RU2807277C2 - Pyrimidine compounds and pharmaceutical compositions containing them for the prevention or treatment of cancer - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula 14 or its stereoisomer or tautomer, where in formula 14 E^a represents either hydrogen, hydroxy or a C₁-C₄alkoxy group; E^b represents either hydrogen, halogen, a C₁-C₄alkyl group or a C₁-C₄fluoroalkyl group; E^c and E^d each independently represents either hydrogen or hydroxy group; X' represents either hydrogen or hydroxy group; k is equal to an integer from 0 to 4; each Q independently represents either hydroxy, halogen, a C₁-C₄alkyl group, a hydroxy-C₁-C₄alkyl group, or a C₁-C₄alkoxy group; and Z' is a monovalent functional group represented by formula 15, where in formula 15 n is an integer from 1 to 5; each A independently represents a functional group selected from hydroxy, a C₁-C₄alkyl group, and a hydroxy-C₁-C₄alkyl group, and when n is two or more, then the two A can be spiro-linked to form 4.7-diazaspiro[2.5]octane; and L represents either hydrogen, a C₁-C₄alkyl group, a hydroxy group or a hydroxy-C₁-C₄alkyl group. The invention also relates to a method of inhibiting FLT3 kinase activity and a method of treating FLT3-mediated disease based on compounds of formula 14.

EFFECT: obtaining of new compounds that can be used in medicine for the treatment of cancer.

19 cl, 7 tbl, 32 ex

Description

Field of technology

The present invention relates to new pyrimidine compounds, methods for their preparation and their pharmaceutical use.

Prior Art

Kinases mediate a reaction in which a phosphate group from high-energy molecules, particularly ATP (adenosine triphosphate), is transferred to a substrate. Kinases stabilize phosphoric anhydride bonds and place the substrate and phosphate group in a specific position to increase the rate of the reaction. In most cases, the transition state resulting from interaction with a negatively charged phosphate group is electrostatically stabilized by surrounding positively charged amino acids, and some kinases can coordinate with the phosphate group using a metal cofactor.

Kinases can be classified as, for example, protein kinases, lipid kinases and carbohydrate kinases according to their substrate and characteristics. Proteins, lipids or carbohydrates can differ in their activity, reactivity, ability to bind to other molecules, etc. depending on the state of phosphorylation. Kinases affect intracellular signal transduction and regulate complex biological mechanisms in cells. Due to phosphorylation, some molecules may have increased or decreased activity, and their ability to interact with other molecules may be controlled. Because many kinases respond to environmental conditions or signals, cells can control intracellular molecules using kinases depending on the situation. As such, the kinase plays a critical role in cell growth, differentiation, proliferation, survival, metabolism, signal transduction, cellular transport, secretion and many other cellular reaction pathways.

Kinases have been discovered in a variety of species, including bacteria, fungi, insects, and mammals, and so far 500 or more kinases have been discovered in humans.

Protein kinases can increase or decrease the activity of a protein, act as a marker for stabilization or degradation, place a protein into a specific cellular compartment, or initiate or disrupt interactions of a protein with other proteins. Protein kinases are known to constitute the majority of kinases and are considered an important research target. Protein kinases regulate, together with phosphatase, proteins and enzymes, as well as cellular signal transduction. Although cellular proteins are regulated by numerous covalent bonds, few of these bonds are reversible. Accordingly, we can say that protein phosphorylation has a regulatory function. Protein kinases can often have multiple substrates, and sometimes a particular protein can act as a substrate for at least one kinase. For this reason, protein kinases are named using factors that regulate their activity. For example, calmodulin-dependent protein kinase is regulated by calcium and influenza. In some cases, kinases can be classified into subgroups. For example, cyclic AMP-dependent protein kinases type I and type II contain identical enzyme subunits, but their regulatory subunits that bind to cyclic AMP are different from each other.

Protein kinase is an enzyme that catalyzes the phosphorylation of the hydroxy group found on tyrosine, serine and threonine residues of proteins and plays an important role in the transduction of growth factor signals that induce cell growth, differentiation and proliferation (Melnikova, I. et al., Nature Reviews Drug Discovery, 3 (2004), 993), and it is reported that abnormal expression or mutation of a particular kinase often occurs in cancer cells.

One of the ways in which cells recognize external stimuli can be through recognition through tyrosine kinase, which is a receptor in the cell membrane. Receptor tyrosine kinase (RTK) consists of an extracellular portion facing outward from the cell, an intracellular portion facing the intracellular cytoplasm, and a transmembrane portion extending across the plasma membrane between the extracellular portion and the intracellular portion. The extracellular portion of the receptor is the portion to which a particular ligand binds, and the intracellular portion functions to transmit the activation signal of the ligand-activated receptor into the cell. The RTK has a domain with tyrosine kinase activity in the C-terminal region facing the cell interior, and when a particular ligand binds to the extracellular portion, the kinase enzyme of the C-terminal tyrosine kinase domain facing the cytoplasmic region of the receptor protein is activated and the two RTKs cross-phosphorylate tyrosines on C - ends of neighboring RTKs. This process of tyrosine phosphorylation is an important process in the transmission of signals corresponding to extracellular stimulation into cells. There are many known receptors that have tyrosine kinase activity to transmit extracellular stimuli into cells based on this mechanism. Examples of such receptors are FLT3, VEGFR and SYK.

Among them, FMS-like tyrosine kinase 3 (FLT3), which is a receptor tyrosine kinase, is normally expressed in hematopoietic progenitor cells by hematopoietic blast cells and plays an important role in normal stem cell expression and the immune system. Abnormal overexpression and mutations of FLT3 are frequently found in patients with leukemia. In particular, various FLT3 mutations such as D835V, D835Y and internal tandem duplication (ITD) are found in acute myelogenous leukemia (AML). AML is a hematopoietic stem cell disorder characterized by abnormal proliferation and differentiation of blast cells in the myeloid and peripheral blood. FLT3 has recently been considered as one of the most important targets in the therapeutic aspects of AML.

RAS and p53 gene mutations in adult AML have been reported to account for approximately 20% and 5% of adult AML cases, respectively, while FLT3 gene mutations are found in approximately 30% of adult AML cases. The most common problem associated with AML is that FLT3 mutations, which are responsible for poor prognosis, are activated. FLT3 mutations are classified into two types: one is internal tandem duplications (ITDs) in the juxtamembrane domain, and the other is point mutations in the tyrosine kinase domain (TKD). Approximately 23% of patients with early AML experience activation of FLT3-ITD, the most commonly detected mutation. Patients with an ITD mutation have a poor prognosis and a high relapse rate. The other major FLT3 mutation is the FLT3 TKD mutation, which accounts for approximately 7% of initial AML cases. Point mutations at aspartate residue 835 (D835), which are replaced by various amino acids, are among the most common mutations, although they are less common than ITD mutations. Additionally, the other major mode of FLT3 activation in AML is overexpression of wild-type FLT3 protein.

Activating ITD mutations in FLT3 occur in approximately 20% of patients with acute myelogenous leukemia and are associated with a poor prognosis. Studies have shown that FLT3-ITD is a driver lesion that causes the pathogenesis of malignancy and may be an effective therapeutic target in human AML (Non-Patent Document 1). Mutations in the FLT3 gene frequently occur in AML and are usually accompanied by ITD mutations in the juxtamembrane domain coding region or point mutations in the tyrosine kinase domain (TKD). FLT3-ITD mutations and FLT3-TKD mutations cause ligand-independent proliferation due to dimerization of components and activation of the FLT3 receptor. A high degree of FLT3-ITD mutation on the wild-type allele is associated with poor prognosis in adults and children (Non-Patent Document 2). Other types of leukemia, such as chronic myelomonocytic leukemia (CMML), may also have an activating FLT3 mutation. Thus, FLT3 with activated mutations is an important target for several types of cancer (Non-Patent Document 3 and Non-Patent Document 4).

It is known that the vascular endothelial growth factor receptor (VEGFR) is a kinase that is involved in the regulation of the process of angiogenesis. Solid tumors require more nutrients and oxygen than normal tissue. Consequently, insufficient blood supply occurs compared with normal conditions, and overexpression or activation of VEGFR causes neovascularization involved in angiogenesis necessary for the growth and proliferation of tumor cells (Non-Patent Document 5). Therefore, various clinical studies have been conducted to treat tumors by inhibiting angiogenesis, and several promising results have been obtained. In addition, VEGF plays an important role in blood cancers and is overexpressed in various malignant solid tumors. It is known that overexpression of VEGF has a high correlation with the painful progression of malignant tumors. VEGFRs are classified according to subtypes including VEGFR-1, VEGFR-2 and VEGFR-3. VEGFR-2 (KDR) is a typical target in tumor diseases expressing VEGFR. Representative diseases caused by overexpression of VEGFR-2 are lung cancer, breast cancer, non-Hodgkin's lymphoma, ovarian carcinoma, pancreatic cancer, etc. VEGF, which is a ligand for VEGFR, may have angiogenic activity and may promote tumor growth through a direct pro-survival effect in tumor cells (non-patent document).

Splenic tyrosine kinase (SYK) is expressed primarily in blood cells and plays an important role in the signaling pathways of other immunoreceptors such as B cell receptors and mast cells. SYK is expressed in non-hematopoietic cells such as neural cells and vascular endothelial cells. Recent studies indicate that SYK is involved in the oxidation of various cellular stimuli including IL-1, TNF-α and ITGB1. SYK is known to be a good potential target in many hematological malignancies, autoimmune diseases and other inflammatory responses (Non-Patent Document 7 and Non-Patent Document 8).

Prior Art Documents

(Non-Patent Document 1) Catherine et al., Nature, 2012, 485: 260-263

(Non-Patent Document 2) A S Moore et al., Leukemia, 2012, 26: 1462-1470

(Non-Patent Document 3) Cancer Cell, (2007), 12: 367-380

(Non-Patent Document 4) Current Pharmaceutical Design (2005), 11: 3449-3457

(Non-Patent Document 5) Kliche, S. et al., J., Life, 52, (2002), 61

(Non-Patent Document 6) Simons, M. et al., Nature Reviews Drug Discovery, 17, (2016), 611

(Non-Patent Document 7) Liu et al., Journal of Hematology & Oncology (2017) 10:145

(Non-Patent Document 8) Yamada T et al., J. Immunol., (2001) 167, 283-288

Description of the invention

Technical problem

New pyrimidine compounds with kinase inhibitory activity have been proposed.

Methods for preparing pyrimidine compounds have been proposed.

Pharmaceutical applications of pyrimidine compounds have been proposed.

The solution of the problem

Additional aspects will be set forth in part in the description that follows, and in particular will be obvious from the description, or may be learned by practice of the presented embodiments.

According to an aspect of the embodiment, there is provided a compound selected from the compound represented by Formula 1, and a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof:

Formula 1

where in formula 1

R ¹ represents hydrogen, halogen, hydroxy group, C ₁ -C ₄ alkoxy group or -NR _a R _b ,

where each of R _a and R _b independently represents hydrogen or a C ₁ -C ₄ alkyl group;

R ² represents hydrogen, halogen, cyano group, nitro group, amino group, carboxamide group, formyl group, halogen-C ₁ -C ₄ alkyl group or C ₁ -C ₄ alkyl group;

R represents hydrogen, halogen, hydroxy group, halogen-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkyl group, C ₂ -C ₄ alkenyl group or C ₂ -C ₄ alkynyl group;

each R ⁴ independently represents hydrogen, halogen, hydroxy group, cyano group, nitro group, amino group, -S(=O) _l -R _c , halogen-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, hydroxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, -NR _d R _e , -CO ₂ R _e or -CO-NR _d R _e ,

where R _c represents a C ₁ -C ₄ alkyl group or -NR _d R _e ,

each of R _d and R _e independently represents hydrogen or a C ₁ -C ₄ alkyl group,

l is equal to an integer from 0 to 2, and

k is equal to an integer from 0 to 4;

each of R ⁵ and R ⁶ independently represents hydrogen, halogen, hydroxy, nitro, amino, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkyl;

R ⁷ represents a hydroxy-C ₁ -C ₄ alkyl group, a C _{1 -C 4} alkyl group, a C _{2 -C 4 alkenyl group, a C 2 -C 4} alkynyl group, a C ₃ -C ₇ cycloalkyl group or a C ₃ -C ₉ heterocycloalkyl group group,

wherein a C ₃ -C ₇ cycloalkyl group or a C ₃ -C ₉ heterocycloalkyl group is unsubstituted or substituted with a halogen, a C ₁ -C ₄ alkyl group or a halogen-C ₁ -C ₄ alkyl group; and

X represents H or OH;

where, when X represents OH, then the compound represented by formula 1 includes the tautomeric structure represented by formula 2,

Formula 2

R ³ , R ⁴ and k in formula 2 are the same as described in relation to formula 1;

Y is -(CH ₂ ) _m -, -(CH ₂ ) _m -O-(CH ₂ ) _n -, -(CH ₂ ) _m -CO-(CH ₂ ) _n -, -(CH ₂ ) _m - NR ⁸ -(CH ₂ ) _n - or -(CH ₂ ) _m -SO ₂ (CH ₂ ) _n -,

where R ⁸ represents hydrogen or a C ₁ -C ₄ alkyl group,

each of m and n is independently equal to an integer from 0 to 2; And

Z is represented by formula 3,

Formula 3

where in formula 3

represents a C ₃ -C ₁₀ cycloalkyl group or a C ₂ -C ₁₁ heterocycloalkyl group;

R ⁹ represents a halogen, hydroxy group, cyano group, nitro group, amino group, thiol group, formyl group, halogen-C ₁ -C ₄ alkyl group, C _1- C ₄ alkoxy group, linear or branched hydroxy-C ₁ -C ₄ alkyl group, linear or branched C ₁ -C ₄ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, C ₃ -C ₁₀ cycloalkyl group,

C ₂ -C ₉ heterocycloalkyl group, hydroxy-C ₂ -C ₉ heterocycloalkyl group, linear or branched hydroxy-C ₁ -C ₄ alkylcarbonyl group, -NR ¹⁰ R ¹¹ , -COR ¹² , -COOR ¹² or -SO ₂ R ¹³ ,

q is equal to an integer from 0 to 5,

where when is piperazine or piperidine, then q is not equal to 0, and

where two or more R ⁹ are connected or condensed with to form a 7-12 membered bicycloalkyl group, heterobicycloalkyl group, spirocycloalkyl group or spiroheterocycloalkyl group;

each of R ¹⁰ and R ¹¹ independently represents hydrogen, a hydroxy-C ₁ -C ₄ alkyl group, a halogen-C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkyl group, a C ₂ -C ₄ alkenyl group, or a C ₂ -C ₄ alkynyl group;

R ¹² represents hydrogen, hydroxy group, hydroxy-C ₁ -C ₄ alkyl group, halogen-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group group, a C ₃ -C ₁₀ cycloalkyl group or a C ₂ -C ₉ heterocycloalkyl group;

R ¹³ represents hydroxy, halogen _{C 1} -C ₄ alkyl group, C ₁ -C ₄ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, C ₃ -C ₁₀ cycloalkyl group, C ₂ -C ₉ a heterocycloalkyl group, an aryl group or -NR _f R _g , and

each of R _f and R _g independently represents hydrogen or a C ₁ -C ₄ alkyl group.

According to an aspect of another embodiment, methods for preparing these compounds are provided.

According to an aspect of another embodiment, pharmaceutical compositions for the prevention or treatment of cancer contain these compounds or pharmaceutically acceptable salts thereof as an active ingredient.

According to an aspect of another embodiment, pharmaceutical compositions for the prevention or treatment of FLT3-mediated disease contain these compounds or pharmaceutically acceptable salts thereof as an active ingredient.

According to an aspect of another embodiment, pharmaceutical compositions for inhibiting FLT3 kinase activity contain these compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.

According to an aspect of another embodiment, methods are provided for reducing FLT3 activity in a subject in need by using these compounds.

According to an aspect of another embodiment, methods are provided for treating FLT3-mediated disease using these compounds.

Advantageous effects of the invention

The compound according to one aspect of the present invention has excellent FLT3 inhibitory activity and is therefore suitable for effective use in the prevention or treatment of cell proliferative diseases caused by abnormal FLT3 activity, such as cancer, eg leukemia.

Principle of invention

The present invention will now be described in more detail.

Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one skilled in the art to which this invention relates. Although illustrative methods or substances are listed herein, other similar or equivalent methods or substances are also included within the scope of the present invention. Also, numerical values set forth herein are intended to include the value “about” unless expressly stated otherwise. All publications disclosed by reference are incorporated in their entirety herein by reference.

According to an aspect of the present invention, there is provided a compound selected from the compound represented by Formula 1, and a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof.

The residues indicated as R ¹ -R ¹⁷ , X, Y, Z, Z', A, B, Q, L or E ^a -E ^d can be understood in the same way as understood by one skilled in the art.

The term "halogen" includes fluorine, chlorine, bromine or iodine unless otherwise specified, and may mean, for example, but is not limited to, fluorine or chlorine.

The term "alkyl" refers to a saturated monovalent hydrocarbon radical. The term “alkenyl” as used herein refers to a monovalent hydrocarbon radical containing at least one carbon-carbon double bond, where each double bond may have an E- or Z-steric configuration. The term "alkynyl" as used herein refers to a monovalent hydrocarbon radical containing at least one carbon-carbon triple bond. Such alkyl group, alkenyl group and alkynyl group may be linear, that is, straight chain, or may have side chains. As defined above, the number of carbon atoms in the alkyl group may be 1, 2, 3, 4, 5 or 6; or 1, 2, 3 or 4. Examples of alkyl include methyl, ethyl, propyl, including n-propyl and isopropyl, n-butyl, sec-butyl, butyl, including isobutyl and tert-butyl, pentyl, including including n-pentyl, 1-methylbutyl, isopentyl, neopentyl and tert-pentyl, hexyl, including n-hexyl, 3,3-dimethylbutyl and isohexyl. The double bond of the alkenyl group and the triple bond of the alkynyl group can each be in any position. Examples of alkenyl and alkynyl are 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-enyl (=propargyl), but-2-enyl, but-3-enyl, hex-4-enyl and hex-5-enyl. In the case where each of the compounds is sufficiently stable and suitable for the desired use as, for example, a pharmaceutical substance, a substituted alkyl group, a substituted alkenyl group and a substituted alkynyl group may be substituted at any position.

The term "cycloalkyl", unless otherwise indicated, refers to a substituted or unsubstituted cyclic alkyl group, and an example of a mono- or multi-cyclic group is a mono- or bicycloaliphatic group. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamant-1-yl, decahydronaphthyl group, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl silt , 2-oxo-bicyclo[2.2.1]hept-1-yl or any suitable isomer thereof, but not limited to.

The term "bicycloalkyl group" as used herein refers, unless otherwise indicated, to a saturated carbocycle containing two rings, and includes a fused carbocycle in which the two rings have two adjacent atoms in common as part of those rings, and a bridged a carbocycle in which two rings share two non-adjacent atoms as part of those rings. For example, a 7-12 membered bicycloalkyl refers to a fused carbocycle or a bridged carbocycle, each of which has a total of two rings consisting of 7-12 atoms.

The term “heterocycloalkyl” as used herein refers, unless otherwise indicated, to a substituted or unsubstituted monocyclic or polycyclic alkyl containing at least one heteroatom selected from O, N and S, for example 1 to 4 heteroatoms. Examples of a monoheterocycloalkyl group include piperazinyl, piperidinyl, piperazinyl-1-oxide, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, diazabicycloheptanyl, diazabicyclooctane and diazaspirooctane, and groups similar thereto, but not limited to.

The term “heterobicycloalkyl” as used herein refers, unless otherwise indicated, to a bicycloalkyl containing one or more heteroatoms selected from O, N, and S, and includes a fused heterobicycloalkyl group and a bridged heterobicycloalkyl group. The term "bridging" as used herein refers to a valence bond, a single atom or straight chain of atoms, that connects two different parts within a molecule. Also, a pair of tertiary or more carbon atoms linked by bridges are called "bridge heads". In other words, carbon atoms that are simultaneously part of two or more rings are called bridge heads, and the bonds connected to these bridge heads are called bridges. The term "bridged compound" as used herein refers to a compound in which two or more rings share one or more pairs of carbon atoms.

Examples of the fused heterobicycloalkyl group include, but are not limited to, indole, quinoline, thiazolo[4,5-b]pyridine, quinoline and the like. Examples of bridged heterobicycloalkyl include, but are not limited to, 7-12 membered heterobicycloalkyls such as diazabicyclo[2.2.1]heptane or diazabicyclo[3.2.1]octane.

The term "spiro" as used herein refers, unless otherwise defined, to two rings that share one atom and the two rings are not bridged to each other. The term "spirocycloalkyl" as used herein refers, unless otherwise defined, to a saturated carbocycle consisting of two rings that share only one carbon atom as part of the rings. Examples of spirocycloalkyl include, but are not limited to, a 7-12 membered spirocycloalkyl group such as diazaspiro[2.5]octane. The term "heterospirocycloalkyl" refers, unless otherwise defined, to a spirocycloalkyl containing at least one heteroatom selected from O, N and S. The expression "spiro compound" as used herein refers to a linker having one atom in common if no other definition given.

The term "aryl" as used herein refers, unless otherwise indicated, to an aromatic group, which may be substituted or unsubstituted, such as, but not limited to, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracene, or any isomer thereof. .

The term “heteroaryl” as used herein refers, unless otherwise indicated, to a monocyclic or bicyclic or higher aromatic group containing at least one heteroatom selected from O, N and S, for example 1 to 4 heteroatoms. 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 the like. Examples of bicyclic heteroaryl include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl, and the like.

The term "alkylene bridge" refers, unless otherwise defined, to a linear or branched divalent hydrocarbon bridge that links two different carbon atoms having identical ring structure, may consist of carbon and hydrogen atoms, is not unsaturated and may have, for example, 3-6 carbon atoms, and its examples are propylene, n-butylene, etc. An alkylene bridge can link any two carbon atoms in a ring structure. At least one methylene in the alkylene bridge may be replaced by at least one selected from -O-, -S-, -S(O)-, -S(O) ₂ and -N(R')-, where R ' may represent hydrogen, a C ₁ -C ₆ alkyl group, a C ₃ -C ₇ cycloalkyl group, or an aryl. In the present specification, a numerical range specified using the term "up to" refers to a range including numerical values specified before and after this term as the lower limit and the upper limit, respectively.

In an illustrative embodiment of an aspect of the present invention, R ¹ in a compound of Formula 1 may be hydrogen, a C ₁ -C ₄ alkoxy group, or a hydroxy group.

In an embodiment, R ¹ in a compound of Formula 1 may be hydrogen, halogen, hydroxy or a C ₁ -C ₄ alkoxy group.

In an embodiment, R ² in a compound of Formula 1 may be hydrogen, halogen, a C ₁ -C ₄ alkyl group, or a halogen-C _1-4 alkyl group.

In an embodiment, R ³ in a compound of Formula 1 may be hydrogen, a hydroxy group or a C ₁ -C ₄ alkyl group. In an embodiment, R ³ may be hydrogen.

In an embodiment, R ⁴ in a compound of Formula 1 may be hydrogen, halogen, hydroxy group, cyano group, nitro group, amino group, halogen-C _{1 -4} alkyl group, C ₁ -C ₄ alkoxy group, hydroxy-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkyl group, C ₂ -C ₄ alkenyl group or C ₂ -C ₄ alkynyl group. In an embodiment, R ⁴ may be hydrogen, halogen, hydroxy, C ₁ -C ₄ alkoxy, hydroxy-C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkyl.

In an embodiment, each of R ⁵ and R ⁶ in a compound of formula 1 can independently represent hydrogen, halogen, hydroxy, cyano or a C ₁ -C ₄ alkyl group. In an embodiment, R ⁵ and R ⁶ can each independently be hydrogen or hydroxy.

In an embodiment, R ⁷ in a compound of formula 1 may represent a C ₃ -C ₇ cycloalkyl group. In an embodiment, R ⁷ may be cyclopropyl.

In an embodiment, Y in a compound of formula 1 may be -(CH ₂ ) _m -, -(CH ₂ ) _m -O-(CH ₂ ) _n - or -(CH ₂ ) _m -CO-(CH ₂ ) _n -, where each of m and n independently may be equal to an integer from 0 to 2. In an embodiment, Y may be -(CH ₂ ) _m -, where m may be equal to an integer selected from 1 and 2.

In an embodiment, Z in a compound of formula 1 may be a compound represented by formula 3:

Formula 3

where in formula 3

may be a C ₃ -C ₁₀ cycloalkyl group or a C ₂ -C ₁₁ heterocycloalkyl group;

R ⁹ may be a halogen, hydroxy group, cyano group, nitro group, amino group, thiol group, formyl group, halogen-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, linear or branched hydroxy-C ₁ -C ₄ alkyl group , linear or branched C ₁ -C ₄ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, C ₃ -C ₁₀ cycloalkyl group, C ₂ -C ₉ heterocycloalkyl group, hydroxy-C ₂ -C ₉ heterocycloalkyl group, linear or branched hydroxy-C _1-4 alkylcarbonyl group, -COR ¹² , -COOR ¹² or -SO ₂ R ¹³ ,

q can independently be equal to an integer from 0 to 5,

where when is piperazine or piperidine, then q cannot be 0, and

2 or more R ⁹ can be associated with each other or condensed with with the formation of a 7-12-membered bicycloalkyl group;

each of R ¹⁰ and R ¹¹ independently may be hydrogen, a hydroxy-C ₁ -C ₄ alkyl group, a halogen-C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkyl group, a C ₂ -C ₄ alkenyl group, or a C ₂ -C ₄ alkynyl group;

R ¹² represents hydrogen, hydroxy group, hydroxy-C _1-4 alkyl group, halogen-C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group , C ₃ -C ₁₀ cycloalkyl group or C ₂ -C ₉ heterocycloalkyl group;

R ¹³ represents hydroxy, halogen _{C 1} -C ₄ alkyl group, C ₁ -C ₄ alkyl group, C ₂ -C ₄ alkenyl group, C ₂ -C ₄ alkynyl group, C ₃ -C ₁₀ cycloalkyl group, C ₂ -C ₉ a heterocycloalkyl group, an aryl group or -NR _f R _g , and

each of R _f and R _g independently represents hydrogen or a C ₁ -C ₄ alkyl group.

In the example of formula 3

may be C _{3 -C 6} heterocycloalkyl containing one or two heteroatoms selected from O, N and S;

R ⁹ may independently represent hydrogen, a hydroxy group, a linear or branched hydroxy-C ₁ -C ₄ alkyl group, a linear or branched C ₁ -C ₄ alkyl group, a C ₃ -C ₁₀ cycloalkyl group, a _{C 2} -C ₉ heterocycloalkyl group, hydroxy-C ₂ -C ₉ heterocycloalkyl group, -NR ¹⁰ R ¹¹ or -COR ¹² ,

each of R ¹⁰ and R ¹¹ independently can represent hydrogen, a hydroxy-C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkyl group; And

R ¹² may represent hydrogen, a hydroxy group, a hydroxy-C ₁ -C ₄ alkyl group, a halogen-C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkyl group.

In an illustrative embodiment, in a compound of formula 1

X represents H or OH,

where when X is OH, then the compound represented by Formula 1 may include the tautomeric structure represented by Formula 2:

Formula 2

R ³ , R ⁴ and k in formula 2 are the same as described in relation to formula 1.

In an illustrative embodiment, in a compound of formula 1

X represents H or OH,

where when X represents OH, then the compound represented by formula 1 may include the tautomeric structure represented by formula 2;

R ¹ may represent hydrogen, hydroxy, a C ₁ -C ₄ alkoxy group or a C ₁ -C ₄ alkyl group;

R ² may represent hydrogen, halogen, a C ₁ -C ₄ alkyl group or a halogen-C ₁ -C ₄ alkyl group;

R ³ may be hydrogen;

R ⁴ may represent hydrogen, halogen, hydroxy, C ₁ -C ₄ alkoxy, hydroxy-C ₁ -C ₄ alkyl group or C ₁ -C ₄ alkyl group;

k can be an integer from 0 to 2;

each of R ⁵ and R ⁶ independently can represent hydrogen or hydroxy;

R ⁷ may be cyclopropyl;

Y may be -(CH ₂ ) _m -, -(CH ₂ ) _m -O-(CH ₂ ) _n - or -(CH ₂ ) _m -CO-(CH ₂ ) _n -;

each of m and n is independently equal to an integer from 0 to 2; and Z may be Formula 3:

Formula 3

where in formula 3

may be C ₃ -C ₆ heterocycloalkyl containing one or two heteroatoms selected from O, N and S;

R ⁹ independently may represent a hydroxy, hydroxy-C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkyl group, a C ₃ -C ₁₀ cycloalkyl group, a C ₂ -C ₉ heterocycloalkyl group, a hydroxy-C ₂ -C ₉ heterocycloalkyl group group, -NR ¹⁰ R ¹¹ or -COR ¹² ,

each of R ¹⁰ and R ¹¹ independently can represent hydrogen, a hydroxy-C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkyl group;

R ¹² may represent hydrogen, a hydroxy-C ₁ -C ₄ alkyl group, a halogen-C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkyl group, and

q can independently be equal to an integer from 0 to 3.

In the example of the compound represented by Formula 1, when is piperazinyl or piperidinyl, then q cannot be equal to 0.

In the example of the compound represented by Formula 1, Z may be any one selected from Formulas 11-13.

Formula 11

Formula 12

Formula 13

where in formula 11-13

each of V and W may independently be N or CH, provided that each of V and W is not both CH,

R ¹⁴ may be hydrogen, halogen, linear or branched C ₁ -C ₄ alkyl group, linear or branched hydroxy-C ₁ -C ₄ alkyl, hydroxy group, -NR ¹⁶ R ¹⁷ , linear or branched hydroxy-C ₁ -C ₄ an alkylcarbonyl group, a C ₂ -C ₉ heterocycloalkyl group, a hydroxy-C ₂ -C ₉ heterocycloalkyl group, a linear or branched halogen-C ₁ -C ₄ alkyl group and a linear or branched C ₁ -C ₄ alkoxy group,

R ¹⁵ may independently represent a linear or branched C ₁ -C ₄ alkyl group, a linear or branched hydroxy-C ₁ -C ₄ alkyl group or halogen,

R ¹⁴ and R ¹⁵ may be linked to each other, or R ¹⁴ or R ¹⁵ fused with a cyclic compound represented by one of formulas 11-13 to form a 7-12 membered bicycloalkyl group, heterobicycloalkyl group, spirocycloalkyl group or spiroheterocycloalkyl group,

each of R ¹⁶ and R ¹⁷ may independently represent hydrogen, a linear or branched C ₁ -C ₄ alkyl group, or a linear or branched hydroxy-C ₁ -C ₄ alkyl group,

p can be an integer from 0 to 4, and

each of s and t can independently be equal to an integer from 0 to 5 when R ¹⁴ is hydrogen, and an integer from 0 to 4 when R ¹⁴ is not hydrogen.

Examples of 7-12 membered bicycloalkyl formed by coupling R ¹⁴ and R ¹⁵ to each other or condensing R ¹⁴ or R ¹⁵ with a cyclic compound represented by any of Formulas 11-13 are diazabicycloheptanyl and diazabicyclooctanyl. In an embodiment, the 7-12 membered bicycloalkyl may be 2,5-diazabicyclo[2.2.1]heptanyl or 3,8-diazabicyclo[3.2.1]octanyl. An example of a 7-12 membered spirocycloalkyl formed by coupling R ¹⁴ and R ¹⁵ to each other or condensing R ¹⁴ or R ¹⁵ with a cyclic compound represented by any of Formulas 11-13 may be a diazaspirooctanyl group, for example diazaspiro[2.5]octanyl.

In the example of the compound represented by Formula 1, R ⁷ may represent a C ₃ -C ₇ cycloalkyl group, and Z may represent a substituted or unsubstituted C ₂ -C ₁₁ heterocycloalkyl group. C ₃ -C ₇ cycloalkyl may be, for example, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Z may be, for example, C ₃ -C ₇ cycloalkyl, unsubstituted or substituted with halogen, hydroxy, cyano, nitro, amino, halogen-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy-C ₁ -C ₄ alkyl or C ₁ -C ₄ alkyl, but not limited to them. C ₃ -C ₇ cycloalkyl may be, and is not limited to, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl, or tetrahydrofuranyl.

In the compound according to embodiment, R ⁷ may be cyclopropyl and Z may be piperazinyl substituted with a C ₁ -C ₄ alkyl group, for example dimethylpiperazinyl. A compound according to an embodiment may have an improved pharmacokinetic profile and improved metabolic stability, such as microsomal stability.

In an embodiment, the compound of formula 1 may be selected from the compound represented by formula 14 and its stereoisomer, tautomer, solvate or pharmaceutically acceptable salt:

Formula 14

where in formula 14

E ^a may represent hydrogen, a hydroxy group or a C ₁ -C ₄ alkoxy group;

E ^b may represent hydrogen, halogen, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ fluoroalkyl group;

E ^c and E ^d may each independently represent hydrogen or a hydro x group;

X' may represent hydrogen or hydroxy; k can be equal to an integer from 0 to 4;

Q may independently represent hydroxy, halogen, a C ₁ -C ₄ alkyl group, a hydroxyC ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group; And

Z' may represent a monovalent functional group represented by Formula 15:

Formula 15

where n in formula 15 can be an integer from 1 to 8;

A may independently represent a functional group selected from hydroxy, a C ₁ -C ₄ alkyl group and a hydroxy-C ₁ -C ₄ alkyl group, where when n is two or more, then the two A may be bonded to each other to form an alkylene bridge to form Z', which is a 7-12 membered bridged heterobicycloalkyl ring, or two A can be spiro-linked to form a 7-12 membered spiroheterocycloalkyl ring;

L may represent hydrogen, a C ₁ -C ₄ alkyl group, a hydroxy group, or a hydroxy-C ₁ -C ₄ alkyl group.

A compound selected from a compound of formula 14 and its stereoisomer, tautomer, solvate or pharmaceutically acceptable salt may have improved properties compared to other compounds having a similar chemical structure, in terms of a pharmacokinetic profile that is suitable for oral administration, and metabolic stability, such as microsmal stability.

The term "pharmacokinetic profile" as used herein refers to the absorption, distribution, in vivo changes, and excretion profile of a drug from which the physiological and biochemical effects of the drug on a living organism and their mechanism of action, i.e., response, can be identified. body to drugs.

The term "metabolic stability", such as microsomal stability, as used herein, refers to the degree of stability of metabolic organs following drug administration, and can influence the pharmacokinetic parameters of the drug, such as clearance and oral bioavailability. As an experiment to predict the extent of drug metabolism by major organs in vitro, a metabolically active system such as a microsome or liver hepatocyte can be used to measure metabolic stability.

In an embodiment, E ^b may be a halogen, n may be an integer from 2 to 4, and may be an alkyl group, such as methyl, ethyl or propyl.

In an embodiment, E ^b may be halogen, n may be 2, and may be methyl.

In an embodiment, Z' may be 3,5-dimethylpiperazin-1-yl.

In an embodiment, E ^b may be chlorine.

A compound selected from the compound of formula 14 and its stereoisomer, tautomer, solvate or pharmaceutically acceptable salt can effectively control one or more kinases involved in intracellular signal transduction and intracellular complex biomechanisms. For example, the selected compound may act on a receptor tyrosine kinase (RTK) to effectively control the delivery of extracellular stimuli into the cell. In an embodiment, the selected compound can effectively control fms-like tyrosine kinase 3 (FLT3), which is often abnormally expressed or mutated in leukemia patients, and splenic tyrosine kinase (SYK), which acts on the epithelial growth factor receptor (VEGFR) signaling pathway, which involved in controlling the process of angiogenesis, and other immunoreceptors such as B-cell receptors and mast cells. The compound according to the embodiment effectively suppresses the mutation or overexpression of FLT3 and simultaneously the overexpression or overactivation of VEGFR, thereby blocking the supply of nutrients and oxygen to the tumor and suppressing SYK. Accordingly, the compound may be useful for the treatment of acute myelogenous leukemia (AML) that exhibits resistance to FLT3 inhibitors. The term "overall survival (OV)" as used herein refers to the period of time from random assignment to death in clinical trials. FLT3-ITD-positive acute myeloid leukemia (AML) is a disease with very low OV. SYK is overexpressed and activated in hematologic malignancies, and highly activated SYK is commonly found in FLT3-ITD-positive acute myeloid leukemia (AML), which has a very low OV. Therefore, as a target for the treatment of AML disease, SYK should be considered as an important factor together with FLT3.

The compound according to the embodiment exhibits effective selective inhibitory activity against SYK as well as FLT3, thereby significantly improving the treatment efficacy of acute myeloid leukemia (AML) and improving OV time.

In an embodiment, L represents hydrogen, a C ₁ -C ₄ alkyl group, a hydroxy group, or a hydroxy-C ₁ -C ₄ alkyl group;

E ^b is a halogen, such as chlorine, n is 2, and A is methyl.

A compound selected from the compound of formula 14 and its stereoisomer, tautomer, solvate or pharmaceutically acceptable salt, where Z' is 3,5-dimethylpiperazin-1-yl, exhibits excellent inhibitory activity against FLT3 and can effectively suppress the overexpression or overactivation of VEGFR and SYK . In addition, the compound can be effectively used to prevent or treat cell proliferative diseases caused by abnormal activity of FLT3, VEGFR and SYK, to improve the effectiveness of tumor treatment. Therefore, the compound may be useful for the treatment of cancer or leukemia that is resistant to prior art FLT3 inhibitors, such as AML.

In an embodiment, the compound of formula 1 may be a compound selected from the compounds listed in Table 1:

The term "isomer" as used herein refers to a compound having the same molecular formula and a different structure. The compounds of formula 1 according to an aspect of the present invention may exist as various compounds having a ratio of isomers in a three-dimensional aspect, and these isomers and mixtures are within the scope of the present invention. In one or more embodiments, the compounds of formula 1 according to an aspect of the present invention may exist as a stereoisomer or structural isomer, such as a tautomer.

The term "stereoisomer" as used herein refers to a compound that has the same molecular formula and the same atomic bonding order and is different in stereoscopic or optical aspects. That is, a stereoisomer refers to a compound that has the same chemical composition, but differs in an aspect of three-dimensional arrangement, namely, a different arrangement of atoms or groups. Stereoisomer includes geometric isomers, enantiomeric isomers and partial stereoisomers.

The term "geometric isomer" as used herein refers to a type of stereoisomer depending on the direction of the functional group in the molecule, and may be referred to as a cis or trans isomer. Typically these isomers contain non-rotatable double bonds, and the substituents on the compound containing the double bonds may be in the E-form or the Z-form. For example, when a compound contains a 2-substituted cycloalkyl group, then the compound may have a cystitis trans form. When a compound of Formula 1 contains a bridged ring, then the compound may exist as an exo- or endo-isomer.

The term "chiral" as used herein refers to a molecule that has a non-overlapping enantiomeric partner, and the term "achiral" as used herein refers to a molecule that has an overlapping enantiomeric partner. The term "enantiomer" as used herein refers to the case where two molecules having optical activity are mirror symmetric. That is, an enantiomer means an isomer that is not superimposed on the parent molecule and does not have any symmetry elements, including a plane of symmetry and a center of symmetry, and has a stereoscopic center (chiral center). The term "diastereomer" as used herein refers to the case where molecules having two or more chiral centers are not enantiomers, but stereoisomers. Since the compounds of formula 1 according to an aspect of the present invention may have chiral centers or asymmetric carbon centers (missing carbons), the compounds may exist as an enantiomer (R or S isomer), racemate, diastereoisomers, or mixtures thereof, and all of these isomers and mixtures are included in the scope of the present invention. Optically active (R)- and (S)-isomers can be separated using prior art methods, or chiral synthon, or chiral reagents.

The term "structural isomers" as used herein refers to isomers having the same molecular formula but a different atomic bonding order, and may include a tautomer. The term "tautomers" as used herein refers to structural isomers having structures of different energies that are interchangeable across low-energy barriers. For example, a photonic tautomer (also a proton tautomer) involves photon transfer interconversions such as keto-enol and imine-enamine isomerization. Valence tautomers involve interconversions through the rearrangement of some electrons in bound electrons. The compound of Formula 1 according to an aspect and its stereoisomer or tautomer may exist in the form of a solvate. The term "solvate" may include a molecular complex containing a compound and at least one molecule of a pharmaceutically acceptable solvent, such as ethanol or water. A complex in which the solvent molecule is a water molecule is also called a "hydrate".

The compound of formula 1 according to aspect and its stereoisomer, tautomer and solvate may exist in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein refers to a salt that has low toxicity to humans and does not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts of the compound represented by Formula 1 include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, which will be understood by those skilled in the art.

Pharmaceutically acceptable salts can be prepared by standard methods. For example, the compound of formula 1 can be dissolved in a solvent that is miscible with water, such as methanol, ethanol, acetone, 1,4-dioxane, and then the free acid or free base can be added thereto to crystallize to obtain a pharmaceutically acceptable salt .

In another aspect of the present invention, a method for preparing compounds is provided.

In accordance with another aspect of the present invention, there is provided a method for preparing a compound of Formula 1, comprising reacting a compound of Formula 6 with a compound of Formula 7:

Formula 6

Formula 7

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, Y, Z and k in formulas 6 and 7 can be as described in relation to formulas 1 and 2, and V can be a halogen.

Organic base such as triethylamine, diisopropylethylamine, pyridine, etc.; an inorganic base such as sodium carbonate, potassium carbonate, sodium hydride and the like; organic acid such as trifluoroacetic acid, toluenesulfonic acid and the like; or an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid and the like may or may not be added to the reaction solution when carrying out the reaction. The solvent used in the reaction may be any solvent that does not inhibit the reaction, for example a polar aprotic solvent such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or tetrahydrofuran (THF); a polar protic solvent such as methanol, ethanol, 2-propanol or 2-butanol; or a non-polar aprotic solvent such as toluene or 1,4-dioxane. The reaction temperature may range from 0°C to 150°C, for example from room temperature to about 100°C.

In an exemplary embodiment, a compound of formula 1 can be prepared as shown in Reaction Scheme 1:

Reaction scheme 1

The compounds of formulas 4 and 5 can be prepared using ordinary knowledge of organic chemistry.

In Reaction Scheme 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, Y, Z and k can be, respectively, the same as in formulas 1 and 2, and each of V ¹ and V ² independently may be halogen.

To prepare a compound of formula 6 by reacting a compound of formula 4 with a compound of formula 5, the reaction can be carried out by adding an organometallic compound. For example, the organometallic compound may be an alkyl magnesium compound or an alkyl lithium compound.

The solvent used in the reaction may be any solvent that does not inhibit the reaction, for example a polar aprotic solvent such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or THF; a polar protic solvent such as methanol, ethanol, 2-propanol or 2-butanol; or a non-polar aprotic solvent such as toluene or 1,4-dioxane. The reaction temperature may be in the range from 0°C to 150°C, for example from 0°C to 60°C.

To prepare the compound of formula 7,

when Y is -(CH ₂ ) _m -, then m can be equal to an integer from 1 to 2,

when Y is -(CH ₂ ) _m -O-(CH ₂ ) _n -, then m can be equal to 0, and n can independently be equal to an integer from 0 to 2,

when Y is -(CH ₂ ) _m -CO-(CH ₂ ) _n -, then each of m and n can be 0, and

the compound is prepared based on knowledge in the relevant field of organic chemistry, as explained in relation to Preparation Schemes 1-3.

Preparation scheme 1 in the case where Y is -(CH ₂ ) _m -:

m=0,

On the production diagram 1 R ⁵ , R ⁶ , R ⁷ , R ⁹ , and q are the same as described in relation to formulas 1 and 3, and V ³ may be halogen, and L may be Cl, Br, I, OMs, OTs or the like.

Receipt scheme 2

in the case where Y is -(CH ₂ ) _m -O-(CH ₂ ) _n -:

n=0,

On the production diagram 2 R ⁵ , R ⁶ , R ⁷ , R ⁹ , - and q are the same as described in relation to formulas 1 and 3, and L may be Cl, Br, I, OMs, OTs or the like.

Receipt scheme 3

in case Y is -(CH ₂ ) _m -CO-(CH ₂ ) _n -:

On the production diagram 3 R ⁵ , R ⁶ , R ⁷ , R ⁹ , and q are the same as described in relation to formulas 1 and 3.

In another aspect of the present invention, there is provided a method for preparing a compound represented by Formula 1a, comprising reacting a compound represented by Formula 10 and a compound represented by Formula 3:

Formula 10

Formula 3

Formula 1a

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , , X, k and q in formulas 10, 3 and 1a are the same as described in relation to formulas 1, 2 and 3.

The reaction can be carried out by adding or not adding a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like to the reaction solution; an organic base such as triethylamine, diisopropylethylamine and pyridine; an inorganic base such as sodium carbonate, potassium carbonate and sodium hydride; organic acid such as trifluoroacetic acid, toluenesulfonic acid and the like; or an inorganic acid such as hydrochloric acid, sulfuric acid and phosphoric acid. The solvent used in the reaction may be any solvent that does not inhibit the reaction, and examples of the solvent include 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 non-polar aprotic solvent such as toluene or 1,4-dioxane. The reaction temperature may be in the range from 0°C to 150°C, for example room temperature.

The compound of formula 10 can be prepared using ordinary knowledge of organic chemistry.

In an embodiment, the compound represented by formula 1a can be prepared using the method illustrated in Reaction Scheme 2.

Reaction scheme 2

In the Reaction Scheme 2 R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , , X, k and q are the same as described in relation to formulas 1, 2 and 3, and V ² represents a halogen.

To obtain the compound of formula 10 from the compound of formula 9, the compound of formula 9 is oxidized using an oxidizing agent such as MnO ₂ and then washed with an organic solvent such as methylene chloride, followed by concentration and purification of the resulting organic layer.

To prepare a compound of Formula 9 by reacting a compound of Formula 8 with a compound of Formula 6, the solvent used in the reaction can be any solvent that does not inhibit the reaction. For example, the reaction can be carried out by adding or not adding an organic base such as triethylamine, diisopropylethylamine and pyridine to the reaction solution; an inorganic base such as sodium carbonate, potassium carbonate and sodium hydride; organic acid such as trifluoroacetic acid, toluenesulfonic acid and the like; or inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; and the base or acid equivalent may be from 0.1 to 5 equivalents based on one equivalent of Compound 1 of Formula B. The solvent used in the reaction may be any solvent that does not inhibit the reaction, and examples of the solvent include a polar aprotic solvent such 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 non-polar aprotic solvent such as toluene or 1,4-dioxane. The reaction temperature may range from 0°C to 150°C, for example from 50°C to about 100°C.

Although the method for preparing the compound of Formula 1 is described by way of specific examples, the specific reaction conditions, such as the amount of reaction solvent, base and reagent used, are not limited to those described in the present specification and should not be construed as limiting the scope of the present invention.

In another aspect of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of cancer containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Cancer may include leukemia such as acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute promyelocytic leukemia (APL), hairy cell leukemia, chronic neutrophilic leukemia (CNL ) or the like

In one embodiment, the cancer may be leukemia.

In an embodiment, leukemia may include AML, ALL or CML.

In another aspect of the present invention, a pharmaceutical composition for the prevention or treatment of CC3-mediated disease is provided, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

In another aspect of the present invention, a pharmaceutical composition for inhibiting FLT3 kinase activity is provided, comprising a compound of the aspect or a pharmaceutically acceptable salt thereof and a pharmacologically acceptable excipient.

In an exemplary embodiment, the pharmaceutical composition may contain a pharmaceutically acceptable excipient or additive. The pharmaceutical composition of the present invention can be prepared in a standard manner and can be prepared in various oral dosage forms such as tablet, pill, powder, capsule, syrup, emulsion and microemulsion; or in parenteral dosage forms, such as forms for intramuscular, intravenous or subcutaneous administration.

When the pharmaceutical composition of the present invention is formulated in the form of an oral composition, examples of a carrier or additive suitable for use include a diluent, a disintegrant, a binder, a lubricant, a surfactant, a suspending agent and an emulsifier. When the pharmaceutical composition of the present invention is prepared in injection form, examples of the carrier or additive may include water, saline solution, aqueous glucose solution, pseudosaccharide solution, alcohol, glycol, ether (for example, polyethylene glycol 400), oil, fatty acid, fatty acid ester acids, glyceride, surfactant, suspending agent and emulsifier. Such preparation methods are well known to those skilled in the pharmaceutical field.

In an embodiment, a compound of Formula 1 as an active ingredient included in a pharmaceutical composition can be administered to a subject or patient in an effective amount for treatment or prevention. The compound of formula 1 can be administered orally or parenterally as directed. When the compound is administered orally, the active ingredient may be administered in an amount ranging from 0.01 milligram (mg) to 1000 mg, such as 0.01 mg to 500 mg, such as 0.1 mg to 300 mg, such as 0.1 to 100 mg per kilogram (kg) of body weight per day. When administering the compound parenterally, the active ingredient may be administered one to several times in an amount ranging from 0.01 mg to 100 mg, for example 0.1 mg to 50 mg per kg body weight per day. The composition can be administered once or in several divided doses. The dosage for the subject or patient should be determined based on the patient's body weight, age, sex, medical condition, diet, time of administration, route of administration, severity of disease, etc. It should be kept in mind that the practitioner may adjust the dose accordingly. The dose is not intended to limit the scope of the invention in any aspect.

In another aspect of the present invention, there is provided a method of preventing or treating cancer by using a compound according to the aspect. In an embodiment, the method may include administering to the subject a compound selected from a compound of formula 1 according to aspect and a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof. The subject may be a patient. In another aspect of the present invention, there is provided a method of inhibiting FLT3 activity in a target subject by using a compound according to the aspect.

In another aspect of the present invention, there is provided a method of treating a FLT3-mediated disease by using a compound according to the aspect.

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

In an embodiment, the dosage, number of administrations, or route of administration of the compound used for treatment may vary depending on the subject being treated, the severity of the disease or condition, the rate of administration, and the judgment of the attending physician. The dosage for a person weighing 70 kg may range from 0.1 to 2000 mg per day, for example from 1 to 1000 mg or from 10 to 2000 mg. The number of administrations may range from a single administration to multiple administrations, such as 1 to 4 times or according to treatment/break schedules, and the route of administration may be the oral or parenteral route. In one or more embodiments, the dosage may be less than the range described above. In one or more embodiments, the dosage may be a dosage greater than the range described above without causing harmful side effects. In the latter case, the dosage can be divided into several small portions administered throughout the day. Physicians of ordinary skill in the relevant field can determine and prescribe the dosage of the compound as prescribed. For example, physicians may administer a dosage of a compound according to an embodiment of the present invention at a level that is below that required to achieve the target therapeutic effect and then gradually increase the dosage until the target effect is achieved.

In one embodiment of the method, the compound according to one aspect of the present invention as an active ingredient can be used alone or in combination with one or more other pharmaceutical drugs known for the treatment of cancer, tumor or leukemia, or pharmaceutical carriers. In one embodiment, a compound selected from the compound represented by Formula 1 and a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof may be administered with other inhibitors of FLT3 kinase activity or other agents of various mechanisms that increase the effectiveness of inhibition of FLT3 kinase activity, or enhance synergistic effect in reducing FLT3 activity, or enhance the therapeutic effect against FLT3-mediated disease.

The term "treatment" as used herein includes treating, ameliorating, ameliorating or controlling the course of a disease. The term “treating” or “treating” as used herein refers to suppressing a disease, such as suppressing a disease, condition or disorder, preventing further development of pathology and/or symptoms, ameliorating a disease, or reversing pathology and/or symptoms, e.g. reducing the severity of a disease, in a subject who experiences or exhibits a pathology or symptom of a disease, condition or disorder.

The term "providing a warning" or "preventing" as used herein refers to preventing a disease, such as preventing a disease, condition or disorder in a subject who may be predisposed to the disease, condition or disorder but is not yet experiencing or exhibiting the pathology or symptom of a disease.

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

The terms “having,” “may have,” “including,” or “may include” may refer to the presence of a feature (eg, a component such as quantity, component, etc.) and do not exclude the presence of additional features.

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

Example 1: 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-fluoro-1H-indol- 3-yl)pyrimidin-2-amine

Technological operation 1. Preparation of 3-bromo-5-nitrobenzoic acid

500 g (2991.86 mmol) of 3-nitrobenzoic acid were dissolved in 1.4 l of concentrated (conc.) sulfuric acid (H ₂ SO ₄ ) and the temperature was raised to 60°C. 652 g (3590.23 mmol) N-bromosuccinimide was added to this solution three times within 1 hour, and the resulting mixture was stirred at 60° C. for 2 hours. Immediately after completion of the reaction, ice was added to the reaction mixture. The resulting solid was filtered and oven-dried at 40°C for 16 hours to obtain 730 g of the target compound with a yield of 99.2%.

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

Technological operation 2. Preparation of (3-bromo-5-nitrophenyl)methanol

200 g (812.94 mmol) of 3-bromo-5-nitrobenzoic acid obtained from Process 1 were dissolved in 1.25 L of tetrahydrofuran (THF) and the temperature was reduced to 0°C. 1.6 l (3251.76 mmol) borane dimethyl sulfide (2.0 M in THF) for 1.5 hours. The mixture was stirred at room temperature for 16 hours and then stirred under reflux at 80°C for 1 hour. Immediately after completion of the reaction, the resulting reaction mixture was cooled to room temperature, and saturated sodium hydrogen carbonate was added dropwise. The extraction process was carried out three times using ethyl acetate, and the organic layer was washed with salt water, dried using anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (chloromethylene:methanol = 10:1 (v/v)), and the resulting solution was concentrated under reduced pressure and then crystallized using hexane to obtain 180 g of the target compound in 95.4% yield.

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

Technological operation 3. Preparation of (3-cyclopropyl-5-nitrophenyl)methanol

100 g (431.00 mmol) (3-bromo-5-nitrophenyl)methanol obtained from Process 2 and 111 g (1293.00 mmol) cyclopropyl borate, 9.7 g (43.10 mmol) Pd(OAc ) ₂ , 274.5 g (1293.00 mmol) potassium phosphate and 33.92 g (129.30 mmol) triphenylphosphine were dissolved in a mixed solvent of toluene and H ₂ O (2:1, 1.35 L) and then purged nitrogen for 5 minutes. The reaction mixture was sealed and the temperature was raised to 100°C, then stirred at reflux for 20 hours. Immediately after completion of the reaction, the mixed solution was cooled to room temperature, and the mixed solution was filtered using a celite filter. The celite layer was washed with ethyl acetate. The organic layer was extracted three times from the mixed solution subjected to filtration, and the organic layer was washed with salt water, dried using anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate:hexane = 1:5 (v/v)), and the resulting solution was concentrated under reduced pressure to obtain 62 g of the target compound with a yield of 74.5%.

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).

Technological operation 4. Preparation of (3R,5S)-1-(3-cyclopropyl-5-nitrobenzyl)-3,5-dimethylpiperazine

2 g (10.35 mmol) of (3-cyclopropyl-5-nitrophenyl)methanol obtained from Process 3 was dissolved in a mixed solvent containing tetrahydrofuran and water (1:1, 66 ml), and the temperature was reduced to 0° WITH. Sodium hydroxide (NaOH; 829 mg, 20.70 mmol) and 3.95 g (20.70 mmol) p-toluenesulfonyl chloride were added. After stirring for 1 hour at 0°C, water was added dropwise at room temperature. The extraction process was carried out three times using ethyl acetate, and the organic layer was washed with salt water, dried using anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in 11 ml of N,N-dimethylformamide and 796 mg (5.76 mmol) of potassium carbonate (K ₂ CO ₃ ) and 394 mg (3.45 mmol) of (2R,6S)-2,6-dimethylpiperazine were added. and the resulting mixture was stirred under reflux at 100°C for 1 hour. Immediately after completion of the reaction, the mixed solution was cooled to room temperature, and ethyl acetate and water were added dropwise. The organic layer was extracted, and the organic layer was washed with salt water, dried using anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by HPLC (chloroform:methanol = 10:1 (v/v)), and the resulting solution was concentrated under reduced pressure to obtain 645 mg of the target compound with a yield of 77%.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.95 (s, 1H), 7.76 (s, 1H), 7.37 (s, 1H), 3.53 (m, 2H), 3.44 (t, 4H), 2.39 ( t, 4H), 1.45 (m, 9H), 1.04 (m, 2H), 0.76 (m, 2H).

Technological operation 5. Preparation of 3-cyclopropyl-5-(((3R,5S)-3.5-dimethylpiperazin-1-yl)methyl)aniline

11 ml of 50% ethanol was added to 622 mg (11.14 mmol) of Fe powder and 0.1 ml (0.89 mmol) of concentrated hydrochloric acid (HCl conc.) was slowly added dropwise, and the resulting mixture was stirred while heating with reflux at 110°C for 1.5 hours. (3R,5S)-1-(3-cyclopropyl-5-nitrobenzyl)-3,5-dimethylpiperazine (645 mg, 2.23 mmol) prepared according to Process Step 4 was added to the activated Fe mixture, and the resulting mixture was stirred under heating with reflux at 110°C for 1 hour. Immediately after completion of the reaction, filtration was carried out using a celite filter. A mixed solution of chloroform and methanol and saturated sodium hydrogen carbonate solution was added dropwise to the filtrate. The organic layer was isolated from the mixed solution, washed with salt water, dried using anhydrous sodium sulfate and concentrated under reduced pressure to obtain 518 mg of the target compound with a yield of 90%.

Technological operation 6. Preparation of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-fluoro-1H- indol-3-yl)pyrimidin-2-amine

46 mg (0.17 mmol) 3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)aniline obtained from Process 5 and 50 mg (0.17 mmol) 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole, the production method of which is disclosed in WO 2013014448, was dissolved in 2 ml of 2-butanol, and 34 mg (0. 17 mmol) para-toluenesulfonic acid (p-TsOH). This reaction mixture was stirred under reflux at 120°C for 21 hours. Immediately after completion of the reaction, the mixture was cooled to room temperature, and a saturated sodium hydrogen carbonate solution was added dropwise, followed by extraction using chloroform twice. The extracted organic layer was washed with salt water, dried using anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (chloroform:methanol = 9:1 (v/v)), and the resulting solution was concentrated under reduced pressure to obtain 11 mg of the target compound with a yield of 12%.

MS (IER ⁺ , m/z): 505 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.94 (bs, 1H), 9.50 (s, 1H), 8.60 (m, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.29 (m, 1H), 6.96 (m, 1H), 6.63 (s, 1H), 2.70 (m, 4H), 1.85 (m, 1H), 1.44 (m, 2), 0.92 (m, 8H), 0.60 (m, 2H).

Example 2: 5-chloro-4-(6-chloro-1H-indol-3-yl)-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl) methyl)phenyl)pyrimidin-2-amine

97 mg of the title compound was obtained in 69% yield in substantially the same manner as in Procedure 6 of Example 1 except that 89 mg (0.30 mmol) of 6-chloro-3-(2,5-dichloropyrimidine -4-yl)-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole in Process Step 6 of Example 1.

MS (IER ⁺ , m/z): 521 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 12.01 (s, 1H), 9.54 (s, 1H), 8.58 (d, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 7.55 (m, 1H), 7.46 (m, 1H), 7.36 (s, 1H), 7.11 (m, 1H), 6.65 (s, 1H), 3.37 (s, 2H), 2.85 (m, 2H), 2.71 (d, 2H), 1.84 (m, 1H), 1.60 (m, 2H), 0.95 (d, 7H), 0.89 (m, 2H), 0.61 (m, 2H).

Example 3: 2-((2R,6S)-4-(3-((5-chloro-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl )-2,6-dimethylpiperazin-1-yl)ethan-1-ol

38 mg of the title compound was obtained in 63% yield in essentially the same manner as in Process Step 6 of Example 1 except that 32 mg (0.11 mmol) of 2-((2R,6S)-4-( 3-amino-5-cyclopropylbenzyl)-2,6-dimethylpiperazin-1-yl)ethan-1-ol was used instead of 3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl) methyl)-aniline.

MS (IER ⁺ , m/z): 549 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.94 (bs, 1H), 9.51 (s, 1H), 8.59 (m, 1H), 8.54 (m, 1H), 8.49 (s, 1H), 7.42 (s, 3H), 7.36 (s, 1H), 7.27 (d, 1H), 6.96 (t, 1H), 6.62 (s, 1H), 4.35 (m, 1H), 3.39 (m, 4H), 3.27 (m, 2H), 2.48 (m, 4H), 1.82 (m, 1H), 1.59 (m, 2H), 0.89 (m, 8H), 0.57 (m, 2H).

Example 4: 2-((2R,6S)-4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-amino)-5-cyclopropylbenzyl)-2 ,6-dimethylpiperazin-1-yl)ethan-1-ol

18 mg of the title compound was obtained in 31% yield in essentially the same manner as in Process Step 6 of Example 1 except that 32 mg (0.11 mmol) of 2-((2R,6S)-4-( 3-amino-5-cyclopropylbenzyl)-2,6-dimethylpiperazin-1-yl)ethan-1-ol was used instead of 3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl) methyl)-aniline, and 31 mg (0.11 mmol) of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro -1H-indole.

MS (IER+, m/z): 531 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.90 (bs, 1H), 9.48 (s, 1H), 8.57 (d, 1H), 8.54 (m, 1H), 8.47 (s, 1H), 7.49 (m, 3H), 7.23 (m, 1H), 7.18 (m, 1H), 6.61 (s, 1H), 4.35 (m, 1H), 3.39 (m, 4H), 3.27 (m, 2H), 2.48 (m, 4H), 1.82 (m, 1H), 1.59 (m, 2H), 0.89 (m, 8H), 0.59 (m, 2H).

Example 5: 2-((2R,6S)-4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl )-2,6-dimethylpiperazin-1-yl)ethan-1-ol

28 mg of the title compound was obtained in 47% yield in substantially the same manner as in Procedure 6 of Example 1 except that 32 mg (0.11 mmol) of 2-((2R,6S)-4-( 3-amino-5-cyclopropylbenzyl)-2,6-dimethylpiperazin-1-yl)ethan-1-ol was used instead of 3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl) methyl)-aniline, and 31 mg (0.11 mmol) of 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl) -6-fluoro-1H-indole.

MS (IER+, m/z): 545 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.76 (bs, 1H), 9.45 (s, 1H), 8.45 (m, 3H), 7.43 (d, 1H), 7.25 (s, 1H), 6.94 (d, 1H), 6.61 (s, 1H), 4.35 (m, 1H), 3.39 (m, 4H), 3.27 (m, 2H), 2.48 (m, 4H), 2.40 (s, 3H), 1.82 (m, 1H), 1.59 (m, 2H), 0.89 (m, 8H), 0.59 (m, 2H).

Example 6: (R)-5-chloro-N-(3-cyclopropyl-5-((3-methylpiperazin-1-yl)methyl)-phenyl)-4-(1H-indol-3-yl)pyrimidin-2 -amine

32 mg of the title compound was obtained in 17% yield in essentially the same manner as in Process Step 6 of Example 1 except that 100 mg (0.41 mmol) of (R)-3-cyclopropyl-5-(( 3-methylpiperazin-1-yl)methyl)aniline was used instead of 3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)aniline, and 108 mg (0.41 mmol) 3-(2,5-dichloropyrimidin-4-yl)-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER+, m/z): 473 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.93 (s, 1H), 9.52 (s, 1H), 8.58 (d, 1H), 8.50 (d, 1H), 8.46 (s, 1H), 7.54 (m, 3H), 7.22 (t, 1H), 7.15 (m, 1H), 6.65 (s, 1H), 3.77 (m, 1H), 3.45 (m, 2H), 3.21 (m, 2H), 2.95 (m, 1H), 2.82 (m, 2H), 2.28 (s, 3H), 2.20 (m, 1H), 2.01 (m, 1H), 1.84 (m, 1H), 0.93 (m, 2H), 0.63 ( m, 2H).

Example 7: (R)-5-chloro-N-(3-cyclopropyl-5-((3-methylpiperazin-1-yl)methyl)-phenyl)-4-(6-methyl-1H-indol-3-yl) )pyrimidine-2-amine

39 mg of the title compound was obtained in 38% yield in essentially the same manner as in Process Step 6 of Example 1 except that 53 mg (0.21 mmol) of (R)-3-cyclopropyl-5-(( 3-methylpiperazin-1-yl)methyl)aniline was used instead of 3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)aniline, and 66 mg (0.24 mmol) 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER+, m/z): 487 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.77 (bs, 1H), 9.47 (s, 1H), 8.47 (m, 3H), 7.50 (s, 1H), 7.39 (s, 1H), 7.28 (s, 1H), 6.93 (d, 1H), 6.64 (s, 1H), 3.39 (s, 2H), 2.94 (m, 1H), 2.77 (m, 2H), 2.42 (s, 3H), 2.00 (m, 5H), 1.04 (m, 4H), 0.92 (m, 2H), 0.62 (m, 2H).

Example 8: 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol- 3-yl)pyrimidin-2-amine

30 mg of the title compound was obtained in 7% yield in substantially the same manner as in Process Step 6 of Example 1 except that 222 mg (0.80 mmol) of 3-(2,5-dichloropyrimidin-4-yl) )-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole in Procedure 6 of Example 1.

MS (IER+, m/z): 501 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.76 (bs, 1H), 9.45 (s, 1H), 8.47 (m, 3H), 7.46 (s, 1H), 7.39 (s, 1H), 7.27 (s, 1H), 6.96 (d, 1H), 6.63 (s, 1H), 2.69 (m, 2H), 2.60 (m, 2H), 2.42 (s, 3H), 1.84 (m, 1H), 1.45 (t, 2H), 0.91 (m, 8H), 0.62 (m, 2H).

Example 9: 5-chloro-N-(3-cyclopropyl-5-(((3S,5R)-3-ethyl-5-methylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H- indol-3-yl)pyrimidin-2-amine

30 mg of the title compound was obtained in 29% yield in essentially the same manner as in Process Step 6 of Example 1 except that 55 mg (0.20 mmol) of 3-cyclopropyl-5-(((3S,5R )-3-ethyl-5-methylpiperazin-1-yl)methyl)aniline was used instead of 3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)aniline, and 61 mg (0.22 mmol) 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER+, m/z): 515 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.77 (bs, 1H), 9.45 (s, 1H), 8.47 (m, 3H), 7.46 (s, 1H), 7.39 (s, 1H), 7.27 (s, 1H), 6.96 (d, 1H), 6.63 (s, 1H), 3.36 (m, 2H), 2.70 (m, 4H), 2.42 (s, 3H), 1.85 (m, 1H), 1.50 (m, 2H), 0.93 (m, 11H), 0.61 (m, 2H).

Example 10: 5-chloro-N-(3-cyclopropyl-5-((3,5-dimethylpiperazin-1-yl)-methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine -2-amine

100 mg of the title compound was obtained in 52% yield in essentially the same manner as in Process Step 6 of Example 1 except that 100 mg (0.36 mmol) of 3-cyclopropyl-5-((3,5- dimethylpiperazin-1-yl)methyl)aniline was used instead of 3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)aniline, and 150 mg (0.54 mmol) 3 -(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER+, m/z): 501 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.77 (s, 1H), 9.46 (s, 1H), 8.45 (m, 3H), 7.43 (d, 2H), 7.30 (s, 1H), 6.75 (d, 1H), 6.64 (s, 1H), 2.82 (m, 2H), 2.72 (d, 2H), 2.42 (s, 3H), 1.83 (m, 1H), 1.47 (t, 1H), 0.88 (s, 8H), 0.64 (m, 2H).

Example 11: N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl )pyrimidine-2-amine

409 mg of the title compound was obtained in 31% yield in essentially the same manner as in Procedure 6 of Example 1, except that 700 mg (2.80 mmol) of 3-(2-chloropyrimidin-4-yl)- 6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER+, m/z): 467 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.63 (bs, 1H), 9.20 (s, 1H), 8.44 (d, 1H), 8.28 (d, 1H), 8.19 (m, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.22 (m, 2H), 6.96 (d, 1H), 6.59 (s, 1H), 4.20 (m, 1H), 3.15 (s, 3H), 2.71 (m, 2H), 2.65 (m, 3H), 2.40 (s, 3H), 1.85 (m, 1H), 1.48 (m, 2H), 0.93 (m, 2H), 0.90 (m, 6H), 0.62 ( m, 2H).

Example 12: N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-5-fluoro-4-(6-methyl-1H-indole -3-yl)pyrimidin-2-amine

101 mg of the title compound was obtained in 77% yield in essentially the same manner as in Procedure 6 of Example 1, except that 78 mg (0.30 mmol) of 3-(2-chloro-5-fluoropyrimidine-4 -yl)-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER ⁺ , m/z): 485 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.83 (s, 1H), 9.36 (s, 1H), 8.60 (d, 1H), 8.40 (d, 1H), 8.10 (s, 1H), 7.48 (s, 1H), 7.40 (s, 1H), 7.29 (s, 1H), 7.00 (d, 1H), 6.62 (s, 1H), 3.42 (s, 2H), 2.98 (m, 2H), 2.79 (d, 2H), 2.43 (s, 3H), 1.87 (m, 1H), 1.70 (m, 2H), 1.08 (d, 7H), 0.96 (m, 2H), 0.67 (m, 2H).

Example 13: N-(3-cyclopro1gyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(1H-indol-3-yl)-5 -methylpyrimidin-2-amine

99 mg of the title compound was obtained in 79% yield in substantially the same manner as in Procedure 6 of Example 1, except that 73 mg (0.30 mmol) of 3-(2-chloro-5-methylpyrimidine-4 -yl)-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER+, m/z): 467 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.74 (s, 1H), 9.15 (s, 1H), 8.58 (d, 1H), 8.27 (s, 1H), 8.00 (d, 1H), 7.55 (m, 3H), 7.20 (t, 1H), 7.12 (m, 1H), 6.56 (s, 1H), 3.37 (s, 2H), 2.86 (m, 2H), 2.70 (d, 2H), 2.37 (s, 3H), 1.75 (m, 1H), 1.57 (m, 2H), 0.95 (d, 7H), 0.91 (m, 2H), 0.60 (m, 2H).

Example 14: N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-5-methyl-4-(6-methyl-1H-indole -3-yl)pyrimidin-2-amine

135 mg of the title compound was obtained in 73% yield in essentially the same manner as in Procedure 6 of Example 1, except that 150 mg (0.58 mmol) of 3-(2-chloro-5-methylpyrimidine-4 -yl)-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.64 (s, 1H), 9.15 (s, 1H), 8.44 (d, 1H), 8.25 (s, 1H), 7.92 (d, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.26 (s, 1H), 7.12 (s, 1H), 6.93 (d, 1H), 6.58 (s, 1H), 3.46 (s, 2H), 2.83 (d, 2H), 2.43 (s, 3H), 2.36 (s, 3H), 1.94 (t, 2H), 1.91 (m, 1H), 1.05 (t, 1H), 0.89 (m, 2H), 0.61 ( t, 2H).

Example 15: N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl )-5-(trifluoromethyl)pyrimidin-2-amine

289 mg of the title compound was obtained in 28% yield in essentially the same manner as in Procedure 6 of Example 1 except that 600 mg (1.92 mmol) of 3-(2-chloro-5-(trifluoromethyl) Pyrimidin-4-yl)-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER+, m/z): 535 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.63 (bs, 1H), 9.87 (s, 1H), 8.69 (s, 1H), 8.28 (m, 1H), 7.77 (s, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 6.93 (d, 1H), 6.66 (s, 1H), 4.20 (m, 1H), 3.15 (s, 3H), 2.58 (m, 3H), 2.55 (m, 3H), 2.40 (s, 3H), 1.85 (m, 1H), 1.40 (m, 2H), 0.89 (m, 8H), 0.57 (m, 2H).

Example 16: (3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl )-1H-indol-6-yl)methanol

Technological operation 1. Preparation of (3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)amino)pyrimidine-4 -yl)-1-tosyl-1H-indol-6-yl)methanol

30 mg of the title compound was obtained in 46% yield in essentially the same manner as in Process Step 6 of Example 1 except that 51 mg (0.11 mmol) of (3-(2,5-dichloropyrimidine-4- yl)-1-tosyl-1H-indol-6-yl)methanol was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 9.70 (s, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 8.29-8.03 (m, 2H), 7.53-7.09 (m , 4H), 6.33 (s, 1H), 5.39 (brs, 1H), 4.65 (s, 2H), 2.73 (m, 2H), 2.61 (d, 2H), 2.33 (s, 3H), 1.80 (m, 1H), 1.49 (t, 1H), 0.88 (m, 10H), 0.55 (m, 2H).

Technological operation 2. Preparation of (3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3.5-dimethylpiperazin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl )-1H-indol-6-yl)methanol

18 mg (0.03 mmol) (3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)amino) pyrimidin-4-yl)-1-tosyl-1H-indol-6-yl)methanol obtained from Process 1 of Example 16 was dissolved in a mixed solvent containing methanol and tetrahydrofuran (1 ml, 1:1), and then the temperature was increased to 60°C. 18 mg (0.06 mmol) of cesium carbonate was also added there, and the resulting mixture was stirred at 60°C for 2 hours. Immediately after completion of the reaction, the temperature was reduced to room temperature and an aqueous solution of ammonium chloride was added. The extraction process was carried out three times using chloroform. The resulting material was dried using anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography (MPLC) (chloroform:methanol = 100:5 (v/v)), and the resulting solution was concentrated under reduced pressure to obtain 10 mg of the target compound in 72% yield.

MS (IER+, m/z): 517 [M+H] ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.90 (s, 1H), 9.49 (s, 1H), 8.51 (m, 3H), 7.48 (s, 1H), 7.46 (s, 1H), 7.39 (s, 1H), 7.07 (d, 1H), 6.65 (s, 1H), 5.19 (m, 1H), 4.62 (s, 2H), 4.14 (m, 1H), 3.46 (s, 2H), 3.16 (m, 2H), 2.83 (d, 2H), 1.945 (m, 4H), 1.11 (d, 2H), 0.93 (m, 4H), 0.64 (m, 2H).

Example 17: 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(5-methoxy-6-methyl- 1H-indol-3-yl)pyrimidin-2-amine

11 mg of the title compound was obtained in 13% yield in essentially the same manner as in Process Step 6 of Example 1 except that 50 mg (0.16 mmol) of 3-(2,5-dichloropyrimidin-4-yl) )-5-methoxy-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER+, m/z): 531 [M+H] ⁺

¹ H-NMR (300 MHz, DUSO-d ₆ ): δ 11.64 (s, 1H), 9.45 (s, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 7.85 (s, 1H), 7.38 (m, 2H), 7.22 (s, 1H), 6.61 (s, 1H), 3.50 (s, 3H), 2.72 (m, 2H), 2.65 (m, 2H), 2.27 (m, 4H), 1.65 (m, 1H), 1.59 (m, 2H), 1.21 (m, 2H), 1.07 (m, 6H), 0.82 (m, 2H), 0.51 (m, 2H).

Example 18: 3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl) -6-methyl-1H-indol-5-ol

10 mg of the title compound was obtained in 15% yield in substantially the same manner as in Process Step 6 of Example 1, except that 39 mg (0.13 mmol) of 3-(2,5-dichloropyrimidin-4-yl) )-6-methyl-1H-indol-5-ol was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER+, m/z): 517 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.50 (s, 1H), 9.31 (s, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 7.40 (s, 1H), 7.16 (s, 1H), 6.58 (s, 1H), 3.17-2.56 (m, 4H), 2.26 (m, 3H) , 1.89 (m, 1H), 1.22 (m, 2H), 0.86 (m, 8H), 0.57 (m, 2H).

Example 19: 3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl) -6-methylindolin-2-one

5 mg of the title compound was prepared in 3% yield in substantially the same manner as in Process Step 6 of Example 1 except that 70 mg (0.24 mmol) of 3-(2,5-dichloropyrimidin-4-yl) )-6-methylindol-2-one was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER+, m/z): 517 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 10.65 (s, 1H), 9.68 (s, 1H), 8.57 (s, 1H), 7.21 (m, 2H), 7.09 (m, 1H), 6.96 (m, 2H), 6.56 (s, 1H), 5.12 (s, 1H), 2.82 (m, 2H), 2.72 (m, 2H), 2.27 (s, 3H), 1.73 (m, 3H), 1.17 (m, 3H), 1.08 (m, 6H), 0.90 (m, 2H), 0.52 (m, 2H).

Example 20: 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-methoxy-6-(6-methyl- 1H-indol-3-yl)pyrimidin-2-amine

17 mg of the title compound was obtained in 17% yield in essentially the same manner as in Process Step 6 of Example 1 except that 60 mg (0.19 mmol) of 3-(2,5-dichloro-6-methoxypyrimidine) -4-yl)-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER+, m/z): 531 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.66 (s, 1H), 9.41 (s, 1H), 8.44 (d, 1H), 8.32 (s, 1H), 7.59 (s, 1H), 7.40 (s, 1H), 7.25 (s, 1H), 6.95 (d, 1H), 6.67 (s, 1H), 4.04 (s, 3H), 3.43 (s, 2H), 2.98 (m, 2H), 2.83 (m, 2H), 2.45 (s, 3H), 1.83 (m, 3H), 1.08 (m, 6H), 0.93 (m, 2H), 0.64 (m, 2H).

Example 21: 5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)amino)-6-(6-methyl-1H -indol-3-yl)pyrimidin-4-ol

19 mg (0.04 mmol) 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-methoxy-6- (6-methyl-1H-indol-3-yl)pyrimidin-2-amine prepared according to Example 20 was dissolved in 1 ml of ethanol, and then 0.2 ml of hydrochloric acid was added to this solution, after which it was stirred at a temperature of 80 °C for 16 hours. Immediately after completion of the reaction, the mixture was cooled to room temperature and then ethyl acetate and saturated sodium hydrogen carbonate were added thereto. The organic layer was separated, and it was then dried using anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (chloroform:methanol = 5:1 (v/v)), and the resulting solution was concentrated under reduced pressure to obtain 1.4 mg of the target compound in 7% yield.

MS (IER+, m/z): 517 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.56 (s, 1H), 8.17 (m, 1H), 8.06 (d, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 6.82 (d, 1H), 6.70 (s, 1H), 2.72 (m, 2H), 2.50 (m, 2H), 2.00 (s, 3H), 1.83 (m, 3H), 1.23 (m, 6H), 0.93 (m, 2H), 0.64 (m, 2H).

Example 22: 3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl) -6-methyl-1H-indol-7-ol

25 mg of the title compound was obtained in 41% yield in essentially the same manner as in Process Step 6 of Example 1 except that 50 mg (0.17 mmol) of 3-(2,5-dichloropyrimidin-4-yl) )-6-methyl-1H-indol-7-ol was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

MS (IER+, m/z): 517 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.50 (bs, 1H), 9.45 (s, 1H), 8.95 (bs, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 7.99 (d, 1H), 7.46 (s, 1H), 7.39 (s, 1H), 6.85 (d, 1H), 6.62 (s, 1H), 3.34 (s, 2H), 2.73 (m, 2H), 2.63 (m, 2H), 2.28 (s, 3H), 1.83 (m, 1H), 1.44 (t, 2H), 0.92 (m, 9H), 0.61 (m, 2H).

Example 23: 2-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-cyclopropyl-6-(((3R,5S)-3 ,5-dimethylpiperazin-1-yl)methyl)phenol

5 mg of the title compound was obtained in 5% yield in substantially the same manner as in Process Step 6 of Example 1 except that 56 mg (0.20 mmol) of 2-amino-4-cyclopropyl-6-(( (3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenol was used instead of 3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-aniline, and 85 mg (0.31 mmol) of 3-(2,5-dichloropyrimidin-4-yl)-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro- 1H-indole.

MS (IER+, m/z): 517 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.72 (s, 1H), 8.38 (m, 2H), 8.15 (d, 1H), 8.08 (s, 1H), 7.55 (s, 1H), 7.22 (s, 1H), 6.82 (d, 1H), 6.50 (s, 1H), 3.60 (s, 2H), 2.70 (d, 4H), 2.46 (s, 3H), 1.74 (m, 1H), 1.63 (t, 2H), 0.84 (d, 6H), 0.79 (m, 2H), 0.50 (m, 2H).

Example 24: 4-((5-chloro-4-(6-methyl-1H-indol-3-yl)go1rimidin-2-yl)amino)-2-cyclopropyl-6-(((3R,5S)-3 ,5-dimethylpiperazin-1-yl)methyl)phenol

200 mg of the title compound was obtained in 53% yield in essentially the same manner as in Process Step 6 of Example 1 except that 200 mg (0.73 mmol) of 4-amino-2-cyclopropyl-6-(( (3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenol was used instead of 3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-aniline, and 303 mg (1.09 mmol) of 3-(2-chloro-5-methylpyrimidin-4-yl)-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6- fluoro-1H-indole.

MS (IER+, m/z): 517 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.72 (s, 1H), 11.05 (s, 1H), 9.09 (s, 1H), 8.40-8.32 (m, 4H), 7.26 (s, 2H ), 6.84 (m, 2H), 3.59 (m, 2H), 2.77 (d, 4H), 2.41 (s, 3H), 2.11 (m, 1H), 1.60 (t, 2H), 0.92 (d, 6H) , 0.87 (m, 2H), 0.58 (m, 2H).

Example 25: (R)-5-chloro-N-(3-cyclopropyl-5-((3,3,5-trimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol- 3-yl)pyrimidin-2-amine

Technological operation 1. (3-Amino-5-cyclopropylphenyl)methanol

5.8 g of the title compound was obtained in 95% yield in substantially the same manner as in Process Step 5 of Example 1 except that 7.2 g (37.27 mmol) of (3-cyclopropyl-5-nitrophenyl )methanol was used instead of (3R,5S)-1-(3-cyclopropyl-5-nitrobenzyl)-3,5-dimethylpiperazine.

^1H -NMR (300 MHz, DMSO- _d6 ): δ 6.31 (s, 1H), 6.18 (s, 1H), 6.13 (s, 1H), 4.94 (m, 3H), 4.28 (d, 2H), 1.73 (m, 1H), 0.87 (m, 2H), 0.56 (m, 2H).

Technological operation 2. (3-((5-Chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)methanol

3.5 g of the title compound was obtained in 49% yield in substantially the same manner as in Process Step 6 of Example 1 except that 2.9 g (17.77 mmol) of (3-amino-5-cyclopropylphenyl )methanol was used instead of 3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)aniline, and 7.4 g (26.65 mmol) 3-(2,5- dichloropyrimidin-4-yl)-6-methyl-1H-indole was used instead of 3-(2,5-dichloropyrimidin-4-yl)-6-fluoro-1H-indole.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.78 (s, 1H), 9.48 (s, 1H), 8.50 (m, 3H), 7.53 (s, 1H), 7.38 (s, 1H), 7.28 (s, 1H), 6.96 (d, 1H), 6.67 (s, 1H), 5.10 (t, 1H), 4.42 (d, 1H), 2.43 (s, 3H), 1.84 (m, 1H), 0.93 (m, 2H), 0.65 (m, 2H).

Technological operation 3. 3-((5-Chloro-4-(b-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzaldehyde

5.67 g (14.00 mmol) (3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylphenyl)methanol obtained as a result of Process 2 of Example 25, was dissolved in 200 ml of methylene chloride, and then 14.3 g (140.00 mmol) of manganese dioxide was added to this solution. The resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the resulting mixture was filtered through a filter filled with celite and washed with methylene chloride. The resulting organic layer was concentrated under reduced pressure. The resulting residue was purified by HPLC (ethyl acetate:hexane = 1:4 (v/v)), and the resulting solution was concentrated under reduced pressure to obtain 2.1 g of the title compound in 37% yield.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.81 (s, 1H), 9.90 (s, 1H), 9.78 (s, 1H), 8.50 (m, 3H), 8.15 (s, 1H), 7.81 (s, 1H), 7.25 (d, 2H), 6.94 (d, 2H), 2.42 (s, 3H), 1.97 (m, 1H), 1.02 (m, 2H), 0.75 (m, 2H).

Technological operation 4. Preparation of (R)-5-chloro-N-(3-cyclopropyl-5-((3,3.5-trimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol- 3-yl)pyrimidin-2-amine

140 mg (0.35 mmol) 3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzaldehyde obtained from Process 3 Example 25, and 140 mg (0.70 mmol) of (R)-2,2,6-trimethylpiperazine hydrochloride were dissolved in 2 ml of 1,2-dichloroethane, and to this solution were added 200 mg (0.75 mmol) of sodium triacetoxyborohydride and 0.3 ml (1.74 mmol) diisopropylamine. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, methylene chloride and saturated aqueous sodium hydrogen carbonate were added dropwise. The organic layer was extracted, and the organic layer was washed with salt water, dried using anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by HPLC (methylene chloride:methanol = 25:1 (v/v)), and the resulting solution was concentrated under reduced pressure to obtain 140 mg of the target compound in 78% yield.

MS (IER+, m/z): 515 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.77 (s, 1H), 9.47 (s, 1H), 8.48 (m, 3H), 7.57 (s, 1H), 7.35 (s, 1H), 7.28 (s, 1H), 6.94 (d, 1H), 6.64 (s, 1H), 3.38 (q, 2H), 2.95 (m, 1H), 2.70 (d, 1H), 2.43 (s, 3H), 1.84 (m, 1H), 1.59 (m, 2H), 1.23 (d, 1H), 1.12 (s, 3H), 0.94 (m, 2H), 0.63 (m, 2H).

Example 26: ((2R,6R)-4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)- 6-methylpiperazin-2-yl)methanol

22 mg of the title compound was obtained in 24% yield in essentially the same manner as in Procedure 4 of Example 25 except that 55 mg (0.27 mmol) ((2i?,67?)-6-methylpiperazine -2-yl)methanol hydrochloride was used instead of (R)-2,2,6-trimethylpiperazine hydrochloride.

MS (IER+, m/z): 517 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.80 (s, 1H), 9.49 (s, 1H), 8.48 (m, 3H), 7.50 (s, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 6.95 (d, 1H), 6.65 (s, 1H), 4.99 (m, 1H), 4.10 (m, 1H), 3.42 (s, 2H), 3.16 (d, 2H), 2.97 (m, 2H), 2.80 (m, 2H), 2.43 (s, 3H), 1.85 (m, 3H), 1.23 (m, 2H), 1.04 (d, 3H), 0.94 (m, 2H), 0.65 ( m, 2H).

Example 27: (R)-5-chloro-N-(3-cislopropyl-5-((5-methyl-4,7-diazaspiro[2.5]octan-7-yl)methyl)phenyl)-4-(6- methyl-1H-indol-3-yl)pyrimidin-2-amine

150 mg of the title compound was obtained in 60% yield in essentially the same manner as in Procedure 4 of Example 25, except that 188 mg (1.49 mmol) of (7?)-5-methyl-4,7 -diazaspiro[2.5]octane hydrochloride was used instead of (R)-2,2,6-trimethylpiperazine hydrochloride.

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.77 (s, 1H), 9.46 (s, 1H), 8.47 (m, 3H), 7.47 (s, 1H), 7.40 (s, 1H), 7.28 (s, 1H), 6.95 (d, 1H), 6.64 (s, 1H), 2.71 (d, 2H), 2.62 (d, 2H), 2.42 (s, 3H), 1.87 (m, 1H), 1.50 (q, 2H), 1.23 (q, 2H), 0.92 (m, 8H), 0.62 (m, 2H).

Example 28: 5-chloro-N-(3-cyclopropyl-5-(((3R,5R)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol- 3-yl)pyrimidin-2-amine

17 mg of the title compound was obtained in 9% yield in substantially the same manner as in Procedure 4 of Example 25 except that 149 mg (0.80 mmol) of (2R,6R)-2,6-dimethylpiperazine hydrochloride was used instead of (R)-2,2,6-trimethylpiperazine hydrochloride.

MS (IER+, m/z): 501 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.80 (s, 1H), 9.15 (s, 1H), 8.46 (m, 3H), 7.66 (s, 1H), 7.35 (s, 1H), 7.28 (s, 1H), 6.95 (d, 1H), 6.63 (s, 1H), 3.51 (d, 2H), 2.43 (s, 3H), 2.25 (m, 2H), 1.85 (m, 1H), 1.23 (s, 2H), 0.91 (m, 4H), 0.62 (m, 2H).

Example 29: 5-chloro-N-(3-cyclopropyl-5-(((3S,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol- 3-yl)pyrimidin-2-amine

25 mg of the title compound was prepared in 15% yield in substantially the same manner as in Process 4 of Example 25 except that 75 mg (0.66 mmol) of (2S,6S)-2,6-dimethylpiperazine hydrochloride was used instead of (R)-2,2,6-trimethylpiperazine hydrochloride.

MS (IER+, m/z): 501 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.76 (s, 1H), 9.46 (s, 1H), 8.46 (m, 3H), 7.55 (s, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 6.94 (d, 1H), 6.63 (s, 1H), 3.59 (t, 2H), 3.05 (m, 2H), 2.32 (d, 2H), 1.89 (m, 2H), 1.75 (m, 1H), 1.01 (d, 6H), 0.91 (m, 2H), 0.62 (m, 2H).

Example 30: 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,4,5-trimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H- indol-3-yl)pyrimidin-2-amine

70 mg of the title compound was obtained in 79% yield in essentially the same manner as in Procedure 4 of Example 25 except that 168 mg (0.70 mmol) of (2R,6S)-1,2,6- Trimethylpiperazine trifluoroacetate was used instead of (R)-2,2,6-trimethylpiperazine hydrochloride.

MS (IER+, m/z): 515 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.76 (s, 1H), 9.46 (s, 1H), 8.46 (m, 3H), 7.48 (s, 1H), 7.40 (s, 1H), 7.28 (s, 1H), 6.95 (d, 1H), 6.64 (s, 1H), 4.34 (m, 1H), 3.47 (m, 1H), 2.63 (m, 2H), 2.43 (s, 3H), 2.15 (m, 2H), 1.82 (m, 2H), 1.08 (m, 8H), 0.62 (m, 2H).

Example 31: (2R,6S)-4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)-2 ,6-dimethylpiperazin-1-ol

60 mg of the title compound was obtained in 94% yield in substantially the same manner as in Procedure 4 of Example 25 except that 62 mg (0.37 mmol) of (2R,6S)-2,6-dimethylpiperazine- 1-ol hydrochloride was used instead of (R)-2,2,6-trimethylpiperazine hydrochloride.

MS (IER+, m/z): 517 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.77 (s, 1H), 9.48 (s, 1H), 8.47 (m, 3H), 7.67 (s, 1H), 7.47 (s, 1H), 7.41 (s, 1H), 7.28 (s, 1H), 6.95 (d, 1H), 6.63 (s, 1H), 3.31 (s, 2H), 2.69 (d, 2H), 2.43 (s, 3H), 1.81 (m, 3H), 1.05 (t, 2H), 0.95 (m, 8H), 0.62 (m, 2H).

Example 32: (2R,6S)-4-(3-cyclopropyl-5-((4-(6-methyl-1H-indol-3-yl)-pyrimidin-2-yl)amino)benzyl)-2,6 -dimethylpiperazin-1-ol

1.5 g of the title compound was obtained in 51% yield in essentially the same manner as in Example 25, except that in Process 4 of Example 25, 2.5 g (12.16 mmol) (2R,6S)- 2,6-Dimethylpiperazin-1-ol hydrochloride was used instead of (R)-2,2,6-trimethylpiperazine hydrochloride, and 2.24 g (6.08 mmol) 3-cyclopropyl-5-((4-(6-methyl -1H-indol-3-yl)pyrimidin-2-yl)amino)benzaldehyde was used instead of 3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino )-5-cyclopropylbenzoaldehyde.

MS (IER ⁺ , m/z): 483 [M+H] ⁺

^1H -NMR (300 MHz, DMSO- _d6 ): δ 11.63 (bs, 1H), 9.23 (s, 1H), 8.45 (d, 1H), 8.29 (m, 1H), 8.20 (s, 1H), 7.66 (s, 1H), 7.51 (d, 2H), 7.22 (m, 2H), 6.96 (d, 1H), 6.58 (s, 1H), 2.73 (m, 2H), 2.55 (m, 4H), 1.88 (m, 1H), 1.82 (m, 2H), 0.96 (m, 8H), 0.64 (m, 2H).

Experimental Examples

The kinase inhibitory activity and cell growth inhibitory activity of the above compounds obtained in the Examples were evaluated. The results are as follows.

Experimental Example 1: Evaluation of Kinase Inhibitory Activity

The inhibitory activity of several compounds described above against FLT3-ITD, wild-type (WT) FLT3, VEGFR2 (KDR) and SYK kinase was measured.

The inhibitory activity of the compounds against mutant proteins such as FLT3 WT and ITD was assessed based on LanthaScreen technology developed by Thermo Fisher Scientific Inc. This assay is based on binding an Alexa Fluor® 647-labeled, ATP-competitive kinase inhibitor (kinase tag-236) to the kinase, and fluorescence resonance energy transfer (FRET) signals are measured in the presence of a europium-conjugated antibody. This experiment was carried out in a 384-well plate under conditions including 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl ₂ , 1 mM EGTA and 1% DMSO. After measuring background signal in the absence of proteins such as FLT3 or FLT3-ITD, and measuring non-inhibition signal by adding solvent alone (1% DMSO), a range of concentrations (e.g., 50 nM to 0.05 nM, dilution 1) were used to evaluate the compound: 10) to calculate the kinase inhibitory activity of the evaluated compound in the form of IC ₅₀ . The results are presented in Table 2 below.

As shown in Table 2, the compound of the present invention demonstrated excellent kinase inhibitory activity against FLT3 ITD and WT.

The SYK inhibitory activity of the compounds was assessed based on the z-LYTE technology developed by Thermo Fisher Scientific Inc. In this evaluation method, the fluorescence signals of FRET peptides were measured, the fluorescence of a FRET peptide that is phosphorylated upon binding of a compound to a target was measured, and the fluorescence signals of a non-phosphorylated peptide were measured to identify kinase activity. This experiment was carried out in a 384-well plate under conditions including 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl ₂ , 1 mM EGTA and 1% DMSO. The background signal was measured in the absence of proteins; the non-inhibitory signal was measured when only vehicle (1% DMSO) was added; and the evaluated compound was used at a concentration of 100 nM to calculate the SYK inhibitory activity of the evaluated compound in percent (%). The z-lyte kinase assay kit (Life Technologies, PV 3190) was used for VEGFR, and tests were performed by Life Technologies Inc. Table 3 shows the inhibitory activity of the compound against the corresponding kinase in percentage (%) when the concentration was 100 nM.

As shown in Table 3, the compounds of the present invention have excellent inhibitory activity against VEGFR2 and SYK kinase.

Experimental Example 2: Evaluation of Cell Growth Inhibitory Activity

The human acute myelogenous leukemia (ALL) cell line MOLM-13 (DSMZ no. ACC 554) was incubated in RPMI1640 medium supplemented with 20% heat-activated FBS (fetal bovine serum) at 37°C. The incubated cell line was prepared at 2.0 x ¹⁰⁴ cells/100 μl and then seeded into a 96-well plate. RPMI1640 medium was serially diluted with test compounds in concentrations ranging from 1 μM to 0.01 nM at a ratio of 1:10. After this, incubation was carried out for three days. For the human acute myelogenous leukemia cell line MV-4-11 (ATCC® CRL-9591®), cells were incubated at 37°C in IMDM medium (Iscove's modified Dulbecco's medium) supplemented with 10% FBS. The incubated cell line was prepared at 2.0 x ¹⁰⁴ cells/100 μl and then seeded into a 96-well plate. IMDM medium was treated with serial dilutions of the three test compounds at concentrations ranging from 1 μM to 0.01 nM at a ratio of 1/10. After this, incubation was carried out for three days. The MTS assay was performed to measure cell viability, and the cell line growth inhibition value (GI ₅₀ ) was calculated using GraphPad Prism software. The results for each cell line are presented in Table 4 below.

As shown in Table 4, the compound of the present invention was found to have excellent cell growth inhibitory activity on an acute myelogenous leukemia (ALL) cell line.

Experimental Example 3: Pharmacokinetic Profile Evaluation

After preparing the test substances using the selected solvents, they were administered orally (PO) and intravenously (IV), each once, a certain amount of blood was drawn after a predetermined time, plasma was isolated from the blood, and concentrations were analyzed by LC-MS /MS (liquid chromatography and tandem mass spectrometry). AUC (drug concentration and area under the curve) was calculated using the linear-logarithmic trapezoidal summation formula using non-compartmental analysis in WinNonlin software from plasma concentration-time curves. Bioavailability (BA) was calculated using the calculated AUC value using the following formula: BA (%) = (AUC n.o./AUC i.v.) × (iv dose/po dose) × 100.

As shown in Table 5 and Table 6, the compound according to an embodiment of the present invention exhibited better absorption characteristics suitable for oral administration, such as bioavailability and area under the curve, than control compounds having chemical structures similar to that of the compound.

Experimental Example 4: Method for Measuring Microsomal Stability

To confirm the ability of the test substances to react with intrahepatic CYP450 enzymes, 5 μM of the test substance and 1 mg/ml human liver microsomes were incubated for 1 hour at 37°C in the presence of a NADPH regeneration system. After 1 hour, acetonitrile was added to stop the reaction, and the supernatant after centrifugation was analyzed by HPLC (high performance liquid chromatography). The % residual was calculated using the following equation using the reacted sample value at 1 hour relative to the value at 0 minutes as the maximum value obtained from the analysis. (Maximum value of sample reacted in 1 hour/maximum value of sample reacted in 0 minutes) × 100=% residual.

As shown in Table 7, the compound according to an embodiment of the present invention has improved microsomal stability compared to a control compound having a similar chemical structure.

From the illustrative data, it can be seen that compounds according to an embodiment of the present invention are found to have better pharmacokinetic properties than control compounds having similar substituents and comparable levels of steric hindrance.

The compound according to one aspect of the present invention has excellent FLTS inhibitory activity and is therefore suitable for effective use in the prevention or treatment of cell proliferative diseases caused by abnormal FLT3 activity, such as cancer, eg leukemia.

While the present invention has been specifically shown and described with reference to embodiments thereof, those skilled in the art will appreciate that various changes in form and detail may be made without departing from the spirit and scope of the invention as defined by the appended claims. The embodiment is to be considered in a descriptive sense only and not for purposes of limitation. Accordingly, the scope of the invention is determined not by the detailed description but by the appended claims, and all differences within that scope will be construed as being covered by the present invention.

Claims (68)

1. Compound of formula 14 or its stereoisomer or tautomer , where in formula 14 E ^a represents hydrogen, hydroxy or a C ₁ -C ₄ alkoxy group; E ^b represents hydrogen, halogen, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ fluoroalkyl group; E ^c and E ^d are each independently hydrogen or hydroxy; X' represents hydrogen or hydroxy; k is equal to an integer from 0 to 4; each Q independently represents hydroxy, halogen, a C ₁ -C ₄ alkyl group, a hydroxy-C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group; And Z' represents a monovalent functional group represented by formula 15: , where in formula 15 n is equal to an integer from 1 to 5; each A independently represents a functional group selected from hydroxy, a C ₁ -C ₄ alkyl group and a hydroxy-C ₁ -C ₄ alkyl group, where when n is two or more, then the two A's can be spiro-linked to form 4 ,7-diazaspiro[2.5]octane; And L represents hydrogen, a C ₁ -C ₄ alkyl group, a hydroxy group or a hydroxy-C ₁ -C ₄ alkyl group. 2. A compound according to claim 1, wherein E ^b is halogen, n is 2, and A is methyl. 3. The compound according to claim 1, where Z' represents 3,5-dimethylpiperazin-1-yl. 4. The compound according to claim 1, where E ^b represents chlorine or fluorine. 5. A compound according to claim 1, wherein the compound of formula 1 is selected from the compounds listed below: 1) 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-phenyl)-4-(6-fluoro-1H-indol- 3-yl)pyrimidin-2-amine; 2) 5-chloro-4-(6-chloro-1H-indol-3-yl)-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl )phenyl)pyrimidin-2-amine; 3) 2-((2R,6S)-4-(3-((5-chloro-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl) -2,6-dimethylpiperazin-1-yl)ethan-1-ol; 4) 2-((2R,6S)-4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)-2,6 -dimethylpiperazin-1-yl)ethan-1-ol; 5) 2-((2R,6S)-4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl) -2,6-dimethylpiperazin-1-yl)ethan-1-ol; 6) (R)-5-chloro-N-(3-cyclopropyl-5-((3-methylpiperazin-1-yl)methyl)phenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine ; 7) (R)-5-chloro-N-(3-cyclopropyl-5-((3-methylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine -2-amine; 8) 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-phenyl)-4-(6-methyl-1H-indol- 3-yl)pyrimidin-2-amine; 9) 5-chloro-N-(3-cyclopropyl-5-(((3S,5R)-3-ethyl-5-methylpiperazin-1-yl)methyl)-phenyl)-4-(6-methyl-1H- indol-3-yl)pyrimidin-2-amine; 10) 5-chloro-N-(3-cyclopropyl-5-((3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2 -amine; 11) N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine -2-amine; 12) N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-5-fluoro-4-(6-methyl-1H-indole-3 -yl)pyrimidin-2-amine; 13) N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(1H-indol-3-yl)-5-methylpyrimidin- 2-amine; 14) N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-5-methyl-4-(6-methyl-1H-indole-3 -yl)pyrimidin-2-amine; 15) N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)- 5-(trifluoromethyl)pyrimidin-2-amine; 16) (3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)-methyl)phenyl)amino)pyrimidin-4-yl )-1H-indol-6-yl)methanol; 17) 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-phenyl)-4-(5-methoxy-6-methyl- 1H-indol-3-yl)pyrimidin-2-amine; 18) 3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-phenyl)amino)pyrimidin-4-yl) -6-methyl-1H-indol-5-ol; 19) 3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-phenyl)amino)pyrimidin-4-yl) -6-methylindolin-2-one; 20) 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-phenyl)-4-methoxy-6-(6-methyl- 1H-indol-3-yl)pyrimidin-2-amine; 21) 5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-phenyl)amino)-6-(6-methyl-1H -indol-3-yl)pyrimidin-4-ol; 22) 3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)-phenyl)amino)pyrimidin-4-yl) -6-methyl-1H-indol-7-ol; 23) 2-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-cyclopropyl-6-(((3R,5S)-3, 5-dimethylpiperazin-1-yl)methyl)phenol; 24) 4-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-cyclopropyl-6-(((3R,5S)-3, 5-dimethylpiperazin-1-yl)methyl)phenol; 25) (R)-5-chloro-N-(3-cyclopropyl-5-((3,3,5-trimethylpiperazin-1-yl)methyl)-phenyl)-4-(6-methyl-1H-indol- 3-yl)pyrimidin-2-amine; 26) ((2R,6R)-4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)-6 -methylpiperazin-2-yl)methanol; 27) (R)-5-chloro-N-(3-cyclopropyl-5-((5-methyl-4,7-diazaspiro[2.5]octan-7-yl)-methyl)phenyl)-4-(6- methyl-1H-indol-3-yl)pyrimidin-2-amine; 28) 5-chloro-N-(3-cyclopropyl-5-(((3R,5R)-3,5-dimethylpiperazin-1-yl)methyl)-phenyl)-4-(6-methyl-1H-indol- 3-yl)pyrimidin-2-amine; 29) 5-chloro-N-(3-cyclopropyl-5-(((3S,5S)-3,5-dimethylpiperazin-1-yl)methyl)-phenyl)-4-(6-methyl-1H-indol- 3-yl)pyrimidin-2-amine; 30) 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,4,5-trimethylpiperazin-1-yl)methyl)-phenyl)-4-(6-methyl-1H- indol-3-yl)pyrimidin-2-amine; 31) (2R,6S)-4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)-2, 6-dimethylpiperazin-1-ol; And 32) (2R,6S)-4-(3-cyclopropyl-5-((4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)-amino)benzyl)-2,6- dimethylpiperazin-1-ol. 6. Connection . 7. Connection . 8. Connection . 9. Connection . 10. Connection . 11. A method of treating a FLT3 (FMS-like tyrosine kinase 3)-mediated disease in a subject in need thereof, comprising administering to said subject a compound according to any one of claims. 1-10, wherein said FLT3-mediated disease is cancer. 12. The method of claim 11, wherein the cancer is characterized by abnormal overexpression and/or mutations of FLT3. 13. The method according to claim 11, wherein the cancer is leukemia. 14. The method of claim 13, wherein the leukemia is acute myelogenous leukemia, acute lymphocytic leukemia or chronic myelogenous leukemia. 15. A method of inhibiting FLT3 kinase activity in a subject in need thereof, comprising administering to said subject a compound according to any one of claims. 1-10. 16. The method according to claim 11, wherein the cancer is associated with mutant FLT3. 17. The method of claim 16, wherein the mutant FLT3 has an internal tandem duplication (ITD) mutation. 18. The method of claim 16, wherein the mutant FLT3 contains at least one point mutation in the tyrosine kinase domain (TKD) of FLT3. 19. The method of claim 16, wherein the FLT3 mutation is D835V or D835Y.