Pyrimidine compound and its pharmaceutical use

Abstract

To provide novel pyrimidine compounds having kinase inhibitory activity. The present invention provides a compound selected from the group consisting of substances of Chemical Formula 1, their stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts. JPEG2023027203000118.jpg70131

Description

Technical Field

[0001] The present invention relates to novel pyrimidine compounds, methods for producing the same, and their pharmaceutical uses.

Background Art

[0002] Kinase mediates the reaction of transferring the phosphate group of a high-energy molecule, particularly ATP, to a substrate. The kinase plays a role in stabilizing the phosphoanhydride bond, occupying specific positions of the substrate and the phosphate group, and accelerating the reaction rate. The transition state shown by interacting with the negatively charged phosphate group is almost always electrostatically stabilized through the surrounding positively charged amino acids, and some kinases also utilize metal cofactors to form coordination bonds with the phosphate group.

[0003] Kinases are also classified into various groups such as protein kinases, lipid kinases, and carbohydrate kinases according to substrates and characteristics. Proteins, lipids, or carbohydrates change in activity, reactivity, binding ability with other molecules, etc. depending on the phosphorylation state. Kinases have a wide range of effects on intracellular signal transduction and regulate the complex biological mechanisms inside cells. A certain molecule is either enhanced or inhibited in activity through phosphorylation, and its interaction ability with other molecules is regulated. Since many kinases react to environmental conditions and signals, cells can control intracellular molecules according to the situation through kinases. Therefore, kinases play a very important role in many cell reaction pathways such as cell growth, differentiation, proliferation, survival, metabolism, signal transduction, cell transport, secretion, and others.

[0004] Kinases have been discovered in various species from bacteria to fungi, insects, and mammals, and more than 500 kinases have been discovered in humans to date.

[0005] Protein kinases increase or decrease the activity of proteins, stabilize them, mark them for degradation, localize them to specific cellular compartments, and initiate or disrupt their interactions with other proteins. Protein kinases are known to account for most of the total kinases and have become important research targets. Protein kinases, together with phosphohydrolases, are responsible for the regulatory roles of not only cell signaling but also proteins and enzymes. Although cellular proteins are targets of numerous covalent bonds, reversible covalent bonds, such as phosphorylation reactions, are not many, and thus protein phosphorylation is also explained to have regulatory functions. Protein kinases sometimes have numerous substrates, and sometimes a specific protein also acts as a substrate for one or more kinases. For such reasons, protein kinases are named using factors that regulate their own activity. For example, calmodulin-dependent protein kinases are regulated by calmodulin. Sometimes, kinases are also divided into subgroups. For example, type 1 cyclic and type 2 cyclic AMP-dependent protein kinases are composed of the same enzyme subunits, but other regulatory subunits are regulated by binding to cyclic AMP.

[0006] Protein kinases, as enzymes that catalyze the phosphorylation of the hydroxyl groups located at tyrosine, serine, and threonine residues of proteins, play an important role in growth factor signaling that induces cell growth, differentiation, and proliferation (Melnikova, I. et al., Nature Reviews Drug Discovery, 3(2004), 993), and it has been reported that abnormal expression or mutation of specific kinases is frequent in cancer cells.

[0007] Generally, among the ways in which cells recognize external stimuli, recognition via tyrosine kinase, a receptor on the cell membrane, is known. Receptor tyrosine kinase (RTK) is composed of an extracellular portion exposed to the outside of the cell, an intracellular portion exposed to the intracellular cytoplasm, and a transmembrane portion passing through the plasma membrane located in the middle. The extracellular portion of the receptor is the portion to which a specific ligand binds, and the intracellular portion performs the function of transmitting the activation signal of the receptor activated by the ligand into the cell. Receptor tyrosine kinase has a domain with tyrosine kinase activity at the C-terminal site exposed to the inside of the cell. When a specific ligand attaches to the extracellular portion, the kinase enzyme of the tyrosine kinase domain at the C-terminus exposed in the cytoplasmic portion of the receptor protein is activated, and on the dimer, tyrosine at the mutual C-terminus is phosphorylated. Such a tyrosine phosphorylation process becomes the most important process for transmitting a signal for an external stimulus into the cell. Many receptors with tyrosine kinase activity that transmit an external stimulus into the cell are known with such a mechanism. As typical examples, SRC, EGFR, IR, IGFR, c-fms, VEGFR, FGFR, AXL, CLK2, NUAK1, etc. can be mentioned.

[0008] Among them, VEGFR (vascular endothelial growth factor receptor) is a kinase known to be involved in the regulation of the angiogenesis process. In particular, compared with normal tissues, solid tumors require more nutrients and oxygen, so insufficient blood supply is very important compared with the normal state. Overexpression or overactivation of VEGFR induces angiogenesis and plays a very important role in angiogenesis necessary for the growth and proliferation of tumor cells (Kliche, S. and Waltenberger, J., Life, 52, (2002), 61). Therefore, various clinical studies have been conducted to treat tumors through angiogenesis inhibition, and many promising results have been derived. In addition, VEGF (vascular endothelial growth factor), which plays an important role in blood cancers, is overexpressed in various malignant solid tumors, which is known to have a high correlation with the progression of malignant tumor diseases. The subtypes of VEGFR are composed of VEGFR1, VEGFR2, and VEGFR3. In particular, among them, VEGFR-2 (KDR) is a typical target for tumor diseases with typical VEGFR expression. Representative diseases caused by overexpression of VEGFR-2 include lung cancer, breast cancer, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, and the like. VEGF, which is a ligand of VEGFR, can promote tumor growth through a direct pro-survival effect in tumor cells in addition to its angiogenesis activity ((Simons, M., Gordon, E. and Claesson-Welsh, L., Nature Reviews Drug Discovery, 17, (2016), 611).

[0009] AXL (tyrosine-protein kinase receptor UFO) kinase is a kinase that plays a role in transmitting extracellular matrix signals to the cytoplasm by binding growth factors such as vitamin K-dependent protein growth regulatory gene 6 (GAS6) (Wu, X., et al., Oncotarget, 5, (2014), 9546), and is a kinase that is highly involved in cell proliferation and survival. AXL can mediate cell aggregation by homophilic binding. The AXL protein is expressed in bone marrow stroma and bone marrow cells, tumor cells and tumor vasculature, and in tumor cells, AXL is expressed not only in immune cells such as dendritic cells, macrophages and NK cells, but also in tumor cells. AXL is an element of various cellular processes that include proliferation, invasion and migration, epithelial-mesenchymal transition, stem-vessel formation, and immune regulation, and plays a decisive role in tumorigenesis, growth and spread, is associated with oncogenes, and is related to the survival and proliferation of various tumors including triple-negative breast cancer (TNBC), blood cancer, non-small cell lung cancer (NSCLC), pancreatic cancer and ovarian cancer (Paccez, J. et al., Int. J. Cancer, 134, (2014), 1024).

[0010] NUAK1 kinase, also known as ARK5 (AMPK-related protein kinase 5), has been shown through recent research findings to play an important role in regulating tumor growth and survival through metabolic changes in various cancers, particularly hepatocellular carcinoma. In tumors and metabolic diseases, the physiological and pathological roles of NUAK have been revealed to be important regulators in the regulation of cellular physiological activities such as cell polarity and cell motility, and maintain homeostasis with respect to tumor growth and proliferation through interactions with associated kinases with AMPK (AMP-activated protein kinase). Therefore, it is shown that inhibition of tumors targeting energy homeostasis may be an important strategy against cancer and related diseases (Sun, X et al., J Mol Endocrinol, 51, (2013), R15).

[0011] CLK2 (dual specificity protein kinase) kinase phosphorylates SR (serine / arginine) proteins by interacting with SR proteins of the spliceosomal complex, which is part of the regulatory mechanism for SR proteins to regulate RNA splicing. This protein kinase is involved as a regulatory factor in various tumor cell growth processes and plays a role in the linkage between cell cycle progression, cell death, and telomere length regulation (Araki, S., PLoS ONE, 10, (2015), e0116929).

Prior Art Documents

Non-Patent Documents

[0012]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0013] One aspect of the present invention is to provide a novel pyrimidine compound having kinase inhibitory activity.

[0014] Another aspect of the present invention is to provide a method for producing a pyrimidine compound according to the above aspect.

[0015] Still another aspect of the present invention is to provide a pharmaceutical use of the pyrimidine compound according to the above aspect.

MEANS FOR SOLVING THE PROBLEMS

[0016] One aspect of the present invention provides a compound selected from the group consisting of a substance of the following Chemical Formula 1, its stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts:

[0017]

CHEM.

[0018] In the above Chemical Formula 1, R 1 is hydrogen, halogen, hydroxy or C 1-4 alkoxy, R 2 is hydrogen, halogen, cyano, nitro, amino, carboxamide, formyl, haloC 1-4 alkyl or C 1-4 alkyl, R 3 is hydrogen, haloC 1-4 alkyl, C 1-4 alkyl or C 2-4 alkenyl or C 2-4 alkynyl, each R 4 is independently of one another halogen, hydroxy, cyano, nitro, amino, -SR c、 -S(=O)R c 、 -S(=O) 2 R c 、 halo C 1-4 alkyl, C 1-4 alkoxy, hydroxy C 1-4 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -NR a R b 、 -CO 2 R b or -CO-NR a R b and wherein, R a and R b are each independently hydrogen or C 1-6 alkyl, R c is C 1-4 alkyl or -NR a R b and k is an integer from 0 to 4, R 5 and R 6 are each independently hydrogen, halogen, hydroxy, nitro, amino, C 1-4 alkoxy, hydroxy C 1-4 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl or C 3-9 heterocycloalkyl, wherein, cycloalkyl, heterocycloalkyl may or may not be substituted with halogen, C 1-4 alkyl, halo C 1-4 alkyl, R 7 is hydrogen, linear or branched C 1-6 alkyl, C 3-7 cycloalkyl, C 3-9 heterocycloalkyl, or C 1-4 alkoxy, Y is a direct bond or -(CH 2 )m-, -O-, -O(CH2 ) m -,-(CH 2 ) m O-,-C(=O)-,-NR 9 -,-SO 2 -,-(CH 2 ) m -O-(CH 2 ) n -,-CO(CH 2 ) m -,-(CH 2 ) m CO-,-(CH 2 ) m -CO-(CH 2 ) n -,-(CH 2 ) m NR 9 -,-NR 9 (CH 2 ) m -,-(CH 2 ) m -NR 9 -(CH 2 ) n -,-(CH 2 ) m SO 2 -,-SO 2 (CH 2 ) m -or-(CH 2 ) m -SO 2 -(CH 2 ) n -and, wherein,R 9 is,hydrogen,C 1-4 alkyl,C 3-10 cycloalkyl,orC 3-9 heterocycloalkyl,and, m,andn,are,independently,of,one,another,integers,of,from,1,to,3,and, Z,is,a,structure,of,the,following,chemical,formula,2,

[0019]

Chemical,Formula

[0020] In,the,aforementioned,chemical,formula,2,

[0021] [Chemistry]

[0022] is C 3-10 cycloalkyl or C 2-11 heterocycloalkyl, and each R 10 is, independently of one another, halogen, hydroxy, cyano, nitro, amino, thiol, formyl, linear or branched halo C 1-4 alkyl, linear or branched C 1-4 alkoxy, linear or branched hydroxy C 1-4 alkyl, linear or branched C 1-4 alkyl, linear or branched hydroxy C 1-4 alkylcarbonyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, hydroxy C 2-9 heterocycloalkyl, -NR 11 R 12 , -COR 13 , -COOR 13 or -SO 2 R 14 and R 11 and R 12 are each independently hydrogen, linear or branched hydroxy C 1-4 alkyl, linear or branched halo C 1-4 alkyl, linear or branched C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, and R 13 is hydrogen, hydroxy, hydroxy C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C3-10 Cycloalkyl or C 2-9 is heterocycloalkyl, R 14 is hydroxy, halo C 1-4 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, aryl or -NR a R b is. q is an integer from 0 to 5.

[0023] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, containing the compound of Chemical Formula 1 as an active ingredient.

Effects of the Invention

[0024] The compound of Chemical Formula 1 according to an aspect of the present invention has kinase inhibitory activity, and thus is used in applications where kinase inhibition is required.

Modes for Carrying Out the Invention

[0025] Hereinafter, the present invention will be described in more detail.

[0026] All technical terms used in the present invention are used in the meaning generally understood by those skilled in the art in the related field of the present invention, unless otherwise defined. Also, although desirable methods and samples are described in this specification, those similar to or equivalent to them are also included in the scope of the present invention. Further, the numerical values described in this specification are considered to include the meaning of "approximately" even without explicit indication. The content of all publications described as references in this specification is incorporated herein by reference in its entirety.

[0027] In Chemical Formula 1 above, R 1 to R 15 The residues listed are used in the meaning generally understood by those skilled in the art.

[0028] The term "halogen" includes fluorine, chlorine, bromine or iodine, specifically fluorine and chlorine, if there is no other reference.

[0029] The term "alkyl" refers to a saturated monovalent hydrocarbon radical. The term "alkenyl" used in the present invention refers to a monovalent hydrocarbon radical containing at least one carbon-carbon double bond, where each double bond can have an E or Z configuration. The term "alkynyl" used in the present invention refers to a monovalent hydrocarbon radical containing at least one carbon-carbon triple bond. Such alkyl, alkenyl and alkynyl groups can be linear, i.e., straight-chain, or branched with side chains. According to each definition, within an alkyl group, the number of carbon atoms can be 1, 2, 3, 4, 5 or 6, or also 1, 2, 3 or 4. Examples of alkyl include methyl, ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl, sec-butyl, isobutyl and tert-butyl, pentyl including n-pentyl, 1-methylbutyl, isopentyl, neopentyl and tert-pentyl, and hexyl including n-hexyl, 3,3-dimethylbutyl and isohexyl. Each of the double bonds and triple bonds of the alkenyl group and alkynyl group can be present at any position. Examples of alkenyl and alkynyl include ethenyl, prop-1-enyl, prop-2-enyl (=allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, prop-2-ynyl (=propargyl), but-2-ynyl, but-3-ynyl, hex-4-ynyl or hex-5-ynyl. As long as each compound is sufficiently stable and suitable for a desired purpose, such as use as a pharmaceutical substance, the substituted alkyl, alkenyl and alkynyl groups can be substituted at any position.

[0030] As used herein, the term "cycloalkyl" means a cyclic alkyl, substituted or unsubstituted, unless otherwise indicated, for example, a monocyclic aliphatic or bicyclic aliphatic. For example, it may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, 2,5 - cyclohexadienyl, bicyclo[2.2.2]octyl, adamant - 1 - yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2 - oxobicyclo[2.2.1]hept - 1 - yl, or all possible isomers thereof without limitation.

[0031] As used herein, the term "heterocycloalkyl" means a cyclic alkyl, substituted or unsubstituted, having a single ring or two or more rings and containing one or more, specifically 1 to 4, heteroatoms selected from O, N, and S, unless otherwise indicated. Examples of monocyclic heterocycloalkyls can include, but are not limited to, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, diazabicycloheptanyl, diazabicyclooctanyl, diazaspirooctanyl, and similar groups.

[0032] As used herein, the term "aryl" means an aromatic group, substituted or unsubstituted, unless otherwise indicated, for example, it may include phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, or all possible isomers thereof without limitation.

[0033] As used herein, the term "heteroaryl" means, unless otherwise indicated, a monocyclic or bicyclic or higher aromatic group containing one or more, for example, 1 to 4 heteroatoms selected from O, N, and S. Examples of monocyclic heteroaryl include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and groups similar thereto. Examples of bicyclic heteroaryl include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, purinyl, propyridinyl, and groups similar thereto.

[0034] As used herein, a numerical range expressed using the term "to" means a range that includes the numerical values described before and after the term "to" as the lower and upper limits, respectively.

[0035] In one aspect of the present invention, the compound of Formula 1, in one specific example, R 1 is a compound in which is hydrogen, C 1-4 alkoxy or hydroxy.

[0036] In one specific example, the compound of Formula 1, R 2 is a compound in which is hydrogen, halogen, C 1-4 alkyl or haloC 1-4 alkyl.

[0037] In one specific example, the compound of Formula 1, R 3 is a compound in which is hydrogen.

[0038] In one specific example, the compound of Formula 1, R 4 is a compound in which is hydrogen, halogen, hydroxy, C 1-4Alkoxy, hydroxy C 1-4 alkyl or C 1-4 is also a compound that is alkyl.

[0039] In one specific example, the compound of Chemical Formula 1 is such that R 5 and R 6 are each independently a compound that is hydrogen or hydroxy.

[0040] In one specific example, the compound of Chemical Formula 1 is such that R 7 is C 3-7 cycloalkyl.

[0041] In one specific example, the compound of Chemical Formula 1 is such that Y is -(CH 2 ) m -, -(CH 2 ) m -O-(CH 2 ) n - or -(CH 2 ) m -CO-(CH 2 ) n -, where m and n are each independently an integer of 1 or 2.

[0042] In yet another specific example, the compound of Chemical Formula 1 is such that Z has the structure of Chemical Formula 2.

[0043]

Chemical formula

[0044] At this time, in Chemical Formula 2,

[0045]

Chemical formula

[0046] the heteroatom is 1 or 2 heteroatoms selected from among O, N, and S, and it is C 3- 6 is a heterocycloalkyl, R 10 independently of one another, is hydrogen, hydroxy, linear or branched hydroxyC 1-4 alkyl, linear or branched C 1-4 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, hydroxyC 2-9 heterocycloalkyl, -NR 11 R 12 or -COR 13 and R 11 and R 12 each independently is hydrogen, linear or branched hydroxyC 1-4 alkyl, or linear or branched C 1-4 alkyl, R 13 is hydrogen, hydroxy, linear or branched hydroxyC 1-4 alkyl, linear or branched haloC 1-4 alkyl, or linear or branched C 1-4 alkyl, and q is each independently an integer from 0 to 5.

[0047] In another specific example, the compound of Chemical Formula 1 R 1 is hydrogen, hydroxy, C 1-4 alkoxy or C 1-4 alkyl, R 2 is hydrogen, halogen, C 1-4 alkyl or haloC 1-4 alkyl, R 3 is hydrogen, R 4 is hydrogen, halogen, hydroxy, C 1-4 alkoxy, hydroxyC 1-4 alkyl or C1-4 alkyl, k is an integer from 0 to 2, R 5 and R6 each independently is hydrogen or hydroxy, R 7 is cyclopropyl, Y is a direct bond or -(CH 2 ) m -, -O-, -C(=O)-, -(CH 2 ) m -O-(CH 2 ) n - or -(CH 2 ) m -CO-(CH 2 ) n -, Z is Chemical Formula 2,

[0048]

Chemical Formula

[0049] At this time, in the Chemical Formula 2,

[0050]

Chemical Formula

[0051] is a C 3 - 6 heterocycloalkyl containing 1 or 2 heteroatoms selected from among O, N, and S, each R 10 is independently of one another hydroxy, hydroxy C 1-4 alkyl, C 1-4 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, hydroxy C 2-9 heterocycloalkyl, -NR 11 R 12 or -COR 13 and R 11 and R 12 are each independently hydrogen, hydroxy C 1-4 alkyl or C1-4 is alkyl, R 13 is hydrogen, hydroxy C 1-4 alkyl, halo C 1-4 alkyl or C 1-4 alkyl, and q is an integer from 0 to 3.

[0052] In yet other specific embodiments, the compound of Formula 1 R 1 R 3 R 5 and R 6 are hydrogen, R 2 is hydrogen or halogen, R 4 is C 1-4 alkyl or halogen, R 7 is hydrogen, straight or branched C 1-6 alkyl, C 3-7 cycloalkyl, or C 1-4 alkoxy, Y is a direct bond, -CH 2 -, -O-, ethyleneoxy or -C(=O)-, Z is selected from any one of Formulas 3 to 5,

[0053]

Chemical formula

[0054]

Chemical formula

[0055]

Chemical formula

[0056] At this time, in the above Formulas 3 to 5, V and W are, independently of each other, N or CH, provided that V and W are not CH simultaneously, R 8 is hydrogen, halogen, linear or branched C 1-4 alkyl, linear or branched hydroxy C 1-4 alkyl, hydroxy, -NR 11 R 12 , linear or branched hydroxy C 1-4 alkylcarbonyl, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, linear or branched halo C 1-4 alkyl, and linear or branched C 1-4 alkoxy, and is selected from the group consisting of R 11 and R 12 are, independently of each other, hydrogen, linear or branched C 1-4 alkyl, or linear or branched hydroxy C 1-4 alkyl, each R 15 is, independently of each other, linear or branched C 1-4 alkyl, linear or branched hydroxy C 1-4 alkyl, or halogen, p is an integer from 0 to 4, s and t are independent integers, and when R 8 is hydrogen, they are from 0 to 5, and when R 8 is not hydrogen, they are from 0 to 4.

[0057] More specifically, in this embodiment described above, the compound of Chemical Formula 1 is R 7 is hydrogen or C 3-7 cycloalkyl, Y is a direct bond or -CH 2 -, Z is Chemical Formula 4 or Chemical Formula 5, R 8 is hydrogen, linear or branched C 1-4 alkyl, linear or branched hydroxy C 1-4alkyl, heterocycloalkyl, or hydroxy-substituted heterocycloalkyl, each R 15 is independently of one another a straight-chain or branched C 1-4 alkyl, straight-chain or branched hydroxy C 1-4 alkyl, or halogen.

[0058] In one specific example, the compound of Chemical Formula 1 is also a compound selected from the group consisting of the compounds listed in Table 1 below:

[0059]

Table 1

[0060] JPEG0007684002000012.jpg239163

[0061] JPEG0007684002000013.jpg233164

[0062] JPEG0007684002000014.jpg239163

[0063] JPEG0007684002000015.jpg219164

[0064] As used herein, the term "optical isomer" refers to various stereoisomers and geometric isomers that can exist for the compounds according to the present invention. Since the compounds of Formula 1 according to one aspect of the present invention can have asymmetric carbon centers (chiral carbons), they can exist as enantiomers (R-isomers or S-isomers), racemates, diastereoisomers, or any mixture thereof, and all such isomers and mixtures are included within the scope of the present invention. The optically active (R)-isomers and (S)-isomers can be resolved using conventional techniques or can be prepared using chiral synthons or chiral reagents. When the compound contains a double bond, the substituents can also be in the E-form or Z-form. When the compound contains a 2-substituted cycloalkyl, it can also be in the cis-form or trans-form. Further, when the compound of Formula 1 contains a bridged ring, it also exists as an exo-isomer or endo-isomer. Also, all tautomeric forms are included.

[0065] The compounds of Formula 1 according to the one aspect, and their optical isomers, can exist in solvated forms. The term "solvate" may include a molecular complex containing the compound and one or more pharmaceutically acceptable solvent molecules, such as ethanol or water. The complex in which the solvent molecule is water is also referred to as a "hydrate".

[0066] The compounds of Formula 1 according to the one aspect, their optical isomers, and their solvates can exist in the form of pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salt" means that it must be low in toxicity to the human body and must not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts can include pharmaceutically acceptable free acids, acid addition salts of the basic compounds of Formula 1, alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts), organic bases, and organic base addition salts with the carboxylic acid structure of Formula 1, amino acid addition salts, etc., but are not limited thereto.

[0067] The salt is also produced by a general method. For example, the compound of Chemical Formula 1 described above can be dissolved in a solvent miscible with water such as methanol, ethanol, acetone, or 1,4-dioxane, and then a free acid or free base is added, followed by crystallization to produce it.

[0068] In another uniform phase, the present invention provides a method for producing the compound of Chemical Formula 1, which includes reacting the compound of Chemical Formula 6 and the compound of Chemical Formula 7 below.

[0069]

Chemical Formula

[0070]

Chemical Formula

[0071] In Chemical Formulas 6 and 7 above, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Y, Z, and k are the same as the definitions in Chemical Formulas 1 and 2 above, and V 2 is a halogen.

[0072] The reaction is carried out with or without adding an organic base such as triethylamine, diisopropylethylamine, or pyridine; an inorganic base such as sodium carbonate, potassium carbonate, or sodium hydride; an organic acid such as trifluoroacetic acid or toluenesulfonic acid; or an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid to the reaction solution. The solvent used in the reaction can be any solvent that does not inhibit the reaction, specifically, a polar aprotic solvent such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, or tetrahydrofuran; 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. The reaction temperature can be from 0 to 150 °C, specifically, from room temperature to 100 °C.

[0073] The compound of Chemical Formula 6 and the compound of Chemical Formula 7 can be produced using general knowledge in the field of organic chemistry technology.

[0074] In one specific example, the compound of Chemical Formula 1 is also produced by the method shown in the following Reaction Formula 1.

[0075]

Chemical Formula

[0076] In Reaction Formula 1, the aforementioned R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , Y, Z, and k are as defined in Chemical Formulas 1 and 2, and V 1 and V 2 are each independently a halogen.

[0077] In the step of reacting the compound of Chemical Formula 4 with the compound of Chemical Formula 5 to produce the compound of Chemical Formula 6, the reaction can be carried out by adding an organometallic compound. Specifically, the organometallic compound is an alkylmagnesium compound or an alkyllithium compound.

[0078] The solvent used in the reaction can be any solvent that does not inhibit the reaction. Specifically, polar aprotic solvents such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, and tetrahydrofuran; or nonpolar aprotic solvents such as toluene and 1,4-dioxane can be used. The reaction temperature can be from 0 to 100 °C, specifically, it can also be from 0 to 60 °C.

[0079] In the step of producing the compound of Chemical Formula 7, When Y is -(CH 2 ) m -, m is independently 0 and 1, When Y is -(CH 2 ) m -O-(CH 2 ) n -, m is 0, and n is independently 0 and 2, When Y is -(CH 2 ) m -CO-(CH 2 ) n -, both m and n are 0, As shown in the following Production Formulas 1 to 3, it can be produced by using general knowledge in the field of organic chemical technology.

[0080] When Y is -(CH 2 ) m -;

[0081]

Chemical Formula

[0082] In Production Formula 1 above, the aforementioned R 5 , R6 , R 7 , R 10 , [Chem.]

[0083] and q are as defined in Chemical Formulas 1 and 3, and V 3 is a halogen, and L is Cl, Br, I, OMs, OTs, etc.

[0084] When Y is -(CH 2 ) m -O-(CH 2 ) n -;

[0085] [Chem.]

[0086] In Production Formula 2 above, the aforementioned R 6 , R 7 , R 10 , [Chem.]

[0087] and q are as defined in Chemical Formulas 1 and 3, and L is Cl, Br, I, OMs, OTs, etc.

[0088] When Y is -(CH 2 ) m -CO-(CH 2 ) n -;

[0089] [Chem.]

[0090] In Production Formula 3 above, the aforementioned R 6, R 7 , R 10 ,

Chemical formula

[0091] and q are as defined in Chemical Formulas 1 and 3 above.

[0092] Although the method for producing Chemical Formula 1 has been described with specific examples, the specific reaction conditions, such as the reaction solvent, base, and amounts of reactants used, are not limited to only what is described in this specification and are not to be construed as limiting the scope of the present invention in any way.

[0093] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Chemical Formula 1 according to the aspect of the present invention as an active ingredient.

[0094] In another aspect, the present invention provides a pharmaceutical use of the pharmaceutical composition according to the aspect of the present invention for preventing or treating cancer.

[0095] In another aspect, the present invention provides a pharmaceutical use for manufacturing a medicament for preventing or treating cancer with a compound of Chemical Formula 1 according to the aspect of the present invention.

[0096] In one specific example, the pharmaceutical composition may contain common pharmaceutically acceptable excipients or additives. The pharmaceutical composition of the present invention can be formulated by common methods and can be manufactured into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or parenteral dosage forms such as intramuscular, intravenous, or subcutaneous administration.

[0097] When the pharmaceutical composition of the present invention is manufactured in the form of an oral dosage form, examples of carriers or additives to be used include diluents, disintegrants, binders, lubricants, surfactants, suspending agents or emulsifiers, etc. When the pharmaceutical composition of the present invention is manufactured in the form of an injection, examples of the carrier or additive include water, saline, glucose aqueous solution, similar sugar aqueous solutions, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents or emulsifiers, etc. Such formulation methods are known to those with general knowledge in the field of pharmaceutical formulations.

[0098] The dosage of the compound of Chemical Formula 1, which is the active ingredient, is an amount effective for the treatment or prevention of an individual or patient, and depending on the purpose, oral administration or parenteral administration can be carried out. In the case of oral administration, based on the active ingredient, it is administered in an amount of 0.01 to 1,000 mg per kg of body weight per day, more specifically, 0.1 to 300 mg. In the case of parenteral administration, based on the active ingredient, it is administered in an amount of 0.01 to 100 mg per kg of body weight per day, more specifically, 0.1 to 50 mg, and can be administered in one or several divided doses. The dosage for a specific individual or patient is determined in light of various relevant factors such as the patient's body weight, age, gender, health status, diet, administration time, administration method, and severity of the disease, and it should be understood that it is appropriately adjusted by an expert. The above dosage is not intended to limit the scope of the present invention in any way.

[0099] Still another aspect of the present invention provides a method for preventing or treating cancer, which includes the step of administering to an individual or patient a compound selected from the compound of Chemical Formula 1 according to the above aspect, its optical isomers, solvates, and pharmaceutically acceptable salts.

[0100] Details of the above method for prevention or treatment are directly applicable to the above description regarding the pharmaceutical composition according to an aspect of the present invention.

[0101] As used herein, the term "treatment" is used as a concept that includes any of treatment, improvement, amelioration or management of a disease.

[0102] As used herein, the term "prevent" or "prevention" refers to preventing a disease, for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but has not yet experienced or shown the pathology or symptoms of the disease.

[0103] As used herein, the term "individual" or "patient" refers to any animal including mammals such as mice, rats and other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates and humans.

[0104] Hereinafter, the present invention will be described more specifically by the following Examples and Experimental Examples. However, those Examples and Experimental Examples only help to understand the present invention, and in no sense, the scope of the present invention is limited by them.

[0105] The abbreviations used in the following Production Examples, Production Methods and Examples respectively mean the following:

[0106] BINAP: (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)

[0107] Pd(OAc) 2 : Palladium(II) acetate

Example

[0108] Example 1: 2-(4-(3-((5-chloro-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol Step 1) Production of 4-cyclopropyl-2-nitroaniline

[0109] [Chemical formula]

[0110] 4-Bromo-2-nitroaniline (1.5 g, 6.90 mmol), cyclopropylboronic acid (1.22 g, 13.83 mmol), potassium phosphate (4.5 g, 20.70 mmol), palladium(II) acetate (159 mg, 0.69 mmol), and triphenylphosphine (543 mg, 2.07 mmol) were dissolved in 12 mL of toluene and 6 mL of water, and stirred in a sealed tube at 100 °C for 17 hours. After completion of the reaction, the mixture was cooled to room temperature, and water was added dropwise. The mixture was extracted three times with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MPLC (chloroform:methanol = 100:1 (v / v)), and the resulting solution was concentrated under reduced pressure to obtain 880 mg of the target compound in a 72% yield.

[0111] 1 H-NMR (300 MHz, DMSO-d 6 ): 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)

[0112] Step 2) Preparation of 2-Bromo-4-cyclopropyl-6-nitroaniline

[0113] [Chemical formula]

[0114] The 4-cyclopropyl-2-nitroaniline (880 mg, 4.94 mmol) produced in the above step 1) was dissolved in 16 mL of acetic acid, and N-bromosuccinimide (922 mg, 5.18 mmol) was gradually added at 0 °C. It was stirred at room temperature for 1.5 hours. After the reaction was completed, water was added dropwise. It was extracted three times with diethyl ether, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 1.24 g of the target compound in a 98% yield.

[0115] 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0116] Step 3) Production of 1-bromo-3-cyclopropyl-5-nitrobenzene

[0117]

Chemical formula

[0118] The 2-bromo-4-cyclopropyl-6-nitroaniline (1.24 g, 4.82 mmol) produced in the above step 2) was dissolved in 24 mL of ethanol, and sulfuric acid (1.6 mL, 30.39 mmol) was gradually added at 0 °C. After heating it to 60 °C, sodium nitrite (1.06 g, 15.42 mmol) was gradually added. It was refluxed and stirred at 100 °C for 4 hours. After the reaction was completed, it was cooled to room temperature, and ethyl acetate and water were added. The organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by MPLC (ethyl acetate:hexane = 1:50 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 790 mg of the target compound in a 68% yield.

[0119] 1 H-NMR(300MHz,DMSO-d 6): 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)

[0120] Step 4) Preparation of 2-(4-(3-cyclopropyl-5-nitrophenyl)piperazin-1-yl)ethan-1-ol

[0121]

Chem.

[0122] 1-Bromo-3-cyclopropyl-5-nitrobenzene (790 mg, 3.26 mmol) prepared in Step 3), 1-(2-hydroxyethyl)piperazine (637 mg, 4.89 mmol), tris(dibenzylideneacetone)dipalladium(0) (300 mg, 0.33 mmol), BINAP (207 mg, 0.33 mmol), and cesium carbonate (3.2 g, 9.78 mmol) were dissolved in 6 mL of 1,4-dioxane and stirred in a sealed tube at 100 °C for 15 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and water was added dropwise. The mixture was extracted three times with chloroform and methanol, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MPLC (chloroform:methanol = 10:1 (v / v)), and the resulting solution was concentrated under reduced pressure to obtain 234 mg of the target compound in a 24% yield.

[0123] Step 5) Preparation of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol

[0124]

Chem.

[0125] Iron (220 mg, 3.96 mmol) and hydrochloric acid (0.03 mL, 0.32 mmol) were dissolved in 4 mL of 50% ethanol, and the mixture was refluxed and stirred at 110 °C for 1 hour. To this, 2-(4-(3-cyclopropyl-5-nitrophenyl)piperazin-1-yl)ethan-1-ol (234 mg, 0.79 mmol) prepared in the above step 4) was gradually added. The mixture was refluxed and stirred at 110 °C for 1 hour. After the reaction was completed, it was cooled to room temperature, neutralized with a saturated aqueous sodium hydrogen carbonate solution, filtered through a filter filled with celite, and washed with chloroform and methanol. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MPLC (chloroform:methanol = 8:1 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 152 mg of the target compound in a yield of 74%.

[0126] 1 H-NMR (300 MHz, DMSO-d 6 ): 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)

[0127] Step 6) Preparation of 2-(4-(3-((5-chloro-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol

[0128]

Chemical Structure

[0129] 2-(4-(3-Amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol (50 mg, 0.19 mmol), 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole (54 mg, 0.19 mmol), and p-toluenesulfonic acid monohydrate (36 mg, 0.19 mmol) prepared in step 5) above were dissolved in 1.2 mL of 2-butanol and stirred in a sealed tube at 120 °C for 3.5 h. After the reaction was completed, the mixture was cooled to room temperature, and chloroform, methanol, and saturated sodium hydrogen carbonate solution were added. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MPLC (chloroform:methanol = 7:1 (v / v)), and the resulting solution was concentrated under reduced pressure to obtain 65 mg of the target compound in a 67% yield.

[0130] MS(ESI+,m / z):507[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0131] Example 2: 2-(4-(3-((5-Chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol

[0132]

Chemical Structure

[0133] In step 6) of Example 1, except that 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (50 mg, 0.18 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, the procedure of step 6) of Example 1 was repeated to obtain 72 mg of the target compound in an 89% yield.

[0134] MS(ESI+,m / z):503[M+H] +

[0135] 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0136] Example 3: 5-Chloro-N-(3-cyclopropyl-5-(4-(dimethylamino)piperidin-1-yl)phenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine

[0137]

Chemical formula

[0138] In step 6) of Example 1, except that 1-(3-amino-5-cyclopropylphenyl)-N,N-dimethylpiperidin-4-amine (44 mg, 0.17 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (51 mg, 0.19 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, the procedure of step 6) of Example 1 was repeated to obtain 48 mg of the target compound in a 58% yield.

[0139] MS (ESI+, m / z): 487 [M+H] + 1 1H-NMR (300 MHz, DMSO-d 6 ): 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, 2H)

[0140] Example 4: (S)-1-((1-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperidin-4-yl)(methyl)amino)propan-2-ol

[0141]

Chemical Structure

[0142] In step 6) of Example 1, the procedure of step 6) of Example 1 was repeated except that (S)-1-((1-(3-amino-5-cyclopropylphenyl)piperidin-4-yl)(methyl)amino)propan-2-ol (50 mg, 0.17 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (51 mg, 0.19 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, and 52 mg of the target compound was obtained in 58% yield.

[0143] MS (ESI+, m / z): 531 [M+H] + 1 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)

[0144] Example 5: (S)-1-((1-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperidin-4-yl)(methyl)amino)propan-2-ol

[0145]

Chemical Structure

[0146] In step 6) of Example 1, the procedure of step 6) of Example 1 was repeated, except that (S)-1-((1-(3-amino-5-cyclopropylphenyl)piperidin-4-yl)(methyl)amino)propan-2-ol (50 mg, 0.17 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (50 mg, 0.18 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, and 58 mg of the target compound was obtained in 65% yield.

[0147] MS (ESI+, m / z): 545 [M + H] + 1 H-NMR (300 MHz, DMSO-d 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)

[0148] Example 6: 5-Chloro-N-(3-cyclopropyl-5-(4-(dimethylamino)piperidin-1-yl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0149]

Chemical Structure

[0150] In step 6) of Example 1, the procedure of step 6) of Example 1 was repeated, except that 1-(3-amino-5-cyclopropylphenyl)-N,N-dimethylpiperidin-4-amine (52 mg, 0.20 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (61 mg, 0.22 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, to obtain 86 mg of the target compound in 86% yield.

[0151] MS (ESI+, m / z): 501 [M + H] + 1 1H-NMR (300 MHz, DMSO-d 6): 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)

[0152] Example 7: 2-(4-(3-((5-Chloro-4-(6-methoxy-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol

[0153]

Chemical Structure

[0154] In step 6) of Example 1, the procedure of step 6) of Example 1 was repeated except that 3-(2,5-dichloropyrimidin-4-yl)-6-methoxy-1H-indole (50 mg, 0.17 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, and 5 mg of the target compound was obtained in a 6% yield.

[0155] MS(ESI+, m / z): 519 [M + H] + 1 H-NMR(300 MHz, DMSO-d 6 ): 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)

[0156] (S)-1-(1-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperidin-4-yl)pyrrolidin-3-ol

[0157]

Chem.

[0158] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, (S)-1-(1-(3-amino-5-cyclopropylphenyl)piperidin-4-yl)pyrrolidin-3-ol (50 mg, 0.17 mmol) was used, and instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (51 mg, 0.19 mmol) was used. The procedure of step 6) of Example 1 was repeated, and 68 mg of the target compound was obtained in 76% yield.

[0159] MS(ESI+,m / z):529[M+H] + 1 H-NMR(300MHz,DMSO-d 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)

[0160] Example 9: (S)-1-(1-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperidin-4-yl)pyrrolidin-3-ol

[0161]

Chemical Structure

[0162] In step 6) of Example 1, the procedure of step 6) of Example 1 was repeated except that (S)-1-(1-(3-amino-5-cyclopropylphenyl)piperidin-4-yl)pyrrolidin-3-ol (50 mg, 0.17 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (51 mg, 0.18 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, and 64 mg of the target compound was obtained in a 69% yield.

[0163] MS(ESI+,m / z):543[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0164] Example 10: 5-chloro-N-(3-cyclopropyl-5-(4-(dimethylamino)piperidin-1-yl)phenyl)-4-(6-methoxy-1H-indol-3-yl)pyrimidin-2-amine

[0165]

Chem.

[0166] In step 6) of Example 1, except that 1-(3-amino-5-cyclopropylphenyl)-N,N-dimethylpiperidin-4-amine (44 mg, 0.17 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-6-methoxy-1H-indole (50 mg, 0.17 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, the procedure of step 6) of Example 1 was repeated, and 20 mg of the target compound was obtained in a 23% yield.

[0167] MS(ESI+,m / z):517[M+H] + 1 H-NMR(300MHz,DMSO-d 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)

[0168] Example 11: (S)-1-(1-(3-((5-chloro-4-(6-methoxy-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperidin-4-yl)pyrrolidin-3-ol

[0169]

Chem.

[0170] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, (S)-1-(1-(3-amino-5-cyclopropylphenyl)piperidin-4-yl)pyrrolidin-3-ol (51 mg, 0.17 mmol) and instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methoxy-1H-indole (50 mg, 0.17 mmol) were used. The procedure of step 6) of Example 1 was repeated, and 9 mg of the target compound was obtained in a 10% yield.

[0171] MS(ESI+,m / z):559[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0172] Example 12: 2-(4-(3-((4-(1H-Indol-3-yl)-5-methylpyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol

[0173]

Chemical formula

[0174] In step 6) of Example 1, except that 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (51 mg, 0.21 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, the procedure of step 6) of Example 1 was repeated, and 60 mg of the target compound was obtained in a 67% yield.

[0175] MS(ESI+,m / z):469[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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), 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)

[0176] Example 13: 5-Chloro-N-(3-cyclopropyl-5-(4-morpholino-piperidin-1-yl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0177]

Chemical formula

[0178] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, 3-cyclopropyl-5-(4-morpholino-piperidin-1-yl)aniline (100 mg, 0.33 mmol) was used, and instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (138 mg, 0.50 mmol) was used. Except for this, the process of step 6) of Example 1 was repeated, and 100 mg of the target compound was obtained in a 56% yield.

[0179] MS(ESI+,m / z):543[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0180] Example 14: 5-Chloro-N-(3-cyclopropyl-5-(4-(ethyl(methyl)amino)piperidin-1-yl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0181]

Chemical formula

[0182] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, 1-(3-amino-5-cyclopropylphenyl)-N-ethyl-N-methylpiperidin-4-amine (90 mg, 0.33 mmol) and instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (137 mg, 0.49 mmol) were used. The procedure of step 6) of Example 1 was repeated, and 50 mg of the target compound was obtained in a 30% yield.

[0183] MS(ESI+,m / z):515[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0184] Example 15: 5-Chloro-N-(3-cyclopropyl-5-(4-(diethylamino)piperidin-1-yl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0185]

Chemical formula

[0186] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, 1-(3-amino-5-cyclopropylphenyl)-N,N-dimethylpiperidin-4-amine (90 mg, 0.31 mmol) and instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (131 mg, 0.47 mmol) were used. The procedure of step 6) of Example 1 was repeated, and 50 mg of the target compound was obtained in a 30% yield.

[0187] MS(ESI+,m / z):529[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0188] Example 16: 5-Chloro-N-(3-cyclopropyl-5-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0189]

Chemical formula

[0190] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, 1-(3-amino-5-cyclopropylphenyl)-N,N-dimethylpyrrolidin-3-amine (103 mg, 0.42 mmol) was used, and instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (120 mg, 0.42 mmol) was used. Except for this, the procedure of step 6) of Example 1 was repeated, and 110 mg of the target compound was obtained in a 54% yield.

[0191] MS(ESI+,m / z):487[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0192] Example 17: 2-(4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperazin-1-yl)-2-methylpropan-1-ol

[0193]

Chemical formula

[0194] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)-2-methylpropan-1-ol (67 mg, 0.23 mmol) was used, and instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (70 mg, 0.25 mmol) was used. The procedure of step 6) of Example 1 was repeated, and 36 mg of the target compound was obtained in a 29% yield.

[0195] MS(ESI+,m / z):531[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0196] Example 18: N-(3-(4-aminopiperidin-1-yl)-5-cyclopropylphenyl)-5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0197]

Chemical Structure

[0198] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, tert-butyl (1-(3-amino-5-cyclopropylphenyl)piperidin-4-yl)carbamate (76 mg, 0.23 mmol) and instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (70 mg, 0.25 mmol) were used. The procedure of step 6) of Example 1 was repeated, and 32 mg of the target compound was obtained in a 29% yield.

[0199] MS(ESI+,m / z):473[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):δ 11.77(s,1H), 9.33(s,1H), 8.47(m,3H), 7.28(s1H), 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)

[0200] Example 19: 5-Chloro-N-(3-cyclopropyl-5-(4-(methylamino)piperidin-1-yl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0201]

Chemical formula

[0202] In step 6) of Example 1, except that tert-butyl (1-(3-amino-5-)piperidin-4-yl)(methyl)carbamate (79 mg, 0.23 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (70 mg, 0.25 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, the procedure of step 6) of Example 1 was repeated, and 11 mg of the target compound was obtained in a 10% yield.

[0203] MS(ESI+,m / z):487[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0204] Example 20: 2-(4-(3-((5-chloro-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperazin-1-yl)-2-methylpropan-1-ol

[0205]

Chemical formula

[0206] In step 6) of Example 1, except that 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)-2-methylpropan-1-ol (50 mg, 0.17 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, the procedure of step 6) of Example 1 was repeated, and 30 mg of the target compound was obtained in a 33% yield.

[0207] MS(ESI+,m / z):535[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0208] Example 21: 2-(4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperidin-1-yl)ethan-1-ol

[0209]

Chemical formula

[0210] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, 2-(4-(3-amino-5-cyclopropylphenyl)piperidin-1-yl)ethan-1-ol (64 mg, 0.25 mmol) was used, and instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (103 mg, 0.37 mmol) was used. Except for this, the procedure of step 6) of Example 1 was repeated, and 7 mg of the target compound was obtained in a 6% yield.

[0211] MS(ESI+,m / z):502[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0212] Example 22: 2-(4-(3-((5-chloro-4-(6-chloro-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol

[0213]

Chemical formula

[0214] In step 6) of Example 1, the procedure of step 6) of Example 1 was repeated except that 6-chloro-3-(2,5-dichloropyrimidin-4-yl)-6-chloro-1H-indole (88 mg, 0.29 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, and 84 mg of the target compound was obtained in a 59% yield.

[0215] MS(ESI+,m / z):532[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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), 0.87(m,2H), 0.62(m,2H)

[0216] Example 23: 5-Chloro-N-(3-cyclopropyl-5-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0217]

Chemical formula

[0218] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, 3-cyclopropyl-5-(4-(pyrrolidin-1-yl)piperidin-1-yl)aniline (100 mg, 0.35 mmol) was used, and instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (146 mg, 0.53 mmol) was used. The procedure of step 6) of Example 1 was repeated, and 135 mg of the target compound was obtained in a 73% yield.

[0219] MS(ESI+,m / z):527[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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,2H)

[0220] Example 24: 1-(1-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)piperidin-4-yl)azetidin-3-ol

[0221]

Chemical formula

[0222] In step 6) of Example 1, except that 1-(1-(3-amino-5-cyclopropylphenyl)piperidin-4-yl)azetidin-3-ol (100 mg, 0.35 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (145 mg, 0.52 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, the procedure of step 6) of Example 1 was repeated, and 130 mg of the target compound was obtained in a 71% yield.

[0223] MS(ESI+,m / z):529[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0224] Example 25: 2-(4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenyl)piperazin-1-yl)ethan-1-ol

[0225]

Chemical formula

[0226] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, 2-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-ol (48 mg, 0.19 mmol) was used, and instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (56 mg, 0.21 mmol) was used. Except for this, the process of step 6) of Example 1 was repeated, and 25 mg of the target compound was obtained in a 27% yield.

[0227] MS(ESI+,m / z):479[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0228] Example 26: 2-(4-(3-((5-chloro-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-ol

[0229]

Chemical formula

[0230] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, 2-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-ol (50 mg, 0.177 mmol) was used. Except for this, the process of step 6) of Example 1 was repeated, and 23 mg of the target compound was obtained in a 28% yield.

[0231] MS(ESI+, m / z): 467 [M+H] + 1 H-NMR(300 MHz, DMSO-d 6 ): 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)

[0232] Example 27: 2-(4-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)piperidin-1-yl)ethan-1-ol

[0233]

Chemical Structure

[0234] In step 6) of Example 1, the procedure of step 6) of Example 1 was repeated, except that 2-(4-(3-aminophenyl)piperidin-1-yl)ethan-1-ol (40 mg, 0.18 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (53 mg, 0.20 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, to obtain 20 mg of the target compound in a 25% yield.

[0235] MS(ESI+, m / z): 448 [M+H] + 1 H-NMR(300 MHz, DMSO-d 6): 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, 4H)

[0236] Example 28: 2-(4-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethan-1-ol

[0237]

Chemical Structure

[0238] In step 6) of Example 1, the procedure of step 6) of Example 1 was repeated except that 2-(4-(3-aminophenyl)piperazin-1-yl)ethan-1-ol (42 mg, 0.19 mmol) was used instead of 22-(4-(3-aminocyclopropylphenyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (55 mg, 0.21 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, and 33 mg of the target compound was obtained in 39% yield.

[0239] MS(ESI+, m / z): 449 [M + H] + 1 H-NMR(300 MHz, DMSO-d 6 ): 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)

[0240] Example 29: 5-Chloro-N-(3-(4-(dimethylamino)piperidin-1-yl)phenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine

[0241]

Chemical Structure

[0242] In step 6) of Example 1, except that 1-(3-aminophenyl)-N,N-dimethylpiperidin-4-amine (35 mg, 0.16 mmol) was used instead of 2-(4-(3-aminocyclopropylphenyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (48 mg, 0.18 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, the procedure of step 6) of Example 1 was repeated, and 47 mg of the target compound was obtained in 66% yield.

[0243] MS(ESI+,m / z): 447[M+H] + 1 1H-NMR(300 MHz, DMSO-d 6 ): 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)

[0244] Example 30: 5-Chloro-N-(3-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine

[0245]

Chemical Structure

[0246] In step 6) of Example 1, instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, (S)-1-(3-amino-5-cyclopropylphenyl)-N,N-dimethylpyrrolidin-3-amine (33 mg, 0.16 mmol) and instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (48 mg, 0.18 mmol) were used. Except for this, the procedure of step 6) of Example 1 was repeated, and 26 mg of the target compound was obtained in a 38% yield.

[0247] MS(ESI+,m / z):473[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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,1H)

[0248] Example 31: 2-(4-(3-((5-chloro-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenyl)piperazin-1-yl)ethan-1-ol

[0249]

Chemical formula

[0250] In step 6) of Example 1, except that 2-(4-(3-amino-5-methoxyphenyl)piperazin-1-yl)ethan-1-ol (40 mg, 0.16 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, the procedure of step 6) of Example 1 was repeated, and 40 mg of the target compound was obtained in a 50% yield.

[0251] MS(ESI+,m / z):497[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0252] Example 32: 2-(4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-isopropoxyphenyl)piperazin-1-yl)ethan-1-ol

[0253]

Chemical formula

[0254] In step 6) of Example 1, except that 2-(4-(3-amino-5-isopropoxyphenyl)piperazin-1-yl)ethan-1-ol (50 mg, 0.18 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol and 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (54 mg, 0.20 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, the procedure of step 6) of Example 1 was repeated, and 61 mg of the target compound was obtained in a 67% yield.

[0255] MS (ESI+, m / z): 507 [M+H] + 1 H-NMR (300 MHz, DMSO-d 6 ): 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)

[0256] Example 33: 2-(4-(3-((5-Chloro-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-isopropoxyphenyl)piperazin-1-yl)ethan-1-ol

[0257]

Chemical Structure

[0258] In step 6) of Example 1, the procedure of step 6) of Example 1 was repeated except that 2-(4-(3-amino-5-isopropoxyphenyl)piperazin-1-yl)ethan-1-ol (50 mg, 0.18 mmol) was used instead of 2-(4-(3-amino-5-cyclopropylphenyl)piperazin-1-yl)ethan-1-ol, and 74 mg of the target compound was obtained in 78% yield.

[0259] MS (ESI+, m / z): 525 [M+H] + 1 H-NMR (300 MHz, DMSO-d 6): 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)

[0260] Example 34: 5-Chloro-N-(3-cyclopropyl-5-(piperazin-1-ylmethyl)phenyl)-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-amine

[0261] Step 1) Preparation of 3-bromo-5-nitrobenzoic acid

[0262]

Chemical formula

[0263] 3-Nitrobenzoic acid (11.2 g, 67 mmol) was dissolved in concentrated sulfuric acid (H2SO4, 30 mL), and the temperature was raised to 60 °C. N-Bromosuccinimide (14.3 g, 80.4 mmol) was added in three portions over 15 minutes, and the mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction mixture was added to ice. The resulting solid was filtered and dried in an oven at 50 °C for 12 hours to obtain 16.4 g of the target compound in 99% yield.

[0264] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.59 (s, 1H), 8.51 (s, 1H), 8.38 (s, 1H)

[0265] Step 2) Preparation of (3-bromo-5-nitrophenyl)methanol

[0266]

Chemical formula

[0267] The 3-bromo-5-nitrobenzoic acid (4.0 g, 16.3 mmol) produced in the above step 1) was dissolved in THF (25 mL), and the temperature was cooled to 0 °C. Borane-dimethyl sulfide (2.0 M in THF, 32.5 mL, 65.2 mmol) was gradually added dropwise over 45 minutes. The mixture was stirred at room temperature for 12 hours, and additionally refluxed with stirring at 70 °C for 1.5 hours. After the reaction was completed, it was cooled to room temperature, and an aqueous solution of saturated sodium hydrogen carbonate was added dropwise. After extraction three times with ethyl acetate, it was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (methylene chloride:methanol = 10:1 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 3.0 g of the target compound in an 80% yield.

[0268] 1 H-NMR(300MHz,DMSO-d 6 ):δ 8.23(s,1H), 8.17(s,1H), 7.96(s,1H), 4.63(s,2H)

[0269] Step 3) Production of (3-cyclopropyl-5-nitrophenyl)methanol

[0270]

Chemical formula

[0271] (3-Bromo-5-nitrophenyl)methanol (5 g, 22.93 mmol) produced in the above step 2), cyclopropylboronic acid (5.9 g, 68.80 mmol), and Pd(OAc) 2 (514 mg, 2.29 mmol), potassium phosphate (14.6 g, 68.80 mmol), triphenylphosphine (1.8 g, 6.88 mmol) in toluene / H 2It was dissolved in a mixed solvent (2: 175 mL), and degassed with nitrogen for 5 minutes. The reaction mixture was sealed, heated to 100 °C, and refluxed with stirring for 12 hours. After the reaction was completed, it was cooled to room temperature, and the mixed solution was filtered through a filter filled with celite. The celite layer was washed with ethyl acetate. The organic layer was separated from the filtered mixed solution, washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1:10 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 1.25 g of the target compound in a 50% yield.

[0272] 1 H-NMR (300 MHz, DMSO-d 6 ): 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)

[0273] Step 4) Preparation of 2-(4-(3-nitrobenzyl)piperazin-1-yl)ethan-1-ol

[0274]

Chemical formula

[0275] (3-Cyclopropyl-5-nitrophenyl)methanol (1.0 g, 6.53 mmol) prepared in the above step 3) was dissolved in tetrahydrofuran: water = 10:1 (44 mL), and sodium hydroxide (0.52 g, 13.06 mmol) and p-toluenesulfonyl chloride (1.6 g, 8.49 mmol) were added. It was stirred at room temperature for 2 hours. After the reaction was completed, water was added dropwise. After extraction with ethyl acetate three times, it was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (K 2 CO 3; 1.33 g (9.60 mmol) and 2-(piperazin-1-yl)ethan-1-ol (0.75 g, 5.76 mmol) were added, and the mixture was stirred at 100 °C for 1 hour. After the reaction was completed, the mixed solution was cooled to room temperature, and ethyl acetate and water were added dropwise. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (methylene chloride:methanol = 30:1 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 602 mg of the target compound in a 47% yield.

[0276] 1 H-NMR (300 MHz, DMSO-d 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)

[0277] Step 5) Preparation of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol

[0278]

Chemical formula

[0279] 50% ethanol was added to iron (Fe powder), and concentrated hydrochloric acid (conc. HCl) was gradually added dropwise, and then refluxed and stirred at 120 °C for 1 hour for activation. 2-(4-(3-Nitrobenzyl)piperazin-1-yl)ethan-1-ol (602 mg, 2.27 mmol) prepared in the above step 4) was added to the above-activated iron mixture, and refluxed and stirred at 120 °C for 1 hour. After the reaction was completed, the mixture was filtered through a filter filled with celite, and a chloroform / 2-propanol mixed solution (3:1) and a saturated aqueous sodium hydrogen carbonate solution were added dropwise to the filtrate. In the mixed solution, after separating the organic layer, it was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 330 mg of the target compound in a 62% yield.

[0280] Step 6) Production of 2-(4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)benzyl)piperazin-1-yl)ethan-1-ol

[0281]

Chem.

[0282] 2-(4-(3-Aminobenzyl)piperazin-1-yl)ethan-1-ol (45 mg, 0.19 mmol) produced in the above Step 5) and 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (produced in WO2013014448; 50 mg, 0.19 mmol) were dissolved in 2-butanol, and p-toluenesulfonic acid (p-TsOH; 36 mg, 0.19 mmol) was added. The reaction mixture was refluxed and stirred at 120 °C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added dropwise, and the mixture was extracted twice with methylene chloride. After washing with brine and drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform:methanol = 9:1 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 31 mg of the target compound in a 35% yield.

[0283] MS (ESI+, m / z): 463 [M+H] + 1 H-NMR (300 MHz, DMSO-d 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)

[0284] Example 35: 2-(4-(3-((5-chloro-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxybenzyl)piperazin-1-yl)ethan-1-ol

[0285]

Chem.

[0286] In step 6) of Example 35, except that 2-(4-(3-amino-5-methoxybenzyl)piperazin-1-yl)ethan-1-ol (63 mg, 0.24 mmol) was used instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol and 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole (68 mg, 0.24 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole, the procedure of step 6) of Example 35 was repeated to obtain 79 mg of the target compound in a 59% yield.

[0287] MS(ESI+, m / z): 511 [M+H] + 1 H-NMR(300 MHz, DMSO-d 6 ): 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)

[0288] Example 36: 2-(4-(3-((5-chloro-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)benzyl)piperazin-1-yl)ethan-1-ol

[0289]

Chem.

[0290] In step 6) of Example 35, the procedure of step 6) of Example 35 was repeated except that 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole (59 mg, 0.21 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole, and 53 mg of the target compound was obtained in a 52% yield.

[0291] MS(ESI+,m / z):481[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0292] Example 37: 2-(4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxybenzyl)piperazin-1-yl)ethan-1-ol

[0293]

Chemical formula

[0294] In step 6) of Example 35, the procedure of step 6) of Example 35 was repeated except that 2-(4-(3-amino-5-methoxybenzyl)piperazin-1-yl)ethan-1-ol (50 mg, 0.19 mmol) was used instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol, and 44 mg of the target compound was obtained in a 47% yield.

[0295] MS(ESI+,m / z):493[M+H] + 1 H-NMR(300MHz,DMSO-d 6): 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)

[0296] Example 38: 2-(4-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)piperazin-1-yl)-2-methylpropan-1-ol

[0297]

Chemical Structure

[0298] In step 6) of Example 35, the procedure of step 6) of Example 35 was repeated except that 2-(4-(3-amino-5-cyclopropylbenzyl)piperazin-1-yl)-2-methylpropan-1-ol (40 mg, 0.13 mmol) was used instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol, and 31 mg of the target compound was obtained in a 45% yield.

[0299] MS (ESI+, m / z): 531 [M+H] + 1 H-NMR (300 MHz, DMSO-d 6 ): 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)

[0300] Example 39: (S)-1-((1-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)piperidin-4-yl)(methyl)amino)propan-2-ol

[0301]

Chemical formula

[0302] In step 6) of Example 35, the procedure of step 6) of Example 35 was repeated, except that (S)-1-((1-(3-amino-5-cyclopropylbenzyl)piperidin-4-yl)(methyl)amino)propan-2-ol (50 mg, 0.16 mmol) was used instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol, and 26 mg of the target compound was obtained in a 30% yield.

[0303] MS(ESI+,m / z):545[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0304] Example 40: (S)-1-((1-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)piperidin-4-yl)(methyl)amino)propan-2-ol

[0305]

Chemical formula

[0306] In step 6) of Example 35, instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol, (S)-1-((1-(3-amino-5-cyclopropylbenzyl)piperidin-4-yl)(methyl)amino)propan-2-ol (50 mg, 0.16 mmol) and instead of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (48 mg, 0.17 mmol) were used. The procedure of step 6) of Example 35 was repeated, and 67 mg of the target compound was obtained in 75% yield.

[0307] MS(ESI+,m / z):559[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0308] Example 41: 2-(4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)piperazin-1-yl)-2-methylpropan-1-ol

[0309]

Chemical formula

[0310] In step 6) of Example 35, except that 2-(4-(3-amino-5-cyclopropylbenzyl)piperazin-1-yl)-2-methylpropan-1-ol (43 mg, 0.14 mmol) was used instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol and 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (43 mg, 0.16 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole, the procedure of step 6) of Example 35 was repeated, and 40 mg of the target compound was obtained in a 52% yield.

[0311] MS(ESI+,m / z):545[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0312] Example 42: (S)-1-(1-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)piperidin-4-yl)pyrrolidin-3-ol

[0313]

Chemical formula

[0314] In step 6) of Example 35, the procedure of step 6) of Example 35 was repeated except that (S)-1-(1-(3-amino-5-cyclopropylbenzyl)piperidin-4-yl)pyrrolidin-3-ol (50 mg, 0.16 mmol) was used instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol, and 60 mg of the target compound was obtained in 69% yield.

[0315] MS(ESI+,m / z):543[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0316] Example 43: (S)-1-(1-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)piperidin-4-yl)pyrrolidin-3-ol

[0317]

Chemical formula

[0318] In step 6) of Example 35, instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol, (S)-1-(1-(3-amino-5-cyclopropylbenzyl)piperidin-4-yl)pyrrolidin-3-ol (50 mg, 0.16 mmol) was used, and instead of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (47 mg, 0.17 mmol) was used. The procedure of step 6) of Example 35 was repeated, and 50 mg of the target compound was obtained in a 56% yield.

[0319] MS(ESI+,m / z):557[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0320] Example 44: (S)-1-(1-(3-((5-chloro-4-(6-methoxy-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)piperidin-4-yl)pyrrolidin-3-ol

[0321]

Chemical formula

[0322] In step 6) of Example 35, instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol, (S)-1-(1-(3-amino-5-cyclopropylbenzyl)piperidin-4-yl)pyrrolidin-3-ol (54 mg, 0.17 mmol) and instead of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methoxy-1H-indole (50 mg, 0.17 mmol) were used. The procedure of step 6) of Example 35 was repeated except for this, and 29 mg of the target compound was obtained in a 30% yield.

[0323] MS(ESI+,m / z):573[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0324] Example 45: 1-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)piperidin-4-ol

[0325]

Chemical formula

[0326] In step 6) of Example 35, except that 1-(3-amino-5-cyclopropylbenzyl)piperidin-4-ol (57 mg, 0.23 mmol) was used instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol and 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (96 mg, 0.35 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole, the procedure of step 6) of Example 35 was repeated, and 100 mg of the target compound was obtained in 88% yield.

[0327] MS(ESI+,m / z):488[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0328] Example 46: (S)-5-chloro-N-(3-cyclopropyl-5-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0329]

Chemical formula

[0330] In step 6) of Example 35, instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol, (S)-1-(3-amino-5-cyclopropylbenzyl)-N,N-dimethylpyrrolidin-3-amine (100 mg, 0.37 mmol) was used, and instead of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (153 mg, 0.55 mmol) was used. Except for this, the procedure of step 6) of Example 35 was repeated, and 180 mg of the target compound was obtained in 96% yield.

[0331] MS(ESI+,m / z):501[M+H] + 1 H-NMR(300MHz,DMSO-d 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(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)

[0332] Example 47: 1-(4-(3-((5-chloro-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)piperazin-1-yl)-2-hydroxyethan-1-one

[0333]

Chemical formula

[0334] In step 6) of Example 35, instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol, 1-(4-(3-amino-5-cyclopropylbenzyl)piperazin-1-yl)2-hydroxyethan-1-one (53 mg, 0.18 mmol) was used, and instead of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole, 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole (51 mg, 0.18 mmol) was used. The procedure of step 6) of Example 35 was repeated, and 19 mg of the target compound was obtained in a 19% yield.

[0335] MS(ESI+,m / z):535[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0336] Example 48: 1-(4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)piperazin-1-yl)-2-hydroxyethan-1-one

[0337]

Chemical formula

[0338] In step 6) of Example 35, except that 1-(4-(3-amino-5-cyclopropylbenzyl)piperazin-1-yl)2-hydroxyethan-1-one (53 mg, 0.18 mmol) was used instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (56 mg, 0.20 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole, the procedure of step 6) of Example 35 was repeated, and 31 mg of the target compound was obtained in 32% yield.

[0339] MS(ESI+,m / z):531[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0340] Example 49: 2-(4-(3-((5-chloro-4-(6-ethyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)piperazin-1-yl)ethan-1-ol

[0341]

Chemical formula

[0342] In step 6) of Example 35, the procedure of step 6) of Example 35 was repeated, except that 2-(4-(3-amino-5-cyclopropylbenzyl)piperazin-1-yl)ethan-1-ol (56 mg, 0.20 mmol) was used instead of 2-(4-(3-aminobenzyl)piperazin-1-yl)ethan-1-ol, and 3-(2,5-dichloropyrimidin-4-yl)-6-ethyl-1H-indole (84 mg, 0.30 mmol) was used instead of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole, to obtain 70 mg of the target compound in 65% yield.

[0343] MS(ESI+,m / z):531[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0344] Example 50: (3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenyl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone

[0345] Step 1) Preparation of 3-methoxy-5-chloronitrobenzoyl

[0346]

Chemical formula

[0347] 3-Methoxy-5-nitrobenzoic acid (1.0 g, 5.07 mmol) was dissolved in dichloromethane (10 mL). Oxalyl chloride (0.9 mL, 10.14 mmol) and N,N-dimethylformamide were added dropwise thereto in an amount of 3 to 4 drops. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed under reduced pressure, and 1.09 g of the target compound was obtained in a yield of 99%.

[0348] Step 2) Production of (4-(2-Hydroxyethyl)piperazin-1-yl)(3-methoxy-5-nitrophenyl)methanone

[0349]

Chemical formula

[0350] The 3-methoxy-5-chloronitrobenzoyl (1.09 g, 5.06 mmol) produced in the above Step 1), 2-(piperazin-1-yl)ethan-1-ol (2.0 g, 15.18 mmol) and triethylamine (2.1 mL, 15.18 mmol) were dissolved in dichloromethane (10 mL), and the mixture was stirred at room temperature for 17 hours. After the reaction was completed, water and chloroform were added dropwise. The organic layer was separated and washed twice with water. After washing with brine, it was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by MPLC (chloroform:methanol = 20:1 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 1.08 g of the target compound in a yield of 69%.

[0351] Step 3) Production of (3-Amino-5-methoxyphenyl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone

[0352]

Chemical formula

[0353] Iron (975 mg, 17.46 mmol) and hydrochloric acid (0.12 mL, 1.40 mmol) were dissolved in 12 mL of 50% ethanol, and the mixture was refluxed with stirring at 110 °C for 1 hour. To this, (4-(2-hydroxyethyl)piperazin-1-yl)(3-methoxy-5-nitrophenyl)methanone (1.08 g, 3.49 mmol) prepared in the above step 2) was gradually added. The mixture was refluxed with stirring at 110 °C for 1 hour. After the reaction was completed, it was cooled to room temperature, neutralized with a saturated aqueous sodium hydrogen carbonate solution, filtered through a filter filled with celite, and washed with chloroform and methanol. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MPLC (chloroform:methanol = 8:1 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 806 mg of the target compound in an 83% yield.

[0354] 1 1H-NMR (300 MHz, DMSO-d 6 6): 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)

[0355] Step 4) Preparation of (3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenyl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone

[0356]

Chemical Structure

[0357] (3-Amino-5-methoxyphenyl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (53 mg, 0.19 mmol), 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (50 mg, 0.19 mmol), and p-toluenesulfonic acid monohydrate (36 mg, 0.19 mmol) prepared in step 3) above were dissolved in 1.2 mL of 2-butanol and stirred in a sealed tube at 120 °C for 17 hours. After completion of the reaction, the mixture was cooled to room temperature, and chloroform, methanol, and saturated sodium hydrogen carbonate solution were added. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by MPLC (chloroform:methanol = 7:1 (v / v)), and the resulting solution was concentrated under reduced pressure to obtain 25 mg of the target compound in a 26% yield.

[0358] MS (ESI+, m / z): 507 [M+H] + 1 H-NMR (300 MHz, DMSO-d 6 ): 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)

[0359] Example 51: 1-(2-(3-((5-Chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenoxy)ethyl)piperidin-4-ol

[0360] Step 1) Preparation of 2-amino 3-bromo-5-nitrophenol

[0361]

Chemical formula

[0362] 2-Amino-5-nitrophenol (25 g, 162 mmol) was dissolved in acetonitrile (1.0 L), and N-bromosuccinimide (28.8 g, 170 mmol) was gradually added. After stirring at room temperature for 2 hours, the solvent was removed under reduced pressure. After stirring with an ethyl acetate / hexane mixed solution (1:1), the resulting solid was filtered to obtain 31.5 g of the target compound in 83% yield.

[0363] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 10.66 (s, 1H), 7.83 (s, 1H), 7.46 (s, 1H), 6.15 (s, 2H)

[0364] Step 2) Production of 3-bromo-5-nitrophenol

[0365]

Chemical formula

[0366] The 2-amino 3-bromo-5-nitrophenol (75.6 g, 0.32 mmol) produced in the above step 1) was dissolved in ethanol (1.5 L) and cooled to -10°C. Sulfuric acid (62.3 mL, 1.17 mmol) was added at -10 to -2°C for 30 minutes. The temperature of the reaction mixture was raised to 50°C, and sodium nitrite was gradually added over 30 minutes. The temperature of the reaction mixture was raised to 80°C, and the mixture was refluxed and stirred for 3 hours. After the reaction was completed, the solvent was removed under reduced pressure, and water and ethyl acetate were added dropwise. The organic layer was extracted three times and washed with brine. It was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:hexane = 0.5:10 (v / v)), and the resulting solution was concentrated under reduced pressure to obtain 60 g of the target compound in 85% yield.

[0367] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 10.90 (s, 1H), 7.75 (s, 1H), 7.51 (s, 1H), 7.36 (s, 1H)

[0368] Step 3) Production of 3-Cyclo-5-nitrophenol

[0369] [Chemical formula]

[0370] The 3-bromo-5-nitrophenol (3.0 g, 13.76 mmol) produced in the above Step 2), cyclopropylboronic acid (3.54 g, 41.28 mmol), potassium phosphate (8.8 g, 41.28 mmol), palladium(II) acetate (310 mg, 1.38 mmol), and triphenylphosphine (1.1 g, 4.13 mmol) were dissolved in toluene (30 mL) and water (15 mL), and the mixture was refluxed and stirred at 100 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a filter filled with celite, and washed with chloroform. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by MPLC (chloroform:methanol = 20:1 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 1.52 g of the target compound in a yield of 62%.

[0371] 1 H-NMR (300 MHz, DMSO-d 6 ): 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)

[0372] Step 4) Production of 1-(2-(3-Cyclopropyl-5-nitrophenoxy)ethyl)piperidin-4-ol

[0373] [Chemical formula]

[0374] In the above step 3), 3-cyclo-5-nitrophenol (500 mg, 2.79 mmol) and 1,2-dibromoethane (0.37 mL, 4.19 mmol) were dissolved in acetonitrile (7 mL), and cesium carbonate (2.7 g, 8.37 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed, water and ethyl acetate were added dropwise. After separating the organic layer, it was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (10 mL), and 4-hydroxypiperidine (544 mg, 5.38 mmol) and potassium carbonate (745 mg, 5.38 mmol) were added. The temperature of the reaction mixture was raised to 90 °C, and it was refluxed and stirred for 4 hours. After the reaction was completed, water and ethyl acetate were added dropwise. The organic layer was separated and washed twice with water. After washing with brine, it was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 10:1 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 464 mg of the target compound in a 56% yield.

[0375] 1 H-NMR(300MHz,DMSO-d 6 ):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)

[0376] Step 5) Preparation of 1-(2-(3-amino-5-cyclopropylphenoxy)ethyl)piperidin-4-ol

[0377]

Chemical formula

[0378] The 1-(2-(3-cyclopropyl-5-nitrophenoxy)ethyl)piperidin-4-ol (464 mg, 1.51 mmol) produced in the above step 4) was dissolved in 10 mL of methanol, and Pd / C (50 mg, 10%) was added. The mixture was stirred under hydrogen gas for 3 hours. After the reaction was completed, it was filtered through a filter filled with celite, and the filtrate was removed under reduced pressure to obtain 429 mg of the target compound in a 99% yield.

[0379] Step 6) 1-(2-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenoxy)ethyl)piperidin-4-ol

[0380]

Chemical formula

[0381] 1-(2-(3-Amino-5-cyclopropylphenoxy)ethyl)piperidin-4-ol (100 mg, 0.36 mmol) and 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole (151 mg, 0.54 mmol) produced in the above step 5) were dissolved in 2-butanol, and p-toluenesulfonic acid (p-TsOH; 103 mg, 0.54 mmol) was added. The reaction mixture was refluxed and stirred at 120 °C for 3 hours. After the reaction was completed, it was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added dropwise, and the mixture was extracted twice with methylene chloride. It was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform:methanol = 9:1 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 105 mg of the target compound in a 56% yield.

[0382] MS(ESI+,m / z):518[M+H] + 1 H-NMR(300MHz,DMSO-d 6): 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)

[0383] Example 52: 1-(2-(3-((5-Chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-ethylphenoxy)ethyl)piperidin-4-ol

[0384]

Chemical Structure

[0385] In step 6) of Example 51, the procedure of step 6) of Example 51 was repeated except that 1-(2-(3-amino-5-ethylphenoxy)ethyl)piperidin-4-ol (100 mg, 0.38 mmol) was used instead of 1-(2-(3-amino-5-cyclopropylphenoxy)ethyl)piperidin-4-ol, and 150 mg of the target compound was obtained in 79% yield.

[0386] MS (ESI+, m / z): 518 [M + H] + 1 H-NMR (300 MHz, DMSO-d 6 ): 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)

[0387] Example 53: (R)-2-(3-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenoxy)pyrrolidin-1-yl)ethan-1-ol

[0388] Step 1) Preparation of tert-butyl (R)-3-(3-cyclopropyl-5-nitrophenoxy)pyrrolidine-1-carboxylate

[0389] [Chemical formula]

[0390] 3-Cyclo-5-nitrophenol (3.0 g, 16.74 mmol) prepared in Step 3) of Example 51, tert-butyl (S)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (5.3 g, 20.09 mmol), and cesium carbonate (11.0 g, 33.49 mmol) were dissolved in N,N-dimethylformamide (80 mL) and stirred at 100 °C for 14 hours. After the reaction was completed, the mixture was cooled to room temperature, and water and ethyl acetate were added dropwise. After separating the organic layer, it was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform:methanol = 9:1 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 3.9 g of the target compound in a 67% yield.

[0391] Step 2) Preparation of (R)-2-(3-(3-cyclopropyl-5-nitrophenoxy)pyrrolidinyl)ethan-1-ol

[0392] [Chemical formula]

[0393] The tert-butyl (R)-3-(3-cyclopropyl-5-nitrophenoxy)pyrrolidine-1-carboxylate (3.9 g, 11.19 mmol) produced in the above step 1) was dissolved in dichloromethane (40 mL), and trifluoroacetic acid (12 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the organic solvent was concentrated under reduced pressure. The obtained residue, bromoethanol (1.65 mL, 22.38 mmol) and triethylamine (8.6 mL, 61.55 mmol) were dissolved in N,N-dimethylformamide (30 mL), and the mixture was stirred at room temperature for 17 hours. After the reaction was completed, the mixture was cooled to room temperature, and water and ethyl acetate were added dropwise. The organic layer was separated, washed twice with water, washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 20:1 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 1.8 g of the target compound in a 55% yield.

[0394] 1 H-NMR(300MHz,DMSO-d 6 ):δ 7.47(s,1H), 7.37(m,1H), 7.02(s,1H), 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)

[0395] Step 3) Production of (R)-2-(3-(3-amino-5-cyclopropylphenoxy)pyrrolidin-yl)ethan-1-ol

[0396]

Chemical formula

[0397] Iron (1.7 g, 30.79 mmol) and hydrochloric acid (0.21 mL, 2.46 mmol) were dissolved in 20 mL of 50% ethanol, and the mixture was refluxed and stirred at 110 °C for 1 hour. To this, (R)-2-(3-(3-cyclopropyl-5-nitrophenoxy)pyrrolidin-1-yl)ethan-1-ol (1.8 g, 6.16 mmol) prepared in the above step 2) was gradually added. The mixture was refluxed and stirred at 110 °C for 1 hour. After the reaction was completed, it was cooled to room temperature, neutralized with a saturated aqueous sodium hydrogen carbonate solution, filtered through a filter filled with celite, and washed with chloroform and methanol. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MPLC (chloroform:methanol = 8:1 (v / v)), and the obtained solution was concentrated under reduced pressure to obtain 1.48 g of the target compound in a yield of 87%.

[0398] 1 H-NMR (300 MHz, DMSO-d 6 ): 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)

[0399] Step 4) (R)-2-(3-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenoxy)pyrrolidin-1-yl)ethan-1-ol

[0400]

Chemical formula

[0401] In step 6) of Example 51, the procedure of step 6) of Example 51 was repeated except that (R)-2-(3-(3-amino-5-cyclopropylphenoxy)pyrrolidin-1-yl)ethan-1-ol (230 mg, 0.88 mmol) was used instead of 1-(2-(3-amino-5-cyclophenoxy)ethyl)piperidin-4-ol, and 195 mg of the target compound was obtained in a 44% yield.

[0402] MS(ESI+,m / z):504[M+H] + 1 H-NMR(300MHz,DMSO-d 6 ):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,2H)

[0403] Example 54: 2-(4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenoxy)piperidin-1-yl)ethan-1-ol

[0404]

Chemical formula

[0405] In step 4) of Example 53, the procedure of step 4) of Example 53 was repeated except that 2-(4-(3-amino-5-cyclopropylphenoxy)piperidin-1-yl)ethan-1-ol (250 mg, 0.90 mmol) was used instead of (R)-2-(3-(3-amino-5-cyclopropylphenoxy)pyrrolidin-yl)ethan-1-ol, and 185 mg of the target compound was obtained in a 40% yield.

[0406] MS(ESI+, m / z): 518 [M+H] + 1 H-NMR(300MHz, DMSO-d 6 ): 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)

[0407] Example 55: 2-(4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenoxy)piperidin-1-yl)ethan-1-ol

[0408]

Chemical Structure

[0409] In step 4) of Example 53, the procedure of step 4) of Example 53 was repeated, except that 2-(4-(3-amino-5-methoxyphenoxy)piperidin-1-yl)ethan-1-ol (110 mg, 0.41 mmol) was used instead of (R)-2-(3-(3-amino-5-cyclopropylphenoxy)pyrrolidin-1-yl)ethan-1-ol, and 81 mg of the target compound was obtained in 40% yield.

[0410] MS(ESI+, m / z): 494 [M+H] + 1 H-NMR(300MHz, DMSO-d 6): 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)

[0411] Test Example For the compound produced in the above Example, kinase inhibition evaluation and cell growth inhibition activity were evaluated as follows, and the results are shown below.

[0412] Test Example 1: Kinase Inhibition Activity Evaluation In the said compound, for representative compounds, the inhibitory activities against AXL, CLK2, VEGFR2 (KDR), and NUAK1 kinases were measured. For AXL, the z-lyte kinase assay kit (Life Technologies, PV4122) Tyr peptide 6 was used; for CLK2, the z-lyte kinase assay kit (Life Technologies, PV3179) Ser / Thr peptide 6 was used; for VEGFR, the z-lyte kinase assay kit (Life Technologies, PV3190) was used; and for NUAK1 (ARK5) activity, the Adapta assay kit (Life Technologies, PV5099) was used. The test was conducted by Life Technologies. The activity inhibition (%) against the said kinases at a compound concentration of 100 nM is shown in Tables 2 to 5 below.

[0413] [Table 2]

[0414] [Table 3]

[0415]

Table 4

[0416]

Table 5

[0417] Test Example 2: Evaluation of Cell Growth Inhibitory Activity The RS4-11 cell line was cultured in RPMI1640 culture medium (10% FBS) at 37°C. The cultured cell line was prepared at 2.0×10 4 cells / 100 μL, placed in a 96-well plate, and treated with the test compound serially diluted in a 1 / 10 ratio from 10 μM to 0.1 nM in RPMI1640 medium, and then cultured for 3 days. To measure the viability of the cells, the MTS assay method was used, and the 50% growth inhibitory value (GI 50 ) of the cell line was calculated using GraphPad Prism software. The results are shown in Table 6 below.

[0418]

Table 6

[0419] The MV4-11 cell line was cultured in IMDM medium (10% FBS) at 37°C. The cultured cell line was prepared at 2.0×10 4 cells / 100 μL, placed in a 96-well plate, and treated with the test compound serially diluted in a 1 / 10 ratio from 1 μM to 0.01 nM in IMDM medium, and then cultured for 3 days. To measure the viability of the cells, the MTS assay method was used, and the growth inhibitory value (GI 50 ) of the cell line was calculated using GraphPad Prism software. The results are shown in Table 7 below.

[0420]

Table 7

[0421] As can be seen from the above table, it was found that the compounds of the present invention are excellent in kinase and cell growth inhibitory activities.

[0422] As described above, the present invention has been described mainly with reference to specific examples. Those skilled in the art in the technical field to which the present invention pertains will be able to understand that the present invention is embodied in a modified form within a range not deviating from the essential characteristics of the present invention. Therefore, the above-described specific examples should be considered from an illustrative rather than a limiting perspective. The scope of the present invention is shown not in the above description but in the claims, and all differences within the equivalent range thereof should be construed as being included in the present invention. Aspects according to the present disclosure also include the following aspects. <1> A compound selected from the substance of the following Chemical Formula 1 and its pharmaceutically acceptable salts:

Chemical Formula

Chemical formula

Chemical formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical formula

Table 8

Chemical Structure

Chemical Structure

Chemical Structure

Claims

1. A pharmaceutical composition comprising a compound of the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a patient, the method comprising administering the composition to the patient: 【Chemical 1】 In the above Chemical Formula 1, R １ is hydrogen, halogen, a hydroxy group or C １－４ alkoxy group, R ２ is hydrogen, halogen, cyano group, nitro group, amino group, carboxamide group, formyl group, halo C １－４ alkyl group or C １－４ alkyl group, and R ３ is hydrogen, halo C １－４ alkyl group, C １－４ alkyl group, C ２－４ alkenyl group or C ２－４ alkynyl group, and Each R ４ is, independently of one another, halogen, a hydroxy group, a cyano group, a nitro group, an amino group, —SR ｃ , —S(═O)R ｃ , —S(═O) ２ R ｃ , haloC １－４ alkyl group, C １－４ alkoxy group, hydroxyC １－４ alkyl group, C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, —NR ａ R ｂ , —CO ２ R ｂ or —CO—NR ａ R ｂ and Here, R ａ and R ｂ are each independently hydrogen or a C １－６ alkyl group, R ｃ is a C １－４ alkyl group or -NR ａ R ｂ and k is an integer from 0 to 4, R ５ and R ６ each independently represents hydrogen, halogen, hydroxy group, nitro group, amino group, C １－４ alkoxy group, hydroxy C １－４ alkyl group, C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C ３－１０ cycloalkyl group or C ３－９ heterocycloalkyl group, and Here, C ３－１０ The cycloalkyl group and C ３－９ The heterocycloalkyl group may or may not be substituted with a halogen, a C １－４ alkyl group, or a halo C １－４ alkyl group. R ７ is a C ３－７ cycloalkyl group, Y is a direct bond, or is - (CH ２ ), -O-, -O(CH ｍ ), - (CH ２ ), - (CH ｍ ), - (CH ２ ), - (CH ｍ ), - (CH ９ ), - (CH ２ ), - (CH ２ ), - (CH ｍ ), -O-(CH ２ ), - (CH ｎ ), -CO(CH ２ ), - (CH ｍ ), - (CH ２ ), - (CH ｍ ), - (CH ２ ), - (CH ｍ ), -CO-(CH ２ ), - (CH ｎ ), - (CH ２ ), - (CH ｍ ), -NR ９ ), -NR ９ ), - (CH ２ ), - (CH ｍ ), - (CH ２ ), - (CH ｍ ), -NR ９ ), - (CH ２ ), - (CH ｎ ), - (CH ２ ), - (CH ｍ ), -SO ２ ), -SO ２ ), - (CH ２ ), - (CH ｍ ), - (CH ２ ), - (CH ｍ ), -SO ２ ), - (CH ２ ), - (CH ｎ ), and is Here, R ９ is hydrogen, C １－４ alkyl group, C ３－１０ cycloalkyl group or C ３－９ heterocycloalkyl group, and m and n are each independently an integer from 1 to 3, Z has the structure of the following Chemical Formula 2, [Chemical 2] In the above Chemical Formula 2, [Chemical Formula 3] is C ３－１０ a cycloalkyl group or C ２－１１ a heterocycloalkyl group, and Each R １０ is, independently of one another, 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 C １－４ alkyl group, a linear or branched C １－４ alkoxy group, a linear or branched hydroxy C １－４ alkyl group, a linear or branched C １－４ alkyl group, a linear or branched hydroxy C １－４ alkylcarbonyl group, a C ２－４ alkenyl group, a C ２－４ alkynyl group, a C ３－１０ cycloalkyl group, a C ２－９ heterocycloalkyl group, a hydroxy C ２－９ heterocycloalkyl group, -NR １１ R １２ , -COR １３ , -COOR １３ or -SO ２ R １４ and R １１ and R １２ are each independently hydrogen, a linear or branched hydroxy C １－４ alkyl group, a linear or branched halo C １－４ alkyl group, a linear or branched C １－４ alkyl group, a C ２－４ alkenyl group or a C ２－４ alkynyl group, R １３ is hydrogen, a hydroxy group, hydroxy C １－４ alkyl group, halo C １－４ alkyl group, C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C ３－１０ cycloalkyl group or C ２－９ heterocycloalkyl group, and R １４ is a hydroxy group, halo C １－４ alkyl group, C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C ３－１０ cycloalkyl group, C ２－９ heterocycloalkyl group, aryl group or -NR ａ R ｂ and is q is an integer from 0 to 5.

2. Y is -(CH ２ ) ｍ -, -O- or -C(=O)-, the pharmaceutical composition according to claim 1.

3. Y is -CH ２ - or -(CH ２ ) ２ The pharmaceutical composition according to claim 1 or claim 2, wherein it is

4. R ７ The pharmaceutical composition according to any one of claims 1 to 3, wherein R is a cyclopropyl group.

5. The pharmaceutical composition according to any one of Claims 1 to 4, wherein Z is any one selected from Chemical Formulas 3 to 5: [Chemical Formula 4] 【Chemical Formula 5】 [Chemical Formula 6] Provided that in the above Chemical Formulas 3 to 5, V and W are each independently N or CH, provided that V and W are not both CH at the same time, R ８ is selected from the group consisting of hydrogen, halogen, linear or branched C １－４ alkyl group, linear or branched hydroxy C １－４ alkyl group, hydroxy group, -NR １１ R １２ , linear or branched hydroxy C １－４ alkylcarbonyl group, heterocycloalkyl group, hydroxy-substituted heterocycloalkyl group, linear or branched halo C １－４ alkyl group, and linear or branched C １－４ alkoxy group, and is selected from the group consisting of: R １１ and R １２ are, independently of each other, hydrogen, a linear or branched C １－４ alkyl group, or a linear or branched hydroxy C １－４ alkyl group, and R １５ is, independently of one another, a linear or branched C １－４ alkyl group, a linear or branched hydroxy C １－４ alkyl group, or a halogen, p is an integer from 0 to 4, s and t are integers independent of each other, and R ８ is hydrogen, it is 0 to 5, and R ８ is not hydrogen, it is 0 to 4.

6. R １ is hydrogen, a hydroxy group or C １－４ alkoxy group, and R ２ is hydrogen, halogen, a linear or branched C １－４ alkyl group, or a linear or branched halo C １－４ alkyl group, and R ３ is hydrogen, R ４ is a halogen, a hydroxy group, a linear or branched C １－４ alkoxy group, a linear or branched hydroxy C １－４ alkyl group, or a linear or branched C １－４ alkyl group, and k is an integer from 0 to 2, R ５ and R ６ are each independently hydrogen or a hydroxy group, R ７ is a cyclopropyl group, Y is -(CH ２ ) ｍ -, -(CH ２ ) ｍ -O-(CH ２ ) ｎ - or -(CH ２ ) ｍ -CO-(CH ２ ) ｎ - and [Chemical Formula 7] is a C containing one or two heteroatoms selected from O, N, and S ３ - ６ heterocycloalkyl group, R １０ are each independently a hydroxy group, a linear or branched hydroxy C １－４ alkyl group, a linear or branched C １－４ alkyl group, a C ３－１０ cycloalkyl group, a C ２－９ heterocycloalkyl group, a hydroxy C ２－９ heterocycloalkyl group, -NR １１ R １２ or -COR １３ wherein q is an integer from 0 to 3, R １１ and R １２ are each independently hydrogen, a linear or branched hydroxy C １－４ alkyl group, or a linear or branched C １－４ alkyl group, R １３ is hydrogen, a linear or branched hydroxy C １－４ alkyl group, a linear or branched halo C １－４ alkyl group, or a linear or branched C １－４ alkyl group, and is the pharmaceutical composition according to any one of claims 1 to 5.

7. A pharmaceutical composition comprising a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a patient, the method comprising administering the pharmaceutical composition to the patient: 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 。

8. R １ 、R ３ 、R ５ and R ６ are each hydrogen, R ２ is hydrogen or halogen, R ４ is C １－４ an alkyl group or a halogen, and Y is a direct bond, -CH ２ -, -O-, ethyleneoxy or -C(=O)-, and The pharmaceutical composition according to any one of Claims 1 to 7, wherein Z is any one selected from Chemical Formulas 3 to 5: [Chemical 8] 【Chemical Formula 9】 【Chemical Formula 10】 Provided that in the above Chemical Formulas 3 to 5, V and W are each independently N or CH, provided that V and W are not both CH at the same time, R ８ is selected from the group consisting of hydrogen, halogen, a linear or branched C １－４ alkyl group, a linear or branched hydroxy C １－４ alkyl group, a hydroxy group, -NR １１ R １２ , a linear or branched hydroxy C １－４ alkylcarbonyl group, a heterocycloalkyl group, a hydroxy-substituted heterocycloalkyl group, a linear or branched halo C １－４ alkyl group, and a linear or branched C １－４ alkoxy group, R １１ and R １２ are, independently of each other, hydrogen, a linear or branched C １－４ alkyl group, or a linear or branched hydroxy C １－４ alkyl group, and R １５ is, independently of each other, a linear or branched C １－４ alkyl group, a linear or branched hydroxy C １－４ alkyl group, or a halogen, p is an integer from 0 to 4, s and t are independent integers, and R ８ is hydrogen, it is 0 to 5, and R ８ is not hydrogen, it is 0 to 4.

9. Y is directly bonded or -CH ２ - and Z is Chemical Formula 4 or Chemical Formula 5, R ８ is hydrogen, a linear or branched C １－４ alkyl group, a linear or branched hydroxy C １－４ alkyl group, a heterocycloalkyl group, or a hydroxy-substituted heterocycloalkyl group, and Each R １５ is, independently of one another, a linear or branched C １－４ alkyl group, a linear or branched hydroxy C １－４ alkyl group, or a halogen, and is the pharmaceutical composition according to any one of claims 1 to 8.

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