KR20200105631A - Heteroaryl comprising N derivatives and pharmaceutical composition containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a heteroaryl derivative containing N, and a pharmaceutical composition for preventing or treating cancer containing the same as an active component, wherein the derivative exhibits high inhibitory activity on various protein kinases, and in particular, has excellent RET proto-oncogene enzyme inhibitory ability, and has an excellent inhibitory effect on the proliferation of medullary thyroid cancer cells and lung cancer cells expressing RET fusion genes, thereby being able to be usefully used for treating cancer, for example, medullary thyroid cancer or lung cancer, and in particular, being able to be usefully used for treating cancer in which RET fusion genes are expressed.

Description

Heteroaryl comprising N derivatives and pharmaceutical composition containing the same as an active ingredient {Heteroaryl comprising N derivatives and pharmaceutical composition containing the same as an active ingredient}

It relates to a heteroaryl derivative containing N and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.

Cancer incidence is related to changes in various environmental factors including chemicals, radiation, and viruses, oncogenes, tumor suppressor genes, and genes related to apoptosis and DNA repair. By understanding the mechanism, a new treatment, targeted chemotherapy, became possible.

Targeted therapies are generally made to target molecules characteristic of cancer cells to exert their effects, and the molecular targets are the signal transduction pathway, angiogenesis, and interstitial cells of cancer cells. (matrix), cell cycle regulator (cell cycle regulator), apoptosis (apoptosis) related genes. Currently used as important target therapeutics in treatment include tyrosine kinase inhibitors, signaling pathway inhibitors, and angiogenesis inhibitors.

Phosphorylation of proteins on tyrosine residues is an important component of intracellular signal transduction. Enzymes that can catalyze this reaction are called tyrosine kinase. A large number of transmembrane receptors contain domains with tyrosine kinase activity and are classified as receptor tyrosine kinase (RTK).

RTK transmits extracellular signals in a variety of processes, such as cell growth, differentiation, survival, and programmed cell death. In response to binding to extracellular ligands, RTKs generally dimerize to recognize the phosphorylated form of RTK, inducing intracellular signal transduction and autophosphorylation through interacting effectors. There are many members of this RTK family, one of which is the RET proto oncogene, which encodes the 120 kDa protein RET (a protein that rearranges during transfection). RET is a receptor for growth factors of the glial-inducible neurotrophic factor (GDNF) family. Two ligands for RET have been identified; GDNF and Nutlin (NTN). RET is activated when its ligand binds to a co-receptor, and then the complex interacts with RET (Eng, 1999 Journal Clinical Oncology: 17(1) 380-393).

Activation phosphorylates RET at tyrosine residues and induces signaling for cell growth and differentiation through the RAS-RAF and PI3 kinase pathways and possibly other pathways.

The point mutants that activate RET include three associated dominant inherited cancer syndromes; It is known to cause multiple endocrine neoplasms types 2A and 2B (MEN2A and MEN2B), and familial medullary thyroid cancer (FMTC) (Santoro et al. 2004 Endocrinology: 145, 5448-5451).

In almost all cases of MEN2A and some FTMCs, cysteine substitution occurs in the extracellular and proximal cysteine-rich domains, whereas in 95% of MEN2B there is a single at codon 918 on the kinase domain (M918T). Point mutation occurs. Codon 918 is believed to be located on the substrate recognition pocket in the catalytic core. It is believed that mutations at this site alter the structure of the active loop of the RET catalytic domain, thereby structurally activating RET. The M918T mutation is also found in sporadic medullary cancer, which is associated with the phenotype of advanced disease. In vitro studies show that mutations affect substrate specificity, indicating that RET recognizes and phosphorylates substrates favored 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 Cancer95, 62-66; Santoro et al. 1995 Science267, 381-383; Zhou et al. 1995 Nature273, 536- 539).

As mutations in the RET gene are identified in most of the MEN2 family, molecular diagnostic tests become possible and may also be useful for confirming clinical diagnosis. RET mutation testing can be performed using a protocol based on a 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).

Another member of the RTK family is the vascular endothelial growth factor receptor 2 (VEGFR2 (kinase insertion domain containing receptor, KDR (also referred to as Flk1))). VEGFR2 is a receptor for vascular endothelial growth factor (VEGF). VEGF has 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 vascular permeability (Connolly, et al. al. 1989 J. Biol. Chem 264,20017-20024). Antagonism of VEGF action by sequestration of antibodies and VEGF can inhibit tumor growth (Kim, et al. 1993 Nature 362,841-844). Heterogeneous disruption of the VEGF gene causes fatal defects in vascularisation (Carmeliet, et al. 1996 Nature 380435-439; Ferrara, et al. 1996 Nature 380439-442).

Binding of VEGF to VEGFR2 leads to receptor dimerisation, resulting in VEGFR2 autophosphorylation of certain intracellular tyrosine residues. Autophosphorylation increases the catalytic activity of tyrosine kinase and provides a potential docking site for cytoplasmic signaling such as phospholipase C-γ. This protein interaction mediates intracellular signaling essential to induce cellular responses to proliferation, survival and migration of VEGFR2, e.g., endothelial cells (Ryan et al. 2005 British Journal Cancer: 92 (Suppl. 1) S6 -S13).

Recognition of the important role of VEGF-mediated VEGFR2 signaling in pathological angiogenesis has led to the development of a variety of selective approaches to inhibit VEGFR2 activation. These include small molecule ATP-competitive tyrosine kinase inhibitors, which inhibit autophosphorylation and continuous intracellular signaling in inhibiting ATP binding (Ryan, 2005).

Quinazoline derivatives, which are inhibitors of the VEGF receptor tyrosine kinase, are described in international patent publications WO98/13354 and WO01/32651. In WO98/13354 and WO01/32651, compounds having some activity against endothelial growth factor receptor (EGFR) tyrosine kinase, and having activity against VEGF receptor tyrosine kinase are disclosed.

The compound 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline, which is a VEGFR2 tyrosine kinase inhibitor, is disclosed ( Wedge et al., 2002 Cancer Research 62,4645-4655). This compound is also known under the code number ZD6474 and the generic brand name Vandetanib, Zactima (registered trademark). Hereinafter, the compound is referred to as vandetanib.

Vandetanib was developed as a potent and reversible inhibitor of ATP-binding to VEGFR2 tyrosine kinase. In addition, vandetanib inhibits EGFR tyrosine kinase activity. The EGFR signaling pathway is also an important factor in cancer progression 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.

In 2002, it was reported that vandetanib is a potent inhibitor of ligand-dependent RET tyrosine kinase activity, and that it can inhibit the signaling and modification ability of RET. In addition, it has been reported that vandetanib has a potent growth inhibitory effect on RET-dependent thyroid tumor cell growth in vitro (Carlomagno et al. 2002 Cancer Research: 62, 7284-7290).

Vandetanib inhibited most of the mutated active forms of RET and also 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, accompanied by mutations in the RET gene that induce RET-dependent tumor cell growth. May be (Ryan, 2005).

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

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer containing as an active ingredient a heteroaryl derivative or isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof containing N will be.

Another object of the present invention is to provide a method for preventing or treating cancer containing N-containing heteroaryl derivatives or isomers thereof, solvates thereof, hydrates thereof, or pharmaceutically acceptable salts thereof as an active ingredient.

Another object of the present invention is the use of the heteroaryl derivative or isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the prevention or treatment of cancer. Is to provide.

To achieve the above object,

According to an aspect of the present invention, there is provided a compound represented by the following Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Formula 1,

R ¹ is cyano, C _1-6 Of haloalkyl, straight or branched C _1-6 Alkyl or C _3-7 cycloalkyl;

는 C_5-6의 방향족 고리 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 6원자의 방향족 헤테로 고리를 나타내고, 이 때, 상기 헤테로 방향족 고리는 하나 이상의 직쇄 또는 분지쇄의 C_1-6알킬로 치환될 수 있으며;

_Represents a C _5-6 aromatic ring or a 5 to 6 membered aromatic hetero ring containing at least one hetero atom selected from the group consisting of N, O and S, wherein the heteroaromatic ring is at least one May be substituted with straight or branched C _1-6 alkyl;

R ² is hydrogen or a straight or branched chain C _1-6 Alkoxy;

R ³ is hydrogen or straight or branched C _1-6 alkyl;

R ⁴ is hydrogen, straight or branched C _1-6 Alkoxy or a 5 to 6 membered heteroaryl containing at least one hetero atom selected from the group consisting of N, O and S, and the heteroaryl is halogen or a straight or branched C _1-6 One or more may be substituted with a substituent selected from the group consisting of alkyl; And

B ¹ and B ² are independently N or CH).

According to another aspect of the present invention, a pharmaceutical composition for preventing or treating cancer containing as an active ingredient a compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to provide.

According to another aspect of the present invention, administering to a subject in need a pharmaceutical composition containing the compound represented by Formula 1, its isomer, solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient It provides a method of preventing or treating cancer comprising a.

According to another aspect of the present invention, a compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutical thereof, for use in the manufacture of a medicament for use in the prevention or treatment of cancer. Provides acceptable salt use.

The compound represented by Formula 1 according to the present invention exhibits high inhibitory activity against various protein kinases, and in particular, has excellent RET (ret proto-oncogene) enzyme inhibitory ability, and expresses RET fusion gene for thyroid cancer cells and lung cancer cells. Since its proliferation inhibitory effect is excellent, it can be usefully used in the treatment of cancer, for example, thyroid 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.

Hereinafter, the present invention will be described in detail.

On the other hand, embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, embodiments of the present invention are provided in order to more completely explain the present invention to those having average knowledge in the art. Furthermore, "including" a certain component throughout the specification means that other components may be further included, rather than excluding other components unless specifically stated to the contrary.

In the present specification, “halogen” may be F, Cl, Br, or I.

In the present specification, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with one or more halogen atoms as defined herein. Examples of the haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and N -butyl independently substituted with one or more halogen atoms, such as F, Cl, Br, I. .

In the present specification, "alkyl" may mean a linear or branched acyclic saturated hydrocarbon consisting of carbon atoms. Representative -(C _1-8 alkyl) include -methyl, -ethyl, -N- propyl, -N- butyl, -N- pentyl and -N- hexyl, -N- heptyl and -N- octyl; Branched chain saturated alkyl is -isopropyl, -secondary (sec)-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl, and the like. -(C _1-8 alkyl) may or may not be substituted. For example, a C _1-8 alkyl group may be substituted with phenyl to form a benzyl group.

In the present specification, "cycloalkyl" may refer to a non-aromatic saturated or unsaturated carbon ring. Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1 ,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctyl and cyclooctadienyl are included, but are not limited thereto. The cycloalkyl group may or may not be substituted. In one embodiment, this cycloalkyl group may be a C _3-8 cycloalkyl group.

In the present specification, “aryl” may mean any functional group or substituent derived by removing one hydrogen from an aromatic hydrocarbon ring. The aryl group may be a monocyclic aryl group or a polycyclic aryl group. The number of ring carbon atoms in the aryl group 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 the aryl group include phenyl group, naphthyl group, fluorenyl group, anthracenyl group, phenanthryl group, biphenyl group, terphenyl group, quarterphenyl group, quincphenyl group, sexyphenyl group, triphenylene group, pyrenyl group, benzofluoranthenyl group, and Although senilgi and the like can be illustrated, it is not limited to these.

In the present specification, "heteroaryl" may be an aryl cyclic group including at least one of O, N, P, Si, and S as a heterogeneous element. The number of ring carbon atoms of the heteroaryl group may be 2 or more and 30 or less or 2 or more and 20 or less. Hetero aryl can be monocyclic hetero aryl or polycyclic hetero aryl. Polycyclic hetero aryl may have, for example, a bicyclic or tricyclic structure. Examples of heteroaryl include thienyl, thiophene, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyridinyl, bipyridyl , Pyrimidyl, triazinyl, triazolyl, acridyl group, pyridazinyl group, pyrazinyl, quinolinyl, quinazoline, quinoxalinyl, phenoxazyl, phthalazinyl, pyrimidinyl, pyridopyrimidinyl , Pyrido pyrazinyl, pyrazino pyrazinyl, isoquinoline, indole, carbazole, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazopyrazinyl or pyrazolopyridinyl Il, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole group, benzoxazole, benzoimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophenyl, thieno Thiophene, benzofuranyl, phenanthroline, isoxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, tetrazolyl, phenothiazinyl, dibenzosilol and dibenzofuranyl, etc. It is not limited to these. In one embodiment of the present invention, the heteroaryl may also include an aryl ring fused to a heterocycloalkyl ring or a bicyclic heterocyclo-aryl including a heteroaryl fused to a cycloalkyl ring.

An aspect of the present invention provides a compound represented by the following Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

(In Formula 1,

R ¹ is cyano, C _1-6 Of haloalkyl, straight or branched C _1-6 Alkyl or C _3-7 cycloalkyl;

는 C_5-6의 방향족 고리 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 6원자의 방향족 헤테로 고리이고, 이 때, 상기 헤테로 방향족 고리는 하나 이상의 직쇄 또는 분지쇄의 C_1-6알킬로 치환될 수 있고;

Is a C _5-6 aromatic ring or a 5 to 6 membered aromatic hetero ring containing at least one hetero atom selected from the group consisting of N, O and S, wherein the heteroaromatic ring is at least one straight chain Or may be substituted with branched C _1-6 alkyl;

R ² is hydrogen or a straight or branched chain C _1-6 Alkoxy;

R ³ is hydrogen or straight or branched C _1-6 alkyl;

R ⁴ is hydrogen, straight or branched C _1-6 Alkoxy or a 5 to 6 membered heteroaryl containing at least one hetero atom selected from the group consisting of N, O and S, and the heteroaryl is halogen or a straight or branched C _1-6 One or more may be substituted with a substituent selected from the group consisting of alkyl; And

B ¹ and B ² are independently N or CH).

는

,

또는

이고, 여기서 상기 X¹ 또는 X⁴는 N, O 또는 S이며, 상기 X² 또는 X³은 CH 또는 N이고, 상기 R⁵ 또는 R⁶은 각각 X¹ 또는 X⁴가 N인 경우, 직쇄 또는 분지쇄의 C_1-6의 알킬이고, X¹ 또는 X⁴가 O 또는 S인 경우, 존재하지 않을 수 있다. 보다 구체적으로,

은

,

,

,

,

,

, 또는

일 수 있다.Specifically, the

Is

,

or

And, wherein X ¹ or X ⁴ is N, O or S, X ² or X ³ is CH or N, and R ⁵ or R ⁶ is a straight chain or branched when X ¹ or X ⁴ is N, respectively Of chain C _1-6 Alkyl, and when X ¹ or X ⁴ is O or S, it may not be present. More specifically,

silver

,

,

,

,

,

, or

Can be

,

,

,

, 또는

일 수 있다.Specifically, R ⁴ is hydrogen, methoxy, pyrazolyl, thiazolyl or isoxazolyl, and the pyrazolyl, thiazolyl and isoxazolyl are halogen and linear C _1-3 One or more substituents selected from the group consisting of alkyl may be substituted, and more specifically, R ⁴ is hydrogen, methoxy,

,

,

,

, or

Can be

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

R ¹ is cyano, of C _1-6 Haloalkyl, a linear C _1-6 Alkyl or C _3-7 cycloalkyl;

는

,

또는

이고, 여기서 상기 X¹ 또는 X⁴는 N, O 또는 S이며, 상기 X² 또는 X³은 CH 또는 N이고, 상기 R⁵ 또는 R⁶은 각각 X¹ 또는 X⁴가 N일 때, 직쇄의 C_1-6의 알킬이고, X¹ 또는 X⁴가 O 또는 S일 때, 존재하지 않으며;

Is

,

or

And, wherein X ¹ or X ⁴ is N, O or S, X ² or X ³ is CH or N, and R ⁵ or R ⁶ is each of X ¹ or X ⁴ when N is a straight chain C _Is an alkyl of _1-6 , and when X ¹ or X ⁴ is O or S, does not exist;

R ² is hydrogen or straight-chain C _1-6 alkoxy;

R ³ is hydrogen or straight-chain C _1-6 alkyl;

R ⁴ is hydrogen, a 5-membered heteroaryl containing one or more heteroatoms selected from the group consisting of hydrogen, straight-chain C _1-6 alkoxy or N, O and S, and the heteroaryl is halogen and straight-chain C _1-6 may be substituted with one or more substituents selected from the group consisting of alkyl; And

B ¹ and B ² may independently be N or CH.

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

R ¹ is cyano, of C _1-3 Haloalkyl, straight-chain C _1-3 Alkyl or C _3-6 cycloalkyl;

는

,

또는

이고, 여기서 상기 X¹ 또는 X⁴는 N, O 또는 S이며, 상기 X² 또는 X³은 CH 또는 N이고, 상기 R⁵ 또는 R⁶은 각각 X¹ 또는 X⁴가 N일 때, 직쇄의 C_1-3의 알킬이고, X¹ 또는 X⁴가 O 또는 S일 때, 존재하지 않으며;

Is

,

or

And, wherein X ¹ or X ⁴ is N, O or S, X ² or X ³ is CH or N, and R ⁵ or R ⁶ is each of X ¹ or X ⁴ when N is a straight chain C _1-3 of Alkyl, when X ¹ or X ⁴ is O or S, is absent;

R ² is hydrogen or straight chain C _1-3 Alkoxy;

R ³ is hydrogen or straight chain C _1-3 Alkyl;

R ⁴ is hydrogen, methoxy, pyrazolyl, thiazolyl or isoxazolyl, and the pyrazolyl, thiazolyl and isoxazolyl are halogen and linear C _1-3 One or more may be substituted with a substituent selected from the group consisting of alkyl; And

B ¹ and B ² may independently be N or CH.

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

R ¹ is cyano, trifluoromethyl, linear C _1-3 Alkyl or C _3-5 cycloalkyl;

는

,

또는

이고, 여기서 상기 X¹ 또는 X⁴는 N, O 또는 S이며, 상기 X² 또는 X³은 CH 또는 N이고, 상기 R⁵ 또는 R⁶은 각각 X¹ 또는 X⁴가 N일 때, 메틸이고, X¹ 또는 X⁴가 O 또는 S일 때, 존재하지 않으며;

Is

,

or

And wherein X ¹ or X ⁴ is N, O or S, X ² or X ³ is CH or N, and R ⁵ or R ⁶ is methyl when X ¹ or X ⁴ is N, respectively, Does not exist when X ¹ or X ⁴ is O or S;

R ² is hydrogen or straight chain C _1-3 Alkoxy;

R ³ is hydrogen or straight chain C _1-3 Alkyl;

,

,

,

, 또는

이고; 및R ⁴ is hydrogen, methoxy,

,

,

,

, or

ego; And

B ¹ and B ² may independently be N or CH.

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

R ¹ is cyano, trifluoromethyl, methyl or C _3-4 cycloalkyl;

은

,

,

,

,

,

, 또는

이고

silver

,

,

,

,

,

, or

ego

R ² is hydrogen or methoxy;

R ³ is hydrogen or methyl;

,

,

,

, 또는

이고; 및R ⁴ is hydrogen, methoxy,

,

,

,

, or

ego; And

B ¹ and B ² may independently be N or CH.

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

When R ¹ is C _3-4 cycloalkyl,

은

,

,

,

,

,

, 또는

이고

silver

,

,

,

,

,

, or

ego

R ² is of straight chain C _1-3 Alkoxy, specifically methoxy;

R ³ is of straight chain C _1-3 Alkyl, specifically methyl;

이고; R ⁴ is pyrazolyl substituted with halogen, specifically pyrazolyl substituted with fluoro (F), and more specifically

ego;

B ¹ is N or CH; And

B ² may be N.

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

When R ¹ is cyano, trifluoromethyl,

은

이고

silver

ego

R ² is linear C _1-6 alkoxy, specifically C _1-3 alkoxy, and more specifically methoxy;

R ³ is straight-chain C _1-6 alkyl, specifically C _1-3 alkyl, and more specifically methyl;

이고; R ⁴ is pyrazolyl substituted with halogen, specifically pyrazolyl substituted with fluoro (F), and more specifically

ego;

B ¹ is CH; And

B ² may be N.

Examples of the compound represented by Formula 1 according to the present invention include Example Compounds 1 to 51 listed in [Table 1] to [Table 5] described below, or a pharmaceutically acceptable salt thereof:

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic 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, etc. Get from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Rate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate , Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate , Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

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

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

Further, the present invention includes not only the compound represented by Formula 1 and its pharmaceutically acceptable salts, but also solvates, optical isomers, hydrates, etc. that may be prepared therefrom.

The term "hydrate" is a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force. Or its salt. The hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force. The hydrate may contain 1 equivalent or more, preferably 1 to 5 equivalents of water. These hydrates may be prepared by crystallizing the compound represented by Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof from water or a solvent containing water. The term "solvate" refers to 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-toxic, and/or suitable solvents for administration to humans. The term “isomer” refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula, but structurally or sterically different. Such isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers. All these isomers and mixtures thereof are also included within the scope of the present invention.

Another aspect of the invention, as shown in Scheme A below,

Preparing a compound represented by Formula 4 by reacting a compound represented by Formula 2 with a compound represented by Formula 3 (step 1);

Reducing the compound represented by Formula 4 to prepare a compound represented by Formula 5 (step 2);

Preparing a compound of Formula 7 by reacting a compound represented by Formula 5 with a compound represented by Formula 6 (step 3); And

It provides a method for preparing the compound of Formula 1 including removing the protecting group of the compound represented by Formula 7 (step 4).

[Scheme A]

In Scheme A above,

, R¹, R², R³, R⁴ 및 B²는 상기 화학식 1에서 정의한 바와 같고;

, R ¹ , R ² , R ³ , R ⁴ and B ² are as defined in Formula 1 above;

X is halogen, and THP represents tetrahydropyran used as a protecting group.

Step 1 is a step of preparing a compound represented by Formula 4 in which a carbon-carbon bond is formed by reacting a halogen of the compound represented by Formula 2 with an organic boron of the compound represented by Formula 3. It is not limited as long as it reacts to form a carbon-carbon bond, and a method well known to those skilled in the art may be used. 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.

Step 2 is a step of reducing the ester to a carboxylic acid by reducing the double bond of the compound represented by Formula 4 to a single bond, and a reduction method well known in the art may be used.

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 reaction between the amino group and the carboxyl group is You can use methods well known in the industry.

Step 4 is a step of preparing the compound of Formula 1 by deprotecting the amine protecting group of the compound represented by Formula 7 in the reaction scheme, and is not limited as long as it is a condition capable of removing the amine protecting group, and a method well known to those skilled in the art may be used. . 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.

Another aspect of the invention, as shown in Scheme B below,

Preparing a compound represented by Formula 9 by reacting a compound represented by Formula 2 with a compound represented by Formula 8 (step 1);

Reducing the compound represented by Formula 9 to prepare a compound represented by Formula 10 (step 2);

Reacting a compound represented by Formula 10 with a compound represented by Formula 6 to prepare a compound represented by Formula 11 (step 3); And

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

[Scheme B]

상기 반응식 B에서,

In Scheme B above,

, R¹, R², R³, R⁴ 및 B² 는 상기 화학식 1에서 정의한 바와 같고;

, R ¹ , R ² , R ³ , R ⁴ and B ² are as defined in Formula 1 above;

X is a halogen and represents tetrahydropyran used as a THP protecting group.

Step 1 is a step of preparing a compound represented by Formula 9 in which a carbon-amine bond is formed by reacting a halogen of the compound represented by Formula 2 with an amine of the compound represented by Formula 8. It is not limited as long as it is a condition for forming a carbon-amine bond, and a method well known to those skilled in the art may 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.

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

Step 3 is a step of preparing a compound represented by Formula 11 including an amide bond by reacting a carboxyl group of the compound represented by Formula 10 with an amino group of the compound represented by Formula 6, wherein the reaction between the amino group and the carboxyl group is You can use methods well known in the industry.

Step 4 is a step of preparing the compound of Formula 1 by deprotecting the amine protecting group of the compound represented by Formula 11 in the reaction scheme, and is not limited as long as it is a condition capable of removing the amine protecting group, and a method well known to those skilled in the art may 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.

Each compound represented by Formula 1 according to the present invention can be prepared according to the preparation method shown in the following Examples, but this is only an example, and is not limited thereto, and each preparation step can use a method well known to those skilled in the art. have.

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

The compounds are AMPK-alpha1, AMPK-alpha2, ARK5, AURKA, AURKB, AURKC, AXL, BLK, CSF1R, CSNK2A2, DAPK1, DAPK3, EPHB6, FGFR1, FGFR2, FGFR3, FGFR3 (G697C), FLT3, FGR 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 may exhibit inhibitory activity against one or more protein kinases selected from the group consisting of.

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

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 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, colon cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, barter bulge , Bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, non-sinus cancer, non-small 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 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, unknown primary cancer, gastric lymphoma, stomach cancer, gastric carcinoma, Gastrointestinal interstitial cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, pregnancy villous 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, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, It may be one or more selected from the group consisting of hematologic cancer and thymic cancer.

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

The compound represented by Formula 1 according to the present invention exhibits high inhibitory activity against various protein kinases (see Experimental Example 1), and in particular, has excellent inhibitory activity of RET (ret proto-oncogene) enzymes (see Experimental Example 2), and RET Since the proliferation inhibitory effect of thyroid cancer cells and lung cancer cells expressing a fusion gene is excellent (see Experimental Example 3), it can be usefully used in the treatment of cancer, for example, thyroid cancer or lung cancer, and in particular, RET fusion gene Can be usefully used in the treatment of cancer in which is expressed.

In the pharmaceutical composition according to the present invention, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations at the time of clinical administration, more preferably parenteral It can be a formulation. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose, or lactose ( lactose), gelatin, etc. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as humectants, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations upon clinical administration. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose, or lactose ( lactose), gelatin, etc. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as humectants, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.

The pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection It depends on how to do it.

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 together with a stabilizer or buffer to prepare a solution or suspension, and the ampoule or vial unit dosage form It can be manufactured with The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances, which are conventional methods of mixing, granulation. It can be formulated according to the method of painting or coating.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and troches.These formulations include diluents (e.g., lactose) in addition to the active ingredients. , Dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salt and/or polyethylene glycol). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, boron such as starch, agar, alginic acid or sodium salt thereof. It may contain release or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.

The pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual therapeutic agent or used in combination with other anticancer agents in use. I can.

In another aspect of the present invention, the step of administering to a subject in need a pharmaceutical composition containing a compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient It provides a method for preventing or treating cancer, including.

Another aspect of the present invention is the use of a compound represented by Formula 1 or an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention or treatment of cancer. To provide.

Hereinafter, the present invention will be described in detail by examples and experimental examples.

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.

<Medium pressure liquid chromatography (MPLC) for purification>

Medium pressure liquid chromatography was performed using TELEEDYNE ISCO's CombiFlash Rf +UV.

<Analysis LC-MS (ACQUITY UPLC H-Class Core System)>

Waters' UPLC system (ACQUITY UPLC PDA Detector) was equipped with a Waters' mass QDA Detector was used. The column used was ACQUITY UPLC®BEH C18 (1.7㎛, 2.1X50mm) from Waters, and the column temperature was carried out at 30℃.

Water containing 0.1% formic acid was used for mobile phase A, and acetonitrile containing 0.1% formic acid was used for mobile phase B.

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

<Prep-150 LC System for purification (Preparative-Liquid chromatography UV spectrometry)>

Waters' Prep 150 LC system (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector III) manufactured by Waters was used. The column used was XTERRA®Prep RP18 OBD ^TM (10㎛, 30X300mm) from Waters, and the column temperature was carried out at room temperature.

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

<SFC conditions for separation of chiral compounds>

The 80Q Preparative SFC system manufactured by Waters was used. The column used was CHIRALPAK ^® AS (10㎛, 250X30mm ID) of DAICEL, and the column temperature was carried out at room temperature. It flowed for 130 minutes using methanol to which CO ₂ was added as a mobile phase and 0.1% aqueous ammonia was added as a co-solvent.

<NMR analysis>

NMR analysis was performed using AVANCEIII 400 or AVANCEIII 400 HD manufactured by Bruker, and the data are expressed in parts per million (δ) (ppm).

Commercially available reagents used were used without further purification. Room temperature in the present invention refers to a temperature of about 20 ~ 25 ℃. Concentration under reduced pressure or distillation of the solvent was performed using a rotary evaporator.

<Production Example 1> Methyl 1-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxy Manufacture of rate

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

[Scheme 1]

Step 1: Dissolve 1,4-dioxapyrro[4.5]decane-8-one (30g, 192mmol) in bromoform (388g, 1.54mol), cool to 0 ^o C, and potassium hydroxide (86g, 1.54mol) Was dissolved in methanol (500ml) and slowly added dropwise to the reaction mixture for 4 hours. After stirring at 25 ^o C for 12 hours, water (500ml) was added to the reaction mixture, the organic solvent was concentrated under reduced pressure, extracted with ethyl acetate and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to obtain a liquid methyl 8-methoxy-1,4-dioxapyrro[4.5]decane-8-carboxy. Rate (28g, 47%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.97 (t, J = 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)

Step 2: Methyl 8-methoxy-1,4-dioxapyrro[4.5]decane-8-carboxylate (28g, 121mmol) was dissolved in 1,4-dioxane (300ml) and 6M HCl (260ml) was added. It was added and stirred at room temperature for 6 hours. Cold water was added to the reaction mixture, extracted with ethyl acetate and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain a liquid methyl 1-methoxy-4-oxocyclohexane-1-carboxylate (18.6 g, 100 mmol, 82%).

¹ H NMR (400 MHz, CDCl ₃ ) δ = 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)

Step 3: Pyridine (3.74g, 47mmol) is diluted in toluene (100ml), Tf ₂ O (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) was slowly added dropwise, followed by stirring at 40 ^o C for 12 hours. The reaction mixture was concentrated under reduced pressure and then purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to obtain liquid methyl 1-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3. -En-1-carboxylate (3.2 g, 23%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 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)

Step 4: Methyl 1-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (2.6 g, 8.17 mmol) and 4,4,5,5 -Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.49g, 9.8mmol) , KOAc (3.2 g, 32.7 mmol), Pd(dppf)Cl ₂ . CH ₂ Cl 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, concentrated under reduced pressure, and then purified by medium pressure liquid chromatography (tetrahydrofuran/n-hexane) to obtain a liquid methyl 1-methoxy-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (2.4 g, 8.1 mmol) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 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)

<Production Example 2>( S )-1-(6-(4-fluoro-1 H Preparation of -pyrazol-1-yl)pyridin-3-yl)ethan-1-amine

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

[Scheme 2]

Step 1: 1-(6-chloropyridin-3-yl)ethan-1-one (34g, 218mmol), K ₂ CO ₃ (90g, 655mmol) was dissolved in DMF (300ml) and 4-fluoro-1 H -Pyrazole (28g, 228mmol) was added and stirred at 100 ^o C for 16 hours. The reaction mixture was poured into water (1L) to precipitate a solid. Filtration gave a solid 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one (37.4g, 83%).

MS (m/z): 206.13 [M+1] ⁺ , UPLC rt (min): 1.47

Step 2: 1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethan-1-one (32g, 155mmol) and ( R )-(+)-2 -Methyl-2-propanesulfinamide (64g, 530mmol) was dissolved in toluene (640ml), Ti(OEt) ₄ (213g, 935mmol) was added, followed by stirring at 110 ^o C for 16 hours. Water (80ml) was added to the reaction mixture, extracted with ethyl acetate and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and purified by medium pressure liquid chromatography (ethyl acetate / n- hexane) to a solid (R, E) - N - (1- (6- ( 4-fluoro -1 H -Pyrazol-1-yl)pyridin-3-yl)ethylidine)-2-methylpropane-2-sulfinamide (31g, 53%) was obtained.

MS (m/z): 309.14 [M+1] ⁺ , UPLC rt (min): 1.55

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.88 (d, J = 2.0 Hz, 1H), 8.45-8.43 (dd, J = 4.6, 0.6 Hz, 1H), 8.30-8.28 (dd, J = 8.8, 2.4 Hz, 1H), 8.03-7.99 (d, J = 8.8 Hz, 1H), 7.65-7.64 (d, J = 3.6 Hz, 1H), 2.81 (s, 3H), 1.35 (s, 9H)

Step 3: (R, E) - N - (1- (6- ( 4-fluoro -1 H - pyrazol-1-yl) pyridin-3-yl) ethylidine) -2-methyl-propane -2 -Sulfinamide (31g, 100mmol) was dissolved in tetrahydrofuran (1000ml), cooled to -78 ^° C, and L- selectride (1M, 301.58mL) was slowly added dropwise for 30 minutes. After stirring at -78 ^o C for 1 hour, methanol and water were added to terminate the reaction. Then, the organic layer was combined by extraction with ethyl acetate and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to form a solid ( R ) -N -(( S )-1-(6-(4-fluoro-). 1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (24.4 g, 75%) was obtained.

MS (m/z): 311.21 [M+1] ⁺ , UPLC rt (min): 1.46

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.69-8.68 (dd, J = 4.4, 0.4 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 7.99-7.96 (dd, J = 8.4, 2.4 Hz, 1H), 7.93-7.92 (dd, J = 4.0, 0.4 Hz, 1H), 7.90-7.88 (m, 1H), 5.56-5.55 (d, J = 5.4 Hz, 1H), 4.57-4.51 (m , 1H), 1.53-1.47 (d, J = 6.8 Hz, 3H), 1.11 (s, 9H)

Step 4: ( R ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane- After dissolving 2-sulfinamide (22.8g, 73mmol) in 1,4-dioxane (200ml) and methanol (20ml), 4M HCl/1,4-dioxane (180ml) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, added dropwise to ethyl ether (100ml), filtered, and solid ( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethane -1-amine (17g, 67.8mmol) was obtained.

MS (m/z): 208.21 [M+1] ⁺ , UPLC rt (min): 0.76

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.72-8.69 (m, 4H), 8.61-8.60 (d, J = 2.4 Hz, 1H), 8.19-8.17 (m, 1H), 7.97-7.96 ( m, 1H), 7.95 (s, 1H), 4.55 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H)

<Production Example 3>( S )-1-(6-(4-methyl-1 H Preparation of -pyrazol-1-yl)pyridin-3-yl)ethan-1-amine

The title compound was prepared in a similar manner to Preparation Example 2. (Yield: 40%)

<Production Example 4> ( S )-1-(6-(3,5-dimethyl-1 H Preparation of -pyrazol-1-yl)pyridin-3-yl)ethan-1-amine

In a similar method to Preparation Example 2, the title compound was prepared through Reaction Scheme 3 below.

[Scheme 3]

Step 1: MS: m/z 216.1 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.90-8.89 (dd, J = 0.8, 2.4 Hz, 1H), 8.24-8.16 (dd, J = 2.4, 8.8 Hz, 1H), 7.95-7.89 (dd, J = 0.4, 8.4 Hz, 1H), 5.96 (s, 1H), 2.63 (d, J = 0.8 Hz, 3H), 2.59-2.53 (m, 3H), 2.23 (s, 3H)

Step 2: MS: m/z 319.3 [M+H] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.93-8.92 (d, J = 4.0 Hz, 1H), 8.40-8.37 (dd, J = 2.4, 8.8 Hz, 1H), 7.94-7.91 (d, J = 12.0 Hz, 1H), 6.17 (s, 1H), 2.76 (s, 3H), 2.63 (s, 3H), 2.21 (s, 3H), 1.23 (s, 9H)

Step 3: MS: m/z 321.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.40 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 2.4, 8.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 6.10 (s, 1H), 5.52 (d, J = 5.6 Hz, 1H), 4.53-4.50 (m, 1H), 2.56 (s, 3H), 2.19 (s, 3H), 1.52-4.50 (d, J = 6.8 Hz, 3H), 1.11 (s, 9H)

Step 4: MS: m/z 217.2 [M+H] ⁺

<Preparation Example 5> Preparation of (4-(thiazol-5-yl)phenyl)methanamine

The title compound was prepared through the method shown in Scheme 4 below.

[Scheme 4]

Step 1: tert -butyl N -[(4-bromophenyl)methyl]carbamate (2g, 6.99mmol) and thiazole (535.46mg, 6.29mmol) were dissolved in DMF (20ml) and then Pd(OAc) ₂ ( 313.82mg, 1.40mmol) and KOAc (2.06g, 20.97mmol) were added and stirred at 90 ^o C for 16 hours. Water (100ml) was added to the reaction mixture, extracted with ethyl acetate (100ml*2) and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/n-hexane), and the yellow solid tert -butyl (4-(thiazol-5-yl)benzyl)carbamate (400mg, 13.71%) was obtained.

MS: m/z 291.1 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.05 (s, 1H), 8.01 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 5.00 (br s, 1H), 4.33 (d, J = 5.2 Hz, 2H), 1.46 (s, 9H)

Step 2: tert -butyl N -[(4-thiazol-5-ylphenyl)methyl]carbamate (350mg, 1.21mmol) was dissolved in 4M HCl/ethylacetate (20mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, added dropwise to ethyl ether, and filtered to obtain a yellow solid (4-(thiazol-5-yl)phenyl)methanamine (310mg, crude, HCl salt).

MS: m/z 192.1 [M+H] ⁺

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

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

[Scheme 5]

Step 1: tert -butyl N -[(4-bromophenyl)methyl]carbamate (500mg, 1.75mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro Ran-2-yl)isooxazole (511.13mg, 2.62mmol) was dissolved in DMF (4ml) and then Pd(dppf)Cl ₂ ^. CH ₂ Cl ₂ (142.69 mg, 174.72 μmol), KF (304.53 mg, 5.24 mmol), and water (0.5 mL) were added and stirred at 50 ^° C for 30 minutes. Water (20ml) was added to the reaction mixture, extracted with dichloromethane (30ml*2) and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to form a white solid tert -butyl (4-(isooxazol-4-yl)benzyl)carbamate (164mg) , 34.22%) was obtained.

MS: m/z 275.2 [M+H] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.40 (s, 1H), 9.13 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H ), 4.12 (d, J = 6.0 Hz, 2H), 1.39 (s, 9H)

Step 2: tert -butyl (4-(isooxazol-4-yl)benzyl)carbamate (230mg, 838.45μmol) was dissolved in 4M HCl/ethylacetate (20mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, added dropwise to ethyl ether, and filtered to obtain a pale yellow solid (4-(isooxazol-4-yl)phenyl)methanamine (310mg, crude, HCl salt).

MS: m/z 192.1 [M+H] ⁺

<Production Example 7> 3-Amino-1 H -Preparation of pyrazole-5-carbonitrile

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

[Scheme 6]

Step 1: 3-nitro-1 H -pyrazole-5-carboxylic acid (5g, 31.8mmol) was dissolved in DMF, CDI (10.3g, 63.7mmol) was added, followed by stirring at room temperature for 30 minutes. 7M NH ₃ /MeOH (13.6ml) was added and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl ether and water to obtain a solid target compound 3-nitro-1 H -pyrazole-5-carboxamide (4.3 g, 87%).

MS (m/z): 157.05 [M+1] ⁺ , UPLC rt (min): 0.4

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 13.42 (s, 1H), 8.03 (d, J = 148.3 Hz, 1H), 7.64 (d, J = 45.7 Hz, 1H), 7.04 (s, 1H) ).

Step 2: After dissolving 3-nitro-1 H -pyrazole-5-carboxamide (1g, 6.4mmol) in pyridine (12ml), POCl ₃ (1.2ml) was added and stirred for 6 hours. The reaction mixture was added to ice water to terminate the reaction, extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure to form a solid 3-nitro-1 H -pyrazole-5-carbonitryl (0.7 g, 79%). ) Was obtained.

UPLC r. t. (min): 0.87

Step 3: After dissolving 3-nitro-1 H -pyrazole-5-carbonitrile (0.7g, 5mmol) in acetic acid (14ml) and water (3ml), zinc powder (1.6g, 25mmol) was added and at room temperature. It was stirred for 6 hours. After the reaction mixture was filtered, water and ethyl acetate were added to the filtrate, and the organic layer was extracted by neutralizing with aqueous ammonia. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain a liquid 3-amino-1 H -pyrazole-5-carbonitryl (80 mg, 14%).

MS (m/z): 109.03 [M+1] ⁺ , UPLC rt (min): 0.33

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

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

[Scheme 7]

Step 1: Methyl 4-oxocyclohexanecarboxylate (2g, 12.81mmol) and DIPEA (8.92mL, 51.22mmol) are dissolved in toluene (4ml) and heated at 45°C for 30 minutes. Tf ₂ O (8.45mL, 51.22mmol) was diluted in dichloromethane (20ml) to this mixture, added dropwise at 45°C for 10 minutes, and stirred for 2 hours. After extraction by adding 1N HCl (60mL) and MTBE (60mL*2) to the reaction mixture, the combined organic layer was washed with water (50mL) and brine (50mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain methyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (2.5g, 67.73%) as a yellow liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.82-5.74 (m, 1H), 2.67-2.57 (m, 1H), 2.51-2.38 (m, 4H), 2.21-2.10 (m, 1H), 1.99- 1.87 (m, 1H), 1.37-1.19 (m, 1H)

Step 2: Methyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (1.5g, 5.20mmol) and 4,4,5,5-tetramethyl-2 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.45g, 5.72mmol), KOAc (2.04g , 20.82 mmol), Pd(dppf)Cl ₂ . CH ₂ Cl ₂ (424.98mg, 520.40μmol) was dissolved in 1,4-dioxane (20ml) and stirred at 90 ^° C for 14 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to form a yellow liquid methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioc). Saborolan-2-yl)cyclohex-3-ene-1-carboxylate (0.9g, 40.6%) was obtained.

<Production Example 9>( S )- N -(1-(6-(4-fluoro-1 H Preparation of -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide dihydrochloride

The title compound was prepared through the method shown in Scheme 8 below.

[Scheme 8]

Step 1: tert -butyl 4-oxopiperidine-1-carboxylate (15g, 75mmol) dissolved in bromoform (152g, 602mmol), cooled to 0 ^o C, and potassium hydroxide (33.8g, 602mmol) in methanol Dissolve in (150ml) and slowly add dropwise to the reaction mixture for 4 hours. After stirring at 25 ^° C for 12 hours, water (500ml) was added to the reaction mixture, the organic solvent was concentrated under reduced pressure, extracted with ethyl acetate and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to obtain a liquid 1-( tert -butyl) 4-methyl 4-methoxypiperidine-1,4-di Carboxylate (10.3 g, 50%) was obtained.

MS (m/z): 174.18 [M+1] ⁺ , UPLC rt (min): 1.46

¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.85-3.70 (m,2H), 3.77 (s, 3H), 3.26 (s, 3H), 3.22-3.08 (m, 2H), 1.87 (br d, J = 4.4 Hz, 4H), 1.46 (s, 9H)

Step 2: 1-( tert -butyl) 4-methyl 4-methoxypiperidine-1,4-dicarboxylate (10.3g, 37.7mmol) was dissolved in ethanol (40ml) and tetrahydrofuran (40ml) and then 6N NaOH (10ml) was added, heated to 70 ^o C, and stirred for 3 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted by neutralizing with sodium bicarbonate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain a liquid 1-( tert -butoxycarbonyl)-4-methoxypiperidine-4-carboxylic acid (8.8 g, 90%).

MS (m/z): 160.15 [M+1] ⁺ , UPLC rt (min): 1.36

Step 3: ( S )-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine dihydrochloride (7.1g, 25.5mmol) and 1 -( tert -butoxycarbonyl)-4-methoxypiperidine-4-carboxylic acid (6g, 23mmol), HATU (13.2g, 34.7mmol), DIPEA (20ml) dissolved in DMF (110ml) 2 at room temperature Stirred for hours. The reaction mixture was extracted with ethyl acetate and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to obtain a liquid tert -butyl ( S )-4-((1-(6-(4-fluoro-)). 1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-carboxylate (8.7g, 84%) was obtained.

MS (m/z): 348.24 [M-Boc+1] ⁺ , UPLC rt (min): 1.73

Step 4: tert -butyl ( S )-4-((1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxy Cypiperidine-1-carboxylate (8.7g, 19.4mmol) was dissolved in 1,4-dioxane (30ml) and methanol (30ml), and then 4M HCl/1,4-dioxane (20ml) was added thereto at room temperature. It was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure after filtration was added dropwise to ethyl ether (100ml) and the solid (S) - N - (1- (6- ( 4-fluoro -1 H - pyrazol-1-yl) pyridine-3 Il)ethyl)-4-methoxypiperidine-4-carboxamide dihydrochloride (5.1g, 63%) was obtained.

MS (m/z): 348.24 [M+1] ⁺ , UPLC rt (min): 1.04

<Example 1> (1 r ,4 S )- N -(( S )-1-(6-(4-fluoro-1 H -Pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-((5-methyl-1) H -Pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide; And

<Example 2> (1 s ,4 R )- N -(( S )-1-(6-(4-fluoro-1 H -Pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-((5-methyl-1) H Preparation of -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide

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

[Scheme 9]

Step 1: After dissolving 2,4-dichloroquinazoline (10g, 50mmol), 5-methyl- 1H -pyrazol-3-amine (5.37g, 55mmol), and DIPEA (8.8ml) in DMSO (167ml) It was stirred at 60 ^o C for 2 hours. The reaction mixture was added to water and filtered to obtain a solid 2-chloro- N- (5-methyl-1 H -pyrazol-3-yl)quinazolin-4-amine (13g, 100%).

MS (m/z): 260.11 [M+1] ⁺ , UPLC rt (min): 1.27

Step 2: 2-Chloro- N- (5-methyl-1 H -pyrazol-3-yl)quinazolin-4-amine (5g, 19.2mmol) and DHP (3.52ml, 38.5mmol), PTSA (0.7g , 3.8mmol) was dissolved in tetrahydrofuran (13ml) and stirred at 70 ^o C for 6 hours. The reaction mixture was extracted with ethyl acetate and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/dichloromethane) to form a solid 2-chloro- N- (5-methyl-1-(tetrahydro- 2H -pyran-). 2-yl)-1 H -pyrazol-3-yl)quinazolin-4-amine (3.7 g, 55%) was obtained.

MS (m/z): 344.22 [M+1] ⁺ , UPLC rt (min): 1.24

Step 3: 2-Chloro- N- (5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl)quinazolin-4-amine (3.7 g, 10.8mmol) and methyl 1-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (3.2g, 10.8mmol), K ₂ CO ₃ (5.95g, 43mmol), Pd(PPh ₃ ) ₄ (1.24g, 1mmol) dissolved in 1,4-dioxane (90ml) and water (17ml) and then 120 ^o C was stirred for 6 hours. The reaction mixture was extracted with ethyl acetate and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to a solid of methyl 1-methoxy-4- (4 - ((5-methyl-1- (tetrahydro -2 H-pyran-2-yl) -1 H-pyrazol- 3-yl)amino)quinazolin-2-yl)cyclohex-3-ene-1-carboxylate (4g, 78%) was obtained.

MS (m/z): 478.38 [M+1] ⁺ , UPLC rt (min): 1.24

Step 4: Methyl 1-methoxy-4-(4-((5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl)amino)quinazoline -2-yl)cyclohex-3-ene-1-carboxylate (4g, 8.38mmol), ammonium formate (7.92g, 126mmol), Pd/C (1.78g), Pd(OH) ₂ (0.59g) Was dissolved in ethanol (42ml) and stirred at 80 ^o C for 12 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/dichloromethane) to obtain a solid methyl 1-methoxy-4-(4-((5-methyl-1-(tetrahydro-)). 2H -pyran-2-yl)-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohex-1-carboxylate (4g, 99%) was obtained.

MS (m/z): 480.37 [M+1] ⁺ , UPLC rt (min): 1.22

Step 5: Methyl 1-methoxy-4-(4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1 H -pyrazol-3-yl)amino)quinazoline- 2-yl)cyclohex-1-carboxylate (4g, 8.38mmol) was dissolved in ethanol (20ml) and tetrahydrofuran (20ml), 6N NaOH (7ml) was added, heated to 70 ^o C, and stirred for 3 hours. I did. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted by neutralizing with sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to a solid of methyl 1-methoxy-4- (4 - ((5-methyl-1- (tetrahydro -2H- pyran-2-yl) -1 H-pyrazol -3 -Yl)amino)quinazolin-2-yl)cyclohex-1-carboxylic acid (3.8 g, 98%) was obtained.

MS (m/z): 466.33 [M+1] ⁺ , UPLC rt (min): 1.10

Step 6: Methyl 1-methoxy-4-(4-((5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl)amino)quinazoline -2-yl)cyclohex-1-carboxylic acid (3.8g, 8.16mmol) and ( S )-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethane -1-amine (2.73g, 9.8mmol), DIPEA (7.13ml, 40.8mmol), and HATU (4.03g, 10.61mmol) were dissolved in DMF (30ml) and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (methanol/dichloromethane) to form a solid N -(( S )-1-(6-(4-fluoro-1 H -pyrazole). -1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1 H -pyrazole -3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide (4g, 75%) was obtained.

MS (m/z): 654.44 [M+1] ⁺ , UPLC rt (min): 1.32

Step 7: N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4- ((5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide (4g, 6.12mmol) was dissolved in TFA (12ml) and stirred at 60 ^o C for 30 minutes. Water and ethyl acetate were added to the reaction mixture and neutralized with sodium bicarbonate to extract the organic layer. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, separated and purified using supercritical fluid chromatography to obtain a solid (1 r ,4 S ) -N -(( S )-1-(6-(4-fluoro-1H). -Pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2- Il) Cyclohexane-1-carboxamide (722mg, 21%, Example 1) and (1 s ,4 R ) -N -(( S )-1-(6-(4-fluoro-1 H -Pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2- Il) Cyclohexane-1-carboxamide (1680 mg, 48%, Example 2) was obtained, respectively.

MS (m/z): 570.38 [M+1] ⁺ , 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, NMR, and LC-MS analysis results of Examples 1 to 22 are summarized in Table 1 below.

Example rescue Compound name ¹ H NMR LC-MS
(m/z) One

(1 r ,4 S )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.11 (br s, 1H), 10.24 (br s, 1H), 8.65 (dd, J = 0.6, 4.4 Hz, 1H), 8.58 (br d, J = 8.0 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 2.2 Hz, 1H), 7.79-7.69 (m, 1H), 7.69-7.63 (m, 1H), 7.46 (br t, J = 7.4 Hz, 1H), 6.76 (br s, 1H), 5.15-5.05 (m, 1H), 3.10 (s, 3H), 2.85 (br s, 1H), 2.68 (s, 1H) , 2.25 (s, 3H), 2.22-2.04 (m, 4H), 1.91 (br d, J = 3.8 Hz, 2H), 1.66-1.50 (m, 2H), 1.47 (d, J = 7.2 Hz, 3H)
570.3 [M+H] ⁺ 2

(1 s ,4 R )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.17 (br s, 1H), 10.33-10.28 (m, 1H), 8.70-8.66 (m, 1H), 8.59 (br d, J = 8.4 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 7.99 (dd, J = 2.4, 8.6 Hz, 1H), 7.92 (d, J = 3.8 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.80-7.73 (m, 1H), 7.70-7.64 (m, 1H), 7.47 (br t, J = 7.4 Hz, 1H), 6.87 (s, 1H), 5.07 (quin, J = 7.2 Hz, 1H), 3.19 (s, 3H), 2.80-2.68 (m, 1H), 2.29 (s, 3H), 2.08-1.90 (m, 4H), 1.86-1.62 (m, 4H), 1.47 (d, J = 7.0 Hz, 3H) 570.3 [M+H] ⁺ 3

(1 s ,4 R )-1-methoxy- N -(( S )-1-(6-(4-methyl-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4 -(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.193 (s, 1H), 10.42 (s, 1H), 8.60 (br d, J = 7.6 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.43-8.35 (m, 2H), 7.95 (dd, J = 2.0, 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.81-7.74 (m, 1H), 7.72-7.67 (m, 1H), 7.62 (s, 1H), 7.49 (t, J = 7.6 Hz, 1H), 6.82 (br s, 1H), 5.12-4.97 (m, 1H), 3.19 (s, 3H), 2.81 -2.70 (m, 1H), 2.28 (s, 3H), 2.11 (s, 3H), 2.05-1.93 (m, 4H), 1.83-1.64 (m, 4H), 1.47 (d, J = 6.8 Hz, 3H ) 566.5 [M+H] ⁺ 4

(1 r ,4 S )-1-methoxy- N -(( S )-1-(6-(4-methyl-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4 -(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400MHz, DMSO- d ₆ ) δ = 12.57 (br s, 1H), 8.83 (br d, J =7.4 Hz, 1H), 8.58 (br d, J = 8.4 Hz, 1H), 8.45 (d , J = 2.0 Hz, 1H), 8.39 (s, 1H), 8.07-7.97 (m, 2H), 7.91 (br d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.75 (br s, 1H), 7.66 (s, 1H), 6.80 (br s, 1H), 5.21 (quin, J = 7.2 Hz, 1H), 3.17 (s, 3H), 3.07 (br s, 1H), 2.39-2.38 (m, 2H), 2.31 (s, 3H), 2.23-2.14 (m, 4H), 2.14-1.98 (m, 3H), 1.72-1.48 (m, 5H) 566.5 [M+H] ⁺ 5

(1 r ,4 S )- N -((S)-1-(6-(3,5-dimethyl-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-me Toxoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.40 (d, J = 1.6 Hz, 1H), 8.34-8.18 (m, 1H), 7.91-7.80 (m, 1H), 7.79-7.61 (m, 3H) , 7.41 (t, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.61-6.42 (m, 1H), 5.98 (s, 1H), 5.16 (t, J = 7.2 Hz, 1H), 3.26 (s, 3H), 3.17-3.00 (m, 1H), 2.57 (s, 3H), 2.46-2.32 (m, 2H), 2.28 (s, 3H), 2.23-2.16 (m, 4H) , 2.09 (m, 3H), 1.78-1.67 (m, 2H), 1.56 (d, J = 7.2 Hz, 3H); 580.3 [M+H] ⁺ 580.3 [M+H] ⁺ 6

(1 s ,4 R )- N -(( S )-1-(6-(3,5-dimethyl-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-me Toxoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.04-11.71 (m, 1H), 10.09-9.78 (m, 1H), 8.59-8.47 (m, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 7.2 Hz, 1H), 7.92 (dd, J = 2.4, 8.8 Hz, 1H), 7.79-7.62 (m, 3H), 7.46 (t, J = 6.4 Hz, 1H), 6.85-6.61 (m, 1H), 6.07 (s, 1H), 5.15-5.03 (m, 1H), 3.21 (s, 3H), 2.85-2.70 (m, 1H), 2.58 (s, 3H), 2.29 ( s, 3H), 2.20 (s, 3H), 2.09-1.93 (m, 4H), 1.91-1.72 (m, 4H), 1.52 (d, J = 7.2 Hz, 3H) 580.3 [M+H] ⁺ 7

1-methoxy-4- (4 - ((5-methyl -1 H-pyrazol-3-yl) amino) quinazolin-2-yl) - N - (4- (thiazol-5-yl) benzyl ) Cyclohexane-1-carboxamide ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.78-8.74 (m, 1H), 8.14-8.05 (m, 2H), 7.85-7.66 (m, 2H), 7.58-7.51 (m, 2H), 7.50- 7.40 (m, 1H), 7.37-7.33 (m, 2H), 6.99-6.89 (m, 1H), 6.69-6.63 (m, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.33-3.29 ( m, 3H), 3.08-2.87 (m, 1H), 2.50-2.41 (m, 0.5H), 2.36-2.28 (m, 4H), 2.12-2.03 (m, 6H), 1.80-1.72 (m, 0.7H ) 554.2 [M+H] ⁺ 8

N- (4-(isooxazol-4-yl)benzyl)-1-methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazoline-2- Il) Cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.33-11.98 (m, 1H), 10.67-10.02 (m, 1H), 9.46-9.31 (m, 1H), 9.19-9.05 (m, 1H), 8.65-8.45 (m, 2H), 7.81-7.73 (m, 1H), 7.72-7.63 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H) , 7.37-7.29 (m, 2H), 6.91-6.66 (m, 1H), 4.33-4.13 (m, 2H), 3.24-3.11 (m, 3H), 2.90-2.72 (m, 1H), 2.30-2.22 ( m, 3H), 2.22-2.10 (m, 2H), 2.03-1.90 (m, 3H), 1.86-1.79 (m, 2H), 1.64-1.48 (m, 1H) 538.3 [M+H] ⁺ 9

(1 s ,4 R )-4-(4-((5-cyano-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)- N -(( S )-1-( 6-(4-Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxycyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.48 (s, 1H), 8.83 (d, J = 7.9 Hz, 1H), 8.68 (d, J = 4.5 Hz, 1H), 8.59 (d, J = 8.3 Hz, 1H), 8.44 (d, J = 1.8 Hz, 1H), 8.12 (t, J = 7.6 Hz, 1H), 8.00 (dd, J = 8.5, 2.3 Hz, 2H), 7.91 (d, J = 4.2 Hz, 1H), 7.86 (dd, J = 17.2, 8.1 Hz, 2H), 7.49 (d, J = 6.8 Hz, 1H), 5.07 (p, J = 7.2 Hz, 1H), 3.20 (s, 3H) , 3.17-3.04 (m, 2H), 2.11-1.88 (m, 6H), 1.88-1.64 (m, 3H), 1.48 (d, J = 7.0 Hz, 3H), 1.23 (s, 1H), 0.85 (t , J = 6.7 Hz, 1H) 581.4 [M+H] ⁺ 10

(1 r ,4 S )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(4-((5-(trifluoromethyl)-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.55 (d, J = 4.4 Hz, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.97 (dd, J = 2.0, 8.4 Hz, 1H), 7.87-7.73 (m, 3H), 7.69 (d, J = 8.0 Hz, 1H), 7.55 (t , J = 7.6 Hz, 1H), 6.74 (s, 1H), 5.12 (t, J = 7.6 Hz, 1H), 3.14 (s, 3H), 2.97 (s, 1H), 2.26-2.05 (m, 4H) , 2.03-1.96 (m, 2H), 1.67-1.54 (m, 2H), 1.49 (d, J = 7.2 Hz, 3H) 624.3 [M+H] ⁺ 11

(1 s ,4 R )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(4-((5-(trifluoromethyl)-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.59 (d, J = 4.8 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.13 (d, J = 6.8 Hz, 1H), 7.99 (dd, J = 2.0, 8.8 Hz, 1H), 7.89-7.73 (m, 3H), 7.55 (s, 1H), 6.85 (d, J = 2.0 Hz , 1H), 5.13-5.05 (m, 1H), 3.19 (s, 3H), 2.94-2.76 (m, 1H), 2.10-1.95 (m, 3H), 1.94-1.88 (m, 3H), 1.87-1.74 (m, 2H), 1.52 (d, J = 7.2 Hz, 3H) 624.3 [M+H] ⁺ 12

(1 r ,4 S )-4-(4-((5-cyclopropyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl) -N -(( S )-1-( 6-(4-Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxycyclohexane-1-carboxamide ¹ H NMR (400 MHz, Methanol- d ₄ ) δ = 8.47-8.39 (m, 2H), 8.25 (d, J = 8.4 Hz, 1H), 7.96-7.91 (m, 1H), 7.88-7.83 (m, 1H), 7.82-7.71 (m, 2H), 7.65 (d, J = 4.2 Hz, 1H), 7.53 (br t, J = 7.2 Hz, 1H), 6.69 (br s, 1H), 5.27-5.22 (m , 1H), 3.21 (s, 3H), 3.02-2.85 (m, 1H), 2.40-2.17 (m, 4H), 2.09-1.87 (m, 3H), 1.77-1.60 (m, 2H), 1.59-1.53 (m, 3H), 0.97-0.95 (m, 2H), 0.85-0.73 (m, 2H) 596.4 [M+H] ⁺ 13

(1 s ,4 R )-4-(4-((5-cyclopropyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)- N -(( S )-1-( 6-(4-Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxycyclohexane-1-carboxamide ¹ H NMR (400 MHz, Methanol- d ₄ ) δ = 8.50 (dd, J = 0.6, 4.4 Hz, 1H), 8.44 (d, J = 1.8 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H ), 7.98-7.89 (m, 2H), 7.79 (br dd, J = 2.0, 9.2 Hz, 2H), 7.68 (d, J = 4.4 Hz, 1H), 7.54 (br s, 1H), 6.91-6.69 ( m, 1H), 5.18-5.12 (m, 1H), 3.33 (s, 3H), 2.94-2.75 (m, 1H), 2.22-2.02 (m, 4H), 2.01-1.79 (m, 5H), 1.63- 1.52 (m, 3H), 1.06-0.96 (m, 2H), 0.85-0.74 (m, 2H) 596.4 [M+H] ⁺ 14

(1 r ,4 S )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)furo[3,2- d ]pyrimidin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ = 8.43 (dd, J = 3.6, 12.8 Hz, 3H), 8.01 (d, J = 2.4 Hz, 1H), 7.95-7.90 (m, 1H), 7.89 -7.82 (m, 1H), 7.66 (d, J = 4.0 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.58 (br s, 1H), 5.23-5.13 (m, 1H), 3.21 (s, 3H), 2.93 (tt, J = 4.4, 9.2 Hz, 1H), 2.33-2.14 (m, 7H), 2.07-1.96 (m, 2H), 1.73-1.60 (m, 2H), 1.56 (d , J = 7.2 Hz, 3H) 560.5 [M+H] ⁺ 15

(1 s ,4 R )- N -(( S) -1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)furo[3,2- d ]pyrimidin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ = 8.56 (br d, J = 8.0 Hz, 1H), 8.49 (d, J = 4.4 Hz, 1H), 8.43 (d, J = 1.6 Hz, 1H) , 8.24 (d, J = 2.0 Hz, 1H), 7.98-7.87 (m, 2H), 7.68 (d, J = 4.4 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.65 (s, 1H), 5.14 (quin, J = 7.6 Hz, 1H), 3.30 (s, 3H), 3.00-2.87 (m, 1H), 2.35 (s, 3H), 2.16-2.01 (m, 4H), 1.98-1.78 (m, 4H), 1.57 (d, J = 7.2 Hz, 3H) 560.5 [M+H] ⁺ 16

(1 r ,4 S )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)thieno[2,3- d ]pyrimidin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (s, 1H), 8.64 (d, J = 4.4 Hz, 1H), 8.54 (d, J = 8.2 Hz, 1H), 8.43-8.39 (m, 1H), 8.17 (d, J = 5.4 Hz, 1H), 7.98 (dd, J = 8.5, 1.9 Hz, 1H), 7.90 (d, J = 4.1 Hz, 1H), 7.84 (dd, J = 7.1, 4.6 Hz, 2H), 7.75-7.65 (m, 0H), 6.59 (s, 1H), 5.76 (s, 1H), 5.11 (p, J = 7.0 Hz, 1H), 3.18 (s, 1H), 3.11 (s , 4H), 2.29 (s, 3H), 2.11-1.98 (m, 4H), 1.58 (dq, J = 13.7, 8.2, 6.0 Hz, 2H), 1.47 (d, J = 7.0 Hz, 3H), 1.38- 1.21 (m, 2H), 0.88 (t, J = 6.8 Hz, 1H) 576.3 [M+H] ⁺ 17

(1 s ,4 R )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)thieno[2,3- d ]pyrimidin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.89 (s, 1H), 8.68 (d, J = 4.5 Hz, 1H), 8.54 (d, J = 8.3 Hz, 1H), 8.44 (d, J = 1.9 Hz, 1H), 8.12 (d, J = 5.4 Hz, 1H), 8.00 (dd, J = 8.5, 2.2 Hz, 1H), 7.92 (d, J = 4.2 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 5.9 Hz, 1H), 6.65 (s, 1H), 5.07 (p, J = 7.0 Hz, 1H), 3.18 (s, 3H), 3.05-2.95 (m, 1H), 2.32 (s, 3H), 2.09-1.98 (m, 2H), 1.93 (q, J = 11.7 Hz, 4H), 1.87-1.65 (m, 2H), 1.48 (d, J = 7.1 Hz, 3H ) 576.3 [M+H] ⁺ 18

(1 r ,4 S )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)thieno[3,2- d ]pyrimidin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.53 (s, 1H), 8.65 (d, J = 4.5 Hz, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.47-8.38 (m, 2H), 7.99 (dd, J = 8.6, 2.1 Hz, 1H), 7.92-7.82 (m, 2H), 7.50 (d, J = 5.3 Hz, 1H), 6.50 (s, 1H), 5.14 (p, J = 7.0 Hz, 1H), 3.57 (s, 1H), 3.17 (s, 1H), 3.10 (s, 3H), 3.05 (s, 1H), 2.37-2.26 (m, 2H), 2.24 (s, 3H) , 2.13-1.92 (m, 4H), 1.60-1.50 (m, 2H), 1.48 (d, J = 7.1 Hz, 3H) 576.4 [M+H] ⁺ 19

(1 s ,4 R )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)thieno[3,2- d ]pyrimidin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.16 (s, 1H), 8.68 (d, J = 4.5 Hz, 1H), 8.55 (d, J = 8.2 Hz, 1H), 8.53-8.41 (m, 2H), 8.00 (dd, J = 8.6, 2.3 Hz, 1H), 7.93-7.86 (m, 2H), 7.55 (s, 1H), 6.70 (s, 1H), 5.07 (p, J = 7.2 Hz, 1H ), 3.17 (s, 3H), 3.04 (s, 1H), 2.31 (s, 3H), 2.10-1.86 (m, 6H), 1.85-1.63 (m, 2H), 1.48 (d, J = 7.1 Hz, 3H) 576.4 [M+H] ⁺ 20

(1 r ,4 S )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(9-methyl-6-((5-methyl-1 H -pyrazol-3-yl)amino)-9 H -purin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.22 (s, 1H), 8.73 (s, 1H), 8.64 (d, J = 4.5 Hz, 1H), 8.54 (d, J = 8.1 Hz, 1H) , 8.41 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 8.5, 2.3 Hz, 1H), 7.90 (d, J = 4.2 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H) , 6.28 (s, 1H), 5.06 (t, J = 7.4 Hz, 2H), 3.83 (s, 3H), 3.14 (d, J = 20.7 Hz, 5H), 2.31 (s, 3H), 2.19 (dd, J = 13.0, 5.4 Hz, 1H), 2.09 (s, 5H), 1.98 (d, J = 8.7 Hz, 1H), 1.64 (qd, J = 9.9, 9.2, 4.9 Hz, 2H), 1.46 (d, J = 7.0 Hz, 3H) 574.4 [M+H] ⁺ 21

(1 r ,4 S )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(7-methyl-4-((5-methyl-1 H -pyrazol-3-yl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)cyclohexane -1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 9.73 (s, 1H), 8.65 (d, J = 4.4 Hz, 1H), 8.48-8.35 (m, 2H), 7.98 ( dd, J = 8.6, 2.3 Hz, 1H), 7.90 (d, J = 4.2 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 3.5 Hz, 1H), 6.76 ( d, J = 3.5 Hz, 1H), 6.61 (s, 1H), 5.11 (p, J = 7.2 Hz, 1H), 3.66 (s, 3H), 3.10 (s, 3H), 2.81 (dt, J = 8.9 , 4.5 Hz, 1H), 2.20 (s, 6H), 1.92-1.82 (m, 2H), 1.56 (td, J = 13.5, 3.7 Hz, 2H), 1.46 (d, J = 7.1 Hz, 3H) 573.4 [M+H] ⁺ 22

(1 s ,4 R )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy- 4-(7-methyl-4-((5-methyl-1 H -pyrazol-3-yl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)cyclohexane -1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.92 (s, 1H), 9.73 (s, 1H), 8.69 (dd, J = 4.6, 0.9 Hz, 1H), 8.50 (d, J = 8.3 Hz, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.00 (dd, J = 8.5, 2.3 Hz, 1H), 7.96-7.83 (m, 2H), 7.17-7.03 (m, 1H), 6.79 (d , J = 11.2 Hz, 2H), 5.07 (p, J = 7.2 Hz, 1H), 3.69 (s, 3H), 3.19 (s, 3H), 2.69 (s, 1H), 2.25 (s, 2H), 1.98 (dd, J = 23.6, 13.2 Hz, 4H), 1.83-1.62 (m, 4H), 1.48 (d, J = 7.1 Hz, 3H) 573.4 [M+H] ⁺

<Example 23> N -Benzyl-4-(4-((5-methyl-1) H Preparation of -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide

The title compound was prepared through the method shown in Scheme 10 below.

[Scheme 10]

Step 1: 2-Chloro- N- (5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)quinazolin-4-amine (700mg, 2.04mmol) and methyl 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (900mg, 3.38mmol) was added to 1,4-dioxane at room temperature. (10ml), after dissolving in water (1.3ml), K ₂ CO ₃ (844.17mg, 6.11mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (200mg, 244.91umol) were added and at 90 ^o C for 2 hours Stirred. The reaction mixture was extracted with ethyl acetate and brine, and the organic layers were 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 solid methyl 4-(4-((5-methyl-1-(tetrahydro-2 H -pyran-2)). -Yl)-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohex-3-en-1-carboxylate (670mg, 73.53%) was obtained.

MS: m/z 448.1 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.03 (br d, J = 2.8 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 6.92 (s, 1H), 5.23 (dd, J = 2.4, 10.0 Hz, 1H), 4.12-4.08 (m, 1H), 3.75-3.72 (m, 3H), 3.71-3.65 (m, 1H), 3.04-3.02 (m, 1H), 2.73-2.67 (m, 1H), 2.42 (s, 4H), 2.30-2.21 ( m, 1H), 2.14-2.09 (m, 1H), 1.96-1.84 (m, 2H), 1.82 (s, 5H), 1.63-1.56 (m, 1H)

Step 2: Methyl 4-(4-((5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl)amino)quinazolin-2-yl) Cyclohex-3-ene-1-carboxylate (630mg, 1.41mmol), Pd/C (149.81mg, 10% purity), Pd(OH) ₂ (98.85mg, 140.77umol, 20% purity) in methanol (4mL) ), and then stirred for 1.5 hours at room temperature under a stream of hydrogen. Methyl of the reaction mixture was filtered and concentrated under reduced pressure to solid 4- (4 - ((5-methyl-1- (tetrahydro -2 H-pyran-2-yl) -1 H-pyrazol-3-yl) amino) Quinazolin-2-yl)cyclohexane-1-carboxylate (600mg, 94.81%) was obtained.

MS: m/z 450.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.00 (br s, 1H), 7.87-7.69 (m, 3H), 7.50-7.42 (m, 1H), 7.06-6.95 (m, 1H), 5.33-5.21 (m, 1H), 4.12-4.05 (m, 1H), 3.73-3.71 (m, 3H), 3.70-3.65 (m, 1H), 3.00-2.84 (m, 1H), 2.75-2.68 (m, 1H) , 2.46-2.42 (m, 3H), 2.24-2.05 (m, 6H), 1.94-1.87 (m, 2H), 1.75-1.60 (m, 6H)

Step 3: methyl 4-(4-((5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl) amino) quinazolin-2-yl) After dissolving cyclohexane-1-carboxylate (550mg, 1.22mmol) in water (2mL) and methanol (10mL), NaOH (150mg, 3.75mmol) was added, followed by stirring at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, and an aqueous layer was extracted. 1N HCl was added dropwise to the water layer to titrate the pH to 5-6, and the solid precipitate was filtered and concentrated under reduced pressure to obtain a solid 4-(4-((5-methyl-1-(tetrahydro- 2H -pyran-2-yl)). )-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxylic acid (400mg, 72.60%) was obtained.

MS: m/z 436.3 [M+H] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.33 (s, 1H), 8.60 (d, J = 8.4 Hz, 1H), 7.80-7.73 (m, 1H), 7.71-7.65 (m, 1H) , 7.47 (t, J = 7.6 Hz, 1H), 6.84-6.80 (m, 1H), 5.35 (d, J = 9.6 Hz, 1H), 3.93 (d, J = 11.2 Hz, 1H), 3.65 (dt, J = 3.6, 10.8 Hz, 2H), 2.87-2.76 (m, 1H), 2.75-2.63 (m, 1H), 2.36 (s, 3H), 2.33-2.26 (m, 1H), 2.07-2.00 (m, 4H), 1.91-1.85 (m, 1H), 1.83-1.58 (m, 5H), 1.58-1.44 (m, 3H)

Step 4: 4-(4-((5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclo Hexein-1-carboxylic acid (170mg, 377.52μmol) and phenylmethanamine (50.21mg, 468.55μmol, 51.07μL), HATU (172.25mg, 453.03μmol), DIPEA (222.60mg, 1.72mmol, 0.3mL) in dichloro After dissolving in methane (3mL), the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, 1N HCl (20 mL) was added dropwise, and then filtered to form a solid N -benzyl-4-(4-((5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1). H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide (190mg, 95.93%) was obtained.

MS: m/z 525.4 [M+H] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 14.79-14.48 (m, 1H), 12.21-11.98 (m, 1H), 8.90-8.82 (m, 1H), 8.40-8.31 (m, 1H), 8.11-8.03 (m, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.37-7.27 (m, 2H), 7.25-7.15 (m, 2H) , 7.02-6.75 (m, 1H), 5.47-5.34 (m, 1H), 4.36-4.27 (m, 2H), 3.93 (d, J = 12.0 Hz, 1H), 3.66 (s, 1H), 3.08-2.96 (m, 1H), 2.62-2.59 (m, 1H), 2.33-2.30 (m, 3H), 2.16-1.79 (m, 7H), 1.77-1.47 (m, 7H)

Step 5: N -Benzyl-4-(4-((5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl)amino)quinazoline-2 -Yl)cyclohexane-1-carboxamide (190mg, 362.14umol) was added to 4M HCl/MeOH (90.54μL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dissolved in methanol, adjusted to pH 7-8 using a basic resin, and filtered. The filtered solid was purified by Prep-150 LC System, and the solid racemic mixture N -benzyl-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl ) Cyclohexane-1-carboxamide (30mg, 27.27%) was obtained.

MS: m/z 441.2 [M+H] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.11 (d, J = 1.6 Hz, 1H), 10.21 (s, 1H), 8.57 (d, J = 7.6 Hz, 1H), 8.37-8.12 (m , 1H), 7.82-7.64 (m, 2H), 7.47 (t, J = 7.2 Hz, 1H), 7.36-7.18 (m, 5H), 6.76 (br s, 1H), 4.32-4.24 (m, 2H) , 2.95-2.66 (m, 1H), 2.42-2.18 (m, 5H), 2.12-1.79 (m, 3H), 1.78-1.52 (m, 4H)

Examples 24 to 26 were prepared in a similar manner to Example 23, and the chemical structures, compound names, NMR, and LC-MS analysis results of Examples 23 to 26 are summarized and shown in Table 2 below.

Example rescue Compound name ¹ H NMR LC-MS
(m/z) 23

N -Benzyl-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.11 (d, J = 1.6 Hz, 1H), 10.21 (s, 1H), 8.57 (d, J = 7.6 Hz, 1H), 8.37-8.12 (m , 1H), 7.82-7.64 (m, 2H), 7.47 (t, J = 7.2 Hz, 1H), 7.36-7.18 (m, 5H), 6.76 (br s, 1H), 4.32-4.24 (m, 2H) , 2.95-2.66 (m, 1H), 2.42-2.18 (m, 5H), 2.12-1.79 (m, 3H), 1.78-1.52 (m, 4H) 441.2 [M+H] ⁺ 24

N- (4-methoxybenzyl)-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.32-11.92 (m, 1H), 10.21 (br s, 1H), 8.57 (d, J = 7.6 Hz, 1H), 8.29-8.05 (m, 1H) ), 7.82-7.61 (m, 2H), 7.47 (t, J = 7.2 Hz, 1H), 7.16 (m, 2H), 6.94-6.63 (m, 3H), 4.20 (t, J = 5.6 Hz, 2H) , 3.71 (d, J = 12.4 Hz, 3H), 2.93-2.66 (m, 1H), 2.45-2.31 (m, 2H), 2.26 (m, 3H), 2.06 (d, J = 12.0 Hz, 1H), 1.95-1.80 (m, 2H), 1.78-1.50 (m, 4H) 471.3 [M+H] ⁺ 25

(1 s ,4 R )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4- ((5-methyl-1 H -pyrazol-3-yl) amino) quinazolin-2-yl) cyclohexane-1-carboxamide 540.3 [M+H] ⁺ 26

(1 r ,4 S )- N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4- ((5-methyl-1 H -pyrazol-3-yl) amino) quinazolin-2-yl) cyclohexane-1-carboxamide 540.3 [M+H] ⁺

<Example 27> ( S )- N -(1-(6-(4-fluoro-1 H -Pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxy-1-(4-((5-methyl-1) H Preparation of -pyrazol-3-yl)amino)quinazolin-2-yl)piperidin-4-carboxamide

The title compound was prepared through the method shown in Scheme 11 below.

[Scheme 11]

Step 1: Dissolve 2,4-dichloroquinazoline (10g, 50mmol), 5-methyl-1H-pyrazol-3-amine (5.37g, 55mmol), and DIPEA (8.8ml) in DMSO (167ml) and then 60 ^It was stirred at ^o C for 2 hours. The reaction mixture was added to water and filtered to obtain a solid 2-chloro- N- (5-methyl-1 H -pyrazol-3-yl)quinazolin-4-amine (13g, 100%).

MS (m/z): 260.11 [M+1] ⁺ , UPLC rt (min): 1.27

Step 2: 2-Chloro- N- (5-methyl-1 H -pyrazol-3-yl)quinazolin-4-amine (90mg, 0.347mmol) and (S)-N-(1-(6-( 4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide dihydrochloride (146mg, 0.347mmol), DIPEA (0.2ml, 1.39mmol) was dissolved in ethanol (3ml) and then reacted for 1 hour at 170 ^° C using a microwave reactor. The reaction mixture was extracted with ethyl acetate and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and (S) of purified by Prep LC System-150 Solid - N - (1- (6- ( 4- -1 H -Fluoro-1-yl) pyridin- 3-yl)ethyl)-4-methoxy-1-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)piperidine-4-carboxa Mide (98mg, 50%) was obtained.

MS (m/z): 571.49 [M+1] ⁺ , UPLC rt (min): 1.36

Examples 28 to 45 were prepared in a similar manner to Example 27, and the chemical structures, compound names, NMR, and LC-MS analysis results of Examples 27 to 45 are summarized and shown in Table 3 below.

Example rescue Compound name ¹ H NMR LC-MS
(m/z) 27

(S) - N - (1- (6- (4-fluoro -1 H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (4 - ((5 -Methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)piperidin-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.97 (s, 1H), 11.34 (s, 1H), 8.66 (d, J = 4.6 Hz, 1H), 8.59 (d, J = 8.2 Hz, 2H) , 8.43 (d, J = 2.2 Hz, 1H), 7.99 (dd, J = 8.6, 2.3 Hz, 1H), 7.91 (d, J = 4.3 Hz, 1H), 7.86 (dd, J = 14.5, 7.9 Hz, 2H), 7.71 (d, J = 8.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 6.42 (s, 1H), 5.06 (p, J = 7.2 Hz, 1H), 3.47 (dt, J = 11.7, 7.0 Hz, 2H), 3.19 (s, 3H), 2.30 (s, 3H), 2.07-1.90 (m, 4H), 1.48 (d, J = 7.1 Hz, 3H) 571.5 [M+1] ⁺ 28

(S) -1- (4 - ( (5- cyclopropyl -1 H-pyrazol-3-yl) amino) quinazolin-2-yl) - N - (1- (6- ( 4-fluoro- 1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.00 (s, 1H), 8.66 (d, J = 4.5 Hz, 1H), 8.53 (d, J = 8.2 Hz, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.33 (dd, J = 8.4, 1.4 Hz, 1H), 7.98 (dd, J = 8.5, 2.3 Hz, 1H), 7.92-7.84 (m, 2H), 7.53 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.31 (dd, J = 8.4, 1.2 Hz, 1H), 7.08 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 6.31 (s, 1H), 5.11-4.99 (m, 1H), 4.43 (td, J = 14.7, 13.7, 7.0 Hz, 2H), 3.26 (ddt, J = 13.0, 9.5, 3.7 Hz, 3H), 3.17 (s, 4H), 1.97-1.91 (m , 1H), 1.88-1.74 (m, 4H), 1.47 (d, J = 7.1 Hz, 3H), 1.00-0.90 (m, 2H), 0.70-0.62 (m, 2H) 597.4 [M+1] ⁺ 29

(S) -1- (4 - ( (5- cyclobutyl -1 H-pyrazol-3-yl) amino) quinazolin-2-yl) - N - (1- (6- ( 4-fluoro- 1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.05 (s, 1H), 8.65 (d, J = 4.5 Hz, 1H), 8.53 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 2.2 Hz, 1H), 8.34 (dd, J = 8.3, 1.4 Hz, 1H), 7.97 (dd, J = 8.5, 2.3 Hz, 1H), 7.90 (d, J = 4.4 Hz, 1H), 7.85 (d , J = 8.5 Hz, 1H), 7.54 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.32 (dd, J = 8.5, 1.2 Hz, 1H), 7.09 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 6.54 (s, 1H), 5.05 (p, J = 7.2 Hz, 1H), 4.45 (ddt, J = 16.9, 13.0, 3.8 Hz, 2H), 3.50 (p, J = 8.4 Hz, 1H ), 3.34-3.21 (m, 3H), 3.17 (s, 4H), 2.32 (ddp, J = 11.6, 8.0, 3.6 Hz, 2H), 2.11 (tdd, J = 12.9, 9.8, 5.4 Hz, 2H), 1.97 (dq, J = 10.6, 8.4 Hz, 1H), 1.89-1.70 (m, 6H), 1.46 (d, J = 7.0 Hz, 3H) 611.4 [M+1] ⁺ 30

(S) - N - (1- (6- ( 4-fluoro -1 H - pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (7-methyl-4 -((5-methyl-1 H -pyrazol-3-yl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)piperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.33 (s, 1H), 8.66 (d, J = 4.5 Hz, 1H), 8.62 (d, J = 8.2 Hz, 1H), 8.42 (d, J = 2.2 Hz, 1H), 7.98 (dd, J = 8.6, 2.3 Hz, 1H), 7.91 (d, J = 4.2 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 3.6 Hz, 1H), 6.70 (d, J = 3.6 Hz, 1H), 6.13 (s, 1H), 5.06 (p, J = 7.2 Hz, 2H), 4.16 (dd, J = 19.2, 14.0 Hz, 2H) , 3.64 (s, 3H), 3.39 (dd, J = 13.6, 6.9 Hz, 2H), 3.19 (s, 3H), 2.29 (s, 3H), 2.01-1.84 (m, 4H), 1.48 (d, J = 7.1 Hz, 3H) 574.5 [M+1] ⁺ 31

( S )-1-(4-((5-cyclopropyl-1 H -pyrazol-3-yl)amino)-7-methyl-7 H -pyrrolo[2,3- d ]pyrimidine-2- yl) - N - (1- (6- (4- -1 H -fluoro-pyridin-3-yl-pyrazol-1-yl)) ethyl) -4-methoxypyrrolidine piperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.65 (dd, J = 20.1, 6.4 Hz, 2H), 8.42 (s, 1H), 8.03-7.82 (m, 3H), 7.03 (s, 1H) , 6.67 (s, 1H), 6.08 (s, 1H), 5.11-5.00 (m, 1H), 4.19 (s, 3H), 3.61 (s, 4H), 3.18 (d, J = 3.1 Hz, 3H), 1.90 (d, J = 27.9 Hz, 6H), 1.47 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 8.0 Hz, 2H), 0.73 (d, J = 5.3 Hz, 2H) 600.5 [M+1] ⁺ 32

( S )-1-(4-((5-cyclobutyl-1 H -pyrazol-3-yl)amino)-7-methyl-7 H -pyrrolo[2,3- d ]pyrimidine-2- yl) - N - (1- (6- (4- -1 H -fluoro-pyridin-3-yl-pyrazol-1-yl)) ethyl) -4-methoxypyrrolidine piperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.58 (s, 1H), 8.66 (dd, J = 4.6, 0.9 Hz, 1H), 8.52 (d, J = 8.3 Hz, 1H), 8.41 (d , J = 2.2 Hz, 1H), 7.97 (dd, J = 8.5, 2.3 Hz, 1H), 7.90 (dd, J = 4.3, 0.8 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 6.78 (d, J = 3.5 Hz, 1H), 6.62 (d, J = 3.5 Hz, 1H), 6.52 (s, 1H), 5.05 (p, J = 7.2 Hz, 1H), 4.43-4.31 (m, 2H) , 3.56 (s, 3H), 3.47 (p, J = 8.4 Hz, 2H), 3.30 (s, 2H), 3.23 (q, J = 8.7, 5.2 Hz, 3H), 3.17 (s, 3H), 2.30 ( ddp, J = 11.4, 7.8, 3.6 Hz, 2H), 2.15-2.02 (m, 2H), 1.87 (s, 4H), 1.78 (q, J = 4.6 Hz, 2H), 1.46 (d, J = 7.1 Hz , 3H) 614.5 [M+1] ⁺ 33

(S) - N - (1- (6- (4-fluoro -1 H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (4 - ((5 -Methyl-1 H -pyrazol-3-yl)amino)furo[3,2- d ]pyrimidin-2-yl)piperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.47 (s, 1H), 8.67 (d, J = 4.5 Hz, 1H), 8.60 (d, J = 8.2 Hz, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.32 (s, 1H), 7.99 (dd, J = 8.6, 2.3 Hz, 1H), 7.92-7.84 (m, 2H), 7.00 (s, 1H), 6.33 (s, 1H), 5.76 (s, 1H), 5.06 (p, J = 7.2 Hz, 1H), 4.27 (t, J = 14.6 Hz, 2H), 3.48-3.39 (m, 2H), 3.18 (s, 3H), 2.27 (s , 3H), 2.00-1.85 (m, 4H), 1.48 (d, J = 7.0 Hz, 3H), 1.23 (s, 2H) 561.5 [M+1] ⁺ 34

(S) -1- (4 - ( (5- cyclopropyl -1 H - pyrazol-3-yl) amino) furo [3,2- d] pyrimidin-2-yl) - N - (1- ( 6-(4-Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.16 (s, 1H), 9.86 (s, 1H), 8.66 (d, J = 4.4 Hz, 1H), 8.41-8.36 (m, 2H), 7.93 -7.85 (m, 3H), 7.68 (d, J = 6.0 Hz, 1H), 7.03 (d, J = 6.0 Hz, 1H), 6.41 (s, 1H), 4.98 (p, J = 7.1 Hz, 1H) , 4.70-4.60 (m, 2H), 3.33 (s, 1H), 2.91 (tt, J = 13.6, 3.5 Hz, 2H), 2.24 (s, 3H), 1.89 (s, 1H), 1.77 (td, J = 9.9, 8.8, 5.0 Hz, 2H), 1.52 (dtd, J = 25.7, 12.6, 4.0 Hz, 2H), 1.40 (d, J = 7.0 Hz, 3H) 587.4 [M+1] ⁺ 35

(S) -1- (4 - ( (5- cyclobutyl -1 H - pyrazol-3-yl) amino) furo [3,2- d] pyrimidin-2-yl) - N - (1- ( 6-(4-Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.88 (s, 1H), 8.66 (d, J = 4.5 Hz, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.97 (dd, J = 8.5, 2.4 Hz, 1H), 7.90 (d, J = 4.2 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 2.1 Hz, 1H), 6.43 (s, 1H), 5.04 (p, J = 7.2 Hz, 1H), 4.29 (dd, J = 17.3, 13.2 Hz, 2H ), 3.48 (p, J = 8.5 Hz, 2H), 3.21 (d, J = 9.4 Hz, 2H), 3.16 (s, 3H), 3.09 (s, 1H), 2.30 (dt, J = 7.6, 3.7 Hz , 2H), 2.18-1.91 (m, 5H), 1.86 (d, J = 13.4 Hz, 2H), 1.79-1.73 (m, 2H), 1.46 (d, J = 7.1 Hz, 4H) 601.4 [M+1] ⁺ 36

(S) - N - (1- (6- (4-fluoro -1 H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (4 - ((5 -Methyl-1 H -pyrazol-3-yl)amino)thieno[3,2- d ]pyrimidin-2-yl)piperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.45 (s, 1H), 8.69-8.65 (m, 1H), 8.60 (d, J = 8.2 Hz, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.26 (s, 1H), 7.99 (dd, J = 8.6, 2.3 Hz, 1H), 7.94-7.83 (m, 2H), 7.53 (s, 1H), 6.36 (s, 1H), 5.06 (p , J = 7.2 Hz, 1H), 4.33 (s, 2H), 3.52-3.38 (m, 2H), 3.18 (d, J = 5.8 Hz, 7H), 2.28 (s, 3H), 2.03-1.85 (m, 4H), 1.48 (d, J = 7.1 Hz, 3H) 577.4 [M+1] ⁺ 37

(S) -1- (4 - ( (5- cyclopropyl -1 H - pyrazol-3-yl) amino) furnace to Im [3,2- d] pyrimidin-2-yl) - N - (1 -(6-(4-Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.70 (s, 1H), 8.68-8.65 (m, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 2.3 Hz , 1H), 7.97 (dd, J = 8.5, 2.3 Hz, 1H), 7.93-7.84 (m, 4H), 7.06 (d, J = 5.3 Hz, 1H), 6.18 (s, 1H), 5.05 (p, J = 7.2 Hz, 1H), 4.38-4.26 (m, 2H), 3.23 (dp, J = 10.6, 3.5 Hz, 3H), 3.17 (d, J = 1.6 Hz, 4H), 1.88 (d, J = 8.9 Hz, 1H), 1.84 (dt, J = 8.0, 4.3 Hz, 3H), 1.80-1.70 (m, 2H), 1.46 (d, J = 7.1 Hz, 3H), 0.98-0.88 (m, 3H), 0.68 -0.62 (m, 2H) 603.4 [M+1] ⁺ 38

( S )-1-(4-((5-cyclobutyl-1 H -pyrazol-3-yl)amino)thieno[3,2- d ]pyrimidin-2-yl)- N -(1 -(6-(4-Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.65 (d, J = 4.8 Hz, 1H), 8.59 (d, J = 7.9 Hz, 1H), 8.42 (s, 1H), 8.20 (s, 1H) ), 8.01-7.94 (m, 1H), 7.91 (t, J = 3.6 Hz, 1H), 7.89-7.83 (m, 1H), 7.24 (s, 1H), 6.42 (s, 1H), 5.12-4.99 ( m, 1H), 4.21 (d, J = 17.2 Hz, 2H), 3.52 (s, 2H), 3.47-3.36 (m, 2H), 3.18 (d, J = 5.0 Hz, 4H), 2.38-2.27 (m , 2H), 2.11-2.05 (m, 6H), 1.97 (s, 3H), 1.47 (t, J = 6.0 Hz, 3H) 617.4 [M+1] ⁺ 39

(S) - N - (1- (6- (4-fluoro -1 H-pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (4 - ((5 -Methyl-1 H -pyrazol-3-yl)amino)thieno[2,3- d ]pyrimidin-2-yl)piperidine-4-carboxamide 577.4 [M+1] ⁺ 40

( S )-1-(4-((5-cyclopropyl-1 H -pyrazol-3-yl)amino)thieno[2,3- d ]pyrimidin-2-yl)- N -(1 -(6-(4-Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.09 (s, 1H), 8.65 (d, J = 4.5 Hz, 1H), 8.42-8.34 (m, 3H), 7.94-7.84 (m, 3H) , 7.60-7.52 (m, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.44 (s, 1H), 4.98 (p, J = 7.1 Hz, 1H), 4.75 (td, J = 9.3, 4.7 Hz, 2H), 2.95 (td, J = 11.2, 9.6, 4.0 Hz, 2H), 2.26 (s, 3H), 1.91 (s, 4H), 1.78 (td , J = 10.2, 8.0, 4.2 Hz, 2H), 1.54 (dqd, J = 25.0, 12.3, 4.1 Hz, 2H), 1.40 (d, J = 7.0 Hz, 3H) 603.3 [M+1] ⁺ 41

( S )-1-(4-((5-cyclobutyl-1 H -pyrazol-3-yl)amino)thieno[2,3- d ]pyrimidin-2-yl)- N -(1 -(6-(4-Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.94 (s, 1H), 8.65 (dd, J = 4.5, 0.9 Hz, 1H), 8.53 (d, J = 8.2 Hz, 1H), 8.41 (d , J = 2.2 Hz, 1H), 7.97 (dd, J = 8.6, 2.3 Hz, 1H), 7.92-7.83 (m, 2H), 7.68 (d, J = 6.0 Hz, 1H), 7.05 (d, J = 6.0 Hz, 1H), 6.53 (s, 1H), 5.05 (p, J = 7.2 Hz, 1H), 4.35 (ddt, J = 16.5, 13.2, 4.2 Hz, 2H), 3.49 (p, J = 8.4 Hz, 1H), 3.27 (td, J = 10.6, 8.0, 3.9 Hz, 3H), 3.16 (s, 3H), 2.31 (ddp, J = 11.5, 8.0, 3.6 Hz, 2H), 2.16-2.03 (m, 2H) , 1.96 (dq, J = 10.8, 8.4 Hz, 1H), 1.90 (s, 2H), 1.89-1.72 (m, 5H), 1.46 (d, J = 7.0 Hz, 3H) 617.4 [M+1] ⁺ 42

(S) - N - (1- (6- ( 4-fluoro -1 H - pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (7-methyl-6 -((5-methyl-1 H -pyrazol-3-yl)amino)-7 H -purin-2-yl) piperidine-4-carboxamide 575.4 [M+1] ⁺ 43

( S )-1-(6-((5-cyclopropyl-1 H -pyrazol-3-yl)amino)-7-methyl-7 H -purin-2-yl)- N -(1-(6 -(4-Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.46 (s, 1H), 8.66 (d, J = 4.5 Hz, 1H), 8.63 (s, 1H), 8.56 (d, J = 8.2 Hz, 1H ), 8.41 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 8.5, 2.3 Hz, 1H), 7.91 (d, J = 4.3 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H ), 6.12 (s, 1H), 5.04 (p, J = 7.1 Hz, 2H), 4.20 (t, J = 14.7 Hz, 3H), 4.09 (s, 3H), 3.32-3.25 (m, 2H), 3.16 (s, 3H), 1.98-1.90 (m, 1H), 1.47 (d, J = 7.1 Hz, 4H), 1.27-1.14 (m, 3H), 0.99-0.93 (m, 2H), 0.66-0.61 (m , 2H) 601.5 [M+1] ⁺ 44

(S) - N - (1- (6- ( 4-fluoro -1 H - pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (9-methyl-6 -((5-methyl-1 H -pyrazol-3-yl)amino)-9 H -purin-2-yl)piperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.34 (s, 1H), 8.67 (d, J = 4.5 Hz, 1H), 8.51 (d, J = 8.3 Hz, 1H), 8.42 (d, J = 2.3 Hz, 1H), 7.98 (dd, J = 8.5, 2.3 Hz, 1H), 7.90 (d, J = 4.2 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 6.34 (s, 1H ), 5.05 (p, J = 7.2 Hz, 1H), 4.41-4.31 (m, 2H), 3.61 (s, 3H), 3.23 (ddt, J = 12.8, 8.5, 3.7 Hz, 4H), 3.17 (s, 3H), 2.22 (s, 3H), 1.88-1.83 (m, 2H), 1.77 (ddd, J = 20.2, 11.6, 4.6 Hz, 2H), 1.46 (d, J = 7.1 Hz, 3H) 575.4 [M+1] ⁺ 45

( S )-1-(6-((5-cyclopropyl-1 H -pyrazol-3-yl)amino)-9-methyl-9 H -purin-2-yl)- N -(1-(6 -(4-Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.67 (d, J = 4.5 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H), 8.42 (d, J = 2.3 Hz, 1H), 7.98 (dd, J = 8.5, 2.3 Hz, 1H), 7.92-7.82 (m, 4H), 6.21 (s, 1H), 5.05 (p, J = 7.1 Hz, 2H), 4.34 (t, J = 14.3 Hz , 3H), 3.60 (s, 3H), 3.27 (s, 4H), 3.17 (s, 3H), 1.90 (dd, J = 8.6, 4.9 Hz, 1H), 1.47 (d, J = 7.1 Hz, 4H) , 1.23 (s, 3H), 0.93-0.90 (m, 2H), 0.66-0.61 (m, 2H) 601.5 [M+1] ⁺

<Example 46> N -Benzyl-4-methoxy-1-(4-((5-methyl-1) H Preparation of -pyrazol-3-yl)amino)quinazolin-2-yl)piperidin-4-carboxamide

The title compound was prepared through the method shown in Scheme 12 below.

[Scheme 12]

Step 1: 1-( tert -butyl) 4-methyl 4-methoxypiperidine-1,4-dicarboxylate (1.2g, 4.39mmol) was dissolved in methanol (10mL) and then 4M HCl/MeOH (60mL) was added. It was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a solid methyl 4-methoxypiperidine-4-carboxylate (0.8 g, 86.91%).

¹ H NMR (400 MHz, Methanol- d ₄ ) δ = 3.79 (s, 3H), 3.30-3.25 (m, 2H), 3.28 (s, 3H), 3.22-3.19 (m, 2H), 2.27-2.09 ( m, 4H)

Step 2: Methyl 4-methoxypiperidine-4-carboxylate (150 mg, 715.41 μmol), DIPEA (462.31 mg, 3.58 mmol, 623.06 μL), KI (118.76 mg, 715.41 μmol) in DMF (10 mL) After dissolving 2-chloro- N- (5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl)quinazolin-4-amine (270.56mg, 786.95 μmol) was added and stirred at 60 ^o C for 12 hours. The reaction mixture was extracted with ethyl acetate and brine, and the organic layers were 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 solid methyl 4-methoxy-1-(4-((5-methyl-1-(tetrahydro-2)). H -pyran-2-yl)-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)piperidine-4-carboxylate (300mg, 87.26%) was obtained.

MS: m/z 481.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.64-7.46 (m, 4H), 6.68 (s, 1H), 5.23 (br d, J = 2.6 Hz, 1H), 4.50-4.42 (m, 2H), 3.77 (s, 3H), 3.68 (dt, J = 2.0, 11.4 Hz, 2H), 3.58-3.44 (m, 2H), 3.34 (s, 3H), 2.39 (s, 3H), 2.16-1.98 (m, 6H), 1.92 (br d, J = 13.2 Hz, 2H), 1.60 (br d, J = 9.6 Hz, 2H)

Step 3: Methyl 4-methoxy-1-(4-((5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl)amino)quinazoline After dissolving -2-yl)piperidine-4-carboxylate (250mg, 520.23umol) in water (1mL) and methanol (5mL), NaOH (50mg, 1.25mmol) was added, followed by stirring at room temperature for 16 hours. 1N HCl is added to the reaction mixture to titrate the pH to 4-5. Add ethyl acetate to extract the aqueous layer and freeze-dried to make solid 4-methoxy-1-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)piperi Din-4-carboxylic acid (120mg, 49.44%) was obtained.

MS: m/z 467.3 [M+H] ⁺

Step 4: 4-methoxy-1-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)piperidine-4-carboxylic acid (110mg, 235.78umol ) And phenylmethanamine (147.45mg, 1.38mmol, 0.15mL), HATU (107.58mg, 282.94umol), and DIPEA (371.00mg, 2.87mmol, 0.5mL) in dichloromethane (3mL) and 1 at room temperature. Stirred for hours. The reaction mixture was extracted with dichloromethane and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by Prep-150 LC System to obtain a solid N -benzyl-4-methoxy-1-(4-((5-methyl-1 H -pyrazol-3-yl)amino. )Quinazolin-2-yl)piperidine-4-carboxamide (50mg, 44.97%) was obtained.

MS: m/z 472.1 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ = 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, J = 5.6 Hz, 1H), 6.57-6.33 (m, 1H), 4.65 (d, J = 12.0 Hz, 2H), 4.47 (d, J = 6.0 Hz, 2H ), 3.43-3.28 (m, 5H), 2.30 (s, 3H), 2.22-2.16 (m, 2H), 1.92 (d, J = 14.4 Hz, 2H)

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

Example rescue Compound name ¹ H NMR LC-MS
(m/z) 46

N -Benzyl-4-methoxy-1-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)piperidine-4-carboxamide ¹ H NMR (400 MHz, CDCl ₃ ) δ = 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, J = 5.6 Hz, 1H), 6.57-6.33 (m, 1H), 4.65 (d, J = 12.0 Hz, 2H), 4.47 (d, J = 6.0 Hz, 2H ), 3.43-3.28 (m, 5H), 2.30 (s, 3H), 2.22-2.16 (m, 2H), 1.92 (d, J = 14.4 Hz, 2H) 472.1 [M+H] ⁺

<Example 47> N -Benzyl-1-(4-((5-methyl-1 H Preparation of -pyrazol-3-yl)amino)quinazolin-2-yl)piperidin-4-carboxamide

The title compound was prepared through the method shown in Scheme 13 below.

[Scheme 13]

Step 1: 2-Chloro- N- (5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl)quinazolin-4-amine (300mg, 872.57 μmol), methyl piperidine-4-carboxylate (187.41mg, 1.31mmol), KI (28.97mg, 174.51μmol), and DIPEA (742.00mg, 5.74mmol, 1.00mL) were dissolved in DMF (10mL) and then 80 ^o Stirred at C for 12 hours. The reaction mixture was extracted with ethyl acetate and brine, and the organic layers were 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 liquid methyl 1-(4-((5-methyl-1-(tetrahydro- 2H -pyran-2)). -Yl)-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)piperidine-4-carboxylate (315mg, 59.18%) was obtained.

MS: m/z 451.3 [M+H] ⁺

Step 2: Methyl 1-(4-((5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl)amino)quinazolin-2-yl) Piperidine-4-carboxylate (280mg, 621.49μmol) was dissolved in tetrahydrofuran (5mL), NaOH (100mg, 2.50mmol) and water (1mL) were added, followed by stirring at room temperature for 12 hours. Water was added to the reaction mixture and washed with ethyl acetate. 1N HCl (10 mL) was added dropwise to the water layer to adjust the pH to 7, and the organic layer was extracted using ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and 1 - (4 of solid - ((5-methyl-1- (tetrahydro -2 H-pyran-2-yl) -1 H-pyrazol-3-yl) amino) Quinazolin-2-yl) piperidine-4-carboxylic acid (260mg, 89.09%) was obtained.

MS: m/z 437.1 [M+H] ⁺

Step 3: 1- (4 - ((5-methyl-1- (tetrahydro -2H- pyran-2-yl) -1 H-pyrazol-3-yl) amino) quinazolin-2-yl) piperidin Din-4-carboxylic acid (230mg, 514.45μmol), phenylmethanamine (55.12mg, 514.45μmol, 56.08μL), DIPEA (66.49mg, 514.45μmol, 89.61μL), HATU (195.61mg, 514.45μmol) dichloromethane After dissolving in phosphorus (4mL), it was stirred at room temperature for 12 hours. The reaction mixture was poured into water (20 mL) to precipitate a solid. By filtration of the solid N-benzyl-1- (4 - ((5-methyl-1- (tetrahydro -2 H-pyran-2-yl) -1 H-pyrazol-3-yl) amino) quinazolin- 2-day) piperidine-4-carboxamide (160mg, 59.17%) was obtained.

MS: m/z 526.2 [M+H] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.31-9.98 (m, 1H), 8.44-8.32 (m, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.42-7.35 (m, 1H), 7.34-7.28 (m, 2H), 7.23 (d, J = 7.2 Hz, 3H), 7.11 (t, J = 7.2 Hz, 1H), 6.52 (s, 1H), 5.34 (dd, J = 2.0 , 10.0 Hz, 1H), 4.76 (d, J = 12.0 Hz, 2H), 4.26 (d, J = 6.0 Hz, 2H), 3.92 (d, J = 12.0 Hz, 1H), 3.64 (t, J = 3.2 , 10.8 Hz, 1H), 2.94 (t, J = 12.4 Hz, 2H), 2.33 (s, 3H), 2.05-1.95 (m, 1H), 1.91-1.66 (m, 4H), 1.63-1.47 (m, 4H)

Step 4: N -Benzyl-1-(4-((5-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl)amino)quinazoline-2 -Yl) Piperidine-4-carboxamide (130mg, 247.32μmol) was dissolved in methanol (2mL), and then 4M HCl/MeOH (10mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was stirred at 50 ^o C for 12 hours. The resulting solid was filtered and purified by Prep-150 LC System to obtain a solid N -benzyl-1-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl) Piperidine-4-carboxamide (26mg, 23.81%) was obtained.

MS: m/z 442.2 [M+H] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.21-11.97 (m, 1H), 9.97 (s, 1H), 8.42-8.23 (m, 2H), 7.59-7.48 (m, 1H), 7.35- 7.28 (m, 3H), 7.26-7.19 (m, 3H), 7.12-7.05 (m, 1H), 6.43 (s, 1H), 4.78 (d, J = 13.2 Hz, 2H), 4.26 (d, J = 6.0 Hz, 2H), 3.31 (s, 1H), 2.92 (t, J = 12.0 Hz, 2H), 2.26 (s, 3H), 1.82-1.78 (m, 2H), 1.56 (dd, J = 3.6, 12.4 Hz, 2H)

Examples 48 to 51 were prepared in a similar manner to Example 47, and the chemical structures, compound names, NMR, and LC-MS analysis results of Examples 47 to 51 are summarized in Table 5 below.

Example rescue Compound name ¹ H NMR LC-MS
(m/z) 47

N -Benzyl-1-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)piperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.21-11.97 (m, 1H), 9.97 (s, 1H), 8.42-8.23 (m, 2H), 7.59-7.48 (m, 1H), 7.35- 7.28 (m, 3H), 7.26-7.19 (m, 3H), 7.12-7.05 (m, 1H), 6.43 (s, 1H), 4.78 (d, J = 13.2 Hz, 2H), 4.26 (d, J = 6.0 Hz, 2H), 3.31 (s, 1H), 2.92 (t, J = 12.0 Hz, 2H), 2.26 (s, 3H), 1.82-1.78 (m, 2H), 1.56 (dd, J = 3.6, 12.4 Hz, 2H) 442.2 [M+H] ⁺ 48

(S) - N - (1- (6- (4- fluorophenyl -1 H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4 - ((5-methyl -1 H -Pyrazol-3-yl)amino)quinazolin-2-yl)piperidine-4-carboxamide 541.4 [M+1] ⁺ 49

(S) - N - (1- (6- (4- fluoro -1 H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (7-methyl-4 - ((5- Methyl-1 H -pyrazol-3-yl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)piperidine-4-carboxamide 544.4 [M+1] ⁺ 50

(S) - N - (1- (6- (4- fluorophenyl -1 H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4 - ((5-methyl -1 H -Pyrazol-3-yl)amino)thieno[3,2- d ]pyrimidin-2-yl)piperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.46 (s, 1H), 8.67 (d, J = 4.5 Hz, 1H), 8.56 (d, J = 7.6 Hz, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.27 (s, 1H), 7.94 (dd, J = 8.5, 2.3 Hz, 1H), 7.91 (d, J = 4.3 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H) , 7.54 (s, 1H), 6.36 (s, 1H), 4.99 (p, J = 7.1 Hz, 1H), 4.60 (d, J = 11.7 Hz, 2H), 3.26 (dt, J = 18.5, 9.1 Hz, 2H), 2.62 (tt, J = 11.0, 4.0 Hz, 1H), 2.28 (s, 3H), 1.94-1.84 (m, 2H), 1.65 (dqd, J = 28.9, 12.1, 4.0 Hz, 2H), 1.42 (d, J = 7.0 Hz, 3H) 547.3 [M+1] ⁺ 51

(S) - N - (1- (6- (4- fluorophenyl -1 H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4 - ((5-methyl -1 H -Pyrazol-3-yl)amino)thieno[2,3- d ]pyrimidin-2-yl)piperidine-4-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.16 (s, 1H), 9.86 (s, 1H), 8.66 (d, J = 4.4 Hz, 1H), 8.41-8.36 (m, 2H), 7.93 -7.85 (m, 3H), 7.68 (d, J = 6.0 Hz, 1H), 7.03 (d, J = 6.0 Hz, 1H), 6.41 (s, 1H), 4.98 (p, J = 7.1 Hz, 1H) , 4.70-4.60 (m, 2H), 3.33 (s, 1H), 2.91 (tt, J = 13.6, 3.5 Hz, 2H), 2.24 (s, 3H), 1.89 (s, 1H), 1.77 (td, J = 9.9, 8.8, 5.0 Hz, 2H), 1.52 (dtd, J = 25.7, 12.6, 4.0 Hz, 2H), 1.40 (d, J = 7.0 Hz, 3H) 547.4 [M+1] ⁺

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

In order to evaluate the inhibitory activity of the compound according to the present invention to more enzymes, the following experiment was performed. Specifically, for Examples 15, 19, and 22 selected from the example compounds of the present invention, the enzyme (kinase) selectivity was determined by requesting DiscoverX, and the experiment was conducted using a scanMAX ^TM Kinase analysis panel. I did. At this time, the concentration of the drug treated with the enzyme was 1 μM in DMSO, and the control percentage (% control) was determined in the same manner as in Equation 1 below, and the results are shown in Table 6 below.

[Equation 1]

(Example compound-positive control) / (negative control-positive control) x 100

Here, the positive control refers to a compound showing a 0% control percentage, and the negative control refers to a 100% control percentage with DMSO. In addition, the enzyme selectivity of the present invention was determined to have activity against the enzyme if the control percentage for each enzyme was <35% (ie, less than 35%).

Example 15 Example 19 Example 22 Example 15 Example 19 Example 22 AMPK-alpha1 5.3 1.3 1.8 KIT(D816V) 0.3 2 0 AMPK-alpha2 2.1 0.7 8 KIT(L576P) 5.4 0 0.6 ARK5 4.7 1.4 1.3 KIT(V559D) 1.1 0.2 0 AURKA 9.5 4.3 2.5 KIT(V559D,T670I) 8 2.8 1.1 AURKB 29 20 15 KIT(V559D,V654A) 27 19 13 AURKC 3 0.1 1.4 LCK 0.65 One 0.1 AXL 5.2 6.2 2.6 MAP3K2 30 16 4.5 BLK 1.2 2.1 0.2 MEK5 23 27 15 CSF1R 2.3 0.6 0.35 MERTK 13 4.7 0.4 CSNK2A2 6.7 21 33 MLK2 26 12 9.1 DAPK1 22 6.9 22 MLK3 6.1 2.8 1.2 DAPK3 9.8 6.7 24 NEK7 30 28 4.2 EPHB6 11 10 0.35 NEK9 26 22 6.8 FGFR1 0.4 0.15 0.15 PDGFRA 8 5.5 3.2 FGFR2 7.6 1.4 0.8 PDGFRB 0.1 0 0 FGFR3 9.7 2.3 0.85 PLK4 0.55 0.2 0.15 FGFR3(G697C) 7.6 5.1 1.8 PYK2 0.35 0.2 0.25 FGR 23 16 6.5 RET 0 0 0 FLT1 0.15 0.1 0.05 RET(M918T) 0.2 0.2 0.2 FLT3 2.1 0 1.1 RET(V804L) 0 0 0 FLT3(D835H) 0.1 0.35 0 RET(V804M) 0 0 0 FLT3(D835V) 0 0.9 0 RIOK3 10 4.7 5.2 FLT3(D835Y) 0.5 0.2 0.05 ROS1 7.2 4.5 2.9 FLT3(ITD) 0.2 0 0.05 RSK2(Kin.Dom.1-N-terminal) 20 11 3.9 FLT3(ITD,D835V) 0 4 0 RSK3(Kin.Dom.1-N-terminal) 6.5 0.75 0.7 FLT3(ITD,F691L) 0.2 0 0 SLK 9.9 2.9 0.75 FLT3(K663Q) 0.4 0.5 0 SNARK 15 7.3 4.4 FLT3(N841I) 0.6 0 3.1 SRC 0.3 0.4 0.1 FLT3(R834Q) 5.5 6.8 1.4 STK16 7.8 9.4 3 FLT3-autoinhibited 6 9.9 2.3 SYK 4.3 3.8 1.8 FLT4 0 0 0 TIE1 30 13 18 GCN2(Kin.Dom.2,S808G) 16 2.5 1.6 TNK1 3.4 4.3 0.9 HCK 5.9 1.3 0.85 TNK2 9.7 3.9 0.5 JAK1 (JH1domain-catalytic) 3.1 0.4 1.6 TRKA 0 3.5 0 JAK2 (JH1domain-catalytic) 0 0.95 0 TRKB 6.1 11 2.6 JAK3 (JH1domain-catalytic) 0 0 0 TRKC 0.95 4.7 1.4 KIT 2.7 0.5 0.1 TYK2 (JH1domain-catalytic) 0.7 4.5 0.15 KIT(A829P) 0 0 0 YES 17 5.3 3.1 KIT(D816H) 5.2 4.2 2.9 YSK4 4.3 6.6 4.9

As can be seen in Table 6, the compounds according to the present invention are AMPK-alpha1, 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 For (V804M), RIOK3, ROS1, RSK2, RSK3, SLK, SNARK, SRC, STK16, SYK, TIE1, TNK1, TNK2, TRKA, TRKB, TRKC, TYK2, YES, YSK4 kinases. You can see what you have. This indicates that the compounds according to the present invention have inhibitory activity against the enzymes listed above, and from this suggests that there is a useful effect when used in diseases related to the enzymes listed above. Therefore, the derivative compounds according to the present invention are AMPK-alpha1, AMPK-alpha2, ARK5, AURKA, AURKB, AURKC, AXL, BLK, CSF1R, CSNK2A2, DAPK1, DAPK3, EPHB6, FGFR1, FGFR2, FGFR3, FGFR3 (G697C) according to the present invention. , 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. .

<Experimental Example 2> RET (ret proto-oncogene) enzyme inhibitory ability evaluation

In order to evaluate the inhibitory activity of the example compounds according to the present invention to RET (ret proto-oncogene) enzyme, the following experiment was performed. The example compound was reacted with a purified human RET (658-end, signalchem) enzyme to evaluate the enzyme inhibitory ability in the following manner. The reaction buffer was 40mM Tris-HCl pH 7.4, 20mM MgCl ₂ , 0.5 mg/mL BSA, and 50uM DTT composition was used, and all the test materials were reacted on the reaction buffer. In the test, human RET (658-end, 0.8ng) enzyme, purified ATP (10uM), and a specific substrate solution were reacted at 25℃ for 1 hour, and then the enzyme activity was measured using in vitro ADP-Glo ^TM kinase assay (promega). And confirmed. Luminescence was measured by reacting the enzyme activity reaction solution, the ADP-Glo reaction solution, and the enzyme activity detection solution in a 2:2:1 ratio. The degree of inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control group without compound treatment, and at this time, the concentration of each compound that inhibits 50% inhibition of the enzyme activity was IC ₅₀ (nM) value. Was decided. The IC ₅₀ of each compound was determined with three data sets and calculated using Prism (version 7.01, GraphPad) software. The results are shown in Table 7 below.

<Experimental Example 3> Evaluation of medullary thyroid cancer and lung cancer cell proliferation inhibitory activity expressing RET fusion gene

ve), Ba/F3 KIF5B-RET, Ba/F3 KIF5B-RET(V804M) 세포에 대한 각 실험화합물의 성장저해활성을 측정한 결과를 나타내었다. In order to evaluate the inhibitory activity of the compound according to the present invention against proliferation of medullary thyroid cancer cells and lung cancer cells expressing the RET fusion gene, the following experiment was performed. Among the lung cancer cell lines expressing the RET fusion gene, LC-2/ad cells were cultured after 10% FBS (HyClone) was added to RPMI:F12 (1:1) (Invitrogen), and TT cells, a thyroid medullary cancer cell line, were 10% F-12 (Invitrogen) to which FBS was added was 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 are cultured by adding 1 ug/ml puromycin (Invitrogen) to the same medium. For cells, 24 hours before compound treatment, 3000-5000 cells were aliquoted into each well of a white clear bottom 96 well plate (Corning). The compound was diluted in dimethyl sulfoxide (diluted by 3 times, total concentration of 12) and injected 0.5ul each so that the final concentration was 0.3nM-50uM. For the measurement of living cells, 72 hours after compound treatment, after storing for 10 minutes at room temperature using CellTiter-Glo luminescent cell-viability reagent (Promega), the luminescence intensity was measured using a reader (SynergyNeo, Biotek). Each test was repeated three times. The result was calculated as the cellular equipment ratio (%) compared to the control. Graphs were drawn using the GraphPad Prism version 5.0 program and the IC ₅₀ (nM) values were calculated. In Table 7 below, LC-2/ad, Ba/F3 (na

ve), Ba/F3 KIF5B-RET, Ba/F3 KIF5B-RET (V804M) The results of measuring the growth inhibitory activity of each test compound on cells are shown.

Example Enzyme assay (IC ₅₀ , nM) Cell assay (GI ₅₀ , nM) RET
(wild) RET
(V804M) CCDC6-RET Ba/F3
(naive) LC-2/ad Ba/F3
KIF5B-RET Ba/F3
KIF5B-RET
(V804M) One 36.4 2 4.8 <0.508 <0.508 1003 9.1 58 210 3 10.6 4 126.7 5 124 6 5.5 7 12.8 8 8.6 9 4806 106 417 10 116.8 11 98.9 12 44.6 13 4.1 14 429 522.7 15 1.2 <0.508 <0.508 888 4.9 42 142 16 95.8 234.6 17 16.8 <0.508 3.28 1127 2 8 26 18 27 44.4 19 0.8 <0.508 2.62 1601 2 10 35 20 167 15,000 1551 2073 7789 21 203 22 2.2 1.41 5.32 1254 4 16 43 23 159.2 24 17.3 25 83.5 237 26 19.6 10 27 0.12 0.95 0.75 2150 13 28 47.4 2.5 0.95 5.4 29 37.8 6.8 30 0.2 0.9 0.72 4638 5 31 46.3 4.26 2.37 3 32 25.3 6.2 33 0.2 <0.51 <0.51 4 34 14.8 1.35 0.52 5.9 35 11.5 25.8 36 2.4 <0.51 <0.51 9 37 28.6 3.56 0.85 4.2 38 39.1 9.9 39 1.3 <0.51 <0.51 3 40 69.7 3.97 1.1 4.3 41 111 9.2 42 4.5 <0.51 <0.51 44 43 5.4 1.65 0.68 26.3 44 7.9 3.44 2.35 22 45 23.7 3.12 3.08 27.2 46 77.2 47 32.4 48 0.6 0.79 0.62 15,000 9 49 5.4 3.26 2.62 1282 23 50 1.3 0.78 0.64 1134 10 51 6.1 0.86 0.72 587 6

As shown in Table 7 above, the compound of the present invention has excellent RET (ret proto-oncogene) enzyme inhibitory ability and excellent inhibition of proliferation of thyroid medullary cancer cell lines and lung cancer cell lines expressing RET fusion gene. I can confirm. In particular, it can be seen that the compound of the present invention exhibits a specific inhibitory activity against the RET fusion gene, as the bar shows selectively superior inhibitory activity against the RET fusion gene than the RET wild type. Accordingly, the compound according to the present invention can inhibit cancer cell proliferation, as confirmed in the above experiment, and thus can be usefully used as a pharmaceutical composition for the prevention and treatment of cancer diseases, for example, thyroid cancer and lung cancer.

Claims (15)

A compound represented by the following Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1,
R ¹ is cyano, C _1-6 Of haloalkyl, straight or branched C _1-6 Alkyl or C _3-7 cycloalkyl;

_Represents a C _5-6 aromatic ring or a 5 to 6 membered aromatic hetero ring containing at least one hetero atom selected from the group consisting of N, O and S, wherein the heteroaromatic ring is at least one May be substituted with straight or branched C _1-6 alkyl;
R ² is hydrogen or a straight or branched chain C _1-6 Alkoxy;
R ³ is hydrogen or straight or branched C _1-6 alkyl;
R ⁴ is hydrogen, straight or branched C _1-6 Alkoxy or a 5 to 6 membered heteroaryl containing at least one hetero atom selected from the group consisting of N, O and S, and the heteroaryl is halogen or a straight or branched C _1-6 One or more may be substituted with a substituent selected from the group consisting of alkyl; And
B ¹ and B ² are independently N or CH).
The method of claim 1,

Is

,

or

And, wherein X ¹ or X ⁴ is N, O or S, and X ² or X ³ is CH or N,
When each of R ⁵ or R ⁶ is X ¹ or X ⁴ is N, the straight or branched chain of C _1-6 Alkyl, and when X ¹ or X ⁴ is O or S, it is not present,
A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1,

silver

,

,

,

,

,

, or

sign,
A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ⁴ is hydrogen, methoxy, pyrazolyl, thiazolyl or isoxazolyl, and the pyrazolyl, thiazolyl and isoxazolyl are halogen and linear C _1-3 Which may be substituted with one or more substituents selected from the group consisting of alkyl,
A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ⁴ is hydrogen, methoxy,

,

,

,

, or

sign,
A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ¹ is cyano, C _1-6 Haloalkyl, a linear C _1-6 Alkyl or C _3-6 cycloalkyl;

Is

,

or

And, wherein X ¹ or X ⁴ is N, O or S, X ² or X ³ is CH or N, and R ⁵ or R ⁶ is each of X ¹ or X ⁴ when N is a straight chain C _Is an alkyl of _1-6 , and when X ¹ or X ⁴ is O or S, does not exist;
R ² is hydrogen or straight-chain C _1-6 alkoxy;
R ³ is hydrogen or straight-chain C _1-6 alkyl; And
R ⁴ is hydrogen, a 5-membered heteroaryl containing at least one hetero atom selected from the group consisting of hydrogen, linear C _1-6 alkoxy or N, O and S, and the heteroaryl is halogen and linear C _1-6 may be substituted with one or more substituents selected from the group consisting of alkyl,
A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ¹ is cyano, of C _1-3 Haloalkyl, straight-chain C _1-3 Alkyl or C _3-5 cycloalkyl;

Is

,

or

And wherein X ¹ or X ⁴ is N, O or S, X ² or X ³ is CH or N, and R ⁵ or R ⁶ is methyl when X ¹ or X ⁴ is N, respectively, Does not exist when X ¹ or X ⁴ is O or S;
R ² is hydrogen or straight chain C _1-3 Alkoxy;
R ³ is hydrogen or straight chain C _1-3 Alkyl; And
R ⁴ is hydrogen, methoxy, pyrazolyl, thiazolyl or isoxazolyl, and the pyrazolyl, thiazolyl and isoxazolyl are halogen and linear C _1-3 Which may be substituted with one or more substituents selected from the group consisting of alkyl,
A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ¹ is cyano, trifluoromethyl, straight-chain C _1-3 alkyl, C _3-4 cycloalkyl;

Is

,

or

And wherein X ¹ or X ⁴ is N, O or S, X ² or X ³ is CH or N, and R ⁵ or R ⁶ is methyl when X ¹ or X ⁴ is N, respectively, Does not exist when X ¹ or X ⁴ is O or S;
R ² is hydrogen or straight-chain C _1-3 alkoxy;
R ³ is hydrogen or straight-chain C _1-3 alkyl; And
R ⁴ is hydrogen, methoxy,

,

,

,

, or

sign ,
A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ¹ is cyano, trifluoromethyl, methyl or C _3-4 cycloalkyl;

silver

,

,

,

,

,

, or

ego
R ² is hydrogen or methyl;
R ³ is hydrogen or methoxy; And
R ⁴ is hydrogen, methoxy,

,

,

,

, or

sign,
A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
The compound represented by Formula 1 is any one selected from the following compound group,
Compounds, isomers thereof, solvates thereof, hydrates thereof, or pharmaceutically acceptable salts thereof:
<1> (1 r ,4 S ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide;
<2> (1 s ,4 R ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide;
<3> (1 s ,4 R )-1-methoxy- N -(( S )-1-(6-(4-methyl-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl )-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide;
<4> (1 r ,4 S )-1-methoxy- N -(( S )-1-(6-(4-methyl-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl )-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide;
<5> (1 r ,4 S ) -N -((S)-1-(6-(3,5-dimethyl-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)- 1-methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide;
<6> (1 s ,4 R ) -N -(( S )-1-(6-(3,5-dimethyl-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)- 1-methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide;
<7> l-methoxy-4- (4 - ((5-methyl -1 H-pyrazol-3-yl) amino) quinazolin-2-yl) - N - (4- (thiazol-5 Yl)benzyl)cyclohexane-1-carboxamide;
<8> N- (4-(isooxazol-4-yl)benzyl)-1-methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazoline -2-yl)cyclohexane-1-carboxamide;
<9> (1 s ,4 R )-4-(4-((5-cyano-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)- N -(( S )- 1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxycyclohexane-1-carboxamide;
<10> (1 r ,4 S ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(4-((5-(trifluoromethyl)-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide;
<11> (1 s ,4 R ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(4-((5-(trifluoromethyl)-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide;
<12> (1 r ,4 S )-4-(4-((5-cyclopropyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)- N -(( S )- 1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxycyclohexane-1-carboxamide;
<13> (1 s ,4 R )-4-(4-((5-cyclopropyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)- N -(( S )- 1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxycyclohexane-1-carboxamide;
<14> (1 r ,4 S ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)furo[3,2- d ]pyrimidin-2-yl)cyclohexane-1-carboxamide ;
<15> (1 s ,4 R ) -N -(( S) -1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)furo[3,2- d ]pyrimidin-2-yl)cyclohexane-1-carboxamide ;
<16> (1 r ,4 S ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)thieno[2,3- d ]pyrimidin-2-yl)cyclohexane-1-car Radiation mide;
<17> (1 s ,4 R ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)thieno[2,3- d ]pyrimidin-2-yl)cyclohexane-1-car Radiation mide;
<18> (1 r ,4 S ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)thieno[3,2- d ]pyrimidin-2-yl)cyclohexane-1-car Radiation mide;
<19> (1 s ,4 R ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)thieno[3,2- d ]pyrimidin-2-yl)cyclohexane-1-car Radiation mide;
<20> (1 r ,4 S ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(9-methyl-6-((5-methyl-1 H -pyrazol-3-yl)amino)-9 H -purin-2-yl)cyclohexane-1-carboxamide;
<21> (1 r ,4 S ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(7-methyl-4-((5-methyl-1 H -pyrazol-3-yl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl) Cyclohexane-1-carboxamide;
<22> (1 s ,4 R ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-1- Methoxy-4-(7-methyl-4-((5-methyl-1 H -pyrazol-3-yl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl) Cyclohexane-1-carboxamide;
<23> N -Benzyl-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide;
<24> N- (4-methoxybenzyl)-4-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-car Radiation mide;
<25> (1 s ,4 R ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4- (4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide;
<26> (1 r ,4 S ) -N -(( S )-1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4- (4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)cyclohexane-1-carboxamide;
<27> (S) - N - (1- (6- ( 4-fluoro -1 H - pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (4 ((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)piperidine-4-carboxamide;
<28> (S) -1- ( 4 - ((5- cyclopropyl -1 H - pyrazol-3-yl) amino) quinazolin-2-yl) - N - (1- (6- (4- Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxamide;
<29> (S) -1- ( 4 - ((5- cyclobutyl -1 H - pyrazol-3-yl) amino) quinazolin-2-yl) - N - (1- (6- (4- Fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxamide;
<30> (S) - N - (1- (6- ( 4-fluoro -1 H - pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (7- Methyl-4-((5-methyl-1 H -pyrazol-3-yl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)piperidine-4-carboxa Maid;
<31>( S )-1-(4-((5-cyclopropyl-1 H -pyrazol-3-yl)amino)-7-methyl-7 H -pyrrolo[2,3- d ]pyrimidine -2-yl)- N -(1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxa Maid;
<32>( S )-1-(4-((5-cyclobutyl-1 H -pyrazol-3-yl)amino)-7-methyl-7 H -pyrrolo[2,3- d ]pyrimidine -2-yl)- N -(1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxa Maid;
<33> (S) - N - (1- (6- ( 4-fluoro -1 H - pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (4 ((5-methyl-1 H -pyrazol-3-yl)amino)furo[3,2- d ]pyrimidin-2-yl)piperidine-4-carboxamide;
<34> (S) -1- ( 4 - ((5- cyclopropyl -1 H - pyrazol-3-yl) amino) furo [3,2- d] pyrimidin-2-yl) - N - ( 1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxamide;
<35> (S) -1- ( 4 - ((5- cyclobutyl -1 H - pyrazol-3-yl) amino) furo [3,2- d] pyrimidin-2-yl) - N - ( 1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxamide;
<36> (S) - N - (1- (6- ( 4-fluoro -1 H - pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (4 ((5-methyl-1 H -pyrazol-3-yl)amino)thieno[3,2- d ]pyrimidin-2-yl)piperidine-4-carboxamide;
<37>( S )-1-(4-((5-cyclopropyl-1 H -pyrazol-3-yl)amino)thieno[3,2- d ]pyrimidin-2-yl) -N -(1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxamide;
<38>( S )-1-(4-((5-cyclobutyl-1 H -pyrazol-3-yl)amino)thieno[3,2- d ]pyrimidin-2-yl) -N -(1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxamide;
<39> (S) - N - (1- (6- ( 4-fluoro -1 H - pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (4 ((5-methyl-1 H -pyrazol-3-yl)amino)thieno[2,3- d ]pyrimidin-2-yl)piperidine-4-carboxamide;
<40>( S )-1-(4-((5-cyclopropyl-1 H -pyrazol-3-yl)amino)thieno[2,3- d ]pyrimidin-2-yl) -N -(1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxamide;
<41>( S )-1-(4-((5-cyclobutyl-1 H -pyrazol-3-yl)amino)thieno[2,3- d ]pyrimidin-2-yl) -N -(1-(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxamide;
<42> (S) - N - (1- (6- ( 4-fluoro -1 H - pyrazol-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (7- Methyl-6-((5-methyl-1 H -pyrazol-3-yl)amino)-7 H -purin-2-yl)piperidine-4-carboxamide;
<43> (S) -1- ( 6 - ((5- cyclopropyl -1 H - pyrazol-3-yl) amino) -7-methyl -7 H - purin-2-yl) - N - (1 -(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxamide;
<44> (S) - N - (1- (6- (4- -1 H -Fluoro-1-yl) pyridin-3-yl) ethyl) -4-methoxy-1- (9- Methyl-6-((5-methyl-1 H -pyrazol-3-yl)amino)-9 H -purin-2-yl)piperidine-4-carboxamide;
<45> (S) -1- ( 6 - ((5- cyclopropyl -1 H - pyrazol-3-yl) amino) -9-methyl-9 H - purin-2-yl) - N - (1 -(6-(4-fluoro-1 H -pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidin-4-carboxamide;
<46> N -Benzyl-4-methoxy-1-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)piperidine-4-carboxa Maid;
<47> N -Benzyl-1-(4-((5-methyl-1 H -pyrazol-3-yl)amino)quinazolin-2-yl)piperidine-4-carboxamide;
<48> (S) - N - (1- (6- (4- fluoro -1 H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4 - ((5-methyl -1 H -pyrazol-3-yl)amino)quinazolin-2-yl)piperidin-4-carboxamide;
<49> (S) - N - (1- (6- (4- -1 H -Fluoro-ethyl-3-yl) pyrazol-1-yl)) - l- (7-methyl-4- ( (5-methyl-1 H -pyrazol-3-yl)amino)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)piperidine-4-carboxamide;
<50> (S) - N - (1- (6- (4- fluoro -1 H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4 - ((5-methyl -1 H -pyrazol-3-yl)amino)thieno[3,2- d ]pyrimidin-2-yl)piperidine-4-carboxamide; And
<51> (S) - N - (1- (6- (4- fluoro -1 H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4 - ((5-methyl -1 H -pyrazol-3-yl)amino)thieno[2,3- d ]pyrimidin-2-yl)piperidine-4-carboxamide.
A pharmaceutical composition for preventing or treating cancer containing a compound represented by Formula 1 of claim 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
The method of claim 11,
The compounds are AMPK-alpha1, AMPK-alpha2, ARK5, AURKA, AURKB, AURKC, AXL, BLK, CSF1R, CSNK2A2, DAPK1, DAPK3, EPHB6, FGFR1, FGFR2, FGFR3, FGFR3 (G697C), FLT3, FGR 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, characterized in that it exhibits inhibitory activity against one or more protein kinases selected from the group consisting of , Pharmaceutical composition.
The method of claim 11,
The compound is characterized in that it exhibits RET (ret proto-oncogene) enzyme inhibitory activity, pharmaceutical composition.
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, colon cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, barter bulge cancer , Bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, non-sinus cancer, non-small 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 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, stomach cancer, gastric carcinoma, Gastrointestinal interstitial cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, pregnancy villous 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, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, It is characterized in that at least one cancer selected from the group consisting of hematologic cancer and thymic cancer, the pharmaceutical composition.
The method of claim 11,
The cancer is characterized in that the cancer expressing the RET fusion gene, pharmaceutical composition.