz, MeOD) δ 8.63 - 8.55 (m, 2H), 8.45 (s, 1H), 8.36 (s, 1H), 7.71 - 7.53 (m, 3H), 7.38 (dd, J = 8.0, 2.0 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 4.66 (p, J = 6.7 Hz, 1H), 4.04 (s, 3H), 2.91 (q, J = 7.8 Hz, 4H), 2.10 (p, J = 7.4 Hz, 2H), 1.57 (d, J = 6.7 Hz, 6H). 207

¹ H NMR (300 MHz, MeOD) δ 8.67 - 8.56 (m, 2H), 8.47 (s, 1H), 8.37 (s, 1H), 7.71 - 7.61 (m, 2H), 7.26 - 7.13 (m, 3H) , 4.67 (p, J = 6.7 Hz, 1H), 4.05 (s, 3H), 3.04 - 2.85 (m, 4H), 2.16 - 2.04 (m, 2H), 1.57 (d, J = 6.7 Hz, 6H). 208

¹ H NMR (300 MHz, MeOD) δ 8.40 (s, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 7.61 - 7.49 (m, 2H), 7.33 (d, J = 8.1 Hz, 1H) ), 7.29 - 7.13 (m, 4H), 4.93 - 4.77 (m, 1H), 4.59 (p, J = 6.6 Hz, 1H), 3.82 (s, 3H), 3.44 (s, 3H), 3.37 (dd, J = 15.9, 7.8 Hz, 2H), 3.04 (dd, J = 15.8, 6.8 Hz, 2H), 1.51 (d, J = 6.7 Hz, 6H). 209

¹ H NMR (400 MHz, MeOD) δ 8.39 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.55 (dd, J = 8.1) , 1.9 Hz, 1H), 7.37 - 7.17 (m, 5H), 5.69 (t, J = 7.8 Hz, 1H), 4.59 (p, J = 6.7 Hz, 1H), 3.83 (s, 3H), 3.45 (s) , 3H), 3.17 - 3.04 (m, 1H), 2.98 - 2.88 (m, 1H), 2.66 - 2.55 (m, 1H), 2.11 - 2.00 (m, 1H), 1.52 (d, J = 6.7 Hz, 6H) ). 210

¹ H NMR (300 MHz, MeOD) δ 8.57 - 8.46 (m, 2H), 8.42 (s, 1H), 8.34 (s, 1H), 7.11 - 7.06 (m, 2H), 4.73 - 4.48 (m, 2H) , 3.98 (s, 3H), 3.27 - 2.67 (m, 4H), 2.63 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 1.89 (br s, 2H), 1.61 - 1.41 (m, 8H), 1.11 (t, J = 7.2 Hz, 2H). 211

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.18 (s, 1H), 8.52 (s, 1H), 8.31 (s, 1H), 8.08 (br s, 01), 8.01 (d, J = 8.7 Hz) , 1H), 7.72 (s, 1H), 7.65 - 7.57 (m, 2H), 7.48 (dd, J = 8.7, 2.2 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 4.63 (hept, J = 6.6 Hz, 1H), 4.11 (t, J = 8.5 Hz, 2H), 3.81 (s, 3H), 3.42 (s, 2H), 3.17 (t, J = 8.5 Hz, 2H), 2.15 (s, 3H), 1.45 (d, J = 6.6 Hz, 6H). 212

¹ H NMR (300 MHz, DMSO) δ 10.05 (s, 1H), 8.64 (s, 1H), 8.57 (s, 1H), 8.45 - 8.23 (m, 3H), 8.04 - 7.95 (m, 1H), 7.74 - 7.64 (m, 2H), 7.62 (d, J = 1.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 4.68 (p, J = 6.6 Hz, 1H), 4.10 (t, J = 8.5 Hz, 2H), 3.98 (s, 3H), 3.16 (t, J = 8.5 Hz, 2H), 2.15 (s, 3H), 1.48 (d, J = 6.6 Hz, 6H) 213

¹ H NMR (300 MHz, MeOD) δ 8.63 - 8.54 (m, 2H), 8.44 (s, 1H), 8.34 (s, 1H), 7.58 - 7.50 (m, 2H), 5.43 - 5.21 (m, 1H) , 4.65 (p, J = 6.7 Hz, 1H), 4.29 - 4.05 (m, 2H), 4.02 (s, 3H), 3.03 - 2.83 (m, 2H), 1.57 (d, J = 6.7 Hz, 6H), 1.22 (t, J = 7.1 Hz, 3H). 214

¹ H NMR (300 MHz, Acetone-d6) δ 9.44 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.69 (d , J = 1.9 Hz, 1H), 7.63 (dd, J = 8.1, 1.9 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 4.62 (p, J = 6.6 Hz, 1H), 3.85 (s, 3H), 3.46 (s, 3H), 2.88 (dt, J = 10.5, 7.4 Hz, 4H), 2.14 - 2.00 ( m, 4H), 1.50 (d, J = 6.7 Hz, 6H). 215

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.95 (s, 1H), 8.52 (s, 1H), 8.31 (s, 1H), 8.09 (br s, 1H), 7.68 - 7.57 (m, 2H) , 7.42 (d, J = 8.0 Hz, 1H), 7.30 - 7.21 (m, 1H), 7.21 - 7.08 (m, 2H), 4.63 (p, J = 6.7 Hz, 1H), 3.81 (s, 3H), 3.42 (s, 3H), 2.89 (dt, J = 20.5, 7.4 Hz, 4H), 2.01 (p, J = 7.5 Hz, 2H), 1.45 (d, J = 6.6 Hz, 6H). 216

¹ H NMR (300 MHz, Chloroform- d ) δ 8.49 (d, J = 8.2 Hz, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.30 (s, 1H), 7.80 (s, 1H) ), 6.96 - 7.02 (m, 2H), 4.54 (m, 1H), 3.90 (s, 3H), 2.84 - 3.03 (m, 2H), 2.65 - 2.74 (m, 4H), 2.41 (m, 1H), 1.90 - 1.99 (m, 2H), 1.78 - 1.86 (m, 4H), 1.56 - 1.69 (m, 2H), 1.54 (d, J = 6.7 Hz, 6H). 217

¹ H NMR (300 MHz, Chloroform- d ) δ 8.47 (d, J = 8.7 Hz, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.76 (s, 1H) ), 6.91 - 6.98 (m, 2H), 4.52 (m, 1H), 3.86 (s, 3H), 2.47 - 3.05 (m, 8H), 1.73 - 1.95 (m, 2H), 1.45 - 1.63 (m, 6H) ), 1.50 (d, J = 6.7 Hz, 6H), 1.33 - 1.45 (m, 3H). compare
compound 1

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.60 (d, J = 6.0 Hz, 1H), 8.51 (s, 1H), 8.02 (s, 1H), 7.90 (m, 2H), 7.55 (m, 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) compare
compound 2

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

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.81 (t, J = 2.3 Hz, 1H), 8.55 (s, 1H), 8.51 (d, J = 8.3 Hz, 1H), 8.38 (ddd, J = 8.3, 2.3, 1.0 Hz, 1H), 8.27 (dt, J = 8.0, 1.4 Hz, 1H), 8.03 (s, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 7.03 (dd, J = 8.3, 1.8 Hz, 1H), 3.97 (s, 3H), 3.60 - 3.81 (m, 8H). compare
compound
4

DNL-151 (GNE-0877), oral Parkinson's treatment compare
compound 5

DNL-201 (GNE-7915), oral Parkinson's treatment

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

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 in a 5 mL microwave vial mL and 0.2 mL of TFA, and then heated at 110°C for 12 hours. After the reaction, under reduced pressure, MC and saturated NaHCO ₃ aqueous solution were added to extract. The organic layer was dried (Mg ₂ SO ₄ ), filtered, and concentrated. The crude product was dissolved in DCM and separated by column chromatography to obtain 110 mg (31% yield) of the title compound as a white solid.

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

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

100 mg (0.26 mmol) of (4-((4,5-dichloropyrimidin-2-yl) amino)-3-methoxyphenyl)(morpholino)methanone, 3-(4,4,5,5- After adding tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 48.5 mg (0.236 mmol), _{0.35 mL (0.7 mmol) of 2M Na 2} CO ₃ solution, and 2 mL of dioxane, degassed twice and then Pd(PPh) ₃ ) _{After adding 23 mg (0.02 mmol) of 4,} degassing once more, and stirring at 110° C. for 12 hours. After Celite filter, ethyl acetate and water were added, and the extracted organic layer was dried (Mg ₂ SO ₄ ), filtered, and concentrated. The crude product was dissolved in DCM and separated by column chromatography to obtain 67.3 mg (0.158 mmol, 67% yield) of the title compound. obtained as a white solid.

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

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

100 mg (0.26 mmol) of (4-((4,5-dichloropyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone, 4,4,5,5-tetramethyl-2 in a 5 mL microwave vial -(3-nitrophenyl)-1,3,2-dioxaborolane 58.8 mg (0.236 mmol), 2M Na ₂ CO ₃ solution 0.35 mL (0.7 mmol), dioxane 2 mL, degassed twice, and then Pd(PPh ₃ ) ₄ After adding 23 mg (0.02 mmol), degassing one more time, and stirring at 110 ℃ for 12 hours. After Celite filter, ethyl acetate and water were added, and the extracted organic layer was dried (Mg ₂ SO ₄ ), filtered and concentrated. The crude product was dissolved in DCM and separated by column chromatography to obtain 65.3 mg (0.139 mmol, 59% yield) of the title compound. obtained as a white solid.

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

<Example 2. Confirmation of LRRK2 inhibitory activity>

The inhibitory activity against LRRK2 wild type and LRRK2 (G2019S) mutant type was confirmed using the representative compound of the present invention synthesized in Example 1, and the results are shown in Tables 2 and 3. Specifically, the T7 phage strain to which the human-derived wild type kinase of LRRK2 (Accession no. NP_940980.3) or the mutation kinase mutated to G2019S, consisting of the amino acid sequence of amino acids H970 to E2527, was attached to E. Simultaneously grown in a coli host, E. coli was grown in log-phase, infected with T7 phage (multiplicity of infection = 0.4), and then incubated with shaking at 32°C for 90-150 minutes. Thereafter, the lysates of E. coli were centrifuged (6,000 x g) and filtered through a 0.2 μm filter, and then kinases were produced in HEK-293 cells and DNA was attached, resulting in DNA for qPCR detection. -Completed with tagged kinase. Affinity resins for kinase assay were prepared as streptavidin-coated magnetic beads treated with biotinylated small molecule ligands for 30 min at room temperature, and then liganded beads were treated with excess biotin. (blocking) with (biotin), washing with blocking buffer (SeaBlock (Pierce), 1 % BSA, 0.05 % Tween 20, 1 mM DTT) to remove unbound ligand, non-specific phage binding was made to decrease. After that, kinase and ligand-affinity beads and compounds prepared in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT) (10, 50 or 100 nM; concentration used are specified in Table 2 below) was mixed to a final volume of 0.02 ml in a polypropylene 384-well plate, 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, 0.5 μM non-biotinylated affinity ligand). Incubated with shaking for 30 minutes at room temperature. Thereafter, the concentration of each kinase of LRRK2 wild type and LRRK2 (G2019S) mutation type in the eluted sample was measured by qPCR, and the activity value was expressed as a % value (% of ctrl) compared to the control. In the activity evaluation, the commercially available compound was used to make 40x stock with 100% DMSO, and was used in a direct dilution method during the analysis process.

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

Looking at Tables 2 and 3, it was confirmed that the pyrimidine derivative of the present invention is a substance having LRRK2 inhibitory activity. In particular, in the structural formula of Formula 1, R ₄ substituted with a pyrimidine group is a pyrazole group, and R ₅ is a halogen or haloalkyl. In the case of the compound, it can be confirmed that the LRRK2 protein inhibitory activity at a concentration of 50 nM is very superior to that of the compound having other substituents.

<Example 3. Confirmation of blood-brain barrier (BBB) permeability>

The test substance was prepared at a dose of 10 mg/kg, and immediately after the animal was sacrificed 3 hours after oral administration, blood was collected from the heart and centrifuged to prepare a plasma sample. To remove the blood remaining in the body, the brain was extracted after cardiac perfusion using 20ml of saline containing 10U/ml heparin. It was homogenized by adding PBS buffer 3 times the weight of brain tissue. LC-MS/MS (Agilent, Santa Clara, CA, USA) was used for quantitative analysis in the prepared plasma and brain tissue. Separation of the material in LC was performed using a mobile phase composed of 20% water containing 80% acetonitrile and 0.1% formic acid. The total run time per substance was 3 minutes and the flow rate was 0.3 ml/min. For quantification of each substance, multiple reaction detection method (Comparative Compound-4 and Comparative Compound-5 used oral Parkinson's drugs DNL-151 and DNL-201 as LRRK2 protein inhibitors, respectively) was used.

Compound 37, a representative example of the present invention, had an effective concentration of the drug in brain tissue 3 hours after oral administration compared to Comparative Compound-4 (DNL-151) and Comparative Compound-5 (DNL-201), respectively. 1.64 times and 2.77 times excellent results were obtained.

It can be seen that it is effective in neurodegenerative diseases including Parkinson's disease and cancer.

_{From these results, when R 4} substituted with a pyrimidine group in the structural formula of Formula 1 of the present invention is a pyrazole group and R ₅ is a halogen or haloalkyl, the compound has excellent LRRK2 protein inhibitory effect as well as an effect of passing through the blood-brain barrier. It can be seen that it can be very usefully used for the prevention or treatment of degenerative diseases and cancer.

<Formulation Example 1. Preparation of powder>

Compound 37 of the present invention ((4-((5-chloro-4-(1-isopropyl- 1H -pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(don't know Polyno) methanone) 2 g and lactose 1 g were mixed and filled in an airtight bag to prepare a powder.

<Formulation Example 2. Preparation of tablets>

Compound 37 of the present invention ((4-((5-chloro-4-(1-isopropyl- 1H -pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(don't know Polyno) methanone) 100 mg, microcrystalline cellulose 100 mg, lactose hydrate 60 mg, low-substituted hydroxypropyl cellulose 20 mg, and magnesium stearate 2 mg were mixed, and then tableted according to a conventional tablet manufacturing method to obtain tablets. prepared.

<Formulation Example 3. Preparation of capsules>

Compound 37 of the present invention ((4-((5-chloro-4-(1-isopropyl- 1H -pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(don't know Polyno) methanone) 100 mg, microcrystalline cellulose 100 mg, lactose hydrate 60 mg, low-substituted hydroxypropyl cellulose 20 mg, and magnesium stearate 2 mg were mixed, and then the above components were prepared according to a conventional capsule preparation method. The mixture was mixed and filled into gelatin capsules to prepare capsules.

<Formulation Example 4. Preparation of Pills>

Compound 37 of the present invention ((4-((5-chloro-4-(1-isopropyl- 1H -pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(don't know Polino) methanone) 90 mg, glutinous rice starch 5 mg and purified water 5 mg, and dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as an additive to inhibit hygroscopicity were mixed in small amounts, followed by 100 mg according to a conventional method. made a pill of

<Formulation Example 5. Preparation of injection>

Compound 37 of the present invention ((4-((5-chloro-4-(1-isopropyl- 1H -pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(don't know Polyno) methanone) 10 mg, an appropriate amount of sterile distilled water for injection, and an appropriate amount of a pH adjuster were mixed, and the content of the above ingredients per 1 ampoule (2 ml) was prepared according to a conventional method for preparing an injection.

Claims (6)

A compound represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

R′ is substituted with a _{C 1} -C ₆ alkoxy or halo C ₁ -C _{6 alkoxy substituent;}
R ₁ is substituted with hydrogen, halogen, hydroxy, cyano, amino, amide, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or halo C ₁ -C ₆ alkoxy;
R ₂ is substituted with substituted or unsubstituted pyrazol-4yl,
wherein said substituted pyrazol-4yl is halogen, hydroxy, cyano, amino, amide, nitro, C ₁ -C ₆ alkylsulfonyl, acetyl, methyloxycarbonyl, substituted or unsubstituted C ₁ -C ₆ alkyl , substituted or unsubstituted benzyl, substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₂ heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₂ aryl, or substituted or substituted with one or more substituents selected from the group consisting of unsubstituted C ₄ -C _{12 heteroaryl,}
again wherein said substituted alkyl, benzyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ heterocycloalkyl, C ₆ -C ₁₂ aryl, C ₄ -C ₁₂ heteroaryl are halogen, hydroxy, cyano, amino , amide, 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 substituted with a halogen or halo C ₁ -C ₆ alkyl substituent;
R ₄ may be represented by the following B-1 to B-30,

R ₆ is independently selected from the group consisting of hydrogen, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkylsulfonate, or C ₁ -C ₆ alkylamino substituted with one or more substituents;
R ₇ is independently substituted with one or more substituents selected from the group consisting of hydrogen, halogen, halo C ₁ -C ₆ alkyl, or C ₁ -C _{6 alkyl;}
R ₈ is independently hydrogen, halogen, amino, hydroxy, cyano, C ₁ -C ₆ dialkylamino, aminosulfonyl, C ₁ -C ₆ alkylsulfonamino, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyloxy, or C ₁ -C ₆ alkoxy substituted with one or more substituents;
R ₉ is 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 1} selected from the group consisting of -C ₆ alkylamino, C ₁ -C ₆ alkoxy, morpholine, piperidine, pyrrolidine, oxetanyl, piperidine substituted with C 1 -C _{6 alkyl, or acetate} substituted with one or more substituents;
R ₁₀ is independently substituted with one or more substituents selected from the group consisting of hydrogen, C ₁ -C _{6 alkyl, phenyl, oxetanyl, or acetate;}
R ₁₁ is combined with hydrogen or R ₁₀ and is substituted with a saturated or unsaturated C ₅ -C _{6 heterocycloalkyl substituent;}
R ₁₂ is hydrogen or C ₁ -C ₆ 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 alkyl;
Ak is C ₁ -C ₆ alkyl;
k is independently 0, 1, or 2, wherein k is not simultaneously 0;
l is independently 1 or 2;
m is 0, 1, 2, 3, or 4;
n is independently 0 or 1,
W is independently C, CH or N;
Y is a substituent selected from the group consisting of O or S; and
Z is substituted with O or SO _{2 ;}
A compound represented by Formula 1, characterized in that it is an optical isomer or a pharmaceutically acceptable salt thereof. According to claim 1,
The compound of Formula 1 is
(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound One);
(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidine- 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)(morphopoly no)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)(mor polyno)methanone (compound 8);
methyl 2-(4-(5-chloro-2-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazole-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-(pyridin-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 11);
(4-((5-chloro-4-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 12);
(4-((5-chloro-4-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 13);
(4-((5-chloro-4-(1-phenyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (compound 14);
(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-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 17);
(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-methylpiperazine) -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-methoxy Phenyl)(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-methoxy ethyl)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)(morphopoly no)methanone (Compound 28);
(3-methoxy-4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-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-isopropylpiperazine-1 -yl)methanone (Compound 34);
(4-((5-chloro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy Phenyl)(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)pyridin-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-methylpiperidine-4 -yl)benzamide (Compound 38);
(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(2-hydroxypropane -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-difluoropyr peridin-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-morpholinoazetidine- 1-yl)methanone (Compound 43);
1-(4-(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzoyl)piperazine-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-phenyl piperazin-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)(morphopoly no)methanone (Compound 49);
(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-(oxetane-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)methane on (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-methylpiperidine- 4-yl)benzamide (Compound 60);
(4-((5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazine-1- I) methanone (Compound 61);
(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazine-1 -yl)methanone (Compound 62);
(4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morphopoly no)methanone (Compound 63);
(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-isopropylpiperazine- 1-yl)methanone (Compound 64);
(2-fluoro-4-((4-(1-isopropyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxy Phenyl)(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-hydroxy propan-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-aza spiro[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-(oxetane-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-morpholinoazetidine -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-isopropylpiperidine -4-yl)methanone (Compound 75);
(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methoxypiperidine- 1-yl)methanone (Compound 76);
(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-oxa-9-aza spiro[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)piperazine- 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-hydroxyazetidine- 1-yl)methanone (Compound 83);
(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(1,1-dioxido Thiomorpholino)methanone (Compound 84);
(4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpipe Razin-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-isopropyl piperazin-1-yl)methanone (Compound 88);
((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(4-((5-chloro-4-(1-isopropyl-1H-pyrazole-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-aza spiro[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);
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)p peridin-1-yl)methanone (Compound 94);
((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(4-((5-chloro-4-(1-isopropyl-1H-pyrazole-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-methylpi peridin-4-yl)benzamide (Compound 96);
(R)-(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxyphenyl)(3-hydro Roxypyrrolidin-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-methylpiperazine-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)(morphopoly no) methanethione (Compound 106);
(4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl)(4-methyl piperazin-1-yl)methanone (Compound 108);
(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-methoxybenz amide (Compound 113);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-fluorophenyl)-3-methoxybenz amide (Compound 114);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorophenyl)-3-methoxybenz amide (Compound 115);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-cyanophenyl)-3-methoxybenz amide (Compound 116);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanophenyl)-3-methoxybenz amide (Compound 117);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenz amide (Compound 118);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2-fluorobenzyl)-3-methoxybenz amide (Compound 119);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-fluorobenzyl)-3-methoxybenz amide (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-methyl Toxybenzamide (Compound 127);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-cyanobenzyl)-3-methoxybenz amide (Compound 128);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-indene-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-methoxybenz amide (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)benz amide (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-methyl piperidin-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-pyra zol-4-yl)benzamide (Compound 144);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(1-isopropyl-1H-pyrazole-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-methoxybenz amide (Compound 152);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxybenzyl)-3-methoxybenz amide (Compound 153);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxybenzyl)benz amide (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-methoxybenz amide (Compound 158);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(3-hydroxyphenyl)-3-methoxybenz amide (Compound 159);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(4-hydroxyphenyl)-3-methoxybenz amide (Compound 160);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(2-methoxyphenyl)benz amide (Compound 161);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3-methoxyphenyl)benz amide (Compound 162);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(4-methoxyphenyl)benz amide (Compound 163);
4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-N-(2,3-dihydro-1H-indene-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-methyl benzyl)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-methoxy benzamide (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)benz amide (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)benz amide (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-methoxybenz amide (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-methyl Toxybenzamide (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)benz amide (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-indene-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-indene-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-indene-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-indene-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-indene-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-indene-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-(pyrrolidine- 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);
A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of. A pharmaceutical composition for preventing or treating neurodegenerative diseases, comprising the compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 4. The method of claim 3,
The neurodegenerative disease is Parkinson's disease, Alzheimer's disease, Huntington's disease, Pick's disease, amyotrophic axonal sclerosis, prion disease, motor neuron disease, spinal cerebellar ataxia, spinal muscular atrophy, Creutzfeldt-Jakob disease and alcoholic dementia selected from the group consisting of A pharmaceutical composition for preventing or treating neurodegenerative diseases, characterized in that. A pharmaceutical composition for preventing or treating cancer comprising the compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 6. The method of claim 5,
The cancer disease is renal cancer, thyroid cancer, breast cancer, liver cancer, a pharmaceutical composition for preventing or treating cancer, characterized in that selected from the group consisting of brain cancer.