WO2020175968A1 - N-containing heteroaryl derivative and pharmaceutical composition comprising same as active ingredient - Google Patents

Abstract

The present invention relates to an N-containing heteroaryl derivative and a pharmaceutical composition for the prevention or treatment of cancer, comprising same as an active ingredient, wherein the derivative exhibits high inhibitory activity against various protein kinases, particularly high inhibitory efficacy against ret proto-oncogene (RET) enzymes, and has an excellent effect of inhibiting the proliferation of medullary thyroid cancer cells and lung cancer cells, which express the RET fusion gene, and thus can be effectively used in the treatment of cancer, for example, medullary thyroid cancer or lung cancer. In particular, the derivative can be effectively used in the treatment of cancer in which the RET fusion gene is expressed.

Description

2020/175968 1»（：1^1{2020/002925 Specification

Title of the invention: Heteroaryl derivatives including and

Pharmaceutical composition technology field containing as an active ingredient

[1] It relates to a heteroaryl derivative containing N and a pharmaceutical composition for the prevention or treatment of cancer containing it as an active ingredient.

Background

[2] Cancer incidence is caused by various environmental factors including chemicals, radiation, and viruses.

Factors and oncogenes, tumor suppressor genes, apoptosis and changes in genes related to DNA repair, etc. are related to the molecular weight of these cancers.

By understanding the mechanism, a new treatment, targeted chemotherapy, became possible.

[3] Targeted therapies generally target molecules that cancer cells have

Targeted and made to show its effect, and molecular targets are the signal transduction pathway of cancer cells, angiogenesis, matrix, and cell cycle regulators. These are genes related to apoptosis, apoptosis, etc. Currently, important target therapeutic agents in treatment include tyrosine kinase inhibitors, signal transduction pathway inhibitors, and angiogenesis inhibitors.

[4] The phosphorylation of proteins on tyrosine residues is an important component of intracellular signal transduction. The enzyme that can categorize this reaction is called tyrosine kinase. A large number of transmembrane receptors are tyrosine kinase. It contains an active domain and the receptor tyrosine

It is classified as a kinase (RTK).

[5] RTK is similar to cell growth, differentiation, survival and programmed cell death.

In response to binding to extracellular ligands, RTK recognizes the typically dimerized and phosphorylated form of RTK, and transmits and automatically transmits intracellular signals through interacting effectors. Induce phosphorylation. There are many members of this RTK family, one of which is RET

As a proto oncogene, it encodes the 120 kDa protein RET (a protein that rearranges during transfection). RET is a receptor for growth factors of the neuroglia-inducing propensity neuron factor (GDNF) family. The two ligands for RET are

Was sympathized; GDNF and Nutlin (NTN). RET is activated when its ligand binds to a co-receptor, and the complex then interacts with RET (Eng, 1999 Journal Clinical Oncology: 17(1) 380-393).

[6] Activation phosphorylates RET at tyrosine residues, and signal transduction for cell growth and differentiation through the RAS-RAF and PI3 kinase pathways and possibly other pathways. 2020/175968 1»（：1^1{2020/002925 Induce.

[7] RET-activating point mutants are known to cause three associated dominant inherited cancer syndromes; multiple endocrine neoplasms types 2A and 2B (MEN2A and MEN2B), and familial gonadotropin (FMTC). Yes (Santoro et al. 2004

Endocrinology: 145, 5448-5451).

[8] For almost all MEN2A and some FTMCs, extracellular and membranous proximity

Cysteine substitution occurs in the cysteine-rich domain (juxtamembrane cysteine-rich domain), whereas in 95% of MEN2B, a single point mutation occurs at codon 918 on the kinase domain (M918T). Codon 918 is believed to be located on the substrate recognition pocket in the catalytic core; mutations at this site change the structure of the active loop of the RET catalytic domain, thereby structurally activating RET. The M918T mutation is sporadic

It is also found in medullary cancer, which is related to the phenotype of progressive disease. In vitro studies have shown that mutations affect substrate specificity, indicating that RET recognizes and phosphorylates substrates preferred by non-receptor tyrosine kinases such as c-src and c-abl (Eng et al. 1996 JAMA276, 1575-1579; Ponder et al. 1999 Cancer Research 59, 1736-1741; Schilling et al. 2001 International Journal of

Cancer 95, 62-66; Santoro et al. 1995 Science 267, 381-383; Zhou et al. 1995

Nature 273, 536-539).

[9] As mutations in the RET gene are identified in most of the MEN2 family, molecular diagnostic tests become possible and may be useful for clinical diagnosis confirmation. The RET mutation test can be performed using a protocol based on the polymerase chain reaction, where the target axon sequence is amplified for direct sequencing or restriction endonuclease digestion. (Zhong et al. 2006 Clinica Chimica Acta 364, 205-208).

[1] Another member of this RTK family is vascular endothelial growth factor receptor 2 (VEGFR2 (kinase insertion domain containing receptor, KDR (also referred to as Flkl))). VEGFR2 is a receptor for vascular endothelial growth factor (VEGF). VEGF is used for both normal angiogenesis and disease-related angiogenesis (Jakeman, et al. 1993 Endocrinology 133, 848-859; Kolch, et al. 1995 Breast Cancer Research and Treatment 36, 139-155) and vascularization.

It is considered to be an important stimulant of permeability (Connolly, et al. 1989 J. Biol. Chem264, 20017-20024). The antagonism of VEGF action by isolation of antibody and VEGF can inhibit tumor growth (Kim, et al. al. 1993 Nature 362, 841-844). Heterotypic disruption of the VEGF gene causes fatal defects in vascularisation (Carmeliet, et al. 1996 Nature 380435-439; Ferrara, et al. 1996 Nature 380439-442).

[11] The binding of VEGF to VEGFR2 induces receptor dimerisation, resulting in the autophosphorylation of VEGFR2 of specific intracellular tyrosine residues. Autophosphorylation increases the catalytic activity of tyrosine kinase, and phospholipase CY and Same cytoplasm 2020/175968 1»（：1^1{2020/002925 Provides a potential docking site for signaling. This protein interaction is responsible for the proliferation, survival and migration of VEGFR2, e.g. endothelial cells. It mediates intracellular signaling, which is essential to induce a cellular response to response (Ryan et al. 2005 British Journal Cancer: 92(Suppl.l) S6-S13).

[12] Recognition of the important role of VEGF-mediated VEGFR2 signaling in pathologic angiogenesis has led to the development of a variety of selective approaches to inhibit VEGFR2 activation, including small molecule ATP-competitive tyrosine kinase inhibitors, which are ATP. In binding inhibition, automatic phosphorylation and continuous intracellular signal transduction do not occur (Ryan, 2005).

[13] VEGF receptors Quinazoline derivatives, which are inhibitors of tyrosine kinase, are described in International Patent Publication Nos. W098/13354 and WO01/32651.

In W098/13354 and WO01/32651, compounds that have some activity against endothelial growth factor receptor (EGFR) tyrosine kinase and have activity against VEGF receptor tyrosine kinase are disclosed.

[14] VEGFR2 tyrosine kinase inhibitor, compound

4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline has been disclosed (Wedge et al., 2002 Cancer Research 62 , 4645-4655). This compound is also known as Zactima (registered trademark), which has the code number ZD6474 and the generic brand name Vandetanib. Hereinafter, the compound is referred to as vandetanib.

[15] Vandetanib was developed as a potent and reversible inhibitor of ATP-binding to VEGFR2 tyrosine kinase. Bandetanib also inhibits EGFR tyrosine kinase activity. The EGFR signaling pathway is also an important factor in the progression of cancer where abnormal EGFR activity increases tumor cell proliferation, survival and invasion, as well as VEGF overexpression. Inhibition of EGFR signaling has been shown to induce selective apoptosis in tumor endothelial cells.

[16] In 2002, vandetanib was a potent agent of ligand-dependent RET tyrosine kinase activity.

As an inhibitor, it has been reported that it can inhibit the signaling and transformation ability of RET. In addition, it has been reported that vandetanib has a strong growth inhibitory effect on RET-dependent thyroid tumor cell growth in vitro (Carlomagno et al. 2002 Cancer Research: 62, 7284-7290).

[17] Vandetanib also inhibited most of the mutated active forms of RET and wild-type receptors. Therefore, inhibition of VEGFR2 and EGFR tyrosine kinase, as well as inhibition of RET tyrosine kinase by vandetanib, may confer additional anti-tumor effects in tumor treatment, which is accompanied by mutations in the RET gene that induce RET-dependent tumor cell growth. May be (Ryan, 2005).

Detailed description of the invention

Technical task 2020/175968 1»（：1^1{2020/002925

[18] An object of the present invention is to provide a heteroaryl derivative or isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof containing N.

[19] Another object of the present invention is to provide an N-containing heteroaryl derivative or isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

It is to provide a pharmaceutical composition for the prevention or treatment of cancer containing as an active ingredient.

[2] Another object of the present invention is a heteroaryl derivative containing N or

It is to provide a method for preventing or treating cancer comprising an isomer, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[21] Another object of the present invention is to manufacture pharmaceuticals for the prevention or treatment of cancer.

To provide the use of a heteroaryl derivative or an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof comprising the above for use.

Problem solving means

[22] To achieve the above objectives,

[23] According to one aspect of the present invention, a compound represented by Formula 1 below, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is provided:

[26] (In Formula 1,

[27] Ano, _ ₆ haloalkyl, linear or branched _ ₆ alkyl, or (: is _3-7 kill;

[28] selected from the group consisting of _5-6 aromatic rings or 0 and 8

It represents an aromatic heterocycle of 5 to 6 atoms containing at least one heteroatom at least one, in which case, the heteroaromatic ring may be substituted with at least one linear or branched (: alkyl;

[29] is hydrogen or alkoxy in a linear or branched chain (:);

[3 is II ³ is hydrogen or alkyl of linear or branched (:;

[31] II ⁴ is hydrogen, straight or branched (: alkoxy or consisting of 0 and 3

5 to containing at least one heteroatom selected from the group 2020/175968 1»（：1^1{2020/002925

6-membered heteroaryl, wherein the heteroaryl may be substituted with one or more substituents selected from the group consisting of halogen or straight or branched Q_ ₆ alkyl; And

[32] B ¹ and B ² are independently N or CH).

[33] According to another aspect of the present invention, a compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof

Provides a pharmaceutical composition for preventing or treating cancer containing as an active ingredient.

[34] According to another aspect of the present invention, a compound represented by Formula 1 above, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof

It provides a method for preventing or treating cancer, including administering a pharmaceutical composition containing an active ingredient to a subject in need.

[35] According to another aspect of the present invention, for use in the prevention or treatment of cancer

Provides a use of a compound represented by Formula 1 above, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament.

Effects of the Invention

[36] The compound represented by Formula 1 according to the present invention is used in various protein kinases.

It exhibits high inhibitory activity against cancer, especially, has excellent inhibitory ability to inhibit RET (ret proto-oncogene) enzyme, and has excellent inhibitory effect on the proliferation of thyroid cancer cells and lung cancer cells that express RET fusion genes. It can be usefully used in the treatment of cancer or lung cancer, and in particular, it can be usefully used in the treatment of cancer in which the RET fusion gene is expressed.

Best mode for carrying out the invention

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

[38] On the other hand, embodiments of the present invention may be modified into various other forms,

The scope of the invention is not limited to the embodiments described below. Further, the embodiments of the present invention are provided in order to more fully explain the present invention to those who have average knowledge in the relevant technical field. To "contain" a component in its entirety means that there is no specific contrary statement.

It does not mean that components can be excluded, but other components can be included.

[39] In this specification, “halogen” may be F, Cl, Br, or I.

[4 In this specification, "haloalkyl" may mean straight or branched chain alkyl (hydrocarbons) having carbon atoms substituted with one or more halogen atoms as defined herein. Examples of haloalkyls include one or more halogens. Atoms include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and -butyl independently substituted with F, Cl, Br, I. 2020/175968 1»（：1^1{2020/002925

[41] In this specification, "alkyl" may refer to a linear or branched acyclic saturated hydrocarbon of carbon atoms. Typical-(Valkyl) is -methyl, -ethyl, #propyl, -butyl, -pentyl. And--nuclear,--heptyl and--octyl; branched chain saturated alkyl is -isopropyl, -secondary () -butyl, -isobutyl, -tertiary) -butyl,

-Isopentyl, 2 -methylpentyl, 3 -methylpentyl, 4 -methylpentyl, 2, 3 -dimethylbutyl, etc. may be included. -. (V alkyl) may be unsubstituted doelsudo substituted e.g., _ ₈ alkyl group may be substituted by phenyl and achieve the benzyl group.

[42] In this specification, "cycloalkyl" may mean a non-aromatic saturated or unsaturated carbon ring. Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclonuxyl, cyclohexanyl, and

1 ,3 -cyclohexadienyl, 1 ,4 -cyclohexadienyl,cycloheptyl,

1,3-cycloheptadienyl, 1,3, 5-cycloheptatrienyl, cyclooctyl and cyclooctadienyl are included, but are not limited to.

The cycloalkyl group may or may not be substituted. In one embodiment, this cycloalkyl group may be (: _3-8 cycloalkyl groups).

[43] In the present specification, "aryl" may mean any functional group or substituent derived by the removal of one hydrogen from an aromatic hydrocarbon ring. The aryl group may be a monocyclic aryl group or a polycyclic aryl group. The number of cyclic carbon atoms may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of aryl groups include phenyl group, naphthyl group, fluorenyl group, anthracenyl group, phenanthryl group, biphenyl group, terphenyl group, quarter Phenyl group, quincphenyl group, sexyphenyl group, triphenylene group, pyrenyl group, benzofluoranthenyl group, chrysenyl group, etc. can be exemplified, but are not limited thereto.

[44] In the present specification, "heteroaryl" is a heterogeneous element, wherein one or more of 0, I ⁵ , and 3

The number of carbon atoms forming a ring of the heteroaryl group may be 2 or more and 30 or 2 or more and 20 or less. Heteroaryl may be monocyclic heteroaryl or polycyclic heteroaryl. Polycyclic heteroaryl, for example , May have a bicyclic or tricyclic structure. Examples of heteroaryl include thienyl, thiophene, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, oxa Diazolyl, triazolyl, pyridinyl, bipyridyl, pyrimidyl, triazinyl, triazolyl, acridyl group, pyridazinyl group, pyrazinyl, quinolinyl, quinazoline, quinoxalinyl, phenoxazyl, Phtharazinyl, pyrimidinyl, pyridopyrimidinyl, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole,

Imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl,

Pyrazolopyrimidinyl, imidazopyrazinyl or pyrazolopyridinyl, aryl carbazole, heteroaryl carbazole, alkyl carbazole group, benzoxazole, benzoimidazole,

Benzothiazole, benzocarbazole, benzothiophene, dibenzothiophenyl,

Thienothiophene, benzofuranyl, phenanthroline, isoxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, tetrazolyl, phenothiazinyl, 2020/175968 1» (: 1^1{2020/002925 dibenzosilol and dibenzofuranyl, etc.), but are not limited thereto. In one embodiment of the present invention, the heteroaryl is also fused to a heterocycloalkyl ring. Bicyclic heterocyclo-aryl including heteroaryl fused to an aryl ring or a cycloalkyl ring.

[45] One aspect of the present invention provides a compound represented by Formula 1 below, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[46] [Formula 1]

[48] (In Formula 1,

[49] ano, ₆ haloalkyl, straight or branched (: alkyl or (: „

Kill;

[5 is selected from the group consisting of _5-6 aromatic rings or 0 and 8

It is a 5 to 6 membered aromatic heteroring containing one or more one or more heteroatoms, in which case, the heteroaromatic ring may be substituted with one or more straight or branched _ ₆ alkyl;

[51] II ² is hydrogen or linear or branched (: alkoxy within;

[52] II ³ is hydrogen or alkyl of linear or branched (:;

[53] is hydrogen, straight-chain or branched (: in alkoxy or consisting of 0 and 3

5 to containing at least one heteroatom selected from the group

6-membered heteroaryl, wherein the heteroaryl may be substituted with one or more substituents selected from the group consisting of halogen or straight or branched 0 alkyl; And

이다). [54] and: independently

to be).

[55]

If it is alkyl and X ^I or X ⁴ is 0 or 3, it may not be present. 2020/175968 1»（：1^1{2020/002925

[56] Specifically, the is hydrogen, methoxy, pyrazolyl, thiazolyl or

Isoxazolyl, and the pyrazolyl, thiazolyl and isoxazolyl are at least one substituent selected from the group consisting of halogen and straight chain alkyl of _ ₃

[57] In another embodiment of the present invention, in the compound represented by Formula 1,

[58] gasiano, _ ₆ haloalkyl, straight chain _ ₆ alkyl or (： _3-7 of

Cycloalkyl;

Does not exist;

[6 is II ² is hydrogen or linear (: _{1 6} alkoxy;

[61] is hydrogen or linear (: _{1 6} alkyl;

[62] element ⁴ is a 5 atom containing one or more hydrogen, one or more heteroatoms selected from the group consisting of linear (: alkoxy or 0 and 3)

이루어지는 군으로부터선택되는치환기로하나이상치환될수있고;및 Heteroaryl, and the heteroaryl is halogen

One or more may be substituted with a substituent selected from the group consisting of; and

[63] and: can independently be N or.

[64] In another embodiment of the present invention, in the compound represented by Formula 1,

[65] silver cyano, ₃ haloalkyl, straight chain _ ₃ alkyl or (: _3-6

Cycloalkyl; 2020/175968 1»(：1/10公020/002925

, (¾ ⁵ or is, wherein XI or

^-4

X ⁴ is 0 or 3, and X ² or X ³ is or N, and ⁵ or ⁶ of yo are, respectively, when X ¹ or X ⁴ is N, straight-chain _ ₃ alkyl, X ¹ or X ⁴ is When 0 or 3, it does not exist;

67; II ² is hydrogen or straight-chain _ ₃ alkoxy;

68; is hydrogen or a straight chain of ₃ _ alkyl;

69; is hydrogen, methoxy, pyrazolyl, thiazolyl or isoxazolyl, and the pyrazolyl, thiazolyl and isoxazolyl is one or more substituted with a substituent selected from the group consisting of halogen and linear _ ₃ alkyl Can be; and

And can independently be N or (：!!

In another embodiment of the present invention, in the compound represented by Formula 1, is cyano, trifluoromethyl, linear _ ₃ alkyl or (: _3-5 cycloalkyl;

[73] ，, 資 5 or, wherein XI or

.4

X ⁴ is 0 or 3, the X ² or silver or N, the ^ or yo ⁶ is methyl, when X ¹ or X ⁴ is N, respectively, and when X ¹ or X ⁴ is 0 or 3, there is no ;

II ² is hydrogen or straight chain _ ₃ alkoxy;

]]]]]]

402561 is hydrogen or linear _ ₃ alkyl;

777 777 661

Is hydrogen, methoxy,, ^| ） ^| =\ -，or

0, 此; and

77] and can independently be N or (：!!

78] In another embodiment of the present invention, in the compound represented by Formula 1,

79] is cyano, trifluoromethyl, methyl or (: _3-4 cycloalkyl;

2020/175968 1»（：1/10公020/002925 이고 80]

2020/175968 1»（：1/10公020/002925 and

Yo ² is hydrogen or methoxy;

Is hydrogen or methyl;

Is hydrogen, methoxy, or

0, ``shadow'' and ``mi''

84] and can independently be N or (：!!

85] In another embodiment of the present invention, in the compound represented by Formula 1,

86] is (： _3-4 cycloalkyl,

87]

Is a straight-chain _ ₃ alkoxy, specifically methoxy;

I ³ is the _ ₃ alkyl of straight chain, specifically euroneun methyl;

]]]

29038 1

9 98888861 is pyrazolyl substituted with halogen, specifically pyrazolyl substituted with fluoro, more specifically, \;

[91] is N or (:!!; and

[92] can be N.

[93] In another embodiment of the present invention, in the compound represented by Formula 1,

[94] isiano, in the case of trifluoromethyl,

[95] Ego

Is a straight-chain (: alkoxy, specifically _ ₃ alkoxy, more specifically methoxy;

[97] II ³ is a straight-chain (: alkyl, specifically _ ₃ alkyl, more specifically 2020/175968 1» (: 1^1{2020/002925 methyl;

[98] is pyrazolyl substituted with halogen, specifically

Pyrazolyl, more specifically

[99] is (：!!; and

[100] can be N.

[101] Examples of the compounds represented by Chemical Formula 1 according to the present invention include Example Compounds 1 to 51 listed in [Table 1] to [Table 5] described below, or their pharmaceutically

Acceptable salts are:

[102] Butyl butyl butyl butyl butyl

[103] The compound represented by the above formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed by a pharmaceutically acceptable free acid (6^) is useful. Inorganic acids such as silver hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylate, phenyl-substituted alkanoate, hydroxy alkanoate and alkanedioate, aromatic It is obtained from non-toxic organic acids such as acids, aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, and the like. Types of pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide. , Fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, Sebacate, fumarate, maleate, butin-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,

Hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,

(3-hydroxybutyrate, glycolate, malate, tartrate,

Methanesulfonate, propanesulfonate, naphthalene-1 -sulfonate,

Naphthalene-2-sulfonate, mandelate, etc. are included.

[104] The acid addition salt according to the present invention can be prepared by conventional methods, for example

The derivative of Formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., and the precipitate produced by adding an organic acid or an inorganic acid is filtered and dried, or the solvent and excess acid are distilled under reduced pressure and then dried. 2020/175968 1»（：1^1{2020/002925 Can be produced by crystallization in organic solvent.

[105] In addition, bases can be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts, for example, dissolve the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, and use insoluble compound salts.

It is obtained by filtration, evaporation, and drying of the filtrate. In this case, it is pharmaceutically suitable to prepare sodium, potassium or calcium salts as metal salts. In addition, the corresponding salts are alkali metal or alkaline earth metal salts as appropriate salts (e.g. silver nitrate ) And obtained by reacting.

[106] Further, the present invention is a compound represented by Chemical Formula 1 and a pharmaceutical thereof

In addition to acceptable salts, solvates, optical isomers, and hydrates that may be prepared therefrom are included.

[107] The term "hydrate" refers to a non-covalent intermolecular force.

stoichiometric combined by force) or

It refers to a compound of the present invention or a salt thereof containing a non-stoichiometric amount of water. The hydrate of the compound represented by Formula 1 above of the present invention is a stoichiometric quantity that is bound by force between non-covalent molecules. It may contain a stoichiometric or non-stoichiometric amount of water. The hydrate may contain at least 1 equivalent, preferably, from 1 to 5 equivalents of water. Such hydrates may contain water or water containing water.

It can be prepared by crystallizing the compound represented by the above formula 1 of the present invention from a solvent, isomers thereof, or pharmaceutically acceptable salts thereof.

"Solvate" means a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor include volatile, non-stoichiometric solvents. There are toxic, and/or suitable solvents for administration to humans. The term “isomer” refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but differs structurally or stereoscopically. Such isomers are tautomers. Structural isomers such as tautomers, stereoisomers such as R or S isomers, geometric isomers (trans, cis) and optical isomers with an asymmetric carbon center are all included. All of these isomers and mixtures thereof It is also included in the scope of the present invention.

[108] Another aspect of the present invention, as shown in Scheme A below,

[109] By reacting a compound represented by Formula 2 with a compound represented by Formula 3

Preparing a compound represented by Chemical Formula 4 (step 1);

[110] By reducing the compound represented by the formula (4), the compound represented by the formula (5)

Manufacturing step (step 2);

[111] By reacting a compound represented by Chemical Formula 5 with a compound represented by Chemical Formula 6

Preparing a compound of formula 7 (step 3); and

[112] It provides a method for producing a compound of Formula 1, including the step of removing the protecting group of the compound represented by Formula 7 (step 4).

[113] [Scheme A] 2020/175968 1»（：1/10公020/002925

[114]

[115] Scheme above

화학식 1에서정의한바와같고; [116] 0|,, John ² ,

As defined in Formula 1;

[117] X is a halogen used as a protecting agent

11）년1'（¾）） 11）을나타낸다. Tetrahydro

11) Year 1'(¾)) 11).

[118] Step 1 is the halogen of the compound represented by Chemical Formula 2 and

This is a step of producing a compound represented by Formula 4 in which a carbon-carbon bond (15011 (1) is formed by reacting the organic boron of the compound), and is not limited as long as it is a condition in which a carbon-carbon bond is formed by reacting halogen and organic boron. In the present invention, the reaction was carried out under the same conditions as in Example 1, but this is only an example, and is not limited thereto.

[119] Step 2 is a step of reducing the ester to a carboxylic acid by converting the double bond of the compound represented by Formula 4 into a single bond, and a reduction method widely known in the art can be used.

[120] Step 3 is a step of preparing a compound represented by Formula 7 including an amide bond by reacting a carboxyl group of the compound represented by Formula 5 with an amino group of the compound represented by Formula 6, wherein the amino group and the carboxyl group The reaction can use methods well known in the art.

[121] Step 4 is a step of deprotecting the amine protecting group of the compound represented by Chemical Formula 7 in the reaction formula to prepare the compound of Chemical Formula 1. The condition is not limited as long as the amine protecting group can be removed, and a method widely known to those skilled in the art can be used. have. In the present invention, the reaction was carried out under the same conditions as in Example 1, but this is only an example, and is not limited thereto.

[122] Another aspect of the present invention is as shown in the following reaction equation:

[123] A step of preparing a compound represented by Formula 9 by reacting a compound represented by Formula 2 with a compound represented by Formula 8 ( _£ ? One);

[124] The compound represented by the chemical formula by reducing the compound represented by the formula (9) 2020/175968 1»（：1/10公020/002925 Manufacturing step (step 2);

[125] Step of preparing a compound represented by Formula 11 by reacting a compound represented by Formula W with a compound represented by Formula 6 (6 to 3); And

[126] It provides a method for producing a compound of Formula 1, including the step of removing the protecting group of the compound represented by Formula 11 (step 4).

[127] [Scheme B]

[128]

In the above reaction formula: 6,

[129] As defined in Formula 1;

[13 is X is halogen, 11

It represents a tetra _{hydro-pyran-11)} in 1 _(¾)) 11).

[131] Step 1 is a halogen of a compound represented by Formula 2 and a compound represented by Formula 8

This is a step of preparing a compound represented by Chemical Formula 9 in which a carbon-amine bond (15011(1) is formed by reacting the amine of the compound, and it is not limited as long as it is a condition to make a carbon-amine bond by reacting a halogen and an amine, and it is widely used by those skilled in the art. A known method can be used. In the present invention, the reaction was carried out under the same conditions as in Example 27, but this is only an example, and is not limited thereto.

[132] Step 2 is a step of reducing the ester of the compound represented by Formula 9 to a carboxylic acid, and a reduction method widely known in the art may be used.

[133] Step 3 is a step of preparing a compound represented by Formula 11 including an amide bond by reacting a carboxyl group of a compound represented by the formula and an amino group of the compound represented by Formula 6, wherein the reaction of the amino group and the carboxyl group Can use methods well known in the art.

[134] Step 4 is a step of preparing a compound of Formula 1 by deprotecting the amine protecting group of the compound represented by Formula 11 in the reaction formula, and is not limited as long as the conditions for removing the amine protecting group, and methods widely known to those skilled in the art can be used. have. In the present invention, the reaction was carried out under the same conditions as in Example 27, but this is an example. 2020/175968 1»（：1^1{2020/002925, but it is not limited to this.

[135] Each compound represented by Chemical Formula 1 according to the present invention can be manufactured according to the manufacturing method shown in the following examples, but this is only an example, and is not limited thereto, and each manufacturing step can be performed using a method widely known to those skilled in the art. Can

[136] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer comprising a compound represented by Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[137] The compounds are AMPK-alphal, AMPK-alpha2, ARK5, AURKA, AURKB, AURKC, AXL, BLK, CSF1R, CSNK2A2, DAPK1, DAPK3, EPHB6, FGFR1, FGFR2, FGFR3, FGFR3 (G697C) , FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q ), FLT4, GCN2, HCK, JAK1, JAK2, JAK3, KIT, KIT(A829P),

KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I),

KIT(V559D,V654A), LCK, MAP3K2, MEK5, MERTK, MLK2, MLK3, NEK7, NEK9, PDGFRA, PDGFRB, PLK4, PYK2, RET, RET(M918T), RET(V804L), RET(V804M), RIOK3, It can exhibit inhibitory activity against one or more protein kinases selected from the group consisting of ROS1, RSK2, RSK3, SLK, SNARK, SRC, STK16, SYK, TIE1, TNK1, TNK2, TRKA, TRKB, TRKC, TYK2, YES, and YSK4. have.

[138] In addition, the compound may exhibit RET (ret proto-oncogene) enzyme inhibitory activity.

[139] The cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer,

Medullary thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, mycosis fungoides, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell cancer, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer ,Pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinal blastoma, choroidal melanoma, barter bulge cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, arsenic Cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma,

Pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal cow cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, Urethral cancer, primary cancer, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal interstitial cancer, Wilms cancer, breast cancer, sarcoma, penis cancer, pharyngeal cancer, pregnancy chorionic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, Metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal carcinoma, auditory nerve sheath, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer,

It may be one or more selected from the group consisting of lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.

In addition, the cancer may be a cancer that expresses the RET fusion gene.

[141] The compound represented by Formula 1 according to the present invention is used in various protein kinases. 2020/175968 1»（：1^1{2020/002925 shows high inhibitory activity (refer to Experimental Example 1), in particular, RET (ret proto-oncogene) enzyme inhibitory activity is excellent (refer to Experimental Example 2), RET fusion gene Expressing

Since the proliferation inhibitory effect of thyroid cancer cells and lung cancer cells is excellent (refer to Experimental Example 3), it can be usefully used in the treatment of cancer, for example, thyroid cancer or lung cancer, and in particular, treatment of cancer in which the RET fusion gene is expressed. It can be usefully used for

[142] In the pharmaceutical composition according to the present invention, represented by the above formula 1

The compound or its pharmaceutically acceptable salt may be administered in various oral and parenteral formulations at the time of clinical administration, but more preferably may be parenteral formulations. In the case of formulations, commonly used intermediate agents, extenders, and binders It is prepared using diluents or excipients such as, wetting agents, disintegrants, surfactants, etc. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc.

Solid preparations are prepared by mixing one or more compounds with at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also prepared. Liquid preparations for oral administration include suspensions, solution solutions, emulsions, syrups, etc., which are commonly used simple diluents, liquid paraffin, and various excipients, such as humectants, sweeteners, fragrances, and preservatives. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions include vegetable oils such as propylene glycol, polyethylene glycol, and olive oil, ethylol. Injectable esters such as rate can be used.

[143] The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof can be administered in various oral and parenteral formulations when administered clinically. In the case of formulation, commonly used medium-sized agents, bulking agents, binding agents, and It is prepared using diluents or excipients such as wetting agents, disintegrants, surfactants, etc. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are at least one in one or more compounds. Examples of the above excipients, starch, calcium carbonate,

It is prepared by mixing sucrose, lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. As liquid preparations for oral administration, suspensions, solution solutions, emulsions, syrups, etc. are used. In addition to the commonly used simple diluent, liquid paraffin, various excipients, for example, wetting agents, sweeteners, fragrances, and preservatives may be included.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions include vegetable oils such as propylene glycol, polyethylene glycol, olive oil, and ethyl oleate. Injectable esters, etc. may be used.

[144] A pharmaceutical composition containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is 2020/175968 1»（：1^1{2020/002925 Subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

[145] At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed in water with a stabilizer or buffer to prepare a solution or a suspension, and this The composition can be prepared in a vial unit dosage form. The composition is a pharmaceutically acceptable carrier, a sterilized and/or preservative, a stabilizer, a hydrating agent or an emulsifying agent, an adjuvant such as a salt and/or a buffer for controlling the osmotic pressure, and other therapeutic agents. It can contain useful substances and can be formulated according to the usual method of mixing, granulating or coating.

[146] Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. These formulations include diluents (eg: It contains lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). May contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases disintegrants such as starch, agar, alginic acid or its sodium salt, or It may contain boiling mixtures and/or absorbents, colorants, flavors, and sweeteners.

[147] A pharmaceutical composition for preventing or treating cancer containing a compound represented by Formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient is administered as an individual therapeutic agent or used in combination with other anticancer agents in use. Can be administered and used.

[148] Another aspect of the present invention is to provide a pharmaceutical composition containing as an active ingredient a compound represented by Chemical Formula 1, isomers thereof, solvates thereof, hydrates thereof, or pharmaceutically acceptable salts thereof. It provides a method for preventing or treating cancer comprising the step of administering.

[149] Another aspect of the present invention is in the manufacture of pharmaceuticals used for the prevention or treatment of cancer.

To provide the use of the compound represented by Chemical Formula 1 or an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use.

[15] Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

[151] However, the following examples and experimental examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following examples and experimental examples.

[152] <Medium pressure liquid chromatography for purification;

MPLC)＞

[154] For medium pressure liquid chromatography, TELEEDYNE ISCO's CombiFlash Rf +UV was used.

[154] ＜Analysis LC-MS (ACQUITY UPLC H-Class Core System) ñ 2020/175968 1»（：1^1{2020/002925

[155] Waters' UPLC system (ACQUITY UPLC PDA Detector) equipped with a Waters mass QDA Detector was used. The column used was Waters' ACQUITY UPLC®BEH C18 (1.7/ffli, 2.1X50mm), and the column temperature Was carried out at 30 °C.

[156] Mobile phase A was used in water containing 0.1% formic acid, and mobile phase B was used in acetonitrile containing 0.1% formic acid.

[157] Gradient condition (10-100% B for 3 minutes, moving speed =0.6ml/min)

[158] ＜Prep-150 LC System for purification (Preparative-Liquid chromatography UV

spectrometry)＞

[159] Waters !Prep 150 LC system (2545 Quaternary gradient module, 2998

Waters' equipment was used for Photodiode Array Detector, Fraction collector HI). The column used was Waters' XTERRA®Prep RP18 OBDä (10^in, 30X300mm) and the column temperature was carried out at room temperature.

[160] Gradient condition (3- 100% B for 120 minutes, moving speed =40ml/min)

[161] <SFC conditions for separation of chiral compounds>

[162] The 80Q Preparative SFC system manufactured by Waters was used.

DAICEL's CHIRALPAPAS GO/ffliJSOXSOmm lD), and the column temperature was carried out at room temperature. C0 ₂ as a mobile phase and methanol to which 0.1% ammonia water was added as a co-solvent was used for 130 minutes.

[163] <NMR analysis>

[164] NMR analysis was performed using AVANCEm 400 or AVANCEm 400 HD manufactured by Bruker.

The data were presented in parts per million (6) (ppm).

[165] The commercially used reagent was used without additional purification. In the present invention, room temperature refers to a temperature of about 20 25 ^O C. A rotary evaporator was used for concentration under reduced pressure or solvent distillation.

[166] <Preparation Example 1> Methyl 1-methoxy-4 (4, 4, 5, 5 tetramethyl-1,3, 2 dioxaborolan- 2-yl) cyclohex-3 -ene -1 -Manufacture of carboxylate

[167] The title compound was prepared through the method shown in Scheme 1 below.

[168] [Scheme 1]

[170] Step 1: Dissolve 1,4 -dioxapyrro [4.5] decane-8 -one (3, 1921^101) in bromoform (388 silver, 1.5411101) and cool with 0。 (: potassium hydroxide ( 86 1.5411101) methanol

Dissolve in (5001111) and slowly add dropwise to the reaction mixture for 4 hours. After stirring at 25。 (:) for 12 hours, add water (5001111) to the reaction mixture and concentrate the organic solvent under reduced pressure. 2020/175968 1»（：1^1{2020/002925 The organic layer was combined by extraction with ethyl acetate and salt water.

After drying with sodium sulfate, decompression and concentration

Purified by medium pressure liquid chromatography (ethyl acetate /n-hexene) to obtain a liquid methyl 8 -methoxy-1,4 -dioxapyrro [4.5] decane-8 -carboxylate (28g, 47%).

Obtained.

[171] >H NMR (400 MHz, CDC1 ₃ ) d = 3.97 (t, / = 2.8Hz, 4H), 3.76 (s, 3H), 3.27 (s, 3H), 2.05-2.00 (m, 4H), 1.88-1.80 (m, 2H), 1.67-1.63 (m, 2H)

[172] Step 2: Methyl 8 -methoxy-1,4 -dioxapyrro [4.5] decane-8 -carboxylate (28g,

121mmol) was dissolved in 1,4-dioxane (300ml), and then 6M HC1 (260ml) was added and stirred at room temperature for 6 hours. Cold water was added to the reaction mixture, followed by extraction with ethyl acetate and salt water to combine the organic layer. .Organic layer

After drying with sodium sulfate, it is concentrated under reduced pressure to

1-methoxy-4 -oxocyclohexene- 1-carboxylate (18.6g, 100mmol, 82%) was obtained.

[173]'H NMR (400 MHz, CDC1 ₃ ) d = 3.73 (s, 3H), 3.30 (s, 3H), 2.57-2.46 (m, 2H), 2.30

-2.21 (m, 4H), 2.13-2.05 (m, 2H)

[174] Step 3: Pyridine (3.74g, 47mmol) was diluted in toluene (100ml) and Tf ₂ 0 (14.5g,

51mmol) is diluted in toluene (10ml) and slowly added dropwise at room temperature, and methyl 1-methoxy- 4-oxocyclohexane- 1-carboxylate (8g, 43mmol) is slowly added dropwise and stirred at 40°C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by medium pressure liquid chromatography (ethyl acetate /n-hexene), and the liquid methyl 1-methoxy -4-(((trifluoromethyl)sulfonyl)oxy)cyclohex -3 -N-1-carboxylate (3.2g, 23%) was obtained.

[175]'H NMR (400 MHz, CDC1 ₃ ) d = 5.68 (m, 1H), 3.80 (s, 3H), 3.32-3.26 (s, 3H), 2.75

-2.65 (m, 1H), 2.62-2.48 (m, 2H), 2.41-2.31 (m, 1H), 2.26-2.08 (m, 2H)

[176] Step 4: methyl

1-methoxy -4-(((trifluoromethyl)sulfonyl)oxy)cyclohex- 3 -ene -1-carboxylate (2.6g, 8.17mmol) and

4, 4, 5, 5 -tetramethyl- 2-(4, 4, 5, 5 -tetramethyl- 1,3, 2 -dioxaborolan- 2 -yl)- 1,3, 2 -dioxabo Lorraine (2.49g, 9.8mmol), KOAc (3.2g, 32.7mmol), Pd(dppf)Cl ₂ . CH ₂ C1 ₂ (1.33g, 1.63mmol) was dissolved in 1,4-dioxane (80ml) and stirred at 90°C for 1 hour. The reaction mixture was filtered through Celite and concentrated under reduced pressure.

Liquid methyl 1 -methoxy-4-(4, 4, 5, 5 -tetramethyl-1 ,3, 2 -dioxaborolane-purified by medium pressure liquid chromatography (tetrahydrofuran/n-hexene) 2-yl)cyclohex- 3-ene- 1-carboxylate (2.4g, 8.1mmol) was obtained.

[177]'H NMR (400 MHz, CDC1 ₃ ) d = 6.46 (m, 1H), 3.77 (s, 3H), 3.28 (s, 3H), 2.66-2.57 (m, 1H), 2.42-2.34 (m , 1H), 2.33-2.18 (m, 2H), 2.09-2.01 (m, 1H), 1.98-1.88 (m, 1H) 2020/175968 1»（：1^1{2020/002925

[178] <Preparation Example 2> Preparation of (5)- 1-(6-(4 -fluoro-1 -pyrazole-1 -yl)pyridine-3 -yl)ethane-1 -amine

[179] The title compound was prepared through the method shown in Scheme 2 below.

[180] [Scheme 2]

[181]

[182]

65511111101) was dissolved in DMF (3(X)1111), 4 -fluoro-1 -pyrazole (28 silver, 22811111101) was added and stirred for 16 hours at 100° (:). The reaction mixture was put in water (1¾) and solidified. To precipitate. Filtrate to

1-(6-(4-fluoro-in-pyrazol-1 -yl)pyridin- 3 -yl)ethane-1 -one (37.4 83%) was obtained.

[183] MS (!1): 206.13 +1] ⁺ , 1界1乂: ^ I (111111): 1.47

[184] Step 2: 1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethane-1 -one (32

15511111101) and ()- (+)-2 -methyl- 2 -propanesulfinamide (64 53011111101) was dissolved in toluene (6401111), and then 11 (0¾) ₄ (213 is 93511111101) was added and then 110° (at: The reaction mixture was stirred for 16 hours. Water (801 sine) was added to the reaction mixture, and the organic layer was combined by extraction with ethyl acetate and salt water. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate / hexane). And the solid (及,及)- -(1-(6-(4 -fluoro- 1好

-Pyrazol-1 -yl)pyridine-3 -yl)ethylidine)-2 -methylpropane-2 -sulfinamide (3,

53%).

[185] MS (!1): 309.14 +1] ⁺ , 1界1乂: ^ I知如): 1.55

8.43 ((1(1, / = 4.6, 0.6 [186] ¾ NMR (400 MHz, 0)0 ₃ ) 5 = 8.88 ((!, / = 2.0

8.43 ((1(1, / = 4.6, 0.6

, , , , , 1¾, 7.65-7.64

,,,,,

[187] Step 3: (及,及 )- -(1-(6-(4 -fluoro- monoacid

-Pyrazole-1 -yl)pyridine-3 -yl)ethylidine)-2 -methylpropane-2 -sulfinamide (3, 1(X)11111101) in tetrahydrofuran (10001111) : To cool

-8 new% 出 (no (1 301.5811止) was slowly added dropwise for 30 minutes. After stirring for 1 hour at -78°(:), methanol and water were added to terminate the reaction. Then, the reaction was terminated with ethyl acetate and brine, and the organic layer was extracted. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/hexein) to obtain a solid ()- -( )- 1-(6-(4 -fluoro-1 acid). 2020/175968 1»(：1^1{2020/002925

-Pyrazole-1 -yl)pyridine-3 -yl)ethyl)-2 -methylpropane-2 -sulfinamide (24.4 75%) was obtained.

[188] MS (!1): 311.21 +1] ⁺ , 1界1乂: ^ I (111111): 1.46

8.44 ((!, / = 2.0 [189] ¾ NMR (400 MHz, 0)0 ₃ ) 3 = 8.69-8.68 ((1(1, / = 4.4, 0.4

8.44 ((!, / = 2.0

1¾, 7.90-(!, / = 6.8

[190] Step 4: (及 )- -( )- 1-(6-(4 -fluoro- 1好

-Pyrazolyl)pyridine-3 -yl)ethyl)-2 -methylpropane-2 -sulfinamide (22.8

7311111101) in 1,4-dioxane (2001111), methanol () and 4M

11 (: 1/1,4-Dioxane (1801111) was added and stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure, added dropwise to ethyl ether (1001111), and filtered to obtain a solid (5

)- 1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethane-1 -amine (17, 67.811111101) was obtained.

[191] MS (11): 208.21 ^+1]÷, 111 ⁵ 1乂: ^ I知如): 0.76

[192] ¾ NMR (400 MHz, DMSO-d ₆ ) 3 = 8.72-8.69 (4¾, 8.61-8.60 ((!, / = 2.4

1¾, 8.19-8.17 (111, 1¾, 7.97-7.96 (1¾, 7.95 知, 1¾, 4.55 (1¾, 1.58 ((!, / = 6.8

[193] 5)-1-(6- (4 -methyl-1-pyrazole-1 -yl) pyridine-3 -yl) ethane-1-amine

[194] The title compound was prepared in a similar manner. (Yield: 40%)

[195]

[196] <Preparation Example 4> (5)-1- (6- (3,5-dimethyl-monoacid-pyrazole-1 -yl) pyridine-3 -yl) ethane-1-Preparation of amine

[197] Through the following scheme 3 in a method similar to Preparation Example 2, the title compound

Was prepared.

[198] [Scheme 3]

[199]

2020/175968 1»(：1^1{2020/002925

2020/175968 1»(：1^1{2020/002925

[200] Step 1: MS: ^ 216.1 +印十

1¾, 8.24 - 8.16[201] ¾ NMR (400 MHz, 0001 ₃ ) 5 = 8.90-8.89 ((1(1, / = 0.8, 2.4

1¾, 8.24-8.16

1¾, 7.95 - 7.89 ((¾ / = 0.4, 8.4

1¾, 5.96知, 1¾, 2.63 (山 /((¾ / = 2.4, 8.8

1¾, 7.95-7.89 ((¾ / = 0.4, 8.4

1¾, 5.96知, 1¾, 2.63 (山 /

= 0.8, 2.59-2.53 (3¾, 2.23知, 3¾

: m/z 319.3 [M+H]十 Step [202]

: m/z 319.3 [M+H]十

1¾, 8.40 - 8.37 ((¾ /[203] ¾ NMR (400 MHz, DMSO-d ₆ ) 5 = 8.93-8.92 (山 / = 4.0

1¾, 8.40-8.37 ((¾ /

1¾, 7.94 - 7.91 ((!, / = 12.0

1¾, 6.17知, 1¾, 2.76知, 3¾, 2.63知,= 2.4, 8.8

1¾, 7.94-7.91 ((!, / = 12.0

1¾, 6.17知, 1¾, 2.76知, 3¾, 2.63知,

3¾, 2.21知, 3¾, 1.23知, 911)

[204] Step 3: MS: m/z 321.3 [M+H]

7.90 ((1(1, / = 2.4, 8.8

[205] ¾ NMR (400 MHz, 0001 ₃ ) 3 = 8.40 (山 / = 2.4

7.90 ((1(1, / = 2.4, 8.8

1¾, 6.10知, 1¾, 5.52 ((!, / = 5.6

1¾, 4.53 - 4.50 (111, 1¾, 7.76 ((!, /= 8.4

1¾, 6.10知, 1¾, 5.52 ((!, / = 5.6

1¾, 4.53-4.50 (111,

[211] Step 1: tert-butyl-[(4-bromophenyl)methyl]carbamate (2g, 6.99mmol) and thiazole (535.46mg, 6.29mmol) were dissolved in DMF (20ml) and Pd(OAc) ₂ (313.82mg, 1.40mmol) and KOAc (2.06g, 20.97mmol) were added and stirred at 90°C for 16 hours.

Water (100 ml) was added to the reaction mixture, and the organic layer was combined by extraction with ethyl acetate (100 ml*2) and salt water. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and determined by medium pressure liquid chromatography (ethyl acetate/n-hexane). Then, a yellow solid tert-butal (4-(thiazol-5-yl)benzyl)carbamate (400mg, 13.%) was obtained.

[212] MS: m/z 291.1 [M+H] +

[213]'H NMR (400 MHz, CDC1 ₃ ) d = 8.05 (s, 1H), 8.01 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.32 (d, / = 8.0 Hz, 2H), 5.00 (br s, 1H), 4.33 (d, /= 5.2 Hz, 2H), 1.46 (s, 9H)

[214] Step 2: ten-butal Aq(4 -thiazol-5 -ylphenyl)methyl]carbamate (350mg,

1.21mmol) was dissolved in 4M HC1/ethyl acetate (20 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, added dropwise to ethyl ether, and filtered to form a yellow solid (4-(thiazol-5 -yl)phenyl. ) Methanamine (310mg, crude, HC1 salt) was obtained.

[215] MS: m/z 192.1 [M+H] ⁺

[216] <Preparation Example 6> Preparation of (4-(isooxazol-4-yl)phenyl)methanamine

[217] The title compound was prepared through the method shown in Scheme 5 below.

[218] [Scheme 5] 2020/175968 1»（：1^1{2020/002925

[219]

[22 this

4-(4, 4, 5, 5 -tetramethyl-1,3, 2 -dioxaborolan-2 -yl)isoxazole (511.13mg, 2.62mmol) was dissolved in DMF (4ml) and Pd(dppf) Cl ₂ CH ₂ C1 ₂ (142.69 mg, 174.72 or mol), KF (304.53 mg, 5.24 mmol), and water (0.5 mL) were added, and at 50 C for 30 minutes

Water (20 ml) was added to the reaction mixture, and the organic layer was combined by extraction with dichloromethane (30 ml*2) and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and medium-pressure liquid chromatography (ethyl acetate /n -Hexane) to obtain a white solid ieri-butyl (4-(isooxazole-4 -yl)benzyl)carbamate (164mg, 34.22%).

[221] MS: m/z 275.2 [M+H] ⁺

[222]'H NMR (400 MHz, DMSO-d ₆ ) d = 9.40 (s, 1H), 9.13 (s, 1H), 7.63 (d, / = 8.0 Hz, 2H), 7.28 (d, / = 8.4 Hz, 2H), 4.12 (d, / = 6.0 Hz, 2H), 1.39 (s, 9H)

[223] Step 2: ten-butal (4-(isooxazole-4 -yl)benzyl)carbamate (230mg,

After dissolving in 838.45^01)1- 4M HC1/ethyl acetate (20 mL), the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, added dropwise to ethyl ether, and filtered to form a pale yellow solid (4-(isooxazole-4). -Yl)phenyl)methanamine (310mg, crude, HCl salt) was obtained.

[224] MS: 192.1 +印十

[225] <Preparation Example 7> Preparation of 3-amino-1//-pyrazole-5-carbonitrile

[226] The title compound was prepared through the method shown in Scheme 6 below.

[227] [Scheme 6]

凡 / = 45.7 Hz, 1¾, 7.04知, 1¾

[232] Step 2: 3 _-Nitro -1 -Pyrazole-5 _-Carboxamide (1 silver, 6.4 _1111110 1) was dissolved in pyridine (12 sen) and ?001 ₃ (1.2 sen) was added for 6 hours The reaction mixture was added to ice water to complete the reaction, extracted with dichloromethane, the organic layer was dried with sodium sulfate, and concentrated under reduced pressure to give a solid 3-nitro-1 acid. 2020/175968 1»（：1^1{2020/002925

-Pyrazole-5 -Carbonitril (0.7g, 79%) was obtained.

[233] UPLC V. t. (min): 0.87

[234] Step 3: 3 -nitro- 1//-pyrazole- 5 -carbonitrile (0.7g, 5mmol) acetic acid

After dissolving in (14ml) and water (3ml), zinc powder (1.6g, 25mmol) was added and stirred at room temperature for 6 hours. After the reaction mixture was filtered, water and ethyl acetate were added to the filtrate and neutralized with aqueous ammonia to form an organic layer. Extracted. The organic layer was

After drying with sodium sulfate, it is concentrated under reduced pressure.

-Pyrazole-5 -Carbonitril (80mg, 14%) was obtained.

[235] MS (m/z): 109.03 [M+l] ⁺ , UPLC rt (min): 0.33

[236] <Preparation Example 8> of methyl 4-(4, 4, 5, 5 -tetramethyl-1,3, 2 -dioxaborolan-2 -yl)cyclohex-3 -ene-1-carboxylate Produce

[237] The title compound was prepared through the method shown in Scheme 7 below.

[238] [Scheme 7]

[239]

[24 Step 1: Methyl 4-oxocyclonucleic acid carboxylate (2 12.8111111101) and 1) Table ¾ show

(8.9211^, 51.2211111101) is dissolved in toluene (41 new) and heated at 451 for 30 minutes. To this mixture, 1^0 (8.45!1止, 51.2211111101) was diluted in dichloromethane () and diluted at 45° (: Add 1N^1 (6011^) and MTBE (6011止*2) to the reaction mixture for 10 minutes to extract, and wash the combined organic layer with water (5011止) and salt water (5011止). After drying the organic layer with sodium sulfate, it is concentrated under reduced pressure to

4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (2.5 67.73%) was obtained.

[241] ¾ NMR (400 MHz, 0001 ₃ ) 3 = 5.82-5.74 (1¾, 2.67-2.57 (1¾, 2.51-2.38 知!, 4¾, 2.21-2.10 (111, 1¾, 1.99-1.87 (1¾, 1.37 -) 1.19知!, 1¾

[242] Step 2: methyl

4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (1.5 5.2011111101) and

4, 4, 5, 5 -tetramethyl- 2-(4, 4, 5, 5 -tetramethyl- 1,3, 2 -dioxaborolan- 2 -yl)- 1,3, 2 -dioxabo Lorraine (1.45 is, 5.721^01), 0 (2.04 20.8211111101), Mo (1((¾¾))(：1 ₂ .(：¾(¾ (424.9811¾, 520.40na 11101)) is 1,4 -dioxane (20 After dissolving in sen), the mixture was stirred at 90° for 14 hours.

Yellow liquid was purified by medium pressure liquid chromatography (ethyl acetate / hexein). 2020/175968 1»（：1^1{2020/002925 methyl

4-(4, 4, 5, 5 -tetramethyl-1,3, 2 -dioxaborolan- 2 -yl) cyclohex- 3 -ene-1 -carboxylate (0, 40.6%) was obtained. .

[243] <Preparation Example 9> (thin (1-(6-(4 -fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-4 -methoxy piperidine-4- Preparation of carboxamide dihydrochloride

The title compound was prepared by the method shown in Equation 8.

]

It is dissolved in methanol (1501 shin) and slowly added dropwise to the reaction mixture for 4 hours. After stirring for 12 hours at 25° (:), water (5001111) was added to the reaction mixture, and the organic solvent was concentrated under reduced pressure and extracted with ethyl acetate and salt water to combine the organic layer. The organic layer was dried with sodium sulfate, reduced pressure, and concentrated.

Purified by medium-pressure liquid chromatography (ethyl acetate / hexane) to obtain a liquid 1-current -butyl) 4 -methyl 4 -methoxypiperidine-1,4 -dicarboxylate (10.3 50%)

Obtained.

[248] MS (!1): 174.18 +1] ⁺ , 1界1乂: ^ I (111111): 1.46

[249] ¾ NMR (400 MHz, 0)0 ₃ ) 5 = 3.85-3.70 (111,211), 3.77知, 3¾, 3.26知, 3¾, 3.22-

1.46知, 911) 3.08 (111, 2¾, 1.87

1.46知, 911)

[25 This step 2: 1-(-butyl) 4 -methyl 4-methoxypiperidine-1,4-dicarboxylate (10.3 is,

37.711111101) was dissolved in ethanol (40) and tetrahydrofuran (的), 6N NaOH (1111) was added, heated to 70° (:) and stirred for 3 hours. Water and ethyl acetate were added to the reaction mixture, followed by sodium bicarbonate. The organic layer was dried with sodium sulfate and then concentrated under reduced pressure to give a liquid \-itert.

-Butoxycarbonyl)-4 -methoxypiperidine-4 -carboxylic acid (8.8 90%) was obtained.

[251] MS (11): 160.15 +1] ⁺ , 111 ⁵ 1乂: V. I知如): 1.36

[252] Step 3: (5)- 1-(6-(4 -fluoro-in-pyrazole-1 -yl)pyridin-3 -yl)ethane-1 -amine

Dihydrochloride (7.1 is, 25.5_ ₁₀ 1) and \-

-Butoxycarbonyl)- 4 -methoxypiperidine-4 -carboxylic acid

34.711111101), 1) Table ¾ show () was dissolved in DMF (1101111) and stirred at room temperature for 2 hours. 2020/175968 1»（：1^1{2020/002925 The reaction mixture was extracted with ethyl acetate and salt water, and the organic layer was combined.

After drying the organic layer with sodium sulfate, it is concentrated by decompression.

Purified by medium pressure liquid chromatography (ethyl acetate /!!-Hexane)

-Butyl（5）-4-（（1-（6-（4 -fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl）ethyl）carbamoyl）-4 -methoxypiperidine- 1-Carboxylate (8, 84%) was obtained.

[253] MS（!1）: 348.24 0。+ 1]+, 1界1乂: V. I（111111）: 1.73

[254] Step 4: -Butyl（5）-4-（（1-（6-（4-fluoro- monoacid

-Pyrazole- 1 -yl) pyridine- 3 -yl) ethyl) carbamoyl)-4 -methoxypiperidine- 1 -carboxylate (8.7 19.411111101) was dissolved in 1,4 -dioxane (), methanol () 4M

11（：1/1,4 -Dioxane (201111) was added and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, added dropwise to ethyl ether (1001111), filtered, and solid (flour -（1-（ 6- (4 -Fluoro-1 -pyrazole-1 -yl) pyridine-3 -yl) ethyl) -4 -methoxypiperidine-4 -carboxamide dihydrochloride (5.1 63%) was obtained.

[255] MS（11）: 348.24 ^+1] ⁺ , 111 ⁵ 1乂： V. I（111111）: 1.04

[256] <Example 1> (1/%4 di-()- 1-(6-(4-fluoro-1 -pyrazole-1 -yl) pyridine-3 -yl) ethyl) -1-me Oxy- 4- (4- ((5-methyl-1 -pyrazole-3 -yl) amino) quinazolin-2 -yl) cyclohexene- 1-carboxamide; and

[257] <Example 2> (1 4 及)--()-1- (6- (4-fluoro-1-pyrazole-1-yl) pyridine-3-yl) ethyl)-1-me Preparation of oxy-4- (4- ((5 -methyl-1 -pyrazole-3 -yl) amino) quinazoline-2 -yl) cyclohexene-1-carboxamide

[258] The title compound was prepared through the method shown in Scheme 9 below.

[259] [Scheme 9]

[261] Step 1: 2, 4 -dichloroquinazoline (1, 5 () 11111101) and 5 -methyl-1 -pyrazole-3 -amine

（5.3 years, 55^01）, 1）After recording the table ¾ show (8.81111) in DMSO (1671 scene), at 60° (: for 2 hours) 2020/175968 1» (：1^1{2020/002925) The reaction mixture was added to water, filtered, and solid 2-chloro--(5 -methyl-1 acid -pyrazole-3 -yl) quinazoline -4 -Amine (13 100%) was obtained.

[262] MS（!1）: 260.11 +1] ⁺ , 1界1乂: ]·. I（111111）: 1.27

테트라하이드로퓨란（ ）에 녹인후 70。（:에서 6시간교반하였다.반응혼합물을에틸아세테이트및소금물로 추출하여유기층을합하였다.유기층을황산나트륨으로건조한후감압하여 농축하고중압액체크로마토그래피（에틸아세테이트/다이클로로메테인）로 정제하여고체의 2 -클로로- -（5 -메틸- 1-（테트라하이드로 -2 -피란 -2 -일）- 1好[263] Step 2: 2 -Chloro# (5 -methyl-1 -pyrazole-3 -yl) quinazoline-4 -amine (5 silver, 19.211111101) and

After dissolving in tetrahydrofuran (), the mixture was stirred for 6 hours at 70° (:). The reaction mixture was extracted with ethyl acetate and salt water to combine the organic layer. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure, followed by medium pressure liquid chromatography (ethyl acetate). /Dichloromethane) and purified with solid 2-chloro--(5 -methyl- 1- (tetrahydro -2 -pyran -2 -yl)-1好

-Pyrazole-3-days) Quinazoline-4 -Amine (3Jg, 55%) was obtained.

[264] MS（11）: 344.22 ^+1] ⁺ , 111 ⁵ 1乂： V. I（111111）: 1.24

[265] Step 3: 2 -Chloro#（5 -methyl- 1- (tetrahydro -2 -pyran -2 -yl)-

-Pyrazole-3 -yl) Quinazoline-4 -Amine (3, 10.811111101) and methyl

1 -methoxy- 4- (4, 4, 5, 5 -tetramethyl-1,3, 2 -dioxaborolan-2 -yl)cyclohex- 3 -ene-1-

111111101) is dissolved in 1,4 -dioxane (901111) and water (171111), then 120 to 6 hours

The reaction mixture was extracted with ethyl acetate and salt water to combine the organic layer. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to form a solid methyl 1-methoxy 4- (4- ((5-methyl 1- (tetra)). Hydro -2 -pyran -2 -yl)-1 -pyrazole-3 -yl) amino )quinazoline-2 -yl) cyclohex-3 -ene-1 -carboxylate (4 78%) was obtained.

[266] MS（11）: 478.38 ^+1] ⁺ , 111 ⁵ 1乂： V. I知如）: 1.24

[267] Step 4: Methyl 1 -methoxy- 4- (4- ((5 -methyl- 1- (tetrahydro -2 -pyran -2 -yl) -)

- _{pyrazol-3-yl)} amino) quinazolin-2-yl) bicyclo haekseu-3-ene-1 - carboxylic rate (4 8.3811111101), ammonium formate (7.92 is, 12,611,111,101), (1/0 (1.78 Silver) and (1 (01¾ ₂ (0.59 silver)) were dissolved in ethanol (421 acid) and stirred at 80° (::) for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure.

Purified by medium pressure liquid chromatography (ethyl acetate/dichloromethane), solid methyl 1 -methoxy- 4- (4- ((5 -methyl- 1- (tetrahydro -2 -pyran -2 -yl) -) One

-Pyrazol- ₃ -yl)amino)quinazoline-2 -yl)cyclohex-1 -carboxylate (4g _, 99%) was obtained.

[268] MS（11）: 480.37 ^+1] ⁺ , 111 ⁵ 1乂： V. I知如）: 1.22

[269] Step 5: Methyl 1-methoxy- 4- (4- ((5 -methyl- 1- (tetrahydro -211-pyran-2 -yl)-

-Pyrazole- 3 -yl) amino) quinazoline-2 -yl) cyclohex- 1 -carboxylate (4

8.3811111101) was dissolved in ethanol (20) and tetrahydrofuran (), 6N NaOH (71 sine) was added, heated to 70° (::) and stirred for 3 hours. Water and ethyl acetate were added to the reaction mixture, followed by sodium bicarbonate. It was neutralized to give organic vapor. The organic layer is dried with sodium sulfate and concentrated under reduced pressure to

1 -methoxy- 4- (4- ((5 -methyl- 1- (tetrahydro -211-pyran-2 -yl)-1 -pyrazole-3 -yl) amino 2020/175968 1»（：1^1{2020/002925

)Quinazoline-2 -yl)cyclohex- 1-carboxylic acid (3.8g, 98%) was obtained.

[27 MS (m/z): 466.33 [M+l] ⁺ , UPLC rt (min): 1.10

[271] Step 6: Methyl 1-methoxy- 4-(4-((5 -methyl- 1-(tetrahydro -2//-pyran-2 -yl)

-Pyrazol-3 -yl)amino)quinazoline-2 -yl)cyclohex-1-carboxylic acid (3.8g,

8.16mmol) and (S)-l-(6-(4-fluoro- 1H-pyrazol- 1-yl) pyridin- 3 -yl) ethane- 1-amine (2.73g, 9.8mmol), DIPEA (7.13 ml, 40.8 mmol) and HATU (4.03 g, 10.61 mmol) were dissolved in DMF (30 ml) and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate and brine to combine the organic layer. The organic layer was dried over sodium sulfate and then reduced pressure to reduce pressure. Concentrated and purified by medium pressure liquid chromatography (methanol/dichloromethane) to obtain solid AK (幻- 1-(6-(4-fluoro-)

-Pyrazol- 1-yl)pyridin- 3 -yl)ethyl)- 1-methoxy-4-(4-((5 -methyl- 1-(tetrahydro -2H-pyran- 2 -yl)- 1/ /-Pyrazol-3 -yl)amino)quinazoline-2 -yl)cyclohexene-1-carboxamide (4g, 75%) was obtained.

[272] MS (m/z): 654.44 [M+l] ⁺ , UPLC rt (min): 1.32

[273] Step 7: -( )-1-(6-(4 -fluoro-

-Pyrazol- 1-yl)pyridin- 3 -yl)ethyl)- 1-methoxy-4-(4-((5 -methyl- 1-(tetrahydro -2//- pyran-2 -yl)- Dissolve 1//-pyrazole- 3 -yl) amino) quinazoline- 2 -yl) cyclohexane- 1-carboxamide (4g, 6.12mmol) in TFA (12ml) and stir at 60°C for 30 minutes Water and ethyl acetate were added to the reaction mixture, and the organic vapor was extracted by neutralizing with sodium bicarbonate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure.

Separation and purification of solid (lrAS)-N-((S)-1-(6-(4 -fluoro-1H-pyrazol-1-yl)pyridine-3 -yl) using supercritical fluid chromatography Ethyl)- 1-methoxy-4-(4-((5 -methyl- 1//- pyrazole- 3 -yl) amino) quinazolin- 2 -yl) cyclohexene- 1-carboxamide (722mg , 21%, Example 1) and (U4RHV-(0S)-l-(6-(4-fluoro-

-Pyrazol- 1-yl)pyridin- 3 -yl)ethyl)- 1-methoxy -4-(4-((5 -methyl-1H-pyrazol-3 -yl)amino)quinazoline-2 -yl ) Cyclohexene- 1-carboxamide (1680 mg, 48%, Example 2) was obtained, respectively.

[274] MS (m/z): 570.38 [M+l] ⁺ , UPLC rt (min): 1.26

Examples 3 to 22 were prepared in a similar manner to Examples 1 and 2, and the chemical structures, compound names and NMR, and LC-MS analysis results of Examples 1 to 22 are summarized in Table 1 below. 石

卜一 ₁ !

卜一

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石

^0

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[281]

[282] <Example 23> -Benzyl-4-(4-((5-methyl-1好)

-Pyrazole- ₃ -yl) amino) quinazoline-2 -yl) cyclohexane- 1-Manufacture of carboxamide

[283] The title compound was prepared through the method represented by the following reaction scheme.

[284] [Scheme 1 is 2020/175968 1»（：1^1{2020/002925

[286] Step 1: 2 -chloro-

-(5 -Methyl-1 -tetrahydropyran-2 -yl-pyrazole-3 -yl)quinazoline-4 -amine (70011¾, 2.0411111101) and methyl

4-（4, 4, 5, 5 -tetramethyl-1,3, 2 -dioxaborolane-2 -yl)cyclohex-3 -ene-1 -carboxylate (90011¾, 3.3811111101) at room temperature 1 ,4-Dioxane (101111), water (1.3) after being infused ¾00 ₃ （844.1711¾, 6.1111111101), wool (1（（¾¾幻（：1 ₂ ））（：1¾（：1 ₂ （20（¾1¾, 244.911111101） ) Was added and stirred for 2 hours at 90° (:). The reaction mixture was extracted with ethyl acetate and salt water to combine the organic layer. The organic layer was dried with sodium sulfate, concentrated under reduced pressure, and medium pressure liquid chromatography (petroleum ether/ethyl acetate). Purified with solid methyl 4-（4-（（5-methyl- 1-（tetrahydro-2 -pyran-2 -yl）-

-Pyrazole- 3 -yl) amino) quinazoline-2 -yl) cyclohex- 3 -ene -1 -carboxylate (6701^, 73.53%) was obtained.

[287] MS: 448.1 +印十

8.4

[288] ¾ NMR（400 MHz, 0001 ₃ ） 8 = 8.03（1奸（1, /= 2.8

8.4

1¾, 7.73（ᄂ / = 7.6

1¾, 7.45比 / = 8.0

1¾, 6.92知, 1¾,7.80（（1, / = 8.0

1¾, 7.73（b / = 7.6

1¾, 7.45比 / = 8.0

1¾, 6.92知, 1¾,

1¾, 4.12 - 4.08（ 1¾, 3.75 - 3.72（ 3¾, 3.71 - 3.655.23（（¾ / = 2.4, 10.0

1¾, 4.12-4.08（ 1¾, 3.75-3.72（ 3¾, 3.71-3.65

（111, 1¾, 3.04-3.02（ 1¾, 2.73-2.67（ 1¾, 2.42知, 4¾, 2.30-2.21（ 1¾, 2.14-2.09（111, 1¾, 1.96-1.84（ 2¾, 1.82知, 5¾, 1.63-1.56 （1¾

[289] Step 2: Methyl 4-（4-（（5-methyl- 1-（tetrahydro-2 -pyran-2 -yl）-

-Pyrazole- 3 -yl) amino) quinazolin- 2 -yl) cyclohex- 3 -ene -1 -carboxylate (6301^, 1.4111111101), ¥<1/0 (149.811 employment, 10%), (1) （011） ₂ （98.851 employment, 140.771111101, 20%!切) was dissolved in methanol (411 止) and stirred for 1.5 hours at room temperature under a hydrogen stream. The reaction mixture is filtered and concentrated under reduced pressure to

4-（4-（（5 -methyl- 1-(tetrahydro-2 -pyran-2 -yl)-1 -pyrazole-3 -yl)amino）quinazoline-2 -yl)cyclohexene-1 -Acquired carboxylate (60011¾, 94.81%).

[29 MS: 111/ _å 450.2 +印 +

[291] ¾ NMR（400 MHz, 0001 ₃ ） 3 = 8.00（1奸 1¾, 7.87-7.69（ 3¾, 7.50-7.42（ 2020/175968 1»(：1^1{2020/002925

1¾, 7.06-6.95 知1, 1¾, 5.33-5.21 知1, 1¾, 4.12-4.05 (1¾, 3.73-3.71 (3¾, 3.70-3.65 (111, 1¾, 3.00-2.84 (1¾, 2.75-2.68 (1¾, 2.46-2.42 (3¾, 2.24-2.05 (111, 6¾, 1.94-1.87 (2¾, 1.75-1.60知1, 6¾)

[292] Step 3: Methyl 4-(4-((5 -methyl- 1-(tetrahydro -2 -pyran -2 -yl)-

-Pyrazole- ₃ -yl)amino)quinazoline- 2 -yl)cyclohexane- 1 -carboxylate (550 ₁₁ ¾, 1.2211111101) in water (211止), methanol (1 (¾1止)) and then 011 (15 (¾1¾, 3.7511111101) was added and stirred for 16 hours at room temperature. Water and ethyl acetate were added to the reaction mixture, and the water layer was extracted. 1N HC1 was added dropwise to the water layer to titrate 1^ to 5-6, and the solid precipitate was filtered and Concentrate under reduced pressure to obtain solid 4-(4-((5 -methyl- 1-(tetrahydro -2 -pyran -2 -yl)-1 -pyrazol-3 -yl) amino) quinazoline-2 -yl) cyclo Hexein-1 -carboxylic acid (40011¾, 72.60%) was obtained.

[293] MS: 436.3 +印十

7.80 -[294] ¾ NMR (400 MHz, DMSO-J ₆ ) 5 = 10.33 知, 1¾, 8.60 (山 / = 8.4

7.80-

1¾, 6.84 - 6.80 (III, 1¾, 5.35 凡 / = 9.6 1¾, 1¾, 3.93 ((!, / = 11.2 1¾ 1¾, 3.65 (바, / = 3.6, 10.8

2¾, 2.87 -7.73 (111, 1¾, 7.71-7.65 (III, 1¾, 7.47比 / = 7.6)

1¾, 6.84-6.80 (III, 1¾, 5.35 凡 / = 9.6 1¾, 1¾, 3.93 ((!, / = 11.2 1¾ 1¾, 3.65 (bar, / = 3.6, 10.8

2¾, 2.87-

2.76 知1, 1¾, 2.75-2.63 (1¾, 2.36 知, 3¾, 2.33-2.26 知1, 1¾, 2.07-2.00, 4¾, 1.91-1.85 知1, 1¾, 1.83-1.58 知1, 5¾, 1.58-1.44 (3¾

[295] Step 4: 4-(4-((5 -methyl- 1-(tetrahydro -2 -pyran -2 -yl)-

-Pyrazol- 3 -yl)amino)quinazoline- 2 -yl)cyclohexane- 1 -carboxylic acid (17011¾,

377.52 or 11101) and phenylmethanamine (50.211¾, 468.55 or 11101, 51.07^), 1 111 (172.251¾, 453.03 or 11101), [ ⁾ table ¾ show (222.6 (¾1¾, 1.7211111101, 0.311 止) dichloromethane After dissolving in phosphorus (3:1止), the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure and 11 ⁽ Part 1 (2011)) was added dropwise and filtered to obtain a solid -benzyl-4-(4-((5 -). Methyl- 1-(tetrahydro-dioic acid-pyran- 2 -yl)- 1 -pyrazole- 3 -yl)amino)quinazoline- 2 -yl)cyclohexene- 1 -carboxamide (190!! ¾, 95.93%) was obtained.

[296] MS: m/z 525.4, 印十

[297] ¾ NMR (400 MHz, DMSO-J ₆ ) 8 = 14.79-14.48 (III, 1¾, 12.21-11.98 (III, 1¾,

1¾, 3.66知, 1¾, 3.08 -8.90-8.82 (111, 1¾, 8.40-8.31 (1¾, 8.11-8.03 (1¾, 7.91 ((!, / = 7.6 Hz, 1¾, 7.78 (b / = 7.6 Hz, 1¾, 7.37-7.27 (2¾, 7.25- 7.15 (2¾, 7.02-6.75 (1¾, 5.47-5.34 (111, 1¾, 4.36-4.27 (2¾, 3.93 ((!, / = 12.0

1¾, 3.66知, 1¾, 3.08-

2.96 知 1, 1¾, 2.62-2.59 (1¾, 2.33-2.30 (3¾, 2.16-1.79 知 1, 7¾, 1.77-1.47

(Ta 7¾

[298] Step 5: -Benzyl- 4-(4-((5 -methyl- 1-(tetrahydro -2 -pyran -2 -yl)-

-Pyrazole- 3 -yl)amino)quinazoline- 2 -yl)cyclohexane- 1 -carboxamide (19 (¾1¾, 362.141111101) was added to 4M Ha/MeOH (90.54 nanoparticles) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dissolved in methanol, and filtered after adjusting 1^ to 7-8 using a basic resin.

Solid racemic mixture -benzyl- 4-(4-((5 -methyl- monoacid 2020/175968 1»(：1^1{2020/002925

-Pyrazole- 3 -yl) amino) quinazolin- 2 -yl) cyclohexanine- 1 -carboxamide (3 (¾1¾, 27.27%) was obtained.

[299] MS: ^ 441.2 +印 +

1¾, 10.21知, 1¾, 8.57 (山[300] ¾ NMR (400 MHz, DMSO-J ₆ ) 3 = 12.11 ((!, / = 1.6

1¾, 10.21知, 1¾, 8.57 (山

1¾, 8.37 - 8.12 (111, 1¾, 7.82 - 7.64 (III, 2¾, 7.47比 / = 7.2

1¾, 7.36/ = 7.6

1¾, 8.37-8.12 (111, 1¾, 7.82-7.64 (III, 2¾, 7.47 比 / = 7.2)

1¾, 7.36

-7.18 (111, 5¾, 6.76 (1奸 1¾, 4.32-4.24 (2¾, 2.95-2.66 (1¾, 2.42-2.18 (111, 5¾, 2.12-1.79 (3¾, 1.78-1.52 (4¾)))

[301] Examples 24 to 26 were prepared by a method similar to that of Example 23, and the chemical structures, compound names and NMR of Examples 23 to 26, and ^^8 analysis results are summarized in Table 2 below.

2020/175968 1»（：1/10公020/002925

-02

[303] <Example 27> (Ji- (1-(6-(4-fluoro- 1好 2020/175968 1»（：1^1{2020/002925

-Pyrazol- 1 -yl) pyridine-3 -yl) ethyl)-4 -methoxy- 1- (4- ((5 -methyl-monoacid-pyrazole-3 -yl) amino) quinazoline-2- Japan) Preparation of piperidine-4-carboxamide

[304] The title compound was prepared through the method represented by Scheme 11 below.

[305] [Scheme 11]

[306]

[307] Step 1: 2, 4 -dichloroquinazoline (1, 5 () 11111101) and 5 -methyl- 111-pyrazole-3 -amine

(5.3), 55^01), 1) Table ¾ show (8.81111) was dissolved in DMSO (1671 new) and stirred at 60° (::) for 2 hours. The reaction mixture was put in water and filtered, and solid 2-chloro --(5-methyl- monoacid -pyrazole- 3 -yl) quinazoline-4 -amine (13 100%) was obtained.

[308] MS（!1）: 260.11 +1] ⁺ , 1界1乂: ]·. I（111111）: 1.27

[309] Step 2: 2 -Chloro--(5 -methyl-1 -pyrazole-3 -yl) quinazoline-4 -amine (901¾,

0.34711111101) and

）-此（1- (6- (4-fluoro-in-pyrazole- 1 -yl) pyridine-3 -yl) ethyl)-4 -methoxypiperidine- 4-carboxamide dihydrochloride (14611¾ , 0.34711111101), 1) Table ¾ show (0.21111, 1.3911111101) was dissolved in ethanol (31111) and reacted for 1 hour at 170° (::) using a microwave reactor. The reaction mixture was extracted with ethyl acetate and salt water to combine the organic layer. .After drying the organic layer with sodium sulfate, depressurizing and concentrating, purify it to ¾ _£1 ）- 150 1乂: 3 111 to obtain a solid (1-(1- (6- (4-fluoro- 1 好))

-Pyrazol- 1 -yl) pyridine-3 -yl) ethyl)-4 -methoxy- 1- (4- ((5 -methyl-monoacid-pyrazole-3 -yl) amino) quinazoline-2- Day) Piperidine-4-Carboxamide (981 bone, 50%) was obtained.

[31 MS（!1）: 571.49 +1] ⁺ , 1界1乂: V. I知如）: 1.36

[311] Examples 28 to 45 were prepared by a method similar to that of Example 27, and the chemical structures, compound names and NMR, ^^8 analysis results of Examples 27 to 45 are summarized and shown in Table 3 below.

】【Rice ¹ 2--

WO 2020/175968 PCT/KR2020/002925

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[317] <Example 46> -Benzyl -4 -methoxy -1 -(4-((5 -methyl-monoacid

-Pyrazol-3 -yl)amino)quinazoline-2 -yl)piperidine-4-carboxamide

[318] The title compound was prepared through the method represented by Scheme 12 below.

[319] [Scheme 12]

[32 this

[321] Step 1: 1-( -butyl) 4 -methyl 4 -methoxypiperidine- 1,4 -dicarboxylate (ί.2g, 4.3911111101) was dissolved in methanol (1011 small) and 4M HCl/MeOH (60 ： 11 was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to

4-methoxypiperidine-4-carboxylate (0.8 86.91%) was obtained.

[322] ¾ NMR (400 MHz, Methanol -山) 3 = 3.79 知, 3¾, 3.30-3.25 (2¾, 3.28 知, 3¾, 3.22-3.19 (111, 2¾, 2.27-2.09 (4¾)

715.41 ^^01), 1)표¾쇼[323] Step 2: Methyl 4 -methoxypiperidine-4 -carboxy

715.41 ^^01), 1) Table ¾ show

715.41나 11101)를 DMF (10 11止)에 녹인후 2 -클로로- -(5 -메틸- 1-(테트라하이드로 -2 -피란 -2 -일)- 1好 (462.3111¾, 3.5811111101,

715.41 or 11101) is dissolved in DMF (10 11止) and then 2 -chloro- -(5 -methyl- 1-(tetrahydro -2 -pyran -2 -yl)- 1好

-Pyrazole- 3 -yl)quinazoline- 4 -amine (270.5611¾, 786.95 or 11101) was added and stirred at 60° for 12 hours. The reaction mixture was extracted with ethyl acetate and salt water, and the organic layer was combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (petroleum ether/ethyl acetate) to obtain a solid methyl 4 -methoxy- 1-(4-((5 -methyl- 1-(tetrahydro-2)). -Pyran -2 -yl) -1 -pyrazole- 3 -yl)amino)quinazoline -2 -yl)piperidine-4 -carboxylate (30011¾, 87.26%) was obtained.

[324] MS: ^ 481.3 +印十

211), 3.58 - 3.44[325] ¾ NMR (400 MHz, 0001 ₃ ) 3 = 7.64-7.46 (4¾, 6.68知, 1¾, 5.23 (加 (1, / = 2.6)

211), 3.58-3.44

(111, 2¾, 3.34 知, 3 ¾, 2.39 知, 3¾, 2.16-1.98 (6¾, 1.92 (加山 / = 13.2 degrees ¾ 2¾, 1.60 (1, / = 9.6 1¾, 211))

[326] Step 3: Methyl 4 -methoxy- 1-(4-((5 -methyl- 1-(tetrahydro -2 -pyran -2 -yl)- 2020/175968 1»（：1^1{2020/002925

-Pyrazole-3 -yl)amino)quinazoline-2 -yl)piperidine-4 -carboxylate (250mg,

520.23_1) was dissolved in water (lmL) and methanol (5 mL), NaOH (50mg, 1.25mmol) was added and stirred at room temperature for 16 hours. 1N HC1 was added to the reaction mixture, and the pH was adjusted to 4-5. Ethyl acetate Add the water layer to extract and freeze-dry to solid 4 -methoxy- 1-(4-((5 -methyl-1H-pyrazol-3 -yl)amino)quinazoline-2 -yl)piperidine-4 -Carboxylic acid (120mg, 49.44%) was obtained.

[327] MS: m/z 467.3 [M+H] +

[328] Step 4: 4 -methoxy- 1-(4-((5 -methyl-

로로메테인 (3mL)에녹인후 상온에서 1시간교반하였다.반응혼합물을다이클로로메테인및소금물로 추출하여유기층을합하였다.유기층을황산나트륨으로건조한후감압 농축하고 Prep-150 LC System으로정제하여고체의 N -Pyrazol-3 -yl)amino)quinazoline- 2--4 -carboxylic acid (110mg, 235.78umol) and phenylmethanamine (147.45mg, 1.38mm HATU (107.58mg, 282.94umol), DIPEA (371.00mg, 2.87umol) mmol, 0.5

After dissolving in lorometein (3 mL), the mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with dichloromethane and salt water to combine the organic layer. The organic layer was dried with sodium sulfate, concentrated under reduced pressure, and purified with Prep-150 LC System to solidify. N of

-Benzyl-4 -methoxy- 1-(4-((5 -methyl-1H-pyrazol-3 -yl)amino)quinazoline-2 -yl)piperidine-4-carboxamide (50mg, 44.97 %) was obtained.

[329] MS: m/z 472.1 [M+H] +

[33 is'H NMR (400 MHz, CDC1 ₃ ) d = 8.49-8.05 (m, 1H), 7.80-7.65 (m, 1H), 7.62-7.43

(m, 2H), 7.39-7.27 (m, 5H), 7.17-7.06 (m, 1H), 6.85 (t, / = 5.6 Hz, 1H), 6.57-6.33 (m, 1H), 4.65 (d, / = 12.0 Hz, 2H), 4.47 (d, / = 6.0 Hz, 2H), 3.43-3.28 (m, 5H), 2.30 (s, 3H), 2.22-2.16 (m, 2H), 1.92 (d, / = 14.4 Hz, 2H)

[331] The chemical structure, compound name and NMR, LC-MS analysis results of Example 46 are shown in Table 4 below.

It was shown in summary.

[332] [Table 4]

[333] <Example 47> -Benzyl- 1-(4-((5 -methyl- 1好

-Pyrazole-3 -yl)amino)quinazoline- 2 -yl)piperidine-4 -carboxamide

[334] The title compound was prepared through the method represented by Scheme 13 below.

[335] [Scheme 13] 2020/175968 1»（：1^1{2020/002925

[336]

[337] Step 1: 2 -Chloro- -(5 -methyl- 1-(tetrahydro- 2 -pyran- 2 -yl)- 1好

-Pyrazole-3 -yl)quinazoline-4 -amine (30(¾1¾, 872.57^01)4methyl

Piperidine-4 -Carboxylate (187.4111¾, 1.3111111101), XI (28.9711¾, 174.51 ₍ X11101), ( ⁾ Table 3/4 show (742.0(¾1¾, 5.7411111101, 1.0(¾1止)) and DMF (1(¾1止)) After incubation, the mixture was stirred at 80 (:) for 12 hours. The reaction mixture was extracted with ethyl acetate and salt water to combine the organic layer. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure.

Liquid methyl 1-(4-((5 -methyl- 1-(tetrahydro- 2 -pyran- 2 -yl)- 1 -pyrazole- 3) purified by medium pressure liquid chromatography (petroleum ether/ethyl acetate) -Yl)amino)quinazolin- 2 -yl)piperidine-4 -carboxylate (31511¾, 59.18%) was obtained.

[338] MS: 451.3 +印⁺

[339] Step 2: Methyl 1-(4-((5 -methyl- 1-(tetrahydro -2 -pyran -2 -yl) -1)

-Pyrazole-3 -yl)amino)quinazoline- 2 -yl)piperidine-4 -carboxylate (28011¾,

621.49 or 11101) was dissolved in tetrahydrofuran (5:1 止), then 011 (1001 ¾, 2.5011111101) and water (111 止) were added, followed by stirring at room temperature for 12 hours. Water was added to the reaction mixture and washed with ethyl acetate. 11 ⁽ : 1 (1011) was added dropwise to the water layer, titrated to 7 and ethyl acetate was used to extract the organic layer. The organic layer was

After drying with sodium sulfate, it is concentrated under reduced pressure and

1-(4-((5 -methyl- 1-(tetrahydro-2 -pyran-2 -yl)-1 -pyrazol-3 -yl)amino)quinazoline-2 -yl)piperidine-4 -Carboxylic acid (26011¾, 89.09%) was obtained.

[34 MS: 437.1 +印⁺

[341] Step 3: 1-(4-((5 -methyl- 1-(tetrahydro -211-pyran-2 -yl)-

, 11¾, 514.45^01)1-다이클로로메테인 (411止)에녹인후 상온에서 12시간교반하였다.반응혼합물을물 (2011止)에 넣고고체를 석출시킨다.여과하여고체의 -벤질- 1-(4-((5 -메틸- 1-(테트라하이드로 -2산 2020/175968 1»(：1^1{2020/002925 -Pyrazole-3 -yl)amino)quinazoline- 2 -yl)piperidine-4 -carboxylic acid (230!1¾, 514.45^01), phenylme 514.45 ₍ X11101, 56.08^), £) 66.4¾1¾, 514.45^01, 89.64山

, 11¾, 514.45^01)1-Dichloromethane (411止) and stirred for 12 hours at room temperature. The reaction mixture was added to water (2011止) to precipitate a solid. Filtrate to solidify -benzyl- 1- 1- (4-((5 -methyl- 1-(tetrahydro-2 acid 2020/175968 1»(：1^1{2020/002925

-Pyran-2 -yl)-1 -pyrazole-3 -yl)amino)quinazoline-2 -yl)piperidine-4 -carboxamide (160!1¾, 59.17%) was obtained.

[342] MS: 526.2 +印⁺

[343] ¾ NMR (400 MHz, DMSO-J ₆ ) 5 = 10.31-9.98 (1 p 1¾, 8.44-8.32 (III, 2¾, 7.56 (b / = 7.6 Hz, 1¾, 7.42-7.35 (1¾, 7.34 -)) 7.28 (2¾, 7.23 ((!, / = 7.2°¾, 3¾,

1¾, 6.52知, 1¾, 5.34 ((¾ / = 2.0, 10.0

1¾, 4.76凡 / = 12.07.11比 / = 7.2

1¾, 6.52知, 1¾, 5.34 ((¾ / = 2.0, 10.0

1¾, 4.76凡 / = 12.0

2¾, 2.33知, 3¾, 2.05 - 1.95 (1피 1¾, 1.91 - 1.66 (1피 4¾,Hz, 2¾, 4.26 ((!, / = 6.0 Hz, 2¾, 3.92 ((!, /= 12.0 Hz, 1¾, 3.64 0-, 1 = 3.2, 10.8 Hz, 1¾, 2.94 (b /= 12.4

2¾, 2.33知, 3¾, 2.05-1.95 (1P 1¾, 1.91-1.66 (1P 4¾,

1.63-1.47 (111, 4¾

[344] Step 4: -Benzyl- 1-(4-((5 -methyl- 1-(tetrahydro -2 -pyran -2 -yl)-

-Pyrazole- 3 -yl)amino)quinazoline- 2 -yl)piperidine- 4 -carboxamide (13011¾,

After dissolving in 247.32^01)# methanol (211 cows), 4M HCl/MeOH (1011) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to 50°

(Stirred for 12 hours at:. The resulting solid was filtered and 1^1)-150

Purified solid -benzyl-1-(4-((5 -methyl-monoacid)

-Pyrazol-3 -yl)amino)quinazolin-2 -yl)piperidine-4 -carboxamide (26!1¾, 23.81%) was obtained.

[345] MS: 442.2 +印⁺

[346] ¾ NMR (400 MHz, DMSO -成) 5 = 12.21-11.97 (III, 1¾, 9.97知, 1¾, 8.42-8.23

211), 4.26 ((!, / = 6.0

211), 3.31知, 1¾, 2.92(111, 2¾, 7.59-7.48 (1¾, 7.35-7.28 (3¾, 7.26-7.19知 1, 3¾, 7.12-7.05知1, 1¾, 6.43知, 1¾, 4.78 ((!, / = 13.2)

211), 4.26 ((!, / = 6.0

211), 3.31知, 1¾, 2.92

2¾, 2.26知, 3¾, 1.82 - 1.78 (III, 2¾, 1.56 ((1(1, / = 3.6, 12.4

211)(B / = 12.0

2¾, 2.26知, 3¾, 1.82-1.78 (III, 2¾, 1.56 ((1(1, / = 3.6, 12.4

211)

[347] Examples 48 to 51 were prepared by a method similar to Example 47, and the chemical structures, compound names and NMR of Examples 47 to 51, and ^^8 analysis results are summarized in Table 5 below.

2020/175968 1»（：1/10公020/002925

[349]

[35] <Experimental Example 1> Evaluation of various kinase inhibitory activities of the compounds according to the present invention

[351] In order to evaluate the inhibitory activity against more enzymes of the compound according to the present invention, the following experiment was performed. Specifically, for Examples 15, 19 and 22 selected from the example compounds of the present invention, Enzyme (kinase) by requesting Disco verX 2020/175968 1»（：1^1{2020/002925 Selectivity was determined, and an experiment was conducted using the scanMAXä Kinase analysis panel. At this time, the concentration of the drug treated with the enzyme was set to 4 iM in DMSO, The control percentage (% control) was determined in the same manner as in Equation 1 below, and the results are shown in Table 6 below.

[352] [Equation 1]

[353] (Example compound -positive control)/(negative control -positive control) X 100

[354] Here, the positive control refers to a compound exhibiting a control percentage of 0%, and the negative control refers to a control percentage of 100% with DMSO. In addition, the enzyme selectivity of the present invention is the control percentage for each enzyme < If it was 35% (ie, less than 35%), it was judged to have activity against the enzyme.

2020/175968 1»(：1/10公020/002925

[355] [Table 6]

2020/175968 1^»(：1^1{2020/002925

2020/175968 1 ^» (：1^1{2020/002925

2020/175968 1»（：1^1{2020/002925 나열된효소에대하여억제활성을갖고있음을나타내는것이며,이로부터상기 나열된효소와관련된질환에사용시유용한효과가있음을암시하는것이다. 따라서,본발명에따른유도체화합물은따른 AMPK-alphal, AMPK-alpha2, ARK5, AURKA, AURKB, AURKC, AXL, BLK, CSF1R, CSNK2A2, DAPK1, DAPK3, EPHB6, FGFR1, FGFR2, FGFR3, FGFR3(G697C), FGR, FLT1, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT4, GCN2, HCK, JAK1, JAK2, JAK3, KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), LCK, MAP3K2, MEK5, MERTK, MLK2, MLK3, NEK7, NEK9, PDGFRA, PDGFRB, PLK4, PYK2, RET, RET(M918T), RET(V804L), RET(V804M), RIOK3, ROS1, RSK2, RSK3, SLK, SNARK, SRC, STK16, SYK, TIE1, TNK1, TNK2, TRKA, TRKB, TRKC, TYK2, YES, YSK4키나아제관련질환의치료또는예방용조성물로유용하게사용될 수있다. [356] As can be seen from Table 6 above, the compound according to the present invention is AMPK-alphal,

2020/175968 1»（：1^1{2020/002925 It indicates that it has inhibitory activity against the enzymes listed above, and from this implies that it has a useful effect when used in diseases related to the enzymes listed above. Therefore, the derivative compounds according to the present invention are AMPK-alphal, AMPK-alpha2, ARK5, AURKA, AURKB, AURKC, AXL, BLK, CSF1R, CSNK2A2, DAPK1, DAPK3, EPHB6, FGFR1, FGFR2, FG69FR3, FGFR7 , FGR, FLT1, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I) , FLT3(R834Q), FLT4, GCN2, HCK, JAK1, JAK2, JAK3, KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I ), KIT(V559D,V654A), LCK, MAP3K2, MEK5, MERTK, MLK2, MLK3, NEK7, NEK9, PDGFRA, PDGFRB, PLK4, PYK2, RET, RET(M918T), RET(V804L), RET(V804M), RIOK3, ROS1, RSK2, RSK3, SLK, SNARK, SRC, STK16, SYK, TIE1, TNK1, TNK2, TRKA, TRKB, TRKC, TYK2, YES, YSK4 can be usefully used as a composition for the treatment or prevention of kinase-related diseases. .

[357]

[358] <Experimental Example 2> RET (ret proto-oncogene) enzyme inhibition evaluation

[359] The following experiment was performed to evaluate the inhibitory activity of the example compound according to the present invention to the RET (ret proto-oncogene) enzyme. Example Compounds were purified with human RET (658-end, signalchem) enzyme In the reaction buffer, 40mM Tris-HCl pH 7.4, 20mM MgCl ₂ , 0.5 mg/mL BSA, and 50uM DTT composition were used, and all test products were reacted in the reaction buffer. In the test, human RET (658-end, 0.8ng) enzyme, purified ATP (10uM), and a specific substrate solution were reacted for 1 hour on 25 phases, and the enzyme activity was in vitro.

It was confirmed using the ADP-Glo™ kinase assay (promega). 2:2:1 ratio

By reacting enzyme activity reaction solution, ADP-Glo reaction solution, and enzyme activity detection solution

Luminescence was immediately determined. The degree of inhibition of enzyme activity was calculated according to the treatment concentration of each compound based on the fluorescence of the enzyme activity of the solvent control group without compound treatment, and the concentration of each compound that inhibited the enzyme activity inhibition by 50% was IC _The value of ₅₀ (nM) was determined. The IC _5Q of each compound was determined with three data sets and obtained using Prism (version 7.01, GraphPad) software. The results are shown in Table 7 below.

[36 this

[361] <Experimental Example 3> Thyroid cancer and lung cancer cell proliferation expressing RET fusion gene

Inhibitory activity evaluation

[362] In order to evaluate the inhibitory activity against the proliferation of medullary thyroid cancer cells and lung cancer cells expressing the RET fusion gene of the compound according to the present invention, the following experiment was conducted.

Performed. Among the lung cancer cell lines expressing the RET fusion gene, LC-2/ad cells are cultured after adding 10% FBS (HyClone) to RPMLF12 (1:1) (Invitrogen), and 2020/175968 1»（：1^1{2020/002925 For TT cells, a medullary cancer cell line, F-12 (Invitrogen) added with 10% FBS is used. For Ba/F3 cells, RPMI-1640 containing 10% FBS and 5 ng/ml IL-3 (R&D Systems) was used. Transduced Ba/F3 cells were added with lug/ml puromycin (Invitrogen) in the same medium. Cells are cultured 24 hours before the compound is treated, 3000-5000 cells are dispensed per well of a white clear bottom 96 well plate (Coming). The compound is diluted in dimethyl sulfoxide (diluted 3 times, total 12 concentrations) 0.5ul each was injected so that the final concentration was 0.3nM-50uM. Live cells were measured 72 hours after compound treatment using CellTiter-Glo luminescent cell-viability reagent (Promega) and stored for 10 minutes at room temperature. , Using a reader (SynergyNeo, Biotek), the luminous intensity was measured. Each test was repeated three times. The results were compared with the control group.

It was calculated by the cellular equipment rate (%). Graphs were _drawn using GraphPad Prism version 5.0 program and IC _5Q (nM) values were calculated. Table 7 below shows LC-2/ad, Ba/F3 (naive), Ba/F3 KIF5B-RET, Ba/F3 KIF5B- The results of measuring the growth inhibitory activity of each experimental compound against RET (V804M) cells are shown.

2020/175968 1»(：1/10公020/002925

[363] [Table 7]

2020/175968 1»（：1^1{2020/002925

2020/175968 1»（：1^1{2020/002925

[364] As shown in Table 7 above, the exemplary compound of the present invention is RET (ret

Proto-oncogene) enzyme inhibitory ability is excellent, and it can be confirmed that it has superior inhibitory activity against the RET fusion gene selectively than the RET wild type and the proliferation of the thyroid medullary cancer cell line and the lung cancer cell line expressing the RET fusion gene is superior. It can be seen that the compound of the present invention specifically exhibits inhibitory activity against the RET fusion gene. Therefore, the compound according to the present invention is described above. 2020/175968 1»（：1/10公020/002925 As confirmed in the experiment, it can inhibit cancer cell proliferation, making it useful as a pharmaceutical composition for the prevention and treatment of cancer diseases, such as thyroid cancer and lung cancer. Can be used

Claims

2020/175968 1»（：1/10公020/002925 Claims [Claim 1] A compound represented by the following formula (1), its isomer, its solvate, its hydrate, or its pharmaceutically acceptable salt: [Formula 1]

Is cycloalkyl; , _Represents a _5-6 aromatic ring or an aromatic heterocycle of 5 to 6 atoms containing at least one heteroatom selected from the group consisting of _5-6 , wherein the heteroaromatic ring is at least one straight chain Or may be substituted with branched alkyl; II ² is hydrogen or alkoxy of straight or branched chain (:; Is hydrogen or alkyl of linear or branched (:); Is hydrogen, a 5-6 membered heteroaryl containing at least one heteroatom selected from the group consisting of hydrogen, linear or branched (: alkoxy or 0 and 3), and the heteroaryl is halogen, or linear or branched One or more may be substituted with a substituent selected from the group consisting of chain alkyl; and And are independently N or (：!! is). [Claim 2] The method of claim 1, Seogi XI

Of _ ₆ is alkyl, and when X ^I or X ⁴ is 0 or 3, a compound, isomer thereof, solvate thereof, hydrate thereof, or Pharmaceutically acceptable salts. 2020/175968 1»（：1^1{2020/002925 [Claim 3] The method of claim 1,

Compound, isomer thereof, solvate thereof, hydrate thereof, or Pharmaceutically acceptable salts. [Claim 4] The method of claim 1, II ⁴ is hydrogen, methoxy, pyrazolyl, thiazolyl or isoxazolyl, and the pyrazolyl, thiazolyl and isoxazolyl are at least one substituent selected from the group consisting of halogen and linear alkyl of _ ₃ Can be substituted, Compound, isomer thereof, solvate thereof, hydrate thereof, or Pharmaceutically acceptable salts. [Claim 5] The method of claim 1,

Compound, isomer thereof, solvate thereof, hydrate thereof, or Pharmaceutically acceptable salts. [Claim 6] The method of claim 1, Silver cyano, ₆ haloalkyl, straight chain (: alkyl or (: _3-6 Cycloalkyl; X ^I

^{When 4} is 0 or 3, it does not exist; Is hydrogen or alkoxy in a straight chain (:, 2020/175968 1» (: 1^1{2020/002925 is hydrogen or alkyl in a straight chain (:; and Element ⁴ is a 5-membered heteroaryl containing at least one heteroatom selected from the group consisting of hydrogen, linear (: alkoxy or 0 and 3), and the heteroaryl is from the group consisting of halogen and linear alkyl A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a compound thereof, which may be one or more substituted with a selected substituent. Pharmaceutically acceptable salts. [Claim 7] The method of claim 1, Silver cyano, _ ₃ haloalkyl, straight chain _ ₃ alkyl or (: _3-5 Cycloalkyl; I

When, does not exist; II ² is hydrogen or straight chain _ ₃ alkoxy; Is hydrogen or straight-chain _ ₃ alkyl; And II ⁴ is hydrogen, methoxy, pyrazolyl, thiazolyl or isoxazolyl, and the pyrazolyl, thiazolyl and isoxazolyl are at least one substituent selected from the group consisting of halogen and linear alkyl of _ ₃ Can be substituted, Compound, isomer thereof, solvate thereof, hydrate thereof, or Pharmaceutically acceptable salts. [Claim 8] The method of claim 1, Silver cyano, trifluoromethyl, straight chain _ ₃ alkyl, (of _3-4 Cycloalkyl;

When, does not exist; II ² is hydrogen or straight chain _ ₃ alkoxy; Is hydrogen or straight chain _ ₃ alkyl; And 2020/175968 1»（：1^1{2020/002925

Compound, isomer thereof, solvate thereof, hydrate thereof, or Pharmaceutically acceptable salts. [Claim 9] The method of claim 1, High;

Compound, isomer thereof, solvate thereof, hydrate thereof, or Pharmaceutically acceptable salts. [Claim] In paragraph 1, The compound represented by Formula 1 is any one selected from the group of the following compounds, Compound, isomer thereof, solvate thereof, hydrate thereof, or Pharmaceutically acceptable salts: <1> (1/%4thyl-( )- 1-(6-(4 -fluoro-1 -pyrazole-1 -yl)pyridine-3 -yl)ethyl)-1-methoxy-4-( 4- ((5 -methyl-1 -pyrazol-3 -yl)amino)quinazoline-2 -yl)cyclohexane-1 -carboxamide; <2>（1 4 ）- -（ ）- 1- (6- (4 -fluoro-1 -pyrazole-1 -yl) pyridine-3 -yl) ethyl)-1- 2020/175968 1»（：1^1{2020/002925 Methoxy- 4- (4- ((5 -methyl-1 -pyrazole-3 -yl) amino) quinazoline-2 -yl) cyclohexanine- 1-carboxamide; <3>（1 4/?）-1 -methoxy- -（（幻- 1-（6-(4 -methyl-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-4- (4-((5 -methyl-1 -pyrazole-3 -yl)amino)quinazoline-2 -yl)cyclohexene-1-carboxamide; <4> (1 45)-1 -methoxy--()- 1- (6- (4 -methyl-1 -pyrazole-1 -yl) pyridine-3 -yl) ethyl )-4- (4- ((5 -methyl-1 -pyrazole-3 -yl) amino) quinazoline-2 -yl) cyclohexene-1-carboxamide; <5>（1/%45）- -（ ）-1-（6-（3,5 -dimethyl-1 acid-pyrazole-1 -yl）pyridine-3 -yl）ethyl)-1 -methoxy -4- (4- ((5 -methyl-1 -pyrazole-3 -yl) amino) quinazoline-2 -yl) cyclohexanose-1 -carboxamide; <6>（1 4/?）- -（ ）-1-（6-（3,5 -dimethyl-1 -pyrazole-1 -yl）pyridin-3 -yl）ethyl）-1 -methoxy- 4-（4-（（5 -methyl-1 -pyrazole-3 -yl）amino）quinazoline-2 -yl)cyclohexane-1 -carboxamide; <7>1 -Methoxy -4-(4-((5 -methyl-monoacid-pyrazol-3 -yl)amino)quinazoline-2 -yl)#(4-(thiazole-5 -yl) Benzyl) cyclohexene-1 -carboxamide; <8>-(4- (isooxazol-4 -yl) benzyl)-1 -methoxy-4- (4- ((5 -methyl-1 -pyrazole- 3-yl) amino) quinazoline-2 -Sun) Cyclohexanine-1 -Carboxamide; <9>（1 4及）- 4-（4-（（5 -cyano-1 -pyrazole-3 -yl）amino）quinazoline- 2 -yl)-八 （¾-1-（6-（ 4 -Fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-1 -methoxycyclo hexane-1 -carboxamide; <10> (1/%4thyl-( )- 1-(6-(4 -fluoro-1 -pyrazole-1 -yl)pyridine-3 -yl)ethyl)-1-methoxy-4-( 4-((5-(trifluoromethyl)-1 -pyrazole-3 -yl)amino)quinazoline-2 -yl)cyclohexene-1 -carboxamide; <11>（1 4及）- -（ ）- 1-（6-（4 -fluoro-1 -pyrazole-1 -yl）pyridine-3 -yl)ethyl)- 1-methoxy- 4-（ 4-((5-(trifluoromethyl)-1 -pyrazole-3 -yl)amino)quinazoline-2 -yl)cyclohexene-1 -carboxamide; <12>（1/%4 ）-4-（4-（(5 -cyclopropyl-1 -pyrazole-3 -yl)amino）quinazoline- 2-yl)- -（（5）-1-（ 6-(4 -fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-1 -methoxy cyclohexene-1 -carboxamide; <13>（1 4）- 4-（4-（（5 -cyclopropyl-1 -pyrazole-3 -yl）amino）quinazoline- 2-yl)- -（（5）-1-（6- (4 -fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-1 -methoxy cyclohexene-1 -carboxamide; <14> (1/%4thyl-()- 1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridine-3 -yl)ethyl)- 1-methoxy -4-( 4-((5-methyl-monoacid-pyrazole-3-yl)amino)furo[3,2-suppyrimidine-2-yl)cyclohexane-1-carboxamide; <15>（1 4及）- -（（幻- 1-（6-（4-fluoro-1 -pyrazole-1 -yl）pyridine-3-yl）ethyl）- 1-methoxy-4 （4-（（5-methyl-monoacid-pyrazole-3-yl）amino）furo[3, 2-suppyrimidine-2-yl) 2020/175968 1»（：1^1{2020/002925 Iclohaxein-1 -carboxamide; <16> (1/%4thyl-( )- 1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridine-3 -yl)ethyl)-1-methoxy -4-( 4- ((5 -methyl-1 -pyrazole-3 -yl) amino) thieno[2, 3 -suppyrimidine- 2-yl) cyclohexene-1 -carboxide; <17>（1 4及）- -（ ）- 1-（6-（4 -fluoro-1 -pyrazole-1 -yl）pyridine-3 -yl)ethyl)- 1-methoxy -4-（ 4- ((5 -methyl-1 -pyrazole-3 -yl) amino) thieno[2, 3 -suppyrimidine- 2-yl) cyclohexene-1 -carboxide; <18> (1/%4thyl-( )- 1-(6-(4 -fluoro-1 -pyrazole-1 -yl)pyridine-3 -yl)ethyl)-1-methoxy -4-( 4- ((5 -methyl-1 -pyrazole-3 -yl) amino) thieno[3, 2 -suppyrimidine-2 -yl) cyclohexene-1 -carboxide; <19>（1 4及）- -（ ）- 1-（6-（4 -fluoro-1 -pyrazole-1 -yl）pyridin-3 -yl）ethyl)- 1-methoxy -4-（ 4- ((5 -methyl-1 -pyrazole-3 -yl) amino) thieno[3, 2 -suppyrimidine-2 -yl) cyclohexene-1 -carboxide; <20> (1/%4thyl-()- 1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridine-3 -yl)ethyl)-1-methoxy-4-( 9-Methyl-6-((5-methyl-monoacid-pyrazole-3-yl)amino)-9-acid-purine-2-yl)cyclohexane-1-carboxamide; <21> (1，%4 tri-()-1-(6-(4 -fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-: 1-methoxy-4 (7 -Methyl- 4- ((5 -methyl-monoacid-pyrazole-3 -yl)amino) -7-acid-pyrrolo[2, 3]pyrimidine-2 -yl)cyclohexene- 1- Carboxide; <22>（1 4及）- -（ ）- 1-（6-（4 -fluoro-1 -pyrazole-1 -yl）pyridine-3 -yl)ethyl）- 1-methoxy- 4-（ 7 -Methyl- 4- ((5 -methyl-monoacid-pyrazole-3 -yl)amino) -7-acid-pyrrolo[2, 3]pyrimidine-2 -yl)cyclohexene- 1 -car Copy id; <23> -Benzyl- 4- (4- ((5 -methyl-1 -pyrazole-3 -yl) amino) quinazolin-2 -yl) cyclohexene-1 -carboxamide; <24>-(4 -methoxybenzyl)-4- (4- ((5 -methyl-1 -pyrazole-3 -yl) amino) quinazoline-2-yl) cyclohexene-1 -carboxide ; <25>（1 4及）- -（ ）- 1-（6-（4 -fluoro-1 -pyrazole-1 -yl）pyridine-3 -yl)ethyl）- 4- （4-（（5 -Methyl-1 -pyrazole-3 -yl)amino)quinazoline-2 -yl)cyclohexene-1 -carboxamide; <26>（1，%4 thio-（ ）-1-（6-（4 -fluoro-1 -pyrazole-1 -yl）pyridin-3 -yl）ethyl）- 4- （4-（（5 -Methyl-1 -pyrazole-3 -yl)amino)quinazoline-2 -yl)cyclohexene-1 -carboxamide; <27> (Thi-(1_(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3-yl)ethyl)-4-methoxy-1-(4-((5-methyl) -Monoacid-pyrazole-3 -yl) amino) quinazoline-2 -yl) piperidine-4 -carboxamide; <28>（5）-1-（4-（（5 -cyclopropyl-1 -pyrazole-3 -yl)amino）quinazoline-2 -yl)- -(1-（6-（4 -fluoro -1 -pyrazole-1 -yl) pyridine-3 -yl) ethyl)-4 -methoxypiperidine _4 -carboxamide; 2020/175968 1»（：1^1{2020/002925 <29>（5）-1-（4-（（5-cyclobutyl -1 -pyrazole-3 -yl）amino）quinazoline-2 -yl)--（1-（6-（4-fluoro -1 -pyrazole-1 -yl) pyridine-3 -yl) ethyl)-4 -methoxypiperidine-4 -carboxamide; <30> (Thi-(1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-4 -methoxy-1-(7-methyl-4- ((5 -methyl-1 -pyrazole-3 -yl)amino) -7 -pyrrolo[2,3-suppyrimidine-2 -yl)piperidine-4 -carboxamide; <31> (5)-1-(4-((5 -cyclopropyl-1 -pyrazole-3 -yl)amino)-7 -methyl-7好-pyrrolo[2,3-suppyrimidine-2 -Yl)- -(1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-4 -methoxypiperidine-4 -carboxamide; <32> (5)-1-(4-((5 -cyclobutyl -1 -pyrazole-3 -yl)amino) -7 -methyl-7好-pyrrolo [2, 3 -bopyrimidine-2 -Yl)--(1- (6- (4 -fluoro-1 -pyrazole-1 -yl) pyridine-3 -yl) ethyl)-4 -methoxypiperidine-4 -carboxamide; <33> (thin-(1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3-yl)ethyl)-4-methoxy-1-(4-((5-) Methyl-1 -pyrazole-3 -yl) amino) furo[3, 2] pyrimidine-2 -yl) piperidine-4 -carboxamide; <34> (5)-1-(4-((5 -cyclopropyl-1 -pyrazole-3 -yl)amino)furo[3, 2]pyrimidine-2 -yl)- -(1-(6 -(4 -fluoro-1 -pyrazole-1 -yl) pyridine-3 -yl) ethyl) -4 -methoxypiperidine-4 -carboxamide; <35>（5）-1-（4-（（5-cyclobutyl-1 -pyrazole-3 -yl）amino）furo[3, 2] pyrimidine-2 -yl)- -（1-（ 6-(4 -fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-4 -methoxy piperidine-4 -carboxamide; <36> (Thi-(1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-4-methoxy-1-(4-((5 -) Methyl-1 acid-pyrazole-3 -yl) amino) thieno[3, 2] pyrimidine-2 -yl) piperidine-4 -carboxamide; <37> (5)-1-(4- ((5 -cyclopropyl-1 -pyrazole-3 -yl) amino) thieno[3, 2] pyrimidine-2 -yl)--(1- (6- (4-fluoro-1 -pyrazole-1 -yl) pyridine-3 -yl) ethyl) -4-methoxypiperidine-4 -carboxamide; <38>（5）-1-（4-（（5-cyclobutyl-1 -pyrazole-3 -yl）amino）thieno[3, 2]pyrimidine-2 -yl)- -（1 -(6- (4-fluoro-1 -pyrazole-1 -yl) pyridine-3 -yl) ethyl)-4 -methoxypiperidine-4 -carboxamide; <39> (Thi-(1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3-yl)ethyl)-4-methoxy-1-(4-((5-) Methyl-1 acid-pyrazole-3 -yl) amino) thieno[2, 3] pyrimidine-2 -yl) piperidine-4 -carboxamide; <40> (5)-1-(4- ((5 -cyclopropyl-1 -pyrazole-3 -yl) amino) thieno[2, 3] pyrimidine-2 -yl)--(1- (6- (4-fluoro-1 -pyrazole-1 -yl) pyridine-3 -yl) ethyl) -4-methoxypiperidine-4 -carboxamide; <41>（5）-1-（4-（（5-cyclobutyl-1 -pyrazole-3 -yl）amino）thieno[2, 3]pyrimidine-2 -yl)- -（1 -(6- (4 -fluoro-1 -pyrazole- 1 -yl) pyridine-3 -yl) ethyl)-4 -me 的 2020/175968 1» (: 1^1 {2020/002925 Toxipiperidine-4 -carboxamide; <42> (Thi-(1_(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-4-methoxy-1-(7-methyl-6-( (5 -methyl-1 -pyrazole-3 -yl) amino)-7 -purine -2 -yl) piperidine-4-carboxamide; <43> (5)-1-(6-((5 -cyclopropyl-1 -pyrazole-3 -yl)amino) -7 -methyl-7 -purine -2 -yl)- -(1_（6- (4-fluoro-1 -pyrazole-1 -yl) pyridine-3 -yl) ethyl) -4 -methoxypiperidine-4 -carboxamide; <44> (Thi-(1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3-yl)ethyl)-4-methoxy-1-(9-methyl-6- ((5 -methyl-1 -pyrazole-3 -yl) amino) -9 -purine -2 -yl) piperidine -4-carboxamide; <45> (5)-1-(6-((5 -cyclopropyl-1 -pyrazole-3 -yl)amino)-9 -methyl-9 -purine-2 -yl)- -(1-(6 -(4 -fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-4 -methoxypiperidine-4 -carboxamide; <46> -Benzyl-4 -methoxy- 1- (4- ((5 -methyl-1 -pyrazole-3 -yl) amino) quinazoline-2-yl) piperidine-4 -carboxamide; <47> Benzyl- 1- (4- ((5-methyl-monoacid-pyrazole-3 -yl) amino) quinazolin-2 -yl) piperidine-4 -carboxamide; <48> (Thi-(1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-1-(4-((5-methyl-1-pyra) Zol-3 -yl)amino)quinazoline-2 -yl)piperidine-4 -carboxamide; <49> (Thi-(1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3-yl)ethyl)-1-(7-methyl-4-((5-methyl) -1 -pyrazole-3 -yl) amino)-7 -pyrrolo [2, 3 -suppyrimidine-2 -yl) piperidine-4 -carboxamide; <50>（Thi-（1-（6-（4-fluoro-1 -pyrazole-1 -yl）pyridin-3-yl）ethyl）- 1-（4-（（5-methyl-1 -pyra） Zol-3 -yl) amino) thieno [3, 2 -suppyrimidine-2 -yl) piperidine-4-carboxamide; and <51> (Thi-(1-(6-(4-fluoro-1 -pyrazole-1 -yl)pyridin-3 -yl)ethyl)-1-(4-((5-methyl-1-pyra) Zol-3 -yl) amino) thieno [2, 3 -Appyrimidine-2 -yl) piperidine- 4-carboxamide. [Claim 11] A pharmaceutical composition for the prevention or treatment of cancer containing a compound represented by Chemical Formula 1, its isomer, its solvate, its hydrate, or its pharmaceutically acceptable salt as an active ingredient. [Claim 12] The method of claim 11,

2020/175968 1»（：1^1{2020/002925 KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), LCK, MAP3K2, MEK5, MERTK, MLK2, MLK3, NEK7, NEK9, PDGFRA, PDGFRB, PLK4 , PYK2, RET, RET(M918T), RET(V804L), RET(V804M), RIOK3, ROS1, RSK2, RSK3, SLK, SNARK, SRC, STK16, SYK, TIE1, TNK1, TNK2, TRKA, TRKB, TRKC, One or more proteins selected from the group consisting of TYK2, YES, and YSK4 A pharmaceutical composition characterized by exhibiting an inhibitory activity against kinase. [Claim 13] The method of claim 11, The compound is characterized in that it exhibits RET (ret proto-oncogene) enzyme inhibitory activity, a pharmaceutical composition. [Claim 14] The method of claim 11, The cancers are pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, medullary thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia. , Basal cell carcinoma, ovarian epithelial carcinoma, ovarian germ cell carcinoma, male breast cancer, brain cancer, Pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinal blastoma, choroidal melanoma, barter bulge cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cells Lung Cancer, Snow Cancer, Astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, Malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, primary site unknown cancer, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal interstitial cancer, Wilms cancer, breast cancer, sarcoma, penis cancer, pharyngeal cancer, pregnancy chorion disease, uterus Cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal carcinoma, auditory nerve sheath, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous Characterized by at least one cancer selected from the group consisting of epithelial cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer. , Pharmaceutical composition. [Claim 15] The method of claim 11, The cancer is characterized in that it is a cancer that expresses the RET fusion gene, a pharmaceutical composition.