NZ796599A - Pyrimidine compound and pharmaceutical use thereof - Google Patents

Abstract

The present invention relates to a pyrimidine compound of chemical formula 1, a method for preparing the compound, and a pharmaceutical use of the compound for the prevention or treatment of cancer.

Description

The present ion relates to a pyrimidine compound of chemical formula 1, a method for preparing the compound, and a pharmaceutical use of the compound for the prevention or treatment of cancer.

NZ 796599 PYRIMIDINE COMPOUND AND PHARMACEUTICAL USE F -Reference to Related Applications] The present ation is a onal application of New Zealand Patent Application No. 755325, the entire disclosure of which is incorporated into the present specification by this cross-reference.

[Technical Field] [0001a] The present invention is related to a novel pyrimidine compound, a method of ing the same, and a pharmaceutical use of the novel pyrimidine compound.

[Prior Art] Kinases mediate a reaction in which a phosphate group from high-energy molecules, in particular, ATP, is transferred to a substrate. Kinases ize phosphoric anhydride bonds, and locate the substrate and the phosphate group at a specific position to increase a reaction rate. In most cases, the transition state resulting from the interaction with a phosphate group having a negative charge is electrostatically stabilized through surrounding amino acids having a positive charge, and some kinases may be nated with the phosphate group through a metal cofactor.

Kinases can be classified as, for example, protein kinases, lipid kinases, and carbohydrate kinases, according to the substrate and characteristics. Proteins, lipids, or carbohydrates may vary in their activity, reactivity, ability to bind to other molecules, etc., depending on the phosphorylation state. Kinases affect ellular signal transduction and regulate x biological mechanisms within cells. Due to phosphorylation, some molecules may have enhanced or reduced activities, and their ability to interact with other molecules may be controlled. Because many kinases d to environmental conditions or signals, cells may control ellular molecules through kinases, ing on the situation. As such, kinase plays a crucial role in cell growth, differentiation, proliferation, survival, metabolism, signal transduction, cell transport, secretion, and many other cellular reaction pathways. s have been found in a variety of species including bacteria, fungi, insects, and mammals, and 500 or more kinases have been found in humans to date.

Protein s may increase or decrease the activity of a protein, become a marker for stabilization or degradation, place a protein in a specific cell compartment, or initiate or b interactions of a protein with other proteins. Protein kinases are 11498815_1 (GHMatters) P109554.NZ known to account for the majority of kinases and are ered to be an important research target. Protein kinases regulate, together with phosphatase, proteins and enzymes as well as cell signal uction. Although cell proteins are subject to numerous covalent bonds, there are not many of these reversible bonds, such as phosphorylation. Accordingly, it can be said that orylation of proteins has a regulatory function. Protein kinases may often have multiple substrates, and sometimes, a particular n may act as a substrate for at least one . For this reason, protein kinases are named using factors that regulate their activities. For example, a calmodulin-dependent protein kinase is regulated by calmodulin. In some cases, kinases may be fied as sub-groups. For example, type I and type II cyclic AMP-dependent protein kinases include cal enzyme subunits, but their regulatory subunits binding to cyclic AMP are different from each other.

A protein kinase is an enzyme that catalyzes the phosphorylation of the hydroxy group located in ne, serine, and threonine residues of proteins and plays an important role in signaling growth factors that induce cell growth, differentiation, and proliferation kova, I. et al., Nature Reviews Drug Discovery, 3 (2004), 993), and it is reported that abnormal expression or mutation of a specific kinase frequently occurs in cancer cells.

One of the ways that cells recognize external stimuli is recognition via tyrosine kinase, which is a or in the cell membrane. A receptor tyrosine kinase (RTK) consists of an extracellular part exposed to the outside of a cell, an intracellular part exposed to the intracellular cytoplasm, and a transmembrane part passing through the plasma membrane between the extracellular part and the intracellular part. The ellular part of the receptor is the part to which a specific ligand binds, and the intracellular part functions to it the activation signal of the receptor activated by the ligand into the cell. The RTK has a domain having tyrosine kinase activity at the inal region exposed in the cell, and when a specific ligand attaches to the extracellular part, the kinase enzyme of the C-terminal tyrosine kinase domain exposed to the cytoplasmic portion of the receptor protein is activated, and the two RTKs cross-phosphorylate the tyrosines at the C-termials of the neighboring RTKs.

This phosphorylation process of tyrosine is the most important process in the 11498815_1 (GHMatters) P109554.NZ transmission of signals corresponding to extracellular stimulation into cells. There are many known receptors that have ne kinase activities for transmitting extracellular stimuli into cells with this mechanism. Examples of such receptors are SRC, EGFR, IR, IGFR, c-fms, VEGFR, FGFR, AXL, CLK2, and NUAK1.

Among these, vascular endothelial growth factor receptor (VEGFR) refers to a kinase known to be ed in the regulation of angiogenesis. In particular, solid tumors require more nutrients and oxygen than normal tissues. Therefore, compared to normal states, the blood supply is an important factor when blood is insufficient.

Also, overexpression or overactivation of VEGFR induces angiogenesis, which plays an important role in angiogenesis necessary for the growth and eration of tumor cells (Kliche, S. and Waltenberger, J., Life, 52, (2002), 61). Therefore, various al s for the treatment of tumors h inhibition of angiogenesis have been med, and several promising results have been obtained. In addition, VEGF plays an ant role in blood cancer and is overexpressed in various malignant solid tumors. The overexpression of VEGF is known to have a high correlation with disease progression of malignant tumors. VEGFRs are classified according to subtypes including VEGFR-1, VEGFR-2, and VEGFR-3. VEGFR-2 (KDR) is a typical target for tumor es having VEGFR expression. Representative diseases caused by the overexpression of VEGFR-2 is lung cancer, breast cancer, non-Hodgkin's lymphoma, ovarian carcinoma, pancreatic cancer, etc. In addition to its angiogenic activity, VEGF, which is a ligand of VEGFR, may e tumor growth by a direct pro-survival effect in tumor cells (Simons, M., Gordon, E. and Claesson-Welsh, L., Nature Reviews Drug Discovery, 17, (2016), 611).

Tyrosine-protein kinase receptor UFO (AXL) kinase refers to a kinase that functions to transfer signals of extracellular substrates to the cytoplasm by binding growth factors such as vitamin ndent protein growth regulating gene 6 (GAS6) (Wu, X., et al., Oncotarget, 5, (2014), 9546). In addition, AXL kinase is heavily involved in cell proliferation and survival. AXL may mediate cell aggregation by homologous binding. AXL protein is expressed in bone marrow stroma, bone marrow cells, tumor cells, and tumor vasculature. In tumor cells, AXL is expressed not only in immune cells including dendritic cells, macrophages and NK cells, but also in tumor 11498815_1 ters) P109554.NZ cells. AXL is a component in a variety of cellular processes that plays a crucial role in the development, growth, and spread of tumors, including proliferation, invasion and migration, epithelial-mesenchymal transition, stemness, enesis, and immune modulation, is associated with oncogenes, and is associated with the survival and proliferation of various tumors including triple-negative breast cancer (TNBC), blood cancer, all cell lung cancer (NSCLC), pancreatic cancer, and n cancer (Paccez, J. et al., Int. J. Cancer, 134, (2014), 1024).

Recent research results show that NUAK1 kinase, also known as AMPK-related protein kinase 5 (ARK5), plays an ant role in regulating tumor growth and survival through metabolic changes in various carcinomas, in particular, hepatocellular carcinoma. Regarding the physiological and pathological role of NUAK in tumor and metabolic diseases, NUAK is known to act as an ant regulator of cellular physiological ties such as cell polarity and cell motility, and through interaction with a kinase associated with tivated protein kinase (AMPK), NUAK ins homeostasis for tumor growth and proliferation. Thus, a key strategy against anticancer and related diseases may be to inhibit the attainment of energy homeostasis in tumors (Sun, X et al., J Mol Endocrinol, 51, (2013), R15).

Dual specificity protein kinase (CLK2) cts with and phosphorylates a serine/arginine (SR) protein of a spliceosomal complex. The interaction and phosphorylation are part of regulatory mechanisms that allow the SR proteins to regulate RNA splicing. This protein kinase is involved as a regulator in growth processes for various tumor cells and acts as a link among cell cycle progression, apoptosis, and telomere length regulation (Araki, S., PLoS ONE, 10, (2015), e0116929).

[Prior Art Document] 1. Melnikova, I. et al., Nature Reviews Drug Discovery, 3, (2004), 993 2. Kliche, S. et al., Life, 52, (2002), 61 3. , M. et al., Nature Reviews Drug Discovery, 17, (2016), 611 4. Wu, X., et al., Oncotarget, 5, , 9546 5. Paccez, J. et al., Int. J. , 134, (2014), 1024 6. Sun, X et al., J Mol inol, 51, (2013), R15 11498815_1 (GHMatters) P109554.NZ 7. Araki, S., PLoS ONE, 10, (2015), e0116929 osure of the Invention] [Technical Goal of the Invention] In accordance with an aspect of the present invention, provided is a novel pyrimidine compound having kinase tory activity.

In accordance with another aspect of the present invention, provided is a method of preparing the pyrimidine compound.

In accordance with still another aspect of the present ion, provided is a pharmaceutical use of the pyrimidine compound.

[Means for Achieving Technical Goal] In accordance with an aspect of the present invention, provided is a nd selected from a substance of Formula 1, a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof: Formula 1 R7 R1 R6 R2 Z Y N N (R4)k R5 N wherein, in a 1, R1 is hydrogen, a halogen, a hydroxy group, or a C1-4 alkoxy group, R2 is hydrogen, a halogen, a cyano group, a nitro group, an amino group, a carboxamide group, a formyl group, a halo C1-4 alkyl group, or a C1-4 alkyl group, R3 is hydrogen, a halo C1-4 alkyl group, a C1-4 alkyl group, a C2-4 alkenyl group, or a C2-4 alkynyl group, R4(s) are each independently a halogen, a hydroxy group, a cyano group, a nitro group, an amino group, -SRc, -S(=O)Rc, -S(=O)2Rc, a halo C1-4 alkyl group, a C1-4 alkoxy group, a hydroxy C1-4 alkyl group, a C1-4 alkyl group, a C2-4 alkenyl group, a C2-4 l group, -NRaRb, -CO2Rb, or -CO-NRaRb, 11498815_1 (GHMatters) P109554.NZ wherein, Ra and Rb are each independently hydrogen or a C1-6 alkyl group, Rc is a C1-4 alkyl group or -NRaRb, k is an integer from 0 to 4, R5 and R6 are each independently hydrogen, a halogen, a hydroxy group, a nitro group, an amino group, a C1-4 alkoxy group, a hydroxy C1-4 alkyl group, a C1-4 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a C3-10 cycloalkyl group, or a C3-9 cycloalkyl group, wherein, the C3-10 cycloalkyl group and the C3-9 heterocycloalkyl group are each independently unsubstituted or substituted with a halogen, a C1-4 alkyl group, a halo C1-4 alkyl group, R7 is hydrogen, a linear or branched C1-6 alkyl group, a C3-7 cycloalkyl group, a C3-9 heterocycloalkyl group, or a C1-4 alkoxy group, Y is a direct bond, -(CH2)m-, -O-, -O(CH2)m-, -(CH2)mO-, -C(=O)-, -NR9-, -SO2-, -(CH2)m-O-(CH2)n-, -CO(CH2)m-, -(CH2)mCO-, -(CH2)m-CO-(CH2)n-, -(CH2)mNR9-, -NR9(CH2)m-, m-NR9-(CH2)n-, mSO2-, H2)m-, or -(CH2)m-SO2-(CH2)n-, wherein R9 is hydrogen, a C1-4 alkyl group, a C3-10 cycloalkyl group, or a C3-9 cycloalkyl group, and m and n are each independently an integer from 1 to 3, Z is represented by Formula 2: Formula 2 wherein, in a 2, is a C3-10 cycloalkyl group or a C2-11 heterocycloalkyl group, R10(s) are each independently a halogen, a hydroxy group, a cyano group, a nitro group, an amino group, a thiol group, a formyl group, a linear or branched halo C1-4 alkyl group, a linear or branched C1-4 alkoxy group, a linear or branched hydroxy C1-4 alkyl group, a linear or branched C1-4 alkyl group, a linear or branched hydroxy 11498815_1 (GHMatters) P109554.NZ C1-4 alkylcarbonyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a C3-10 cycloalkyl group, a C2-9 heterocycloalkyl group, a hydroxy C2-9 heterocycloalkyl group, -NR11R12, , -COOR13, or -SO2R14, R11 and R12 are each independently hydrogen, a linear or branched hydroxy C1-4 alkyl group, a linear or branched halo C1-4 alkyl group, a linear or branched C1-4 alkyl group, a C2-4 l group, or a C2-4 l group, R13 is hydrogen, a hydroxy group, a hydroxy C1-4 alkyl group, a halo C1-4 alkyl group, a C1-4 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a C3-10 cycloalkyl group, or a C2-9 heterocycloalkyl group, R14 is a hydroxyl group, a halo C1-4 alkyl group, a C1-4 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a C3-10 cycloalkyl group, a C2-9 heterocycloalkyl group, an aryl group, or -NRaRb, and q is an integer from 0 to 5.

In accordance with another aspect of the present invention, provided is a ceutical composition for prevention and treatment of cancer that may include the compound of Formula 1 as an active ingredient.

[Effect of the Invention] Because the compound of Formula 1 according to an aspect of the present invention has kinase inhibitory activity, the nd may be applicable to inhibition of kinase.

[Description of Embodiment] The present invention will be described in further detail.

Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although ary methods or als are listed herein, other similar or equivalent ones are also within the scope of the present ion. Also, the numerical values set forth herein are considered to include the meaning of " unless explicitly stated. All publications disclosed as references herein are incorporated in their entirety by reference. 11498815_1 (GHMatters) P109554.NZ In Formula 1, residues described as R1 to R15 are each used in the meaning as commonly understood by one of ordinary skill in the art.

The term "halogen", unless otherwise stated, e fluorine, chlorine, bromine, or iodine, in particular, ne or chlorine.

The term "alkyl" refers to a saturated monovalent hydrocarbon radical. The term "alkenyl" as used herein refers to a monovalent hydrocarbon radical containing at least one carbon-carbon double bond, wherein each double bond may have a steric configuration of E-form or Z-form. The term yl" as used herein refers to a monovalent arbon radical containing at least one carbon-carbon triple bond.

Such an alkyl group, an alkenyl group, and an alkynyl group may be linear, i.e., straight-chained or branched having a side chain. As defined above, the number of carbon atoms in an alkyl group may be 1, 2, 3, 4, 5, or 6; or 1, 2, 3, or 4. Examples of alkyl include methyl, ethyl, propyl including n-propyl and iso-propyl, n-butyl, sec-butyl, butyl including tyl and a tert-butyl, pentyl including n-pentyl, 1-methylbutyl, iso-pentyl, neo-pentyl, and tert-pentyl, hexyl including n-hexyl, methylbutyl, and iso-hexyl. A double bond of an alkenyl group and a triple bond of an alkynyl group may each be in any position. Examples of alkenyl and alkynyl include ethenyl, propenyl, propenyl(=allyl), butenyl, 2-methylpropenyl, ylbutenyl, hexenyl, hexenyl, propynyl(=propargyl), butynyl, butynyl, hexynyl, or hexynyl. In a case where each of the compounds is sufficiently stable and suitable for a desirable use as, for example, a pharmaceutical substance, a substituted alkyl group, a substituted alkenyl group, and a substituted alkynyl group may be substituted at any position.

The term "cycloalkyl", unless otherwise stated, refers to a substituted or unsubstituted cyclic alkyl, e.g., mono- or bicycloaliphatic group. Examples of lkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, ctyl, cyclooctenyl, 2,5-cyclohexadienyl, o[2.2.2]octyl, tyl, decahydronaphthyl group, oxo cyclohexyl, dioxo cyclohexyl, thio cyclohexyl, 2-oxo bicyclo[2.2.1]heptyl, or any suitable isomer thereof without limitation. 15_1 ters) P109554.NZ The term "heterocycloalkyl" as used herein, unless otherwise stated, refers to a single ring including at least one selected from O, N, and S, in particular, 1 to 4 heteroatoms, or alkyl, which may be tuted or unsubstituted, having at least two rings. Examples of monoheterocycloalkyl include dinyl, linyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, ydrofuranyl, diazabicycloheptanyl, diazabicyclooctanyl, pirooctanyl, and the like, but examples thereof are not limited thereto.

The term "aryl" as used , unless otherwise stated, refers to an aromatic group which may be substituted or unsubstituted, such as phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, or any suitable isomer thereof without limitation.

The term "heteroaryl" as used herein, unless otherwise stated, refers to a monocyclic or bicyclic or higher aromatic group containing at least one heteroatom selected from O, N, and S, for example, from 1 to 4 heteroatoms. Examples of clic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, azolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like, but examples thereof are not limited thereto. Examples of bicyclic heteroaryl include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl, and the like, but examples thereof are not limited thereto.

In the present specification, the numerical range ted by using the term "to" refers to a range including the numerical values described before and after the term as the lower limit and the upper limit, tively.

In an example embodiment of an aspect of the present invention, R1 in the compound of Formula 1 may be hydrogen, a C1-4 alkoxy group or a y group.

In an example embodiment, R2 in the compound of Formula 1 may be hydrogen, halogen, a C1-4 alkyl group or a halo C1-4 alkyl group.

In an e embodiment, R3 in the compound of Formula 1 may be hydrogen. 11498815_1 (GHMatters) P109554.NZ In an example embodiment, R4 in the compound of Formula 1 may be hydrogen, halogen, a hydroxy group, a C1-4 alkoxy group, a hydroxy C1-4 alkyl group or a C1-4 alkyl group.

In an example embodiment, R5 and R6 in the nd of Formula 1 may each independently be hydrogen or a hydroxy group.

In an e ment, R7 in the compound of a 1 may be a C3-7 cycloalkyl group.

In an example embodiment, Y in the compound of Formula 1 may be -(CH2)m-, -(CH2)m-O-(CH2)n-, or m-CO-(CH2)n-, wherein m and n may each independently be an integer selected from 1 and 2.

In an example embodiment, Z in the compound of a 1 may be represented by Formula 2.

Formula 2 wherein, in Formula 2, may be a C3-6 heterocycloalkyl group including one or two heteroatoms selected from O, N, and S, R10(s) may each independently be hydrogen, a hydroxy group, a linear or branched hydroxy C1-4 alkyl group, a linear or branched C1-4 alkyl group, a C3-10 cycloalkyl group, a C2-9 heterocycloalkyl group, a hydroxy C2-9 heterocycloalkyl group, -NR11R12, or -COR13, R11 and R12 may each independently be hydrogen, a linear or branched hydroxy C1-4 alkyl group or a linear or branched C1-4 alkyl group, R13 may be hydrogen, a hydroxy group, a linear or branched hydroxy C1-4 alkyl group, a linear or ed halo C1-4 alkyl group, or a linear or branched C1-4 alkyl group, and q may each independently be an integer from 0 to 5.

In an example embodiment, in the compound of Formula 1, R1 may be hydrogen, a hydroxy group, a C1-4 alkoxy group or a C1-4 alkyl 11498815_1 (GHMatters) P109554.NZ group, R2 may be hydrogen, halogen, a C1-4 alkyl group or a halo C1-4 alkyl group, R3 may be hydrogen, R4 may be hydrogen, halogen, a hydroxy group, a C1-4 alkoxy group, a hydroxy C1-4 alkyl group, or a C1-4 alkyl group, k may be an integer from 0 to 2, R5 and R6 may each independently be hydrogen or a hydroxy group, R7 may be a cyclopropyl group, Y may be a direct bond, m-, -O-, -C(=O)-, -(CH2)m-O-(CH2)n-, or -(CH2)m-CO-(CH2)n-, Z may be represented by Formula 2, Formula 2 wherein, in Formula 2, may be a C3-6 heterocycloalkyl group ing one or two heteroatoms selected from O, N, and S, R10(s) may each independently be a hydroxy group, a hydroxy C1-4 alkyl group, a C1-4 alkyl group, a C3-10 cycloalkyl group, a C2-9 heterocycloalkyl group, a hydroxy C2-9 heterocycloalkyl group, -NR11R12, or -COR13, R11 and R12 may each independently be hydrogen, a hydroxy C1-4 alkyl group or a C1-4 alkyl group, R13 may be hydrogen, a hydroxy C1-4 alkyl group, a halo C1-4 alkyl group, or a C1-4 alkyl group, and q may each independently be an integer from 0 to 3.

In an example ment, in the compound of Formula 1, R1, R3, R5, and R6 may each be hydrogen, R2 may be hydrogen or halogen, R4 may be a C1-4 alkyl group or halogen, R7 may be hydrogen, a linear or branched C1-6 alkyl group, a C3-7 cycloalkyl 15_1 (GHMatters) P109554.NZ group, or a C1-4 alkoxy group, ] Y may be a direct bond, -CH2-, -O-, ethyleneoxy, or -C(=O)-, and Z may be any one selected from Formulae 3 to 5: Formula 3 R15 p V W R8 Formula 4 R15 s Formula 5 R15 t V W R8 wherein, in Formulae 3 to 5, V and W may each independently be N or a CH, provided that at least one of V and W is not CH, R8 may be selected from the group consisting of hydrogen, halogen, a linear or branched C1-4 alkyl group, a linear or branched hydroxy C1-4 alkyl group, a y group, -NR11R12, a linear or branched hydroxy C1-4 alkylcarbonyl group, a heterocycloalkyl group, a hydroxy substituted heterocycloalkyl group, a linear or branched halo C1-4 alkyl group, and a linear or branched C1-4 alkoxy group, R11 and R12 may each independently be a hydrogen, a linear or branched C1-4 alkyl group, or a linear or branched y C1-4 alkyl group, R15 may each independently be a linear or branched C1-4 alkyl group, a linear or branched hydroxy C1-4 alkyl group, or halogen, p may be an integer from 0 to 4, and s and t may each ndently be an r from 0 to 5, provided that R8 is hydrogen, or an an integer from 0 to 4, provided that R8 is not hydrogen. 11498815_1 (GHMatters) P109554.NZ In particular, in the compound of Formula 1, R7 may be hydrogen or a C3-7 cycloalkyl group, Y may be a direct bond or -CH2-, Z may be Formula 4 or Formula 5, R8 may be hydrogen, a linear or branched C1-4 alkyl group, a linear or branched y C1-4 alkyl group, a heterocycloalkyl group or a hydroxy tuted heterocycloalkyl group, and R15 may each independently be a linear or branched C1-4 alkyl group, a linear or branched hydroxy C1-4 alkyl group, or n.

In an example embodiment, the compound of Formula 1 may be selected from the group consisting of compounds shown in Table 1: Table 1 No. Compound 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)cyclopropyl phenyl)piperazineyl)ethaneol 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidine-2yl)amino)cyclopropy lphenyl)piperazineyl)ethaneol -chloro-N-(3-cyclopropyl(4-(dimethylamino)piperidineyl)phenyl)(1H-ind oleyl)pyrimidineamine (S)((1-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylphe nyl)piperidineyl)(methyl)amino)propaneol (S)((1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclo propylphenyl)piperidineyl)(methyl)amino)propaneol -chloro-N-(3-cyclopropyl(4-(dimethylamino)piperidineyl)phenyl)(6-meth yl-1H-indoleyl)pyrimidineamine 3-((5-chloro(6-methoxy-1H-indoleyl)pyrimidineyl)amino)cyclopro pylphenyl)piperazineyl)ethaneol (1-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylphe nyl)piperidineyl)pyrrolidineol (S)(1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclop ropylphenyl)piperidineyl)pyrrolidineol 11498815_1 (GHMatters) P109554.NZ -chloro-N-(3-cyclopropyl(4-(dimethylamino)piperidineyl)phenyl)(6-meth oxy-1H-indoleyl)pyrimidineamine (1-(3-((5-chloro(6-methoxy-1H-indoleyl)pyrimidineyl)amino)cycl opropylphenyl)piperidineyl)pyrrolidineol 2-(4-(3-((4-(1H-indoleyl)methylpyrimidineyl)amino)cyclopropylphenyl) piperazineyl)ethaneol -chloro-N-(3-cyclopropyl(4-morpholinopiperidineyl)phenyl)(6-methyl-1H -indoleyl)pyrimidineamine -chloro-N-(3-cyclopropyl(4-(ethyl(methyl)amino)piperidineyl)phenyl)(6- methyl-1H-indoleyl)pyrimidineamine -chloro-N-(3-cyclopropyl(4-(diethylamino)piperidineyl)phenyl)(6-methyl- 1H-indoleyl)pyrimidineamine -chloro-N-(3-cyclopropyl(3-(dimethylamino)pyrrolidineyl)phenyl)(6-met hyl-1H-indoleyl)pyrimidineamine 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperazineyl)methylpropaneol N-(3-(4-aminopiperidineyl)cyclopropylphenyl)chloro(6-methyl-1H-indo l)pyrimidineamine ro-N-(3-cyclopropyl(4-(methylamino)piperidineyl)phenyl)(6-methyl -1H-indoleyl)pyrimidineamine 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)cyclopropyl phenyl)piperazineyl)methylpropaneol 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperidineyl)ethaneol 2-(4-(3-((5-chloro(6-chloro-1H-indoleyl)pyrimidineyl)amino)cyclopropy lphenyl)piperazineyl)ethaneol -chloro-N-(3-cyclopropyl(4-(pyrrolidineyl)piperidineyl)phenyl)(6-meth yl-1H-indoleyl)pyrimidineamine 1-(1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperidineyl)azetidineol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)methoxyphenyl)pip 11498815_1 (GHMatters) P109554.NZ erazineyl)ethaneol 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)phenyl)pipera -yl)ethaneol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)phenyl)piperidineyl) ethaneol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)phenyl) piperazineyl)ethaneol -chloro-N-(3-(4-(dimethylamino)piperidineyl)phenyl)(1H-indoleyl)pyrimi dineamine ro-N-(3-(3-(dimethylamino)pyrrolidineyl)phenyl)(1H-indoleyl)pyrimi dineamine 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)methoxyph enyl)piperazineyl)ethaneol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)isopropoxyphenyl)p iperazineyl)ethaneol 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)isopropoxy phenyl)piperazineyl)ethaneol -chloro-N-(3-cyclopropyl(piperazineylmethyl)phenyl)(6-fluoro-1H-indole yl)pyrimidineamine 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)methoxybe nzyl)piperazineyl)ethaneol 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)benzyl)pipera zineyl)ethaneol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)methoxybenzyl)pip erazineyl)ethaneol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylbenzyl) piperazineyl)methylpropaneol (S)((1-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylben zyl)piperidineyl)(methyl)amino)propaneol (S)((1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclo propylbenzyl)piperidineyl)(methyl)amino)propaneol 11498815_1 ters) P109554.NZ 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop yl)piperazineyl)methylpropaneol (S)(1-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylben zyl)piperidineyl)pyrrolidineol (S)(1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclop ropylbenzyl)piperidineyl)pyrrolidineol (S)(1-(3-((5-chloro(6-methoxy-1H-indoleyl)pyrimidineyl)amino)cycl opropylbenzyl)piperidineyl)pyrrolidineol 1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclopropylb enzyl)piperidineol (S)chloro-N-(3-cyclopropyl((3-(dimethylamino)pyrrolidineyl)methyl)phen yl)(6-methyl-1H-indoleyl)pyrimidineamine 1-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)cyclopropyl benzyl)piperazineyl)hydroxyethaneone 1-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylbenzyl)piperazineyl)hydroxyethaneone 2-(4-(3-((5-chloro(6-ethyl-1H-indoleyl)pyrimidineyl)amino)cyclopropyl benzyl)piperazineyl)ethaneol (3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)methoxyphenyl)(4-(2-hy thyl)piperazineyl)methanone 1-(2-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenoxy)ethyl)piperidineol 1-(2-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)aminoethylpheno xy)ethyl)piperidineol (R)(3-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclop ropylphenoxy)pyrrolidineyl)ethaneol 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop oxy)piperidineyl)ethaneol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)methoxyphenoxy)pi peridineyl)ethaneol 11498815_1 (GHMatters) P109554.NZ The term "optical isomer" as used herein refers to various stereoisomers and geometrical isomers for the nd ing to the t invention. Since the compounds of formula 1 may have an asymmetric carbon center (asymmetric carbon), the compounds of formula 1 according to an aspect of the present invention may be in form of an enantiomer (R or S isomer), racemate, diastereomer, or any mixture thereof. All these isomers and es are included within the scope of the present invention. The optically active (R)- and (S)-isomers may be resolved using conventional techniques or can be prepared using chiral synthon or chiral reagents.

When a compound includes a double bond, a substituent may be in an E form or an Z form. When a compound includes a cycloalkyl group that has two substituents, the compound may be in a cis-form or a form. In addition, when the compound of Formula 1 includes a bridged ring, the compound may be in a form of an exo-isomer or an endo isomer. The nd of Formula 1 may include all tautomers.

] In accordance with an aspect, the compound of Formula 1 and an optical isomer thereof may be in a form of a solvate. The term "solvate" may include a molecular complex including the compound and at least one pharmaceutically acceptable solvent molecule, e.g., ethanol or water. A x, in which the solvent molecule is water, is also referred to as "hydrate".

In accordance with an aspect, the compound of Formula 1, an optical isomer thereof, and a solvate thereof may be in a form of a pharmaceutically acceptable salt.

The term "pharmaceutically acceptable salt" as used herein refers to a salt that are low in toxicity to humans and do not adversely affect the biological activity and physicochemical properties of the parent compound. A pharmaceutically acceptable salt may include acid addition salts of a pharmaceutically acceptable free acid and a base nd of Formula 1, alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts), organic base addition salts of an organic base group and a carboxylic acid structure of a 1, amino acid addition salts, and the like, but are embodiments not limited thereto.

] The pharmaceutically acceptable salt may be prepared by a conventional method. For example, the compound of a 1 may be ved in a solvent, which may be mixed with water, e.g., methanol, ethanol, acetone, 1,4-dioxane, and 11498815_1 ters) P109554.NZ then a free acid or a free base may be added thereto for crystallization to thereby prepare a pharmaceutically acceptable salt.

In accordance with another aspect of the t invention, provided is a method of preparing the compound of Formula 1 including reacting a compound of Formula 6 with a compound of Formula 7: ] Formula 6 V2 N (R4)k wherein, in ae 6 and 7, R1, R2, R3, R4, R5, R6, R7, Y, Z, and k may respectively be defined the same as those of ae 1 and 2, and V2 may be halogen.

An organic base, e.g., triethylamine, diisopropylethylamine, pyridine, and the like; an inorganic base, e.g., sodium carbonate, potassium carbonate, hydrogenated , and the like; an organic acid, e.g., trifluoroacetic acid, toluenesulfonic acid, and the like; or an inorganic acid, e.g., hydrochloric acid, sulfuric acid, phosphoric acid, and the like, may or may not be added to a reaction solution when performing the reaction. A t used in the reaction may be any solvent that does not inhibit the reaction, for example, a polar aprotic solvent such as dimethylsulfoxide, N, N-dimethylformamide, acetonitrile, or tetrahydrofuran (THF); a polar protic solvent such as methanol, ethanol, 2-propanol, or 2-butanol; or a nonpolar aprotic solvent such as toluene or 1,4-dioxane. A reaction temperature may be in a range of 0 to 150 , for example, from room temperature to about 100 . 15_1 (GHMatters) P109554.NZ The compounds of Formulae 6 and 7 may be prepared using conventional dge in the field of organic chemistry.

] In an example embodiment, the compound of Formula 1 may be prepared as shown in Reaction Scheme 1: Reaction Scheme 1 R6 R1 R1 R7 R1 (R4)k N R2 Z Y R6 NH2 N R2 N N R3 R5 Z Y N N V2 (R4)k N (R4)k H V2 N V1 5 7 R5 N 4 1 wherein, in Reaction Scheme 1, R1, R2, R3, R4, R6, R7, Y, Z, and k may respectively be defined the same as those of Formulae 1 and 2, and V1 and V2 may each independently be halogen.

In preparing the compound of Formula 6 by reacting the compound of Formula 4 with the compound of Formula 5, the reaction may be performed by adding an organometallic compound. For e, the organometallic compound may be an alkyl magnesium compound or an alkyl lithium compound.

] A t used in the reacting may be any solvent that does not inhibit the reaction, for example, a polar aprotic solvent such as dimethylsulfoxide, N, N-dimethylformamide, itrile, or THF; or a nonpolar aprotic solvent such as toluene or 1,4-dioxane. A reaction temperature may be in a range of 0 to 100 , for example, from 0 to 60 .

In preparing the compound of Formula 7, in a case where Y is -(CH2)m-, m may each independently be 0 and 1, in a case where Y is -(CH2)m-O-(CH2)n-, m may be 0, and n may each ndently be 0 and 2, in a case where Y is -(CH2)m-CO-(CH2)n-, m and n may each be 0, and the compound of Formula 7 may be prepared using conventional knowledge in the field of organic chemistry, as shown in Preparation Schemes 1 to 3: ation Scheme 1 in a case where Y is -(CH2)m-: 11498815_1 (GHMatters) P109554.NZ wherein, in Preparation Scheme 1, R5, R6, R7, R10, , and q may tively be defined the same as those of Formulae 1 and 3, V3 may be halogen, and L may be Cl, Br, I, OMs, OTs, or the like, Preparation Scheme 2 in a case where Y is -(CH2)m-O-(CH2)n-: wherein, in Preparation Scheme 2, R6, R7, R10, , and q may respectively be defined the same as those of Formulae 1 and 3, and L may be Cl, Br, I, OMs, OTs, or the like, and Preparation Scheme 3 11498815_1 (GHMatters) P109554.NZ in a case where Y is -(CH2)m-CO-(CH2)n-: wherein, in Preparation Scheme 3, R6, R7, R10, , and q may tively be defined the same as those of Formulae 1 and 3.

] Although the method of the preparing Formula 1 has been described by way of specific examples, specific reaction conditions, such as an amount of a reaction solvent, a base, and a reactant to be used, are not limited to those described in the present specification, and may not be ued as limiting the scope of the the present invention.

In accordance with r aspect of the present invention, provided is a pharmaceutical composition including as an active ingredient the compound of Formula 1 according to an aspect of the present invention.

In accordance with another aspect of the present invention, provided is a pharmaceutical use for the prevention and treatment of cancer of the pharmaceutical composition according to an aspect of the t invention.

In accordance with another aspect of the present invention, provided is a pharmaceutical use of the compound of Formula 1 according to an aspect of the present ion for preparing a medicine for the prevention and treatment of cancer.

In an e embodiment, the pharmaceutical composition may include a pharmaceutically acceptable excipient or additive. The pharmaceutical composition of the present invention may be formulated according to a conventional method and may be formulated into various oral dosage forms such as a tablet, a pill, , a capsule, syrup, emulsion, and microemulsion; or parenteral dosage forms such as intramuscular, intravenous or subcutaneous stration.

When the pharmaceutical composition of the present invention is prepared in a form of an oral formulation, examples of a carrier or additive to be used include a diluent, a disintegrant, a binder, a lubricant, a tant, a suspension, and an emulsifier. When the pharmaceutical ition of the present invention is prepared 11498815_1 (GHMatters) P109554.NZ in a form of an injection, examples of a carrier or additive may include water, saline solution, aqueous glucose solution, pseudosaccharide solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, a surfactant, a suspension, and an emulsifier. Such formulation methods are well known to those of ordinary skill in the ceutical art.

The dose of the compound of a 1 as an active ingredient is an effective amount for treating or ting cancer in a subject or a patient. The compound may be administered orally or parenterally, as desired. When the nd is administered orally, the active ingredient may be administered in an amount in a range of 0.01 milligrams (mg) to 1,000 mg, more particularly, 0.1 mg to 300 mg, per kilogram (kg) of body weight per day. When the compound is administered parenterally, the active ingredient may be administered from one to several times in an amount in a range of 0.01 mg to 100 mg, more particularly, 0.1 mg to 50 mg, per kg of body weight per day. The dose for a particular subject or patient should be determined in light of the patient's weight, age, sex, health condition, diet, time of administration, method of administration, severity of disease, etc. It is to be understood that the dose may be appropriately ed by a practitioner. The dose is not intended to limit the scope of the ion in any way.

In accordance with another aspect of the present invention, provided is a method of preventing or treating cancer, the method ing administering a t or a patient with a compound selected from the nd of Formula 1 according to an aspect of the present invention, an optical isomer f, a e thereof, and a eutically acceptable salt thereof.

Details of the method of preventing or treating may be the same as described above with reference to the pharmaceutical composition according to an aspect of the present invention.

] The term "treatment" as used herein is used as a concept that includes treatment, improvement, amelioration, or management of disease.

The term "preventing" or "prevention" as used herein refers to prevention of a disease, for example, prevention of a disease, condition, or disorder in a subject that may be predisposed to the disease, condition, or disorder but has not yet experienced 11498815_1 (GHMatters) P109554.NZ or exhibited pathology or a symptom of the disease.

The term "subject" or "patient" as used herein refers to any animal, including mammals, for e, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or es and humans.

Hereinafter, the present invention will be described in more detail with reference to the following Examples and Experimental Examples. r, these es and Experimental Examples are intended to help understand the present invention, and the scope of the present ion is not limited thereto in any sense.

The abbreviations used in the following Preparation Examples, preparation methods, and Examples each indicate: BINAP: (2, 2'-bis(diphenylphosphino)-1,1'-binaphthyl) Pd(OAc)2: palladium(II) acetate Example 1: 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperazineyl)ethaneol Step 1) Preparation of 4-cyclopropylnitroaniline ] 1.5 grams (g) (6.90 millimole (mmol)) of 4-bromonitroaniline, 1.22 g (13.83 mmol) of cyclopropylboronic acid, 4.5 g (20.70 mmol) of potassium phosphate, 159 mg (0.69 mmol) of palladium(II) acetate, and 543 mg (2.07 mmol) of triphenylphosphine were dissolved in 12 milliliters (mL) of toluene and 6 mL of water, and then stirred at a ature of 100 in a sealed tube for 17 hours. Once the reaction was complete, the resultant was cooled to room temperature, and water was added dropwise thereto. An extraction process was performed thereon three times using form. The result was dried using anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified using medium pressure liquid chromatography (MPLC) (chloroform:methanol=100:1 , and the resulting solution was concentrated under reduced re to thereby obtain 11498815_1 (GHMatters) P109554.NZ 880 mg of a d compound at a yield of 72%. 1H-NMR (300 MHz, DMSO-d6): δ 7.65 (s, 1H), 7.26 (s, 2H), 7.12 (d, 1H), 6.92 (d, 1H), 1.83 (m, 1H), 0.82 (m, 2H), 0.58 (m, 2H).

Step 2) Preparation of ocyclopropylnitroaniline 880 mg (4.94 mmol) of opropylnitroaniline prepared in Step 1) was dissolved in 16 mL of acetic acid, and 922 mg (5.18 mmol) of N-bromosuccinimide was slowly added thereto at a temperature of 0 . The resultant was stirred at room temperature for 1.5 hours. Once the reaction was complete, water was added dropwise thereto. An extraction process was performed thereon three times using diethylether. The result was dried using anhydrous sodium sulfate, and then concentrated under reduced pressure to thereby obtain 1.24 g of a desired nd at a yield of 98%. 1H-NMR (300 MHz, DMSO-d6): δ 7.88 (s, 1H), 7.59 (s, 1H), 7.16 (m, 2H), 1.95 (m, 1H), 0.88 (m, 2H), 0.64 (m, 2H).

Step 3) Preparation of 1-bromocyclopropylnitrobenzene 1.24 g (4.82 mmol) of 2-bromocyclopropylnitroaniline prepared in Step 2) was dissolved in 24 mL of ethanol. Subsequently, 1.6 mL (30.39 mmol) of ic acid was slowly added thereto at a temperature of 0 . The temperature of the result was allowed to be raised up to 60 , and then 1.06 g (15.42 mmol) of sodium nitrite was slowly added thereto. This mixture was stirred under reflux at a temperature of 100 for 4 hours. Once the reaction was complete, the resultant was cooled to room temperature, and ethyl acetate and water was added thereto. An organic layer was separated therefrom, which was then dried using anhydrous sodium sulfate and concentrated under d pressure. The obtained residue was purified using 11498815_1 ters) P109554.NZ MPLC (ethyl acetate:hexane=1:50 (v/v)), and the resulting solution was concentrated under reduced pressure to thereby obtain 790 mg of a desired compound at a yield of 1H-NMR (300 MHz, DMSO-d6): δ 8.10 (s, 1H), 7.98 (s, 1H), 7.74 (s, 1H), 2.11 (m, 1H), 1.11 (m, 2H), 0.86 (m, 2H).

Step 4) Preparation of 2-(4-(3-cyclopropylnitrophenyl)piperazineyl)ethaneol 790 mg (3.26 mmol) of 1-bromocyclopropylnitrobenzene prepared in Step 3), 637 mg (4.89 mmol) of 1-(2-hydroethyl)piperazine, 300 mg (0.33 mmol) of tris(dibenzylideneacetone)dipalladium(0), 207 mg (0.33 mmol) of BINAP, and 3.2 g (9.78 mmol) of cesium ate were dissolved in 6 mL of 1,4-dioxane, and then the mixture was stirred at a temperature of 100 in a sealed tube for 15 hours. Once the on was complete, the resultant was cooled to room temperature, and water was added dropwise thereto. An extraction process was performed thereon three times using chloroform and methanol. The result was dried using anhydrous sodium sulfate, and then concentrated under reduced pressure. The ed residue was purified using MPLC (chloroform:methanol=10:1 (v/v)), and the resulting solution was concentrated under reduced pressure to thereby obtain 234 mg of a desired compound at a yield of 24%.

Step 5) Preparation of 3-aminocyclopropylphenyl)piperazineyl)ethaneol 220 mg (3.96 mmol) of iron and 0.03 mL (0.32 mmol) of hloric acid were dissolved in 4 mL of 50% ethanol. The mixture was d under reflux at a 11498815_1 (GHMatters) P109554.NZ temperature of 110 for 1 hour. 234 mg (0.79 mmol) of 2-(4-(3-cyclopropylnitrophenyl)piperazineyl)ethaneol prepared in Step 4) was slowly added thereto. This mixture was stirred under reflux at a ature of 110 for 1 hour. Once the reaction was complete, the mixture was cooled to room temperature, and then was neutralized using a saturated sodium hydrogen ate aqueous solution. A filtration process was performed thereon using a celite .

Subsequently, a washing process was performed thereon using chloroform and ol. An organic layer was separated therefrom, which was then dried using anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using MPLC (chloroform:methanol=8:1 (v/v)), and the resulting solution was concentrated under reduced pressure to y obtain 152 mg of a desired compound at a yield of 74%. 1H-NMR (300 MHz, DMSO-d6): δ 5.90 (s, 1H), 5.88 (s, 1H), 5.70 (s, 1H), 4.70 (s, 2H), 4.04 (m, 1H), 3.48 (m, 2H), 2.97 (m, 4H), 2.47 (m, 4H), 2.40 (m, 2H), 1.53 (m, 1H), 0.76 (m, 2H), 0.51 (m, 2H).

Step 6) Preparation of 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)cyclopropylphe perazineyl)ethaneol 50 mg (0.19 mmol) of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol prepared in Step 5), 54 mg (0.19 mmol) of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole, and 36 mg (0.19 mmol of p-toluenesulfonic acid monohydrate were dissolved in 1.2 mL of 2-butanol. Then, the mixture was stirred at a temperature of 120 in a sealed tube for 3.5 hours. Once the on was complete, the mixture was cooled to room temperature, and then, chloroform, methanol, and saturated sodium hydrogen carbonate were added thereto. An organic layer was separated therefrom, which was 11498815_1 (GHMatters) P109554.NZ then dried using ous sodium sulfate and trated under reduced pressure. The obtained residue was purified using MPLC (chloroform:methanol=7:1 (v/v)), and the resulting solution was concentrated under reduced re to thereby obtain 65 mg of a desired compound at a yield of 67%.

MS (ESI+, m/z): 507 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.93 (s, 1H), 9.37 (s, 1H), 8.56 (m, 1H), 8.44 (m, 2H), 7.46 (d, 1H), 7.28 (s, 1H), 7.10 (m, 2H), 6.29 (s, 1H), 4.42 (m, 1H), 4.00 (m, 2H), 3.03 (m, 4H), 2.27 (m, 4H), 1.88 (m, 1H), 0.85 (m, 2H), 0.61 (m, 2H).

Example2: 3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperazineyl)ethaneol 72 mg of a desired compound was obtained at a yield of 89% in substantially the same manner as in Step 6) of Example 1, except that 50 mg (0.18 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 503 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.76 (s, 1H), 9.32 (s, 1H), 8.38 (m, 3H), 7.22 (d, 2H), 6.93 (d, 2H), 6.28 (s, 1H), 4.42 (t, 1H), 3.51 (q, 2H), 3.03 (bs, 4H), 2.37 (m, 9H), 1.81 (m, 1H), 0.88 (m, 2H), 0.64 (m, 2H).

Example 3: -chloro-N-(3-cyclopropyl(4-(dimethylamino)piperidineyl)phenyl)(1H-in doleyl)pyrimidineamine 11498815_1 (GHMatters) P109554.NZ ] 48 mg of a desired compound was obtained at a yield of 58% in substantially the same manner as in Step 6) of Example 1, except that 44 mg (0.17 mmol) of 1-(3-aminocyclopropylphenyl)-N, N-dimethylpiperidineamine was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 51 mg (0.19 mmol) of 3-(2,5-dichloropyrimidineyl)-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 487 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.90 (s, 1H), 9.34 (s, 1H), 8.58 (d, 1H), 8.47 (m, 2H), 7.48 (t, 1H), 7.24 (m, 2H), 7.12 (t, 1H), 6.97 (s, 1H), 6.30 (s, 1H), 3.65 (d, 2H), 2.58 (m, 2H), 2.30 (d, 6H), 1.80 (m, 3H), 1.49 (m, 2H), 0.88 (m, 2H), 0.63 (m, Example 4: (S)((1-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylph enyl)piperidineyl)(methyl)amino)propaneol 52 mg of a desired compound was obtained at a yield of 58% in substantially the same manner as in Step 6) of Example 1, except that 50 mg (0.17 mmol) of (S)((1-(3-aminocyclopropylphenyl)piperidineyl)(methyl)amino)propaneol was used d of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 51 mg (0.19 mmol) of 3-(2,5-dichloropyrimidineyl)-1H-indole was used instead of -dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1. 11498815_1 (GHMatters) P109554.NZ MS (ESI+, m/z): 531 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.91 (s, 1H), 9.34 (s, 1H), 8.58 (d, 1H), 8.47 (d, 1H), 8.44 (s, 1H), 7.51 (d, 1H), 7.24 (m, 3H), 6.95 (s, 1H), 6.29 (s, 1H), 4.18 (bs, 1H), 3.65 (m, 3H), 2.59 (m, 2H), 2.29 (m, 2H), 2.20 (s, 3H), 1.78 (m, 1H), 1.64 (m, 2H), 1.46 (m, 2H), 1.24 (m, 1H), 1.10 (m, 2H), 0.85 (m, 3H), 0.63 (m, 2H).

Example 5: (S)((1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclo propylphenyl)piperidineyl)(methyl)amino)propaneol 58 mg of a desired compound was obtained at a yield of 65% in substantially the same manner as in Step 6) of Example 1, except that 50 mg (0.17 mmol) of (S)((1-(3-aminocyclopropylphenyl)piperidineyl)(methyl)amino)propaneol was used instead of 3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 50 mg (0.18 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 545 [M+H]+ 1H-NMR (300 MHz, 6): δ 11.75 (bs, 1H), 9.32 (s, 1H), 8.39 (m, 3H), 7.27 (d, 2H), 6.90 (m, 2H), 6.29 (s, 1H), 4.18 (bs, 1H), 3.61 (m, 3H), 2.54 (s, 1H), 2.42 (s, 3H), 2.23 (m, 2H), 2.20 (s, 3H), 1.80 (m, 1H), 1.63 (m, 2H), 1.40 (m, 2H), 1.24 (m, 2H), 1.02 (d, 6H), 0.86 (m, 2H), 0.60 (m, 2H).

Example 6: -chloro-N-(3-cyclopropyl(4-(dimethylamino)piperidineyl)phenyl)(6-met hyl-1H-indoleyl)pyrimidineamine 11498815_1 (GHMatters) P109554.NZ 86 mg of a d compound was obtained at a yield of 86% in substantially the same manner as in Step 6) of Example 1, except that 52 mg (0.20 mmol) of 1-(3-aminocyclopropylphenyl)-N, N-dimethylpiperidineamine was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 61 mg (0.22 mmol) of -dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 501 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.77 (bs, 1H), 9.32 (s, 1H), 8.39 (m, 3H), 7.27 (s, 1H), 7.22 (s, 1H), 6.93 (d, 2H), 6.30 (s, 1H), 3.61 (d, 1H), 2.57 (m, 4H), 2.42 (s, 3H), 2.28 (m, 6H), 1.79 (m, 3H), 1.47 (m, 2H), 0.86 (m, 2H), 0.61 (m, 2H).

Example 7: 2-(4-(3-((5-chloro(6-methoxy-1H-indoleyl)pyrimidineyl)amino)cyclopr opylphenyl)piperazineyl)ethaneol HN N 5 mg of a desired nd was obtained at a yield of 6% in substantially the same manner as in Step 6) of Example 1, except that 50 mg (0.17 mmol) of 3-(2,5-dichloropyrimidineyl)methoxy-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 519 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.70 (s, 1H), 9.32 (s, 1H), 8.42 (m, 3H), 7.17 (s, 1H), 6.98 (s, 1H), 6.75 (d, 1H), 6.31 (s, 1H), 3.80 (s, 3H), 3.29 (s, 1H), 3.04 (m, 2H), 1.90 (m, 1H), 0.86 (m, 2H), 0.62 (m, 2H). 11498815_1 (GHMatters) P109554.NZ Example 8: (S)(1-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylphe nyl)piperidineyl)pyrrolidineol 68 mg of a desired compound was obtained at a yield of 76% in substantially the same manner as in Step 6) of e 1, except that 50 mg (0.17 mmol) of (S)(1-(3-aminocyclopropylphenyl)piperidineyl)pyrrolidineol was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 51 mg (0.19 mmol) of 3-(2,5-dichloropyrimidineyl)-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 529 [M+H]+ 1H-NMR (300 MHz, 6): δ 11.91 (s, 1H), 9.34 (s, 1H), 8.58 (d, 1H), 8.47 (d, 1H), 8.44 (s, 1H), 7.45 (d, 1H), 7.19 (d, 2H), 7.09 (t, 1H), 6.97 (s, 1H), 6.30 (s, 1H), 4.92 (bs, 1H), 4.20 (bs, 1H), 3.77 (m, 1H), 3.54 (d, 2H), 2.58 (m, 4H), 2.28 (s, 1H), 1.98 (m, 1H), 1.83 (m, 3H), 1.70 (m, 4H), 0.86 (m, 2H), 0.62 (m, 2H).

Example 9: (S)(1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclo propylphenyl)piperidineyl)pyrrolidineol 64 mg of a desired compound was obtained at a yield of 69% in ntially the same manner as in Step 6) of Example 1, except that 50 mg (0.17mmol) of (S)(1-(3-aminocyclopropylphenyl)piperidineyl)pyrrolidineol was used 11498815_1 (GHMatters) P109554.NZ instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 51 mg (0.18 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 543 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.77 (s, 1H), 9.32 (s, 1H), 8.45 (m, 3H), 7.27 (s, 1H), 7.22 (s, 1H), 6.96 (d, 2H), 6.29 (s, 1H), 4.92 (bs, 1H), 4.20 (bs, 1H), 3.77 (m, 1H), 3.56 (d, 2H), 2.61 (m, 4H), 2.42 (s, 3H), 2.28 (s, 1H), 1.81 (m, 4H), 1.44 (m, 4H), 0.87 (m, 2H), 0.64 (m, 2H).

Example 10: -chloro-N-(3-cyclopropyl(4-(dimethylamino)piperidineyl)phenyl)(6-met H-indoleyl)pyrimidineamine 20 mg of a desired compound was obtained at a yield of 23% in substantially the same manner as in Step 6) of Example 1, except that 44 mg (0.17 mmol) of 1-(3-aminocyclopropylphenyl)-N, N-dimethylpiperidineamine was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 50 mg (0.17 mmol) of 3-(2,5-dichloropyrimidineyl)methoxy-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of e 1.

MS (ESI+, m/z): 517 [M+H]+ 1H-NMR (300 MHz, 6): δ 11.70 (s, 1H), 9.30 (s, 1H), 8.41 (m, 3H), 7.20 (s, 1H), 6.95 (d, 2H), 6.75 (d, 1H), 6.29 (s, 1H), 3.79 (s, 3H), 3.62 (d, 2H), 1.80 (m, 1H), 1.42 (m, 2H), 1.22 (m, 2H), 0.84 (d, 2H), 0.61 (d, 2H).

Example 11: (S)(1-(3-((5-chloro(6-methoxy-1H-indoleyl)pyrimidineyl)amino)cycl opropylphenyl)piperidineyl)pyrrolidineol 11498815_1 (GHMatters) P109554.NZ 9 mg of a d compound was obtained at a yield of 10% in substantially the same manner as in Step 6) of Example 1, except that 51 mg (0.17 mmol) of (S)(1-(3-aminocyclopropylphenyl)piperidineyl)pyrrolidineol was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 50 mg (0.17 mmol) of 3-(2,5-dichloropyrimidineyl)methoxy-1H-indole was used instead of -dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 559 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.70 (s, 1H), 9.41 (s, 1H), 8.41 (m, 3H), 7.17 (s, 1H), 7.10 (d, 2H), 6.74 (d, 2H), 6.29 (s, 1H), 4.78 (brs, 1H), 4.19 (m, 1H), 3.77 (d, 2H), 2.65 (m, 2H), 2.62 (m, 2H), 1.84 (m, 1H), 1.80 (m, 2H), 1.45 (m, 2H), 1.22 (m, 2H), 0.83 (d, 2H), 0.60 (d, 2H).

Example 12: 2-(4-(3-((4-(1H-indoleyl)methylpyrimidineyl)amino)cyclopropylphenyl )piperazineyl)ethaneol 60 mg of a d compound was obtained at a yield of 67% in substantially the same manner as in Step 6) of Example 1, except that 51 mg (0.21 mmol) of 3-(2-chloromethylpyrimidineyl)-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 469 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.69 (s, 1H), 8.96 (s, 1H), 8.52 (d, 1H), 8.29 (s, 1H), 7.96 (m, 1H), 7.46 (m, 1H), 7.25 (s, 1H), 7.19-7.02 (m, 3H), 6.19 (s, 1H), 11498815_1 (GHMatters) P109554.NZ 4.40 (m, 1H), 3.51 (m, 2H), 3.00 (m, 4H), 2.44 (m, 4H), 2.39 (m, 5H), 1.96 (m, 1H), 0.82 (m, 2H), 0.58 (m, 2H).

Example 13: -chloro-N-(3-cyclopropyl(4-morpholinopiperidineyl)phenyl)(6-methyl-1 H-indoleyl)pyrimidineamine 100 mg of a desired compound was obtained at a yield of 56% in substantially the same manner as in Step 6) of Example 1, except that 100 mg (0.33 mmol) of 3-cyclopropyl(4-morpholinopiperidineyl)aniline was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 138 mg (0.50 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used d of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 543 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.76 (s, 1H), 9.54 (s, 1H), 8.50 (m, 3H), 7.28 (s, 1H), 7.23 (s, 1H), 6.96 (m, 2H), 6.29 (s, 1H), 3.57 (s, 6H), 2.60 (m, 6H), 2,42 (s, 3H), 2.10 (m, 1H), 1.79 (m, 3H), 1.40 (q, 2H), 0.84 (m, 2H), 0.61 (m, 2H).

Example 14: ro-N-(3-cyclopropyl(4-(ethyl(methyl)amino)piperidineyl)phenyl)(6- methyl-1H-indoleyl)pyrimidineamine 50 mg of a d compound was obtained at a yield of 30% in substantially the same manner as in Step 6) of Example 1, except that 90 mg (0.33 mmol) of 11498815_1 (GHMatters) P109554.NZ 1-(3-aminocyclopropylphenyl)-N-ethyl-N-methylpiperidineamine was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 137 mg (0.49 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

] MS (ESI+, m/z): 515 [M+H]+ ] 1H-NMR (300 MHz, DMSO-d6): δ 11.76 (s, 1H), 9.32 (s, 1H), 8.45 (m, 3H), 7.25 (d, 2H), 6.97 (m, 2H), 6.29 (s, 1H), 3.62 (d, 2H), 2.59 (m, 4H), 2.42 (s, 3H), 2.18 (s, 3H), 1.79 (m, 1H), 1.68 (d, 2H), 1.45 (q, 2H), 1.20 (m, 1H), 0.98 (t, 3H), 0.86 (m, 2H), 0.62 (m, 2H).

Example 15: -chloro-N-(3-cyclopropyl(4-(diethylamino)piperidineyl)phenyl)(6-methy l-1H-indoleyl)pyrimidineamine 50 mg of a desired compound was obtained at a yield of 30% in substantially the same manner as in Step 6) of Example 1, except that 90 mg (0.31 mmol) of 1-(3-aminocyclopropylphenyl)-N, N-dimethylpiperidineamine was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 131 mg (0.47 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used d of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 529 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.76 (s, 1H), 9.32 (s, 1H), 7.26 (d, 2H), 6.97 (m, 2H), 6.29 (s, 1H), 3.61 (d, 2H), 2.59 (m, 4H), 2.43 (s, 3H), 1.80 (m, 1H), 1.65 (d, 2H), 1.45 (q, 2H), 1.20 (m, 2H), 0.95 (t, 6H), 0.87 (m, 2H), 0.62 (m, 2H).

Example 16: -chloro-N-(3-cyclopropyl(3-(dimethylamino)pyrrolidineyl)phenyl)(6-me thyl-1H-indoleyl)pyrimidineamine 11498815_1 (GHMatters) P109554.NZ 110 mg of a desired compound was obtained at a yield of 54% in substantially the same manner as in Step 6) of e 1, except that 103 mg (0.42 mmol) of 1-(3-aminocyclopropylphenyl)-N, N-dimethylpyrrolidineamine was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 120 mg (0.42 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 487 [M+H]+ ] 1H-NMR (300 MHz, DMSO-d6): δ 11.73 (s, 1H), 9.24 (s, 1H), 8.43 (m, 3H), 7.24 (s, 1H), 6.90 (d, 1H), 6.87 (s, 1H), 6.73 (s, 1H), 5.90 (s, 1H), 3.24 (m, 1H), 3.20 (m, 1H), 2.90 (m, 1H), 2.46 (m, 1H), 2.40 (s, 3H), 1.96 (m, 6H), 1.73 (m, 2H), 0.81 (m, 2H), 0.61 (m, 2H).

] Example 17: 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperazineyl)methylpropaneol 36 mg of a desired compound was obtained at a yield of 29% in substantially the same manner as in Step 6) of Example 1, except that 67 mg (0.23 mmol) of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)methylpropaneol was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 70 mg (0.25 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of -dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 531 [M+H]+ 11498815_1 (GHMatters) P109554.NZ 1H-NMR (300 MHz, DMSO-d6): δ 11.75 (s, 1H), 9.32 (s, 1H), 8.44 (m, 3H), 7.27 (s, 1H), 7.23 (s, 1H), 6.97 (d, 1H), 6.89 (s, 1H), 6.27 (s, 1H), 4.24 (m, 1H), 3.26 (m, 2H), 3.00 (m, 4H), 2.58 (m, 4H), 2.42 (s, 3H), 1.79 (m, 1H), 0.94 (s, 6H), 0.88 (m, 2H), 0.63 (m, 2H).

Example 18: N-(3-(4-aminopiperidineyl)cyclopropylphenyl)chloro(6-methyl-1H-ind oleyl)pyrimidineamine 32 mg of a d compound was obtained at a yield of 29% in substantially the same manner as in Step 6) of Example 1, except that 76 mg (0.23 mmol) of turt-butyl (1-(3-aminocyclopropylphenyl)piperidineyl)carbamate was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 70 mg (0.25 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 473 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.77 (s, 1H), 9.33 (s, 1H), 8.47 (m, 3H), 7.28 (s 1H), 7.19 (m, 1H), 6.97 (m, 2H), 6.31 (s, 1H), 3.67 (d, 2H), 3.11 (m, 1H), 2.73 (m, 3H), 2.43 (s, 3H), 1.82 (m, 3H), 1.54 (m, 3H), 0.90 (m, 2H), 0.63 (m, 2H).

Example 19: -chloro-N-(3-cyclopropyl(4-(methylamino)piperidineyl)phenyl)(6-methy ndoleyl)pyrimidineamine 11 mg of a desired compound was obtained at a yield of 10% in ntially 11498815_1 (GHMatters) P109554.NZ the same manner as in Step 6) of Example 1, except that 79 mg (0.23 mmol) of turt-butyl (1-(3-amino)piperidineyl)(methyl)carbamate was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol and 70 mg (0.25 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 487 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.75 (bs, 1H), 9.30 (s, 1H), 8.46 (m, 3H), 7.27 (s, 1H), 7.19 (s, 1H), 6.96 (d, 1H), 6.93 (s, 1H), 6.29 (s, 1H), 3.54 (m, 2H), 3.33 (s, 3H), 2.63 (m, 4H), 2.42 (s, 3H), 1.81 (m, 3H), 1.23 (m, 2H), 0.86 (2H), 0.62 (2H).

Example 20: 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperazineyl)methylpropaneol 30 mg of a desired compound was obtained at a yield of 33% in substantially the same manner as in Step 6) of Example 1, except that 50 mg (0.17 mmol) of 3-aminocyclopropylphenyl)piperazineyl)methylpropaneol was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol in Step 6) of Example 1.

MS (ESI+, m/z): 535 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.95 (s, 1H), 9.39 (s, 1H), 8.57 (m, 1H), 8.49 (d, 1H), 8.45 (s, 1H), 7.30 (dd, 1H), 7.26 (s, 1H), 6.96 (m, 1H), 6.90 (s, 1H), 6.28 (s, 1H), 4.24 (m, 1H), 3.29 (m, 2H), 3.01 (bs, 4H), 2.60 (bs, 4H), 1.79 (m, 1H), 0.95 (s, 6H), 0.87 (m, 2H), 0.63 (m, 2H).

Example 21: 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperidineyl)ethaneol 11498815_1 ters) P109554.NZ 7 mg of a desired compound was obtained at a yield of 6% in substantially the same manner as in Step 6) of Example 1, except that 64 mg (0.25 mmol) of 2-(4-(3-aminocyclopropylphenyl)piperidineyl)ethaneol was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 103 mg (0.37 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 502 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.78 (s, 1H), 9.43 (s, 1H), 8.49 (m, 3H), 7.51 (s, 1H), 7.29 (s, 1H), 6.95 (d, 1H), 6.57 (s, 1H), 4.44 (m, 1H), 3.52 (s, 2H), 2.98 (d, 2H), 2.43 (s, 3H), 2.06 (m, 2H), 1.83 (m,1H), 1.70 (m, 4H), 1.23 (s, 2H), 0.91 (m, 2H), 0.64 (m, 2H).

Example 22: 3-((5-chloro(6-chloro-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperazineyl)ethaneol 84 mg of a desired compound was obtained at a yield of 59% in ntially the same manner as in Step 6) of Example 1, except that 88 mg (0.29 mmol) of 6-chloro(2,5-dichloropyrimidineyl)chloro-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 532 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.99 (s, 1H), 9.39 (s, 1H), 8.57 (d, 1H), 8.51 (s, 1H), 8.46 (s, 1H), 7.55 (d, 1H), 7.19 (s, 1H), 7.11 (dd, 1H), 6.89 (s, 1H), 6.30 (s, 1H), 4.41 (t, 1H), 3.51 (q, 2H), 3.03 (s, 4H), 2.46 (s, 4H), 2.40 (t, 2H), 1.79 (m, 1H), 11498815_1 ters) P109554.NZ 0.87 (m, 2H), 0.62 (m, 2H).

Example 23: -chloro-N-(3-cyclopropyl(4-(pyrrolidineyl)piperidineyl)phenyl)(6-met hyl-1H-indoleyl)pyrimidineamine 135 mg of a desired compound was obtained at a yield of 73% in substantially the same manner as in Step 6) of e 1, except that 100 mg (0.35 mmol) of 3-cyclopropyl(4-(pyrrolidineyl)piperidineyl)aniline was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 146 mg (0.53 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 527 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.76 (s, 1H), 9.33 (s, 1H), 8.45 (m, 3H), 7.27 (s, 1H), 7.23 (s, 1H), 6.96 (s, 1H), 6.93 (s, 1H), 6.30 (s, 1H), 3.53 (d, 2H), 3.34 (m, 7H), 2.42 (s, 3H), 1.85 (m, 3H), 1.69 (s, 4H), 1,43 (d, 2H), 0.86 (m, 2H), 0.62 (m, Example 24: 1-(1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperidineyl)azetidineol 130 mg of a desired compound was obtained at a yield of 71% in substantially the same manner as in Step 6) of Example 1, except that 100 mg (0.35 11498815_1 (GHMatters) P109554.NZ mmol) of 1-(1-(3-aminocyclopropylphenyl)piperidineyl)azetidineol was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 145 mg (0.52 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 529 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.77 (s, 1H), 9.32 (s, 1H), 8.47 (m, 3H), 7.27 (s, 1H), 7.20 (s, 1H), 6.96 (s, 1H), 6.94 (s, 1H), 5.27 (brs, 1H), 3.73 (m, 5H), 2.72 (m, 5H), 1.90 (m, 3H), 1.31 (m, 2H), 0.88 (m, 2H), 0.62 (m, 2H).

Example 25: 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)methoxyphenyl)pip erazineyl)ethaneol HN N N OMe ] N 25 mg of a desired compound was obtained at a yield of 27% in ntially the same manner as in Step 6) of Example 1, except that 48 mg (0.19 mmol) of 2-(4-(3-aminomethoxyphenyl)piperazineyl)ethaneol was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 56 mg (0.21 mmol) of 3-(2,5-dichloropyrimidineyl)-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 479 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.87 (bs, 1H), 9.39 (s, 1H), 8.58 (d, 1H), 8.44 (m, 2H), 7.49 (d, 1H), 7.22 (m, 1H), 7.13 (m, 1H), 6.96 (s, 2H), 6.10 (s, 1H), 3.63 (s, 3H), 3.52 (m, 2H), 3.39 (m, 2H), 3.05 (m, 4H), 2.46 (m, 2H).

Example 26: 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)phenyl)piper 1-yl)ethaneol 11498815_1 (GHMatters) P109554.NZ 23 mg of a d compound was obtained at a yield of 28 % in ntially the same manner as in Step 6) of Example 1, except that 50 mg (0.177 mmol) of 2-(4-(3-aminophenyl)piperazineyl)ethaneol was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol in Step 6) of Example MS (ESI+, m/z): 467 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.93 (bs, 1H), 9.47 (s, 1H), 8.60 (m, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 7.33 (s, 1H), 7.29 (m, 2H), 7.13 (t, 1H), 6.98 (m, 1H), 6.59 (m, 1H), 4.42 (t, 1H), 3.53 (q, 2H), 3.05 (m, 4H), 2.48 (m, 4H), 2.41 (t, 2H).

Example 27: 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)phenyl)piperidineyl )ethaneol HN N 20 mg of a desired compound was obtained at a yield of 25% in substantially the same manner as in Step 6) of Example 1, except that 40 mg (0.18 mmol) of 2-(4-(3-aminophenyl)piperidineyl)ethaneol was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 53 mg (0.20 mmol) of 3-(2,5-dichloropyrimidineyl)-1H-indole was used d of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 448 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.92 (s, 1H), 9.57 (s, 1H), 8.58 (d, 1H), 8.47 (m, 2H), 7.67 (s, 1H), 7.64 (d, 1H), 7.52 (d, 1H), 7.25 (q, 2H), 7.12 (t, 1H), 6.88 (d, 1H), 4.41 (bs, 1H), 3.43 (m, 2H), 2.94 (m, 2H), 2.41 (m, 3H), 2.03 (m, 2H), 1.61 (m, 11498815_1 (GHMatters) P109554.NZ Example 28: 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)phenyl) piperazineyl)ethaneol HN N 33 mg of a desired compound was obtained at a yield of 39% in substantially the same manner as in Step 6) of Example 1, except that 42 mg (0.19 mmol) of 2-(4-(3-aminophenyl)piperazineyl)ethaneol was used instead of 22-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 55 mg (0.21 mmol) of 3-(2,5-dichloropyrimidineyl)-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 449 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.88 (s, 1H), 9.43 (s, 1H), 8.57 (m, 1H), 8.46 (m, 2H), 7.49 (d, 1H), 7.34 (s, 1H), 7.26 (m, 4H), 6.57 (m, 1H), 4.41 (m, 1H), 3.52 (m, 2H), 3.04 (s, 4H), 2.47 (m, 4H), 2.38 (m, 2H). e 29: -chloro-N-(3-(4-(dimethylamino)piperidineyl)phenyl)(1H-indoleyl)pyrim idineamine ] 47 mg of a desired compound was obtained at a yield of 66% in substantially the same manner as in Step 6) of Example 1, except that 35 mg (0.16 mmol) of 1-(3-aminophenyl)-N, thylpiperidineamine was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 48 mg (0.18 11498815_1 (GHMatters) P109554.NZ mmol) of 3-(2,5-dichloropyrimidineyl)-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of e 1.

MS (ESI+, m/z): 447 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.90 (s, 1H), 9.43 (s, 1H), 8.58 (d, 1H), 8.44 (m, 2H), 7.51 (d, 1H), 7.38 (s, 1H), 7.22 (t, 2H), 7.12 (q, 2H), 6.59 (dd, 1H), 3.61 (m, 3H), 2.60 (t, 2H), 2.20 (s, 6H), 1.78 (d, 2H), 1.44 (m, 2H).

Example 30: -chloro-N-(3-(3-(dimethylamino)pyrrolidineyl)phenyl)(1H-indoleyl)pyri midineamine 26 mg of a desired compound was obtained at a yield of 38% in substantially the same manner as in Step 6) of Example 1, except that 33 mg (0.16 mmol) of (S)(3-aminocyclopropylphenyl)-N, N-dimethylpyrrolidineamine was used d of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 48 mg (0.18 mmol) of -dichloropyrimidineyl)-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 473 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.88 (bs, 1H), 9.38 (s, 1H), 8.58 (d, 1H), 8.47 (d, 1H), 8.43 (s, 1H), 7.48 (d, 1H), 7.21 (t, 1H), 7.11 (m, 3H), 6.98 (s, 1H), 6.20 (m, 1H), 3.48 (m, 2H), 3.29 (m, 2H), 2.94 (t, 1H), 2.78 (m, 1H), 2.12 (s, 6H), 1.73 (m, Example 31: 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)methoxyp henyl)piperazineyl)ethaneol 11498815_1 (GHMatters) P109554.NZ 40 mg of a desired compound was obtained at a yield of 50% in substantially the same manner as in Step 6) of Example 1, except that 40 mg (0.16 mmol) of 2-(4-(3-aminomethoxyphenyl)piperazineyl)ethaneol was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol in Step 6) of Example MS (ESI+, m/z): 497 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.95 (s, 1H), 9.46 (s, 1H), 8.60 (dd, 1H), 8.50 (m, 2H), 7.29 (dd, 1H), 6.99 (m, 3H), 6.13 (s, 1H), 4.43 (t, 1H), 3.66 (s, 3H), 3.52 (q, 2H), 3.06 (bs, 4H), 2.49 (bs, 4H), 2.40 (t, 2H).

] Example 32: 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)isopropoxyphenyl) zineyl)ethaneol 61 mg of a desired compound was obtained at a yield of 67% in ntially the same manner as in Step 6) of Example 1, except that 50 mg (0.18 mmol) of 2-(4-(3-aminoisopropoxyphenyl)piperazineyl)ethaneol was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol, and 54 mg (0.20 mmol) of 3-(2,5-dichloropyrimidineyl)-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole in Step 6) of Example 1.

MS (ESI+, m/z): 507 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.87 (bs, 1H), 9.36 (s, 1H), 8.56 (d, 1H), 8.44 (s, 1H), 7.49 (d, 1H), 7.22 (m, 1H), 7.13 (m, 1H), 6.95 (m, 2H), 6.06 (s, 1H), 4.48 (m, 1H), 4.40 (m, 1H), 3.52 (m, 2H), 3.02 (m, 4H), 2.48 (m, 5H), 1.20 (m, 6H). 11498815_1 (GHMatters) P109554.NZ Example 33: 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)isopropox yphenyl)piperazineyl)ethaneol 74 mg of a desired compound was obtained at a yield of 78% in substantially the same manner as in Step 6) of Example 1, except that 50 mg (0.18 mmol) of 2-(4-(3-aminoisopropoxyphenyl)piperazineyl)ethaneol was used d of 2-(4-(3-aminocyclopropylphenyl)piperazineyl)ethaneol in Step 6) of Example ] MS (ESI+, m/z): 525 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.91 (bs, 1H), 9.39 (s, 1H), 8.59 (m, 1H), 8.46 (s, 2H), 7.28 (d, 1H), 6.97 (m, 3H), 6.07 (s, 1H), 4.48 (m, 1H), 4.40 (m, 1H), 3.50 (m, 2H), 3.27 (m, 4H), 2.48 (m, 3H), 1.17 (m, 6H).

Example 34: -chloro-N-(3-cyclopropyl(piperazineylmethyl)phenyl)(6-fluoro-1H-indol eyl)pyrimidineamine Step 1) Preparation of 3-bromonitrobenzoic acid 11.2 g (67 mmol) of 3-nitrobenzoic acid was dissolved in 30 mL of concentrated (conc.) sulfuric acid ), and the temperature was raised to 60 . 14.3 g (80.4 mmol) of N-bromosuccinimide was added thereto three times for 15 minutes. The mixture was then stirred at a temperature of 60 for 2 hours. Once the on was complete, ice was added to the reaction mixture. The resulting solid was filtered, and then dried at a temperature of 50 in an oven for 12 hours to y 11498815_1 (GHMatters) P109554.NZ obtain 16.4 g of a desired nd at a yield of 99%. 1H-NMR (300 MHz, DMSO-d6): δ 8.59 (s, 1H), 8.51 (s, 1H), 8.38 (s, 1H).

] Step 2) Preparation of (3-bromonitrophenyl)methanol 4.0 g (16.3 mmol) of 3-bromonitrobenzoic acid prepared in Step 1) was dissolved in 25 mL of THF, and the temperature was lowered to 0 . 32.5 mL (65.2 mmol) of borane-dimethyl e (2.0 M in THF) was slowly added dropwise thereto for 45 minutes. The mixture was stirred at room temperature for 12 hours, and then stirred under reflux at a temperature of 70 for 1.5 hours. Once the on was complete, the resultant was cooled to room ature, and saturated sodium en carbonate was added dropwise thereto. An extraction process was performed thereon three times using ethyl acetate, and an organic layer was washed with saline water, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using column chromatography (chloromethylene:methanol=10:1 (v/v)), and the resulting solution was concentrated under reduced pressure to thereby obtain 3.0 g of a desired compound at a yield of 1H-NMR (300 MHz, DMSO-d6): δ 8.23 (s, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 4.63 (s, 2H).

Step 3) Preparation of (3-cyclopropylnitrophenyl)methanol 5 g (22.93 mmol) of (3-bromonitrophenyl)methanol prepared in Step 2), .9 g (68.80 mmol) of cyclopropylboronic acid, 514 mg (2.29 mmol) of Pd(OAc)2, 14.6 g (68.80 mmol) of -potassium ate, and 1.8 g (6.88 mmol) of triphenylphosphine were dissolved in 75 mL of a mixed solvent of toluene and H2O (at a ratio of 2:1), and then purged with en for 5 minutes to remove gas. The reaction mixture was sealed, and the temperature was raised to 100 , followed by 11498815_1 (GHMatters) P109554.NZ stirring under reflux for 12 hours. Once the reaction was complete, the mixture solution was cooled to room ature, and the mixture solution was filtered using a celite filter. The celite layer was washed with ethyl acetate. An organic layer was separated from the mixture solution, and the organic layer was washed with saline water, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using column tography (ethyl acetate:hexane=1:10 , and the ing solution was concentrated under reduced pressure to thereby obtain 1.25 g of a desired compound at a yield of 50%. 1H-NMR (300 MHz, DMSO-d6): δ 8.07 (s, 1H), 7.71 (s, 1H), 7.25 (s, 1H), 4.70 (s, 2H), 1.90 (m, 1H), 1.01 (m, 2H), 0.71 (m, 2H).

] Step 4) Preparation of 2-(4-(3-nitrobenzyl)piperazineyl)ethaneol 1.0 g (6.53 mmol) of (3-cyclopropylnitrophenyl)methanol prepared in Step 3) was dissolved in 44 mL of a solvent (THF:water=10:1). Subsequently, 0.52 g (13.06 mmol) of sodium hydroxide and 1.6 g (8.49 mmol) of p-toluenesulfonyl chloride were added thereto. The e was stirred at room temperature for 2 hours. Once the reaction was complete, water was added dropwise thereto. An tion process was performed n three times using ethyl acetate, and an organic layer was washed with saline water, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 20 mL of N, N-dimethyl formamide, and then, 1.33 g (9.60 mmol) of potassium carbonate (K2CO3) and 0.75 g (5.76 mmol) of 2-(piperazineyl)ethaneol were added o, followed by stirring at a ature of 100 for 1 hour. Once the reaction was complete, the mixture solution was cooled to room temperature, and ethyl acetate and water was added dropwise thereto. An c layer was extracted therefrom, and the organic layer was washed with saline water, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using column chromatography (chloromethylene:methanol=30:1 (v/v)), and the resulting solution was concentrated under reduced pressure to thereby obtain 602 mg 11498815_1 (GHMatters) P109554.NZ of a desired nd at a yield of 47%. 1H-NMR (300 MHz, 6): δ 8.11 (s, 1H), 8.07 (m, 1H), 7.74 (d, 1H), 7.60 (t, 1H), 4.33 (t, 1H), 3.56 (s, 2H), 3.43 (m, 2H), 2.34 (m, 10H).

Step 5) Preparation of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol 50% ethanol was added to iron (Fe) powder, and conc. HCl was slowly added dropwise thereto. The mixture was then stirred under reflux at a ature of 120 for 1 hour to activate the mixture. 602 mg (2.27 mmol) of 3-nitrobenzyl)piperazineyl)ethaneol prepared in Step 4) was added to the activated iron mixture, followed by stirring under reflux at a temperature of 120 for 1 hour. Once the reaction was complete, a filtration process was performed thereon using a celite filter. A mixture solution of chloroform and 2-propanol (3:1) and saturated sodium hydrogen carbonate solution were added dropwise to the filtrate. An organic layer was separated from the mixture on, washed with saline water, dried using anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain 330 mg of a desired compound at a yield of 62%.

Step 6) Preparation of 3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)benzyl)piperazineyl)eth aneol 45 mg (0.19 mmol) of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol prepared in Step 5) and 50 mg (0.19 mmol) of -dichloropyrimidineyl)-1H-indole (prepared according to WO 2013-014448) were dissolved in 2-butanol, and 36 mg (0.19 mmol) of p-toluenesulfonate (p-TsOH) was added thereto. This reaction mixture was d under reflux at a temperature of 120 for 4 hours. Once the reaction was complete, the mixture was cooled to room 11498815_1 (GHMatters) P109554.NZ temperature, and a saturated sodium hydrogen carbonate solution was added dropwise thereto, followed by an extraction process using chloromethylene for 2 times. The extracted organic layer was washed with saline water, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using column chromatography (chloroform:methanol=9:1 (v/v)), and the resulting solution was trated under reduced pressure to thereby obtain 31 mg of a desired compound at a yield of 35%.

MS (ESI+, m/z): 463 [M+H]+ 1H-NMR (300 MHz, 6): δ 11.89 (bs, 1H), 9.58 (s, 1H), 8.55 (d, 1H), 8.48 (m, 2H), 7.70 (m, 2H), 7.49 (d, 1H), 7.20 (m, 2H), 7.12 (t, 1H), 6.91 (d, 1H), 4.32 (m, 1H), 3.66 (m, 5H), 2.34 (m, 9H).

Example 35: 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)methoxyb enzyl)piperazineyl)ethaneol 79 mg of a desired compound was obtained at a yield of 59% in substantially the same manner as in Step 6) of Example 35, except that 63 mg (0.24 mmol) of 2-(4-(3-aminomethoxybenzyl)piperazineyl)ethaneol was used instead of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol, and 68 mg (0.24 mmol) of -dichloropyrimidineyl)fluoro-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)-1H-indole in Step 6) of e 35.

MS (ESI+, m/z): 511 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.96 (bs, 1H), 9.62 (s, 1H), 8.63 (m, 1H), 8.51 (d, 1H), 8.48 (s, 1H), 7.38 (s, 1H), 7.25 (m, 2H), 6.93 (m, 1H), 6.51 (s, 1H), 4.35 (t, 1H), 3.69 (s, 3H), 3.37 (m, 4H), 2.32 (m, 10H). e 36: 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)benzyl)piper 11498815_1 (GHMatters) P109554.NZ azineyl)ethaneol 53 mg of a desired compound was obtained at a yield of 52% in substantially the same manner as in Step 6) of Example 35, except that 59 mg (0.21 mmol) of -dichloropyrimidineyl)fluoro-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)-1H-indole in Step 6) of e 35.

MS (ESI+, m/z): 481 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.94 (bs, 1H), 9.62 (s, 1H), 8.61 (m, 1H), 8.57 (m, 1H), 7.69 (m, 2H), 7.25 (m, 2H), 6.94 (m, 2H), 4.34 (m, 1H), 3.46 (m, 5H), 2.32 (m, 9H).

Example 37: 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)methoxybenzyl)pip erazineyl)ethaneol 44 mg of a desired compound was obtained at a yield of 47% in substantially the same manner as in Step 6) of Example 35, except that 50 mg (0.19 mmol) of 2-(4-(3-aminomethoxybenzyl)piperazineyl)ethaneol was used instead of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol in Step 6) of Example 35.

] MS (ESI+, m/z): 493 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.89 (bs, 1H), 9.56 (s, 1H), 8.60 (d, 1H), 8.48 (m, 2H), 7.49 (d, 1H), 7.38 (s, 1H), 7.37 (m, 3H), 6.49 (s, 1H), 4.33 (m, 1H), 3.66 (s, 2H), 3.40 (m, 5H), 2.32 (m, 9H).

Example 38: 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylbenzyl) piperazineyl)methylpropaneol 11498815_1 ters) P109554.NZ 31 mg of a desired compound was obtained at a yield of 45% in substantially the same manner as in Step 6) of Example 35, except that 40 mg (0.13 mmol) of 2-(4-(3-aminocyclopropylbenzyl)piperazineyl)methylpropaneol was used instead of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol in Step 6) of e 35.

MS (ESI+, m/z): 531 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.92 (s, 1H), 9.50 (s, 1H), 8.59 (d, 1H), 8.50 (d, 1H), 8.45 (s, 1H), 7.51 (m, 3H), 7.22 (t, 1H), 7.12 (t, 1H), 6.63 (s, 1H), 3.77 (m, 1H), 3.24 (bs, 2H), 2.33 (bs, 4H), 1.85 (m, 1H), 1.23 (m, 2H), 0.92 (m, 10H), 0.61 (m, 2H).

Example 39: (S)((1-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylbe nzyl)piperidineyl)(methyl)amino)propaneol 26 mg of a desired compound was obtained at a yield of 30% in substantially the same manner as in Step 6) of Example 35, except that 50 mg (0.16 mmol) of (S)((1-(3-aminocyclopropylbenzyl)piperidineyl)(methyl)amino)propaneol was used instead of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol in Step 6) of Example 35.

] MS (ESI+, m/z): 545 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.94 (s, 1H), 9.51 (s, 1H), 8.60 (d, 1H), 8.50 (d, 1H), 8.45 (s, 1H), 7.51 (m, 3H), 7.22 (t, 1H), 7.12 (t, 1H), 6.62 (s, 1H), 3.66 (bs, 1H), 3.50 (s, 2H), 2.81 (d, 2H), 2.31 (s, 3H), 1.89 (m, 2H), 1.60 (m, 2H), 1.48 (m, 3H), 1.27 (m, 2H), 1.02 (d, 3H), 0.91 (m, 2H), 0.61 (m, 2H). 15_1 (GHMatters) P109554.NZ Example 40: (S)((1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclo propylbenzyl)piperidineyl)(methyl)amino)propaneol 67 mg of a d compound was obtained at a yield of 75% in substantially the same manner as in Step 6) of Example 35, except that 50 mg (0.16 mmol) of (S)((1-(3-aminocyclopropylbenzyl)piperidineyl)(methyl)amino)propaneol was used d of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol, and 48 mg (0.17 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)-1H-indole in Step 6) of Example 35.

MS (ESI+, m/z): 559 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.78 (s, 1H), 9.49 (s, 1H), 8.47 (m, 3H), 7.48 (m, 1H), 7.39 (s, 1H), 7.27 (s, 1H), 6.95 (d, 1H), 6.63 (s, 1H), 3.85 (bs, 1H), 3.50 (m, 2H), 2.82 (d, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 1.86 (m, 3H), 1.63 (m, 2H), 1.51 (m, 3H), 1.24 (m, 2H), 1.03 (d, 3H), 0.91 (m, 2H), 0.62 (m, 2H). e 41: 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylbenzyl)piperazineyl)methylpropaneol 40 mg of a desired compound was obtained at a yield of 52% in substantially the same manner as in Step 6) of Example 35, except that 43 mg (0.14 mmol) of 3-aminocyclopropylbenzyl)piperazineyl)methylpropaneol was used instead of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol, and 43 mg (0.16 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)-1H-indole in Step 6) of Example 35. 11498815_1 (GHMatters) P109554.NZ MS (ESI+, m/z): 545 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.77 (s, 1H), 9.47 (s, 1H), 8.46 (m, 3H), 7.44 (s, 1H), 7.38 (s, 1H), 7.27 (s, 1H), 6.95 (d, 1H), 6.62 (s, 1H), 4.56 (m, 1H), 3.64 (s, 2H), 3.37 (m, 4H), 3.16 (m, 2H), 2.41 (s, 3H), 2.33 (m, 4H), 1.78 (m, 1H), 0.91 (m, 8H), 0.62 (m, 2H).

Example 42: (S)(1-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylben zyl)piperidineyl)pyrrolidineol 60 mg of a desired compound was ed at a yield of 69% in substantially the same manner as in Step 6) of Example 35, except that 50 mg (0.16 mmol) of (S)(1-(3-aminocyclopropylbenzyl)piperidineyl)pyrrolidineol was used instead of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol in Step 6) of e 35.

MS (ESI+, m/z): 543 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.94 (s, 1H), 9.50 (s, 1H), 8.59 (d, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 7.61 (m, 3H), 7.24 (m, 2H), 6.62 (s, 1H), 4.63 (d, 1H), 4.12 (m, 2H), 2.71 (m, 4H), 2.45 (m, 2H), 1.92 (m, 4H), 1.70 (m, 2H), 1.45 (m, 1H), 1.33 (m, 4H), 0.90 (m, 2H), 0.61 (m, 2H).

Example 43: (S)(1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclo propylbenzyl)piperidineyl)pyrrolidineol 50 mg of a d compound was obtained at a yield of 56% in substantially the same manner as in Step 6) of Example 35, except that 50 mg (0.16 mmol) of 11498815_1 (GHMatters) P109554.NZ (S)(1-(3-aminocyclopropylbenzyl)piperidineyl)pyrrolidineol was used d of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol, and 47 mg (0.17 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)-1H-indole in Step 6) of Example 35.

MS (ESI+, m/z): 557 [M+H]+ ] 1H-NMR (300 MHz, DMSO-d6): δ 11.78 (s, 1H), 9.47 (s, 1H), 8.47 (m, 3H), 7.46 (s, 1H), 7.40 (s, 1H), 7.27 (s, 1H), 6.96 (d, 1H), 6.62 (s, 1H), 4.64 (d, 1H), 4.13 (m, 2H), 3.17 (d, 2H), 2.72 (t, 4H), 2.42 (s, 3H), 2.33 (d, 1H), 1.93 (m, 3H), 1.70 (m, 2H), 1.60 (m, 1H), 1.33 (m, 4H), 0.90 (m, 2H), 0.63 (m, 2H).

Example 44: (S)(1-(3-((5-chloro(6-methoxy-1H-indoleyl)pyrimidineyl)amino)cycl opropylbenzyl)piperidineyl)pyrrolidineol 29 mg of a desired compound was obtained at a yield of 30% in substantially the same manner as in Step 6) of Example 35, except that 54 mg (0.17 mmol) of (1-(3-aminocyclopropylbenzyl)piperidineyl)pyrrolidineol was used instead of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol, and 50 mg (0.17 mmol) of 3-(2,5-dichloropyrimidineyl)methoxy-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)-1H-indole in Step 6) of Example 35.

MS (ESI+, m/z): 573 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.71 (s, 1H), 9.45 (s, 1H), 8.49 (m, 3H), 7.41 (d, 2H), 6.97 (s, 1H), 6.75 (d, 1H), 6.62 (s, 1H), 4.62 (s, 1H), 4.33 (s, 1H), 4.12 (s, 1H), 3.79 (s, 3H), 2.72 (m, 4H), 2.25 (m, 1H), 1.89 (m, 4H), 1.70 (m, 2H), 1.45 (m, 1H), 0.95 (m, 4H), 0.90 (m, 2H), 0.61 (m, 2H).

Example 45: 1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclopropyl benzyl)piperidineol 11498815_1 (GHMatters) P109554.NZ 100 mg of a desired compound was ed at a yield of 88% in substantially the same manner as in Step 6) of Example 35, except that 57 mg (0.23 mmol) of 1-(3-aminocyclopropylbenzyl)piperidineol was used instead of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol, and 96 mg (0.35 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)-1H-indole in Step 6) of e 35.

MS (ESI+, m/z): 488 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.82 (s, 1H), 9.52 (s, 1H), 8.53 (m, 3H), 7.47 (d, 2H), 7.32 (s, 1H), 6.99 (d, 1H), 6.68 (s, 1H), 4.59 (s, 1H), 3.48 (m, 2H), 2.70 (m, 2H), 2.46 (s, 3H), 2.05 (m, 2H), 1.87 (m, 1H), 1.72 (d, 2H), 1.41 (d, 2H), 0.92 (m, 2H), 0.65 (d, 2H).

Example 46: (S)chloro-N-(3-cyclopropyl((3-(dimethylamino)pyrrolidineyl)methyl)phe nyl)(6-methyl-1H-indoleyl)pyrimidineamine 180 mg of a d compound was obtained at a yield of 96% in substantially the same manner as in Step 6) of Example 35, except that 100 mg (0.37 mmol) of (S)(3-aminocyclopropylbenzyl)-N, N-dimethylpyrrolidineamine was used instead of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol, and 153 mg (0.55 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)-1H-indole in Step 6) of Example 35.

MS (ESI+, m/z): 501 [M+H]+ 1H-NMR (300 MHz, 6): δ 11.83 (s, 1H), 9.52 (s, 1H), 8.52 (m, 3H), 7.56 (s, 1H), 7.42 (s, 1H), 7.32 (s, 1H), 6.99 (d, 1H), 6.67 (s, 1H), 3.58 (d, 1H), 3.47 11498815_1 (GHMatters) P109554.NZ (m, 2H), 2.87 (m, 1H), 2.65 (t, 1H), 2.47 (s, 3H), 2.32 (m, 2H), 2.19 (s, 6H), 1.88 (m, 2H), 1.70 (m, 1H), 1.09 (t, 1H), 0.93 (d, 2H), 0.65 (d, 2H).

Example 47: 3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)cycloprop yl)piperazineyl)hydroxyethaneone 19 mg of a desired compound was obtained at a yield of 19% in substantially the same manner as in Step 6) of Example 35, except that 53 mg (0.18 mmol) of 1-(4-(3-aminocyclopropylbenzyl)piperazineyl)2-hydroxyethaneone was used instead of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol, and 51 mg (0.18 mmol) of 3-(2,5-dichloropyrimidineyl)fluoro-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)-1H-indole in Step 6) of Example 35.

MS (ESI+, m/z): 535 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.95 (bs, 1H), 9.54 (s, 1H), 8.60 (t, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 7.48 (s, 1H), 7.39 (s, 1H), 7.28 (dd, 1H), 6.92 (m, 1H), 6.66 (s, 1H), 4.50 (t, 1H), 4.04 (d, 1H), 3.40 (bs, 4H), 3.28 (m, 2H), 2.32 (m, 4H), 1.85 (m, 1H), 0.83 (m, 2H), 0.60 (m, 2H).

Example 48: 1-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylbenzyl)piperazineyl)hydroxyethaneone O HN N N NH 31 mg of a desired compound was obtained at a yield of 32% in substantially the same manner as in Step 6) of Example 35, except that 53 mg (0.18 mmol) of 1-(4-(3-aminocyclopropylbenzyl)piperazineyl)2-hydroxyethaneone was used 11498815_1 ters) P109554.NZ instead of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol, and 56 mg (0.20 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidineyl)-1H-indole in Step 6) of Example 35.

MS (ESI+, m/z): 531 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.77 (s, 1H), 9.48 (s, 1H), 8.47 (m, 3H), 7.51 (s, 1H), 7.40 (s, 1H), 7.27 (s, 1H), 6.96 (d, 1H), 6.65 (s, 1H), 4.50 (t, 1H), 4.05 (d, 2H), 3.79 (m, 1H), 3.40 (s, 4H), 3.27 (m, 1H), 2.42 (s, 3H), 2.32 (m, 4H), 1.86 (m, 1H), 0.93 (m, 2H), 0.65 (m, 2H).

] Example 49: 2-(4-(3-((5-chloro(6-ethyl-1H-indoleyl)pyrimidineyl)amino)cyclopropyl benzyl)piperazineyl)ethaneol 70 mg of a desired compound was obtained at a yield of 65% in substantially the same manner as in Step 6) of Example 35, except that 56 mg (0.20 mmol) of 2-(4-(3-aminocyclopropylbenzyl)piperazineyl)ethaneol was used instead of 2-(4-(3-aminobenzyl)piperazineyl)ethaneol, and 84 mg (0.30 mmol) of 3-(2,5-dichloropyrimidineyl)ethyl-1H-indole was used d of 3-(2,5-dichloropyrimidineyl)-1H-indole in Step 6) of Example 35.

MS (ESI+, m/z): 531 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.78 (s, 1H), 9.47 (s, 1H), 8.48 (m, 3H), 7.47 (s, 1H), 7.41 (s, 1H), 7.29 (s, 1H), 6.98 (d, 1H), 6.34 (s, 1H), 4.35 (t, 1H), 3.45 (q, 2H), 2.72 (q, 2H), 2.36 (m, 1H), 1.84 (m, 1H), 1.24 (t, 4H), 0.91 (m, 2H), 0.64 (m, 2H).

Example 50: -chloro(1H-indoleyl)pyrimidineyl)amino)methoxyphenyl)(4-(2-hy droxyethyl)piperazineyl)methanone Step 1) ation of 3-methoxynitrobenzoyl chloride 11498815_1 (GHMatters) P109554.NZ 1.0 g (5.07 mmol) of 3-methoxynitrobenzoate was dissolved in 10 mL of romethane. 0.9 mL (10.14 mmol) of oxalyl chloride and 3 to 4 drops of N, N-dimethylformamide were added thereto. The e was d at room temperature for 3 hours. Once the reaction was complete, a solvent was d under reduced pressure to obtained 1.09 g of a desired compound at a yield of 99%.

Step 2) (4-(2-hydroxyethyl)piperazineyl)(3-methoxynitrophenyl)methanone 1.09 g (5.06 mmol) 3-methoxynitrobenzoyl chloride prepared in Step 1) and 2.0 g (15.18 mmol) of 2-(piperazineyl)ethaneol, and 2.1 mL (15.18 mmol) of triethylamine were dissolved in 10 mL of dichloromethane, and then, the mixture was stirred at room temperature for 17 hours. Once the reaction was complete, water and chloroform were added dropwise thereto. An organic layer was separated rom and washed with water 2 times. The organic layer was washed with saline water and dried using anhydrous sodium sulfate, followed by removal of a solvent under reduced pressure. The obtained residue was purified using MPLC (chloroform:methanol=20:1 (v/v)), and the resulting solution was trated under reduced pressure to thereby obtain 1.08 g of a desired compound at a yield of 69%.

Step 3) (3-aminomethoxyphenyl)(4-(2-hydroxyethyl)piperazineyl)methanone ] 975 mg (17.46 mmol) of iron and 0.12 mL (1.40 mmol) of hydrochloric acid were dissolved in 12 mL of 50% ethanol. The mixture was stirred under reflux at a 11498815_1 (GHMatters) P109554.NZ temperature of 110 for 1 hour. 1.08 g (3.49 mmol) of (4-(2-hydroxyethyl)piperazineyl)(3-methoxynitrophenyl)methanone prepared in Step 2) was slowly added thereto. This mixture was stirred under reflux at a ature of 110 for 1 hour. Once the reaction was complete, the mixture was cooled to room temperature, and then was neutralized using a ted sodium hydrogen carbonate aqueous solution. A filtration process was performed thereon using a celite filter. Subsequently, a washing process was med thereon using chloroform and ol. An organic layer was separated therefrom, which was then dried using anhydrous sodium e and concentrated under reduced pressure. The obtained residue was purified using MPLC (chloroform:methanol=8:1 (v/v)), and the resulting solution was concentrated under reduced pressure to thereby obtain 806 mg of a desired nd at a yield of 83%. 1H-NMR (300 MHz, DMSO-d6): δ 6.13 (s, 1H), 6.07 (s, 1H), 5.97 (s, 1H), 5.23 (bs, 2H), 3.62 (s, 3H), 3.49 (m, 4H), 2.38 (m, 6H).

Step 4) (3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)methoxyphenyl)(4-(2-hydrox yethyl)piperazineyl)methanone 53 mg (0.19 mmol) of (3-aminomethoxyphenyl)(4-(2-hydroxyethyl)piperazineyl)methanone prepared in Step 3), 50 mg (0.19 mmol) of -dichloropyrimidineyl)methyl-1H-indole, and 36 mg (0.19 mmol of enesulfonic acid monohydrate were dissolved in 1.2 mL of 2-butanol. Then, the mixture was stirred at a temperature of 120 in a sealed tube for 17 hours. Once the reaction was complete, the mixture was cooled to room temperature, and then, chloroform, methanol, and saturated sodium hydrogen carbonate were added thereto. An organic layer was separated therefrom, which was then dried using anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified using MPLC (chloroform:methanol=7:1 11498815_1 (GHMatters) P109554.NZ (v/v)), and the resulting solution was concentrated under reduced pressure to thereby obtain 25 mg of a desired compound at a yield of 26%.

MS (ESI+, m/z): 507 [M+H]+ ] 1H-NMR (300 MHz, DMSO-d6): δ 11.93 (bs, 1H), 9.76 (s, 1H), 8.56 (m, 1H), 8.49 (s, 2H), 7.48 (m, 3H), 7.23 (m, 1H), 7.13 (m, 1H), 6.50 (s, 1H), 4.41 (m, 1H), 3.50 (s, 3H), 3.46-3.34 (m, 6H), 2.46 (m, 6H).

Example 51: 1-(2-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop oxy)ethyl)piperidineol Step 1) 2-aminobromonitrophenol ] 25 g (162 mmol) of 2-aminonitrophenol was dissolved in 1.0 L of acetonitrile, and 28.8 g (170 mmol) of N-bromosuccinimide was slowly added thereto.

The mixture was stirred at room temperature for 2 hours, and a t was removed therefrom under reduced pressure. The result was stirred in a mixture solution of ethyl acetate and hexane (1:1). The obtained solid underwent a filtration process to thereby obtain 31.5 g of a desired compound at a yield of 83%. 1H-NMR (300 MHz, DMSO-d6): δ 10.66 (s, 1H), 7.83 (s, 1H), 7.46 (s, 1H), 6.15 (s, 2H).

Step 2) ation of 3-bromonitrophenol ] 75.6 g (0.32 mmol) of 2-aminobromonitrophenol prepared in Step 1) was dissolved in 1.5 L of ethanol. The mixture was cooled to a temperature of -10 . 62.3 mL (1.17 mmol) of sulfuric acid was added thereto at a temperature in a range of -10 to -2 for 30 minutes. The temperature of the reaction mixture was raised to 50 , and sodium nitrite was slowly added thereto for 30 minutes. The temperature of 11498815_1 ters) P109554.NZ the reaction mixture was raised to 80 , and the e was stirred under reflux for 3 hours. Once the reaction was complete, a solvent was d therefrom under reduced pressure, and water and ethyl acetate were added dropwise thereto. An organic layer was extracted therefrom three times, and then washed with saline water. The organic layer was dried using anhydrous sodium sulfate, and then concentrated under d pressure. The obtained e was purified using column chromatography (ethyl acetate:hexane=0.5:10 (v/v)), and the resulting solution was concentrated under d pressure to thereby obtain 60 g of a desired compound at a yield of 85%. 1H-NMR (300 MHz, DMSO-d6): δ 10.90 (s, 1H), 7.75 (s, 1H), 7.51 (s, 1H), 7.36 (s, 1H).

Step 3) Preparation of 3-cyclonitrophenol 3.0 g (13.76 mmol) of 3-bromonitrophenol prepared in Step 2), 3.54 g (41.28 mmol) of cyclopropylboronic acid, 8.8 g (41.28 mmol) of potassium phosphate, 310 mg (1.38 mmol) of palladium(II) acetate, and 1.1 g (4.13 mmol) of triphenylphosphine were dissolved in a mixture of 30 mL of toluene and 15 mL of water, followed by stirring under reflux at a ature of 100 for 16 hours. Once the reaction was te, the mixture was cooled to room temperature, and the mixture was filtered using a celite filter. The resultant was washed with chloroform. An organic layer was ted therefrom, washed with water 2 times, and dried using anhydrous sodium sulfate, followed by removal of a solvent under reduced pressure.

The obtained residue was purified using MPLC (chloroform:methanol=20:1 (v/v)), and the resulting solution was concentrated under reduced pressure to thereby obtain 1.52 g of a desired compound at a yield of 62%. 1H-NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H), 7.34 (s, 1H), 7.29 (s, 1H), 6.86 (s, 1H), 1.99 (m, 1H), 0.98 (m, 2H), 0.70 (m, 2H).

Step 4) Preparation of 11498815_1 (GHMatters) P109554.NZ 1-(2-(3-cyclopropylnitrophenoxy)ethyl)piperidineol 500 mg (2.79 mmol) of 3-cyclonitrophenol prepared in Step 3) and 0.37 mL (4.19 mmol) of 1,2-dibromoethane were dissolved in 7 mL of acetonitrile, followed by addition of 2.7 g (8.37 mmol) of cesium carbonate. The reaction mixture was stirr at room temperature for 24 hours. Once the reaction was complete, water and ethyl acetate were added dropwise o. An organic layer was extracted therefrom, and the organic layer was washed with saline water, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained e was ved in 10 mL of acetonitrile, followed by addition of 544 mg (5.38 mmol) of 4-hydroxypiperidine and 745 mg (5.38 mmol) of potassium carbonate. The temperature of the reaction mixture was raised to 90 , and the mixture was stirred under reflux for 4 hours. Once the reaction was complete, water and ethyl e were added dropwise thereto. An organic layer was separated therefrom and washed with water 2 times. The organic layer was washed with saline water and dried using anhydrous sodium sulfate, followed by removal of a solvent under reduced pressure.

The obtained residue was purified using column tography (dichloromethane:methanol=10:1 (v/v)), and the resulting solution was concentrated under reduced pressure to thereby obtain 464 mg of a d compound at a yield of 1H-NMR (300 MHz, DMSO-d6): δ 7.47 (m, 2H), 7.07 (s, 1H), 4.52 (s, 1), 4.13 (m, 2H), 3.41 (m, 1H), 2.77 (m, 2H), 2.63 (m, 2H), 2.09 (m, 3H), 1.80 (m, 2H), 1.36 (m, 2H), 1.01 (m, 2H), 0.79 (m, 2H).

Step 5) ation of 1-(2-(3-aminocyclopropylphenoxy)ethyl)piperidineol 464 mg (1.51 mmol) of 11498815_1 (GHMatters) P109554.NZ 1-(2-(3-cyclopropylnitrophenoxy)ethyl)piperidineol prepared in Step 4) was dissolved in 10 mL of methanol, followed by addition of 50 mg (10%) of Pd/C. Under hydrogen gas atmosphere, the mixture was stirred for 3 hours. Once the reaction was complete, a filtration process was performed thereon using a celite filter, and the filtrate was removed under reduced re to obtain 429 mg of a desired compound at a yield of 99%.

] Step 6) Preparation of 3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclopropylph enoxy)ethyl)piperidineol HN N HO NH 100 mg (0.36 mmol) of 1-(2-(3-aminocyclopropylphenoxy)ethyl)piperidineol ed in Step 5) and 151 mg (0.54 mmol) of 3-(2,5-dichloropyrimidineyl)methyl-1H-indole were dissolved in 2-butanol, followed by addition of 103 mg (0.54 mmol) of p-TsOH thereto.

This reaction mixture was stirred under reflux at a temperature of 120 for 3 hours.

Once the reaction was complete, the mixture was cooled to room temperature, and a saturated sodium hydrogen ate solution was added dropwise thereto, followed by an extraction process using chloromethylene for 2 times. The extracted organic layer was washed with saline water, dried using anhydrous sodium e, and concentrated under reduced pressure. The obtained residue was purified using column chromatography (chloroform:methanol=9:1 , and the resulting solution was concentrated under reduced pressure to thereby obtain 105 mg of a desired compound at a yield of 56%.

MS (ESI+, m/z): 518 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.77 (s, 1H), 9.46 (s, 1H), 8.48 (m, 3H), 7.29 (d, 2H), 7.04 (s, 1H), 6.95 (d, 1H), 6.25 (s, 1H), 4.52 (d, 1H), 3.93 (t, 2H), 3.43-3.32 (m, 1H), 2.64 (m, 2H), 2.58 (t, 2H), 2.43 (s, 3H), 2.05 (m, 2H), 1.81 (m, 1H), 1.67 (d, 2H), 1.34 (m, 2H), 0.89 (m, 2H), 0.67 (m, 2H). 15_1 (GHMatters) P109554.NZ e 52: 1-(2-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)aminoethylphen oxy)ethyl)piperidineol 150 mg of a desired compound was obtained at a yield of 79% in substantially the same manner as in Step 6) of Example 51, except that 100 mg (0.38 mmol) of 1(3-aminoethylphenoxy)ethyl)piperidineol was used instead of 1-(2-(3-aminocyclopropylphenoxy)ethyl)piperidineol in Step 6) of Example 51.

MS (ESI+, m/z): 518 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.77 (s, 1H), 9.50 (s, 1H), 8.48 (m, 3H), 7.30 (d, 2H), 7.19 (s, 1H), 6.94 (d, 1H), 6.42 (s, 1H), 4.53 (d, 1H), 3.95 (t, 2H), 3.42 (m, 1H), 2.72 (m, 2H), 2.60 (m, 2H), 2.54 (m, 2H), 2.06 (m, 2H), 1.69 (m, 2H), 1.39 (m, 2H), 1.16 (t, 3H).

Example 53: (R)(3-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclo propylphenoxy)pyrrolidineyl)ethaneol Step 1) ation of turt-butyl (R)(3-cyclopropylnitrophenoxy)pyrrolidinecarboxylate 3.0 g (16.74 mmol) of 3-cyclonitrophenol prepared in Step 3) of Example 51, 5.3 g (20.09 mmol) of turt-butyl (S)((methylsulfonyl)oxy)pyrrolidinecarboxylate, and 11.0 g (33.49 mmol) of cesium carbonate were dissolved in 80 mL of N, N-dimethylformamide, followed by 15_1 (GHMatters) P109554.NZ stirring at a temperatre of 100 for 14 hours. Once the reaction was complete, the resultant was cooled to room temperature, and water and ethyl acetate were added dropwise thereto. An organic layer was extracted therefrom, and the organic layer was washed with saline water, dried using anhydrous sodium sulfate, and trated under reduced pressure. The obtained residue was purified using column chromatography (chloroform:methanol=9:1 (v/v)), and the resulting on was concentrated under reduced pressure to thereby obtain 3.9 g of a desired compound at a yield of 67%.

Step 2) Preparation of (R)(3-(3-cyclopropylnitrophenoxy)pyrrolidine-yl)ethaneol 3.9 g (11.19 mmol) of turt-butyl (R)(3-cyclopropylnitrophenoxy)pyrrolidinecarboxylate prepared in Step 1) was dissolved in 40 mL of dichloromethane, followed by dropwise addition of 12 mL of trifluoroacetic acid thereto. The on mixture was d at room temperature for 1 hours. Once the reaction was complete, an organic solvent was concentrated under reduced pressure. The obatined residue, 1.65 mL (22.38 mmol) of bromoethanol, and 8.6 mL (61.55 mmol) of triethylamine were dissolved in 30 mL of N, thylformamide. The e was stirred at room temperature for 17 hours.

Once the reaction was complete, the resultant was cooled to room temperature, and water and ethyl acetate were added dropwise thereto. An organic layer was separated therefrom and washed with water 2 times. The organic layer was washed with saline water and dried using anhydrous sodium sulfate, ed by removal of a t under reduced pressure. The obtained residue was purified using column chromatography (dichloromethane:methanol=20:1 (v/v)), and the resulting solution was concentrated under reduced pressure to thereby obtain 1.8 g of a desired compound at a yield of 55%. 1H-NMR (300 MHz, DMSO-d6): δ 7.47 (s, 1H), 7.37 (m, 1H), 7.02 (s, 1H), 11498815_1 (GHMatters) P109554.NZ 4.97 (m, 1H), 4.43 (m, 1H), 3.45 (m, 2H), 2.81 (m, 1H), 2.71 (m, 2H), 2.04 (m, 1H), 2.20 (m, 1H), 2.06 (m, 1H), 1.75 (m, 1H), 1.01 (m, 2H), 0.77 (m, 2H).

Step 3) Preparation of (R)(3-(3-aminocyclopropylphenoxy)pyrrolidine-yl)ethaneol ] 1.7 g (30.79 mmol) of iron and 0.21 mL (2.46 mmol) of hydrochloric acid were dissolved in 20 mL of 50% ethanol. The mixture was stirred under reflux at a temperature of 110 for 1 hour. 1.8 g (6.16 mmol) of (R)(3-(3-cyclopropylnitrophenoxy)pyrrolidine-yl)ethaneol prepared in Step 2) was slowly added o. This mixture was stirred under reflux at a ature of 110 for 1 hour. Once the reaction was complete, the mixture was cooled to room temperature, and then was neutralized using a saturated sodium hydrogen carbonate aqueous solution. A filtration process was performed thereon using a celite filter.

Subsequently, a washing process was performed thereon using chloroform and methanol. An organic layer was separated therefrom, which was then dried using anhydrous sodium sulfate and concentrated under d pressure. The ed residue was purified using MPLC (chloroform:methanol=8:1 (v/v)), and the resulting solution was concentrated under reduced pressure to thereby obtain 1.48 g of a desired compound at a yield of 87%. 1H-NMR (300 MHz, DMSO-d6): δ 5.83 (m, 2H), 5.71 (s, 1H), 4.88 (brs, 2H), 4.64 (m, 1H), 4.41 (m, 1H), 3.45 (m, 2H), 2.75 (m, 1H), 2.60 (m, 1H), 2.45 (m, 2H), 2.10 (m, 1H), 1.66 (m, 2H), 0.79 (m, 2H), 0.51 (m, 2H).

Step 4) Preparation of (R)(3-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclopropy xy)pyrrolidineyl)ethaneol 11498815_1 (GHMatters) P109554.NZ 195 mg of a desired compound was obtained at a yield of 44% in substantially the same manner as in Step 6) of e 51, except that 230 mg (0.88 mmol) of (R)(3-(3-aminocyclopropylphenoxy)pyrrolidineyl)ethaneol was used instead of 1-(2-(3-aminocyclophenoxy)ethyl)piperidineol in Step 6) of Example 51.

MS (ESI+, m/z): 504 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.76 (bs, 1H), 9.54 (s, 1H), 8.45 (m, 3H), 7.46 (s, 2H), 7.26 (s, 1H), 7.09 (m, 1H), 6.16 (s, 1H), 4.74 (m, 1H), 4.49 (m, 1H), 3.48 (m, 2H), 2.69 (m, 4H), 2.40 (s, 3H), 2.26 (m, 1H), 1.78 (m, 2H), 0.88 (m, 2H), 0.61 (m, e 54: Preparation of 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenoxy)piperidineyl)ethaneol 185 mg of a desired compound was obtained at a yield of 40% in substantially the same manner as in Step 4) of Example 53, except that 250 mg (0.90 mmol) of 2-(4-(3-aminocyclopropylphenoxy)piperidineyl)ethaneol was used instead of (R)(3-(3-aminocyclopropylphenoxy)pyrrolidine-yl)ethaneol in Step 4) of e 53.

MS (ESI+, m/z): 518 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.77 (bs, 1H), 9.53 (s, 1H), 8.40 (m, 3H), 7.46 (s, 1H), 7.43 (s, 1H), 7.10 (m, 2H), 6.22 (s, 1H), 4.53 (m, 1H), 3.46 (m, 2H), 2.40 (s, 3H), 1.81 (m, 4H), 1.78 (m, 2H), 0.88 (m, 2H), 0.61 (m, 2H). 11498815_1 (GHMatters) P109554.NZ Example 55: Preparation of 3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)methoxyphenoxy)p iperidineyl)ethaneol 81 mg of a d nd was obtained at a yield of 40% in substantially the same manner as in Step 4) of Example 53, except that 110 mg (0.41 mmol) of 2-(4-(3-aminomethoxyphenoxy)piperidineyl)ethaneol was used instead of (R)(3-(3-aminocyclopropylphenoxy)pyrrolidine-yl)ethaneol in Step 4) of Example 53.

MS (ESI+, m/z): 494 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): δ 11.90 (bs, 1H), 9.53 (s, 1H), 8.53 (d, 1H), 8.45 (m, 2H), 7.50 (m, 1H), 7.18 (m, 3H), 7.07 (s, 1H), 6.11 (s, 1H), 4.19 (m, 1H), 3.64 (s, 3H), 3.47 (m, 2H), 2.70 (m, 2H), 2.39 (m, 1H), 1.96 (m, 2H), 1.21 (m, 2H).

Experimental Examples The inhibitory activity for kinase and inhibitory activity in cell growth of the foregoing compounds prepared in the Examples were evaluated. The results thereof are as follows. mental Example 1: Evaluation of inhibitory activity for kinase tory activity of the ary compounds among the foregoing compounds with respect to AXL, CLK2, VEGFR2 (KDR), NUAK1 kinases were measured. Z'-LYTE™ Kinase Assay Kit-Tyr 6 Peptide (Cat.No. PV4122, available from Life Technologies) for AXL, Z'-LYTE™ Kinase Assay Kit-Ser/Thr peptide 6 (Cat.No. PV3179, available from Life Technologies) for CLK2, Z'-LYTE™ Kinase Assay Kit (Cat.No. , available from Life Technologies) for VEGFR, and Adapta™ Universal Kinase Assay Kit (Cat.No. PV5099, available from Life Technologies) for ARK5) were used. The experiments were carried out by 11498815_1 (GHMatters) P109554.NZ Life Technologies ation. The results of activity inhibition (%) at a compound concentration of 100 nM for each kinase are shown in Tables 2 to 5.

Table 2 Inhibitory activity (percentage, %) of pyrimidine compound for VEGFR2 kinase Compound Degree of inhibition (%) Example 1 71 Example 2 46 Example 6 62 Example 16 56 Example 17 67 Example 38 99 Example 41 63 Table 3 Inhibitory activity (%) of pyrimidine nd for AXL kinase Compound Degree of inhibition (%) Example 1 52 Example 2 56 Example 6 49 Example 16 27 Example 17 66 Example 38 51 Example 41 50 Table 4 Inhibitory activity (%) of pyrimidine compound for NUAK1 kinase Compound Degree of tion (%) 11498815_1 (GHMatters) P109554.NZ Example 1 84 Example 2 71 Example 6 57 Example 16 67 Example 17 72 Example 38 63 Table 5 tory activity (%) of pyrimidine compound for CLK2 kinase Compound Degree of inhibition (%) Example 1 99 Example 2 91 Example 6 66 e 16 77 Example 17 93 Example 38 97 Experimental e 2: Evaluation of inhibitory activity in cell growth RS4-11 cell line was incubated in an RPMI1640 e medium (10% fetal bovine serum (FBS)) at a temperature of 37 . The incubated cell line was prepared in an amount of 2.0×104 cells/100 μL, and then plated on 96-well plates. The RPMI1640 medium was serially diluted with the test compounds at a concentration in a range of μM to 0.1 nM at a ratio of 1/10. Subsequently, incubation was performed thereon for three days. An MTS test was performed to e cell viability, and the 50% growth inhibition (GI50) value of the cell line was calculated using GraphPad Prism software. The s thereof are shown in Table 6.

Table 6 Inhibitory activity of pyrimidine compound in cell growth Compound GI50 (nM) 11498815_1 (GHMatters) P109554.NZ Example 1 147 Example 7 33 MV4-11 cell line was incubated in an IMDM medium (10% FBS) at a temperature of 37 . The incubated cell line was prepared in an amount of 2×104 cells/100 μL, and then plated on 96-well plates. The IMDM medium was treated with cascade dilution of the test compounds at a concentration in a range of 1 μM to 0.01 nM at a rate of 1/10. Subsequently, incubation was performed thereon for three days.

MTS test was performed to e cell ity, and the 50% growth inhibition (GI50) value of the cell line was calculated using GraphPad Prism software. The results f are shown in Table 7.

Table 7 Inhibitory ty of pyrimidine compound (MV11) in cell growth Compound GI50 (nM) Example 30 0.8 Example 50 1.2 Example 52 0.8 Example 53 1.1 As apparent from the foregoing Tables, it was found that the compounds of the present invention exhibit excellent inhibitory activity for kinase and ent inhibitory activity in cell growth.

] While this invention has been particularly shown and described with reference to example embodiments thereof, it will be tood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. The example embodiments should be considered in descriptive sense only and not for purposes of limitation. Therefore, the scope of the invention is defined not by the detailed ption of the invention but by the , and all differences within 11498815_1 (GHMatters) P109554.NZ the scope will be construed as being included in the present invention. 15_1 (GHMatters) P109554.NZ

Claims (11)

WHAT IS CLAIMED IS:

1. A compound selected from a substance of Formula 1 and a pharmaceutically acceptable salt thereof: Formula 1 R7 R1 R6 R2 Z Y N N (R4)k R5 N wherein, in a 1, R1 is hydrogen, a halogen, a hydroxy group, or a C1-4 alkoxy group, R2 is hydrogen, a halogen, a cyano group, a nitro group, an amino group, a amide group, a formyl group, a halo C1-4 alkyl group, or a C1-4 alkyl group, R3 is hydrogen, a halo C1-4 alkyl group, a C1-4 alkyl group, a C2-4 alkenyl group, or a C2-4 alkynyl group, R4(s) are each independently a halogen, a hydroxy group, a cyano group, a nitro group, an amino group, -SRc, -S(=O)Rc, -S(=O)2Rc, a halo C1-4 alkyl group, a C1-4 alkoxy group, a hydroxy C1-4 alkyl group, a C1-4 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, -NRaRb, -CO2Rb, or -CO-NRaRb, n, Ra and Rb are each independently hydrogen or a C1-6 alkyl group, and Rc is a C1-4 alkyl group or -NRaRb, k is an integer from 0 to 4, R5 and R6 are each independently hydrogen, a halogen, a hydroxy group, a nitro group, an amino group, a C1-4 alkoxy group, a hydroxy C1-4 alkyl group, a C1-4 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a C3-10 cycloalkyl group, or a C3-9 heterocycloalkyl group, n, the C3-10 cycloalkyl group and the C3-9 heterocycloalkyl group are each independently unsubstituted or substituted with a halogen, a C1-4 alkyl group, or a halo C1-4 alkyl group, R7 is hydrogen, a linear or branched C1-6 alkyl group, a C3-7 cycloalkyl group, a C3-9 cycloalkyl group, or a C1-4 alkoxy group, 19373217_1 (GHMatters) P109554.NZ.1 Y is a direct bond, -(CH2)m-, -O-, -O(CH2)m-, -(CH2)mO-, -C(=O)-, -NR9-, -SO2-, -(CH2)m-O-(CH2)n-, -CO(CH2)m-, -(CH2)mCO-, m-CO-(CH2)n-, -(CH2)mNR9-, -NR9(CH2)m-, -(CH2)m-NR9-(CH2)n-, -(CH2)mSO2-, -SO2(CH2)m-, or -(CH2)m-SO2-(CH2)n-, wherein R9 is hydrogen, a C1-4 alkyl group, a C3-10 cycloalkyl group, or a C3-9 cycloalkyl group, and m and n are each independently an integer from 1 to 3, Z is represented by a 2: Formula 2 wherein, in Formula 2, is a C3-10 cycloalkyl group or a C2-11 heterocycloalkyl group, R10(s) are each independently a n, a hydroxy group, a cyano group, a nitro group, an amino group, a thiol group, a formyl group, a linear or branched halo C1-4 alkyl group, a linear or branched C1-4 alkoxy group, a linear or branched hydroxy C1-4 alkyl group, a linear or branched C1-4 alkyl group, a linear or branched hydroxy C1-4 alkylcarbonyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a C3-10 cycloalkyl group, a C2-9 heterocycloalkyl group, a hydroxy C2-9 heterocycloalkyl group, -NR11R12, -COR13, -COOR13, or -SO2R14, R11 and R12 are each independently hydrogen, a linear or branched hydroxy C1-4 alkyl group, a linear or branched halo C1-4 alkyl group, a linear or branched C1-4 alkyl group, a C2-4 alkenyl group, or a C2-4 l group, R13 is hydrogen, a hydroxy group, a hydroxy C1-4 alkyl group, a halo C1-4 alkyl group, a C1-4 alkyl group, a C2-4 l group, a C2-4 alkynyl group, a C3-10 cycloalkyl group, or a C2-9 heterocycloalkyl group, R14 is a hydroxy group, a halo C1-4 alkyl group, a C1-4 alkyl group, a C2-4 alkenyl group, a C2-4 alkynyl group, a C3-10 cycloalkyl group, a C2-9 heterocycloalkyl group, an aryl group, or -NRaRb, and q is an integer from 0 to 5. 11498815_1 ters) P109554.NZ

2. The compound of claim 1, wherein Y is -(CH2)m-, -O-, or -C(=O)-.

3. The compound of claim 1 or 2, wherein Y is -CH2- or -(CH2)2-.

4. The compound of any one of claims 1 to 3, wherein R7 is a C3-7 cycloalkyl group.

5. The compound of any one of claims 1 to 4, wherein R7 is a cyclopropyl group.

6. The compound of any one of claims 1 to 5, wherein Z is any one selected from Formulae 3 to 5: Formula 3 R15 p V W R8 Formula 4 R15 s R15 t V W R8 wherein, in Formulae 3 to 5, V and W are each ndently N or CH, ed that at least one of V and W is not CH, R8 is selected from the group consisting of hydrogen, a halogen, a linear or branched C1-4 alkyl group, a linear or branched hydroxy C1-4 alkyl group, a hydroxy 11498815_1 (GHMatters) P109554.NZ group, -NR11R12, a linear or ed hydroxy C1-4 arbonyl group, a heterocycloalkyl group, a hydroxy substituted heterocycloalkyl group, a linear or branched halo C1-4 alkyl group, and a linear or branched C1-4 alkoxy group, R11 and R12 are each ndently a hydrogen, a linear or branched C1-4 alkyl group, or a linear or branched hydroxy C1-4 alkyl group, R15(s) are each ndently a linear or branched C1-4 alkyl group, a linear or branched hydroxy C1-4 alkyl group, or a halogen, p is an integer from 0 to 4, and s and t are each independently an integer from 0 to 5, provided that R8 is hydrogen, or an integer from 0 to 4, provided that R8 is not hydrogen.

7. The compound of any one of claims 1 to 6, wherein R1 is hydrogen, a hydroxy group, or a C1-4 alkoxy group, R2 is hydrogen, a halogen, a linear or branched C1-4 alkyl group, or a linear or branched halo C1-4 alkyl group; R3 is hydrogen, R4 is a halogen, a y group, a linear or branched C1-4 alkoxy group, a linear or branched hydroxy C1-4 alkyl group, or a linear or branched C1-4 alkyl group, k is an integer from 0 to 2, R5 and R6 are each independently hydrogen or a hydroxy group, R7 is a cyclopropyl group, Y is -(CH2)m-, -(CH2)m-O-(CH2)n-, or -(CH2)m-CO-(CH2)n-, is a C3-6 cycloalkyl group comprising one or two heteroatoms selected from O, N, and S, R10(s) are each independently a hydroxy group, a linear or branched y C1-4 alkyl group, a linear or branched C1-4 alkyl group, a C3-10 cycloalkyl group, a C2-9 heterocycloalkyl group, a hydroxy C2-9 heterocycloalkyl group, -NR11R12, or -COR13, q is an integer from 0 to 3, R11 and R12 are each independently hydrogen, a linear or branched hydroxy C1-4 alkyl group, or a linear or branched C1-4 alkyl group, and R13 is hydrogen, a linear or branched hydroxy C1-4 alkyl group, a linear or 11498815_1 (GHMatters) P109554.NZ branched halo C1-4 alkyl group, or a linear or branched C1-4 alkyl group.

8. The compound of any one of claims 1 to 7, wherein the compound of Formula 1 is selected from the group of Compounds below: No. Compound 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)cyclopropyl phenyl)piperazineyl)ethaneol 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidine-2yl)amino)cyclopropy lphenyl)piperazineyl)ethaneol 5-chloro-N-(3-cyclopropyl(4-(dimethylamino)piperidineyl)phenyl)(1H-ind oleyl)pyrimidineamine (S)((1-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylphe nyl)piperidineyl)(methyl)amino)propaneol (S)((1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclo propylphenyl)piperidineyl)(methyl)amino)propaneol ro-N-(3-cyclopropyl(4-(dimethylamino)piperidineyl)phenyl)(6-meth yl-1H-indoleyl)pyrimidineamine 2-(4-(3-((5-chloro(6-methoxy-1H-indoleyl)pyrimidineyl)amino)cyclopro pylphenyl)piperazineyl)ethaneol (1-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylphe nyl)piperidineyl)pyrrolidineol (S)(1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclop ropylphenyl)piperidineyl)pyrrolidineol 5-chloro-N-(3-cyclopropyl(4-(dimethylamino)piperidineyl)phenyl)(6-meth oxy-1H-indoleyl)pyrimidineamine (1-(3-((5-chloro(6-methoxy-1H-indoleyl)pyrimidineyl)amino)cycl opropylphenyl)piperidineyl)pyrrolidineol 2-(4-(3-((4-(1H-indoleyl)methylpyrimidineyl)amino)cyclopropylphenyl) piperazineyl)ethaneol 5-chloro-N-(3-cyclopropyl(4-morpholinopiperidineyl)phenyl)(6-methyl-1H -indoleyl)pyrimidineamine 11498815_1 (GHMatters) P109554.NZ 5-chloro-N-(3-cyclopropyl(4-(ethyl(methyl)amino)piperidineyl)phenyl)(6- methyl-1H-indoleyl)pyrimidineamine ro-N-(3-cyclopropyl(4-(diethylamino)piperidineyl)phenyl)(6-methyl- 1H-indoleyl)pyrimidineamine 5-chloro-N-(3-cyclopropyl(3-(dimethylamino)pyrrolidineyl)phenyl)(6-met hyl-1H-indoleyl)pyrimidineamine 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperazineyl)methylpropaneol N-(3-(4-aminopiperidineyl)cyclopropylphenyl)chloro(6-methyl-1H-indo leyl)pyrimidineamine 5-chloro-N-(3-cyclopropyl(4-(methylamino)piperidineyl)phenyl)(6-methyl -1H-indoleyl)pyrimidineamine 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)cyclopropyl phenyl)piperazineyl)methylpropaneol 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperidineyl)ethaneol 2-(4-(3-((5-chloro(6-chloro-1H-indoleyl)pyrimidineyl)amino)cyclopropy lphenyl)piperazineyl)ethaneol 5-chloro-N-(3-cyclopropyl(4-(pyrrolidineyl)piperidineyl)phenyl)(6-meth yl-1H-indoleyl)pyrimidineamine 1-(1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenyl)piperidineyl)azetidineol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)methoxyphenyl)pip erazineyl)ethaneol 3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)phenyl)pipera zineyl)ethaneol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)phenyl)piperidineyl) ol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)phenyl) piperazineyl)ethaneol 29 5-chloro-N-(3-(4-(dimethylamino)piperidineyl)phenyl)(1H-indoleyl)pyrimi 11498815_1 (GHMatters) P109554.NZ dineamine 5-chloro-N-(3-(3-(dimethylamino)pyrrolidineyl)phenyl)(1H-indoleyl)pyrimi dineamine 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)methoxyph enyl)piperazineyl)ethaneol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)isopropoxyphenyl)p iperazineyl)ethaneol 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)isopropoxy phenyl)piperazineyl)ethaneol ro-N-(3-cyclopropyl(piperazineylmethyl)phenyl)(6-fluoro-1H-indole yl)pyrimidineamine 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)methoxybe nzyl)piperazineyl)ethaneol 2-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)benzyl)pipera zineyl)ethaneol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)methoxybenzyl)pip erazineyl)ethaneol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylbenzyl) piperazineyl)methylpropaneol (S)((1-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylben zyl)piperidineyl)(methyl)amino)propaneol (S)((1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclo propylbenzyl)piperidineyl)(methyl)amino)propaneol 3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylbenzyl)piperazineyl)methylpropaneol (S)(1-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)cyclopropylben peridineyl)pyrrolidineol (S)(1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclop ropylbenzyl)piperidineyl)pyrrolidineol (S)(1-(3-((5-chloro(6-methoxy-1H-indoleyl)pyrimidineyl)amino)cycl opropylbenzyl)piperidineyl)pyrrolidineol 11498815_1 (GHMatters) P109554.NZ 1-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclopropylb enzyl)piperidineol (S)chloro-N-(3-cyclopropyl((3-(dimethylamino)pyrrolidineyl)methyl)phen yl)(6-methyl-1H-indoleyl)pyrimidineamine 1-(4-(3-((5-chloro(6-fluoro-1H-indoleyl)pyrimidineyl)amino)cyclopropyl benzyl)piperazineyl)hydroxyethaneone 1-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop yl)piperazineyl)hydroxyethaneone 2-(4-(3-((5-chloro(6-ethyl-1H-indoleyl)pyrimidineyl)amino)cyclopropyl benzyl)piperazineyl)ethaneol (3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)methoxyphenyl)(4-(2-hy droxyethyl)piperazineyl)methanone 1-(2-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenoxy)ethyl)piperidineol 1-(2-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)aminoethylpheno xy)ethyl)piperidineol (R)(3-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cyclop ropylphenoxy)pyrrolidineyl)ethaneol 2-(4-(3-((5-chloro(6-methyl-1H-indoleyl)pyrimidineyl)amino)cycloprop ylphenoxy)piperidineyl)ethaneol 2-(4-(3-((5-chloro(1H-indoleyl)pyrimidineyl)amino)methoxyphenoxy)pi neyl)ethaneol

9. The compound of any one of claims 1 to 8, wherein R1, R3, R5, and R6 are each hydrogen, R2 is hydrogen or a halogen, R4 is a C1-4 alkyl group or a halogen, R7 is hydrogen, a linear or branched C1-6 alkyl group, a C3-7 cycloalkyl group, or a C1-4 alkoxy group, Y is a direct bond, -CH2-, -O-, neoxy, or -C(=O)-, and 11498815_1 (GHMatters) P109554.NZ Z is any one selected from Formulae 3 to 5: Formula 3 R15 p V W R8 Formula 4 R15 s Formula 5 R15 t V W R8 n, in Formulae 3 to 5, V and W are each independently N or CH, provided that at least one of V and W is not CH, R8 is selected from the group consisting of hydrogen, a halogen, a linear or branched C1-4 alkyl group, a linear or branched hydroxy C1-4 alkyl group, a hydroxy group, -NR11R12, a linear or ed hydroxy C1-4 alkylcarbonyl group, a heterocycloalkyl group, a hydroxy substituted cycloalkyl group, a linear or branched halo C1-4 alkyl group, and a linear or branched C1-4 alkoxy group, R11 and R12 are each independently hydrogen, a linear or branched C1-4 alkyl group, or a linear or branched y C1-4 alkyl group, R15(s) are each independently a linear or branched C1-4 alkyl group, a linear or branched y C1-4 alkyl group, or a halogen, p is an integer from 0 to 4, and s and t are each independently an integer from 0 to 5, provided that R8 is hydrogen, or an an integer from 0 to 4, provided that R8 is not hydrogen.

10. The compound of any one of claims 1 to 9, wherein 11498815_1 (GHMatters) P109554.NZ R7 is hydrogen or a C3-7 cycloalkyl group, Y is a direct bond or -CH2-, Z is Formula 4 or Formula 5, R8 is en, a linear or branched C1-4 alkyl group, a linear or branched hydroxy C1-4 alkyl group, a heterocycloalkyl group, or a hydroxy substituted heterocycloalkyl group, and R15(s) are each independently a linear or branched C1-4 alkyl group, a linear or branched hydroxy C1-4 alkyl group, or a halogen.

11. A pharmaceutical ition comprising the compound according to any one of claims 1 to 10 in an effective dose for prevention and treatment of cancer. 11498815_1 (GHMatters) P109554.NZ