EA044405B1 - N-CONTAINING HETEROARYL DERIVATIVE AND PHARMACEUTICAL COMPOSITION CONTAINING IT AS AN ACTIVE INGREDIENT FOR PREVENTION OR TREATMENT OF CANCER - Google Patents

Description

Field of technology to which the present invention relates

The present invention relates to an N-containing heteroaryl derivative and a pharmaceutical composition containing it as an active ingredient for the prevention or treatment of cancer.

BACKGROUND OF THE INVENTION

The development of cancer is associated with various environmental factors, including chemicals, radiation and viruses, changes in tumor genes, tumor suppressor genes and apoptosis and genes associated with DNA repair, etc., as well as recent understanding of the molecular mechanism of such types cancer has made it possible to carry out targeted anti-cancer treatment, which represents a new treatment option.

Targeted therapeutics are generally designed to produce effects by targeting molecules that are characteristic of cancer cells, and the molecular targets are genes associated with signal transduction, angiogenesis, matrix, cell cycle regulator, apoptosis, and the like. Examples of such agents used as important therapeutic agents currently used in treatment include signal transduction pathway suppressors, including tyrosine kinase suppressors and angiogenesis suppressors.

Phosphorylation of tyrosine residues in proteins is an important element of intracellular signal transduction. The enzyme that can catalyze this reaction is called tyrosine kinase. A large number of transmembrane receptors include a domain with tyrosine kinase activity and are classified as receptor tyrosine kinases (RTKs).

RTKs transmit extracellular signals in various processes such as cell growth, differentiation, survival and programmed cell death. In response to binding to extracellular ligands, RTKs typically recognize dimerized and phosphorylated forms of RTKs and induce intracellular signaling and autophosphorylation through interacting effectors. There are many members of this family of RTKs, one of which is the RET proto-oncogene, which encodes a 120-kDa protein rearranged during transfection (RET). RET is a receptor for growth factors of the neurotrophic factor (GDNF) family, derived from the glial cell line. Two RET ligands have been identified; GDNF and neutrino (NTN). RET is activated when its ligand binds to a coreceptor and the complex then interacts with RET (Eng, 1999 Journal Clinical Oncology: 17(1) 380-393).

Such activation phosphorylates RET on tyrosine residues and induces signaling for cell growth and differentiation through the RAS-RAF and PI3 kinase pathways and other possible pathways.

RET-activating point mutants are known to cause three associated dominantly inherited cancer syndromes; multiple endocrine neoplasia 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 in some cases of FTMC, the cysteine substitution occurs in the juxtamembrane cysteine-rich domain, whereas in 95% of MEN2B the single-point mutation occurs at codon 918 in the kinase domain (M918T). Codon 918 is thought to be located in the substrate recognition pocket of the catalytic center. Mutations at this site are thought to structurally activate RET by altering the structure of the active loop of the RET catalytic domain. The M918T mutation is also found in sporadic medullary carcinoma, which is associated with a progressive disease phenotype. In vitro studies indicate that mutations affect substrate specificity and thus RET recognizes and phosphorylates substrates preferred by non-receptor tyrosine kinases such as c-src and c-abl (Eng et al. 1996 JAMA276, 1575-1579; Ponder et al. al. 1999 Cancer Research59, 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).

Since mutations in the RET gene are identified in most of the MEN2 family, they enable molecular diagnostic tests and may also be useful in confirming clinical diagnoses. RET mutation testing can be performed using a polymerase chain reaction-based protocol, where the target axon sequence is amplified for direct sequencing or restriction endonuclease digestion (Zhong et al. 2006 Clinica Chimica Acta364, 205-208).

Another member of the RTK family is vascular endothelial growth factor receptor 2 (VEGFR2) (a receptor containing a kinase domain, KDR (also called Flk1)). VEGFR2 is a vascular endothelial growth factor (VEGF) receptor. VEGF is considered an important stimulator of both normal and disease-associated angiogenesis (Jakeman et al. 1993 Endocrinology 133,848-859; Kolch, et al. 1995 Breast Cancer Research and Treatment 36,139155) and vascular permeability (Connolly, et al. 1989 J Biol Chem264, 20017-20024). Antagonism of VEGF through sequestration of antibodies and VEGF can suppress tumor growth (Kim et al. 1993 Nature 362, 841-844). Heterologous cleavage of the VEGF gene causes a fatal vascularization defect (Carmeliet et al.

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1996 Nature 380435-439; Ferrara et al. 1996 Nature 380439-442).

Binding of VEGF to VEGFR2 causes dimerization of the receptor, which leads to VEGFR2 autophosphorylation of specific intracellular tyrosine residues. Autophosphorylation enhances the catalytic activity of tyrosine kinases and provides a potential binding site for cytoplasmic signaling such as phospholipase C-γ. This protein interaction mediates VEGFR2, for example, intracellular signaling required to induce cellular responses regarding endothelial cell proliferation, survival and migration (Ryan et al. 2005 British Journal Cancer: 92(Suppl.1) S6-S13).

Recognition of the important role of VEGF-mediated signaling involving VEGFR2 in pathological angiogenesis has led to the development of various selective approaches to suppress VEGFR2 activation. These include small molecule ATP-competitive tyrosine kinase suppressors that prevent autophosphorylation and ongoing intracellular signaling when ATP binding is inhibited (Ryan, 2005).

Quinazoline derivatives, which are VEGF receptor tyrosine kinase suppressors, are described in international publications WO 98/13354 and WO 01/32651. WO 98/13354 and WO 01/32651 disclose compounds that have partial activity against epidermal growth factor receptor (EGFR) tyrosine kinase and activity against VEGF receptor tyrosine kinase.

The compound 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline, which is a suppressor of the VEGFR2 tyrosine kinase, has been described (Wedge et al., 2002 Cancer Research 62, 4645- 4655). This compound is also known as Zactima® (registered trademark), code number ZD6474 and the generic trade name vandetanib. The compound will be referred to hereinafter as vandetanib.

Vandetanib was developed as a suppressor with potent and reversible ATP binding to the VEGFR2 tyrosine kinase. In addition, vandetanib inhibits EGFR tyrosine kinase activity. The EGFR signaling pathway is an important factor not only in tumor cell proliferation, survival and invasion, but also in cancer progression when VEGF is overexpressed. Inhibition of EGFR signaling has been found to induce selective apoptosis in tumor endothelial cells.

In 2002, vandetanib was reported to be able to inhibit RET signaling and deformability as a potent suppressor of ligand-dependent RET tyrosine kinase activity. In addition, vandetanib has been reported to have a significant suppressive effect on RET-dependent growth of thyroid tumor cells in vitro (Carlomagno et al. 2002 Cancer Research: 62, 7284-7290).

Vandetanib also inhibited most mutated active forms of RET and wild-type receptors. Therefore, inhibition of RET tyrosine kinase by vandetanib, as well as inhibition of VEGFR2 and EGFR tyrosine kinases, may also confer additional antitumor effect in the treatment of tumors accompanied by mutations of the RET gene, which induces RET-dependent tumor cell growth (Ryan, 2005).

Detailed Disclosure of the Present Invention Technical Problem

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

Another object of the present invention is to provide a method for producing a compound.

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

It is yet another object of the present invention to provide a method for preventing or treating cancer, the method comprising an N-containing heteroaryl derivative or isomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide the use of an N-containing heteroaryl derivative or isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the preparation of a drug used for the prevention or treatment of cancer.

Technical solution

To achieve the above objects, in accordance with one aspect of the present invention there is provided a compound of the following chemical formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof

- 2 044405 where Θ' represents furan, thiophene, benzene or cyclopentene,

R ¹ is straight or branched C ₁ -C ₃ -alkyl, where R ¹ is unsubstituted or substituted by at least one halogen, ring B is diazabicycloheptane, piperazine, diazepane or diazaspirooctane, where ring B is unsubstituted or substituted by at least one linear or branched C1-C6-

alkyl,

R ² is pyridinyl, thiazolyl, phenyl, imidazolyl, pyrazinyl, quinolinyl, pyrimidinyl or pyridonyl, wherein R ² is unsubstituted or substituted with at least one R ³ , and

R ³ represents at least one substituent selected from the group consisting of linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ haloalkyl, linear or branched C ₁ -C ₆ alkoxy, halogen , C ₁ -C ₃ -alkanesulfonamido, amino, substituted with at least one linear or branched C ₁ -C ₃ -alkyl, and nitrile.

In accordance with another aspect of the present invention, there is provided a method for producing a compound of Chemical Formula 1, comprising preparing a compound of Chemical Formula 3 from a compound of Chemical Formula 2;

preparing a compound of chemical formula 4 from a compound of chemical formula 3;

preparing a compound of chemical formula 5 from a compound of chemical formula 4;

preparing a compound of chemical formula 6 from a compound of chemical formula 5;

preparing a compound of chemical formula 7 from a compound of chemical formula 6 and preparing a compound of chemical formula 1 from a compound of chemical formula 7

[Chemical formula 2]

G

[Chemical formula 3] m—ΝΗ

ΗΝ

IN G

[Chemical formula 4]

- 3 044405

where R ¹ , R ² O and ring B are the same as defined above respectively,

G represents a leaving group,

PG represents a protecting group and

The B' ring has the same structure as the B ring, but is a form in which one nitrogen atom is protected by a protecting group.

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

Positive effects

The compound of chemical formula 1 of the present invention exhibits excellent inhibitory activity against various protein kinases, in particular, excellent inhibitory ability against the enzyme ret proto-oncogene (RET), and has an excellent effect in inhibiting the proliferation of medullary thyroid cancer cells and lung cancer cells that express the genes RET fusions, and thus the derivative can be effectively used in the treatment of cancer, for example, medullary thyroid cancer or lung cancer, and in particular can be effectively used in the treatment of cancer in which RET fusion genes are expressed.

Principle of invention

Hereinafter, the present invention will be described in detail.

The exemplary embodiments of the present invention may be changed into various other forms, and the scope of the present invention is not limited to the illustrative aspects that will be described below. In addition, illustrative embodiments of the present invention are provided to more fully describe the present invention to one skilled in the art.

- 4 044405 field of technology.

The inclusion of a particular element throughout the description means that it does not exclude other elements, but may additionally include other elements unless otherwise stated.

In the structural formulas of the present description, the symbol -, connecting an atom and/or group, may indicate a single bond, and the symbol = may indicate a double bond. Symbols may be omitted or may be displayed as needed, such as to indicate the bonding atom or binding position.

In the present description, the connection of atoms may include not only the case of direct connection of atoms, but also the case of indirect connection of atoms mediated by other atoms and/or groups. In this case, other atoms and/or groups may be oxygen, sulfur, C ₁ . ₈ αlkylamino, ^^alkylene group or the like, and without limitation, both the atom and/or group may be substituted or unsubstituted.

As used herein, to be substituted or unsubstituted may mean that one hydrogen atom or multiple hydrogen atoms are unsubstituted or substituted with other atoms or substituents, unless otherwise indicated. The substituent may be at least one selected from the group consisting of halogen (chlorine (Cl), iodine (I), bromine (Br), fluorine (F)), C _1-10 alkyl, C _2-10 αlkenyl, C _2-10 αlkynyl, hydroxyl, C _1-10 αlkoxy, amino, nitro, thiol, thioether, imine, cyano, phosphonato, phosphine, carboxy, carbamoyl, carbamic acid, acetal, urea, thiocarbonyl, sulfonyl, sulfonamide, ketone , aldehyde, ester, acetyl, acetoxy, amide, oxygen (= 0), haloalkyl (e.g. trifluoromethyl), substituted aminoacyl and aminoalkyl, carbocyclic cycloalkyl, which may be monocyclic or fused or unfused polycyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocycloalkyl, which may be monocyclic or fused or unfused polycyclic (for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), carbocyclic or heterocyclic, monocyclic or fused or unfused polycyclic aryl (for example, phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuranyl), amino (primary, secondary or tertiary), aryl, aryloxy and aryl-alkyl, but not limited to them. In addition, each of the exemplified substituents may be unsubstituted or re-substituted with a substituent selected from the group of these substituents.

As used herein, a halogen may be F, Cl, Br or I.

As used herein, alkyl may be linear or branched, non-cyclic; cyclical; or the saturated hydrocarbon to which they are associated unless otherwise noted. In addition, C1 ₈ alkyl can mean alkyl containing from 1 to 8 carbon atoms. Non-cyclic alkyl may include, for example, methyl, ethyl, N-propyl, N-butyl, N-pentyl, N-hexyl, N-heptyl, N-octyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2 -methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3dimethylbutyl, etc., but not limited to them. Cyclic alkyl may include, for example, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or the like. The alkyl to which the non-cyclic alkyl and cyclic alkyl are linked includes, for example, but is not limited to, methylcyclopropyl, cyclopropylmethyl, ethylcyclopropyl, cyclopropylethyl, methylcyclobutyl, cyclobutylmethyl, ethylcyclopentyl, cyclopentylmethyl, or the like.

As used herein, the term cycloalkyl may refer, in particular, to a cyclic alkyl from the group of alkyls, where alkyl is as defined above.

As used herein, the term alkoxy may refer to -(O-alkyl) as an alkyl ether group, where alkyl is as defined above. In addition, Cl. ₈ alkOxy may refer to alkoxy containing C ₁ . ₈ alkyl, i.e. -(OC ₁ . ₈ alkyl), and, for example, C ₁ . _{8 α} -alkoxy may include, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, and the like.

As used herein, heterocycloalkyl may refer to a ring containing 1 to 5 heteroatoms selected from N, O and S as the ring-forming atom, and may be saturated or partially unsaturated. Unless otherwise specified, heterocycloalkyl may be a monocyclic ring or a polycyclic ring, such as a spiro ring, a bridged ring, or a fused ring. In addition, heterocycloalkyl containing from 3 to 12 atoms may refer to heterocycloalkyl containing from 3 to 12 atoms forming a ring, and, for example, heterocycloalkyl may include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone , 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1S,4S)-2-azabicyclo [2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane or the like, but not limited to them.

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As used herein, alkylamino can refer to -(NR'R), wherein each of R' and R can be independently selected from the group consisting of hydrogen and C _1-8 alkyl, and each of the selected R' and R can be independently substituted or unsubstituted. In addition, Ci-8 alkylamino can refer to an amino containing C _1-8 alkyl, i.e. -NH(C _1-8 alkyl) or -N-(C _1-8 alkyl) ₂ , and may include, but is not limited to, dimethylamino, diethylamino, methylethylamino, methylpropylamino, or ethylpropylamino.

As used herein, aryl may refer to an aromatic ring in which one hydrogen has been removed from the aromatic hydrocarbon ring, and may be a monocyclic ring or a polycyclic ring. Aryl containing from 3 to 12 atoms may refer to aryl containing from 3 to 12 atoms forming a ring and may include, for example, but is not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, biphenyl, terphenyl or the like them.

As used herein, heteroaryl may refer to an aromatic ring containing one or more N, O and S heteroatoms as the ring-forming atom, and may be a monocyclic ring or a polycyclic ring. In addition, heteroaryl containing from 3 to 12 atoms may refer to heteroaryl containing from 3 to 12 atoms forming a ring, and may include, for example, thienyl, thiophene, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl , oxadiazolyl, triazolyl, pyridinyl, bipyridyl, pyrimidyl, triazinyl, triazolyl, acridyl, pyridazinyl, pyrazinyl, quinolinyl, quinazolin, quinoxalinyl, phenoxazyl, phthalazinyl, pyrimidinyl, pyridopyrimidinyl, pyridopyrazinyl, pyrazinopyrazinyl, isoquinoline, indole, carbazole, im idazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl , pyrazolopyrimidinyl, imidazopyrazinyl or pyrazolopyridinyl, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzoimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophenyl, thienothiophene, benzofuranyl, phenanthroline, isoxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, tetrazolyl, phenothiazinyl, dibenzosilol, dibenzofuranyl , but not limited to them.

As used herein, the term hydrate may refer to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular force, or a salt thereof. The hydrate of the compound of Chemical Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular force. The hydrate may contain at least 1 eq., preferably from 1 to 5 eq. water. Such a hydrate can be obtained by crystallizing the compound of Chemical Formula 1 of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

As used herein, the term solvate may refer to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular force, or a salt thereof. Preferred solvents for the solvate include volatile, non-toxic solvents and/or solvents suitable for human administration.

As used herein, the term isomer may refer to a compound of the present invention that has the same chemical or molecular formula but is structurally or sterically different, or a salt thereof. Such isomers include all structural isomers such as a tautomer, an R- or S-isomer having an asymmetric carbon center, a steric isomer such as a geometric isomer (trans, cis), and an optical isomer (enantiomer). All of these isomers and mixtures thereof are also included within the scope of the present invention.

The present invention provides a compound of the following chemical formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof

[Chemical formula 1] where <9 represents furan, thiophene, benzene or cyclopentene,

R ¹ is straight or branched C ₁ -C ₃ -alkyl, where R ¹ is unsubstituted or substituted by at least one halogen, ring B is diazabicycloheptane, piperazine, diazepane or diazaspirooctane, where ring B is unsubstituted or substituted by at least one linear or branched C1-C6 alkyl,

R ² is pyridinyl, thiazolyl, phenyl, imidazolyl, pyrazinyl, quinolinyl, pyrimidinyl or pyridonyl, wherein R ² is unsubstituted or substituted with at least one R ³ , and

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R ³ represents at least one substituent selected from the group consisting of linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ haloalkyl, linear or branched C ₁ -C ₆ alkoxy, halogen , C ₁ -C ₃ -alkanesulfonamido, amino, substituted with at least one linear or branched C ₁ -C ₃ -alkyl, and nitrile.

In accordance with one embodiment of the present invention, ring B may be 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, piperazine, diazepane, or 4,7-diazaspiro[2.5 ]octane.

In accordance with one embodiment of the B ring, the B ring may be linked to another adjacent group via two nitrogen atoms.

According to another embodiment of the present invention, when R ² is pyridinyl, thiazolyl, phenyl, pyrazinyl, pyrimidinyl or pyridonyl, R ² is substituted with at least one R ³ or when R ² is imidazolyl or quinoline, R ² is not is substituted and R ³ may be at least one substituent selected from the group consisting of linear or branched C ₁ -C ₃ alkyl, linear or branched C ₁ -C ₃ haloalkyl, linear or branched C ₁ -C ₃ - alkoxy, halogen, C ₁ -C ₃ -alkanesulfonamido, amino, substituted with at least one linear or branched C ₁ -C ₃ -alkyl, and nitrile.

Examples of the compound of chemical formula 1 of the present invention include compounds 1 to 37 listed in table. 1 of the following examples, or their pharmaceutically acceptable salts or free bases (when shown as pharmaceutically acceptable salts in Table 1), isomers thereof, solvates thereof, or pharmaceutically acceptable salts thereof.

The compound of Chemical 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 can be used as the salt. The acid addition salt is prepared from inorganic acid such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid and phosphorous acid, non-toxic organic acid such as aliphatic mono- and dicarboxylates, phenyl-alkanoates, hydroxyalkanoates and alkanedionates, aromatic acids, aliphatic and aromatic sulfonic acid, and organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid. Types of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate , heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1,4dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate , toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

The acid addition salt of the present invention can be prepared by a conventional method, for example, by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride and acetonitrile, and adding an organic acid or an inorganic acid to filter and dry the resulting precipitate, or may be obtained by distilling off the solvent and excess acid under reduced pressure, and then drying the solvent and acid to crystallize the resulting product in an organic solvent.

In addition, a pharmaceutically acceptable metal salt can be prepared using a base. An alkali or alkaline earth metal salt is prepared, for example, by dissolving the compound in an excess solution of an alkali metal hydroxide or alkaline earth metal hydroxide, filtering the salt of the insoluble compound, evaporating the filtrate, and drying the resulting product. In this case, preparing a sodium, potassium or calcium salt as the metal salt is pharmaceutically acceptable. In addition, the corresponding salt is prepared by reacting an alkali or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Moreover, the present invention includes not only the compound of Chemical Formula 1 and a pharmaceutically acceptable salt thereof, but also the solvate, optical isomer, hydrate and the like that can be prepared therefrom.

In accordance with another aspect of the present invention, a method for preparing a compound of Chemical Formula 1 may be provided.

A method for producing a compound of chemical formula 1 may include preparing a compound of chemical formula 3 from a compound of chemical formula 2;

preparing a compound of chemical formula 4 from a compound of chemical formula 3; preparing a compound of chemical formula 5 from a compound of chemical formula 4; preparing a compound of chemical formula 6 from a compound of chemical formula 5;

- 7 044405 obtaining a compound of chemical formula 7 from a compound of chemical formula 6 and obtaining a compound of chemical formula 1 from a compound of chemical formula 7.

[Chemical formula 2]

Each of R ¹ , R ² , χ-J* and ring B are the same as defined herein, G is a leaving group, PG is a protecting group, and ring B' has the same structure as the ring B, but is a form in which one nitrogen atom is protected by a protecting group.

The leaving group may be a functional group such as halogen, sulfonic acid ester or alkoxy, and without limitation, as long as it is a functional group capable of producing the target compound by releasing the leaving group from the compound of Chemical Formulas 2 to 5. The protecting group may be functional

- 8 044405 group such as tert-butoxycarbonyl, benzyloxycarbonyl, 3,4-dihydro-2H-pyran and tetrahydro-2Hpyran, but without limitation as long as the functional group is capable of protecting a secondary amine of chemical formulas 4 to 6.

Preparation of a compound of chemical formula 3 from a compound of chemical formula 2 can be given by N-NH

-- ^R ' represents the stage of interaction of a compound of chemical formula 2 with ^H * ^N .

N,N-Diisopropylethylamine (DIPEA) may be further added to the reaction, the reaction temperature may be from about 40 to 100°C, and the reaction time may be from about 10 to 14 hours, and as long as the reaction proceeds smoothly, the reaction cannot be limited the above conditions.

Preparation of a compound of Chemical Formula 4 from a compound of Chemical Formula 3 may be a step of protecting the secondary amine of the pyrazole group from the compound of Chemical Formula 3. The protecting group may be used without limitation provided that it is a functional group capable of protecting the secondary amine and may be, for example, tetrahydro-2H-pyran (THP).

Preparation of a compound of chemical formula 5 from a compound of chemical formula 4 may involve

constitute a stage of interaction of a compound of chemical formula 4 with

The reaction can be carried out in a solvent such as dioxane, to which Pd(dppf)Cl ₂ .CH ₂ Cl ₂ can be further added, the reaction temperature can be from about 80 to 100°C, and the reaction time can be from about 2 to 4 h. As long as the reaction proceeds smoothly, the reaction cannot be limited by the above conditions.

Preparation of a compound of chemical formula 6 from a compound of chemical formula 5 may involve the step of coupling ring B' to a compound of chemical formula 5. Ring B' is a form in which one nitrogen atom of ring B, as defined herein, is protected by a protecting group, protecting the group can be used without limitation as long as it is a protecting group capable of protecting a secondary amine, and tert-butoxycarbonyl (BOC) can be exemplified.

A more specific illustrative embodiment of the present step may be the step of reacting the unprotected secondary amine of ring B' with a compound of Chemical Formula 5 to couple ring B' to the compound of Chemical Formula 5. The step may be carried out in a solvent such as DMSO, to which may further be added K ₂ CO ₃ , the reaction temperature may be from about 100 to 140° C., and the reaction time may be from about 10 to 14 hours. As long as the reaction proceeds smoothly, the reaction cannot be limited to the above conditions.

Preparation of a compound of Chemical Formula 7 from a compound of Chemical Formula 6 may involve the step of deprotecting a protecting group attached to a compound of Chemical Formula 6. The step may deprotect the protecting group by dissolving the compound of Chemical Formula 6 in an HCl solution.

Preparation of a compound of Chemical Formula 1 from a compound of Chemical Formula 7 may involve the step of reacting the compound of Chemical Formula 7 with CHO-R ² . The reaction can be carried out in a solvent such as N,N-dimethylacetamide (DMA), and the compound of Chemical Formula 1 can be formed through a reductive alkylation reaction of an aldehyde with a secondary amine. Any reducing agent that reductively alkylates an aldehyde and a secondary amine can be used without limitation, and NaBH(OAc) ₃ can be used as an example. The reaction temperature may be from about 40 to 80°C, and the reaction time may be from about 3 to 8 hours. As long as the reaction proceeds smoothly, the reaction cannot be limited to the above conditions.

According to yet another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer.

The compound may exhibit inhibitory activity against one or more protein kinases selected from the group consisting of ABL1(H396P)-unphosphorylated, ABL1(H396P)phosphorylated, ABL1(M3 51 T)-phosphorylated, ABL1(Q252H)-phosphorylated,

ABL1(T315I)-unphosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-phosphorylated, AMPK-alpha 1, AURKA, AURKC, AXL, BLK, BTK, CSNK2A1, CSNK2A2, DAPK3, DDR1, DDR2, DLK, EGFR(L747-E749del, А750Р), EGFR(L858R,T790M), EGFR(T790M), EPHB6, FGFR1, FGR, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD) , FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, FRK, GCN2(kinase domain 2, S808G), HCK, ICK, ITK , JAK1(JH1-catalytic domain),

- 9 044405

JAK1(goMeH JH2-nceegoKUHa3a), JAK2(goMeH JHl-catalytic), JAK3(goMeH JHl-catalytic),

KIT(A829P), KIT(D816V), KIT(V559D), LCK, MAP3K2, MEK2, MEK3, MEK5, MERTK, MST1, PDGFRB,

PLK4, RET, RET(M918T), RET(V804L), REt(v804M), RIOK3, SNARK, SRC, SYK, TRKA, TRKB, TRKC,

TYK2(goMeH JHl-catalytic), YES or YSK4.

In addition, the compound may exhibit RET enzyme inhibitory activity.

The cancer may be one or more cancers selected from the group consisting of pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, medullary thyroid carcinoma, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer , lip cancer, mycosis fungoides, acute myelogenous leukemia, acute lymphatic regional leukemia, basal cell carcinoma, epithelial ovarian cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, papilla cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, neuroglioma, renal pelvis 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, urothelial cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid tumors, gastrointestinal stromal cancer, Wilms cancer, breast cancer, sarcoma, genital cancer penis, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumors, vaginal cancer, spinal cord cancer , acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell cancer, lung adenocarcinoma, lung cancer, squamous cell lung cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer , blood cancer and thymus cancer.

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

RET fusion gene refers to a form in which the RET gene encoding the RET receptor tyrosine kinase is linked to one or more other genes, and genes other than the RET gene, including the RET fusion gene, may be a member of the kinesin family 5B (KIF5B), a protein 6 containing, but not limited to, coiled-coil domain domain (CCDC6), nuclear receptor coactivator 4 (NCOA4), or tripartite motif containing 33 (TRIM33).

The compound of chemical formula 1 according to the present invention exhibits excellent inhibitory ability against the ret proto-oncogene enzyme (RET) (see Experimental Example 1) and has an excellent effect in inhibiting the proliferation of medullary thyroid cancer cells and lung cancer cells that express RET fusion genes (see Experimental Example 2), and thus the derivative can be effectively used in the treatment of cancer, such as medullary thyroid cancer or lung cancer, and in particular can be effectively used in the treatment of cancer in which RET fusion genes are expressed.

The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof can be administered in various oral and parenteral dosage forms during clinical administration, more preferably in a parenteral dosage form. When a compound of Chemical Formula 1 is prepared, the compound is prepared using a diluent or auxiliary such as a filler, filler, binder, wetting agent, disintegrant and surfactant that are commonly used. The solid composition for oral administration includes a tablet, pill, powder, granules, capsule and the like, and the solid composition is prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin and the like. with one or more connections. Moreover, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. The liquid composition for oral administration corresponds to a suspension, internal liquid, emulsion, syrup and the like, and the liquid composition may include, in addition to water and liquid paraffin, which are simple diluents commonly used, various auxiliaries, for example, a wetting agent, sweetener, flavoring, preservative and the like. Examples of the formulation for parenteral administration include an aqueous sterile solution, a non-aqueous vehicle, a suspension and an emulsion. As the non-aqueous solvent and suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.

A pharmaceutical composition containing a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is performed using an injection method such as subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

In this case, to formulate the pharmaceutical composition into a composition for parenteral administration, the pharmaceutical composition can be prepared in the form of a solution or suspension by mixing a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof with a stabilizer or buffer in water, and the solution or suspension can be prepared in the form of an ampoule or bottle for administration. The composition may be sterilized and/or contain an excipient such as a preservative, stabilizer, hydrating or emulsion enhancing agent, salt and/or osmotic pressure buffer and other therapeutically useful materials, and the composition may be formulated using a conventional method, such as a mixing, granulating or coating method.

Examples of the oral composition include tablet, pill, hard/soft capsule, solution, suspension, emulsion, syrup, granule, elixir, trochet, etc., and these compositions contain a diluent (for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine) and a lubricant (eg silica, talc, stearic acid and magnesium or calcium salt thereof and/or polyethylene glycol) in addition to the active ingredient.

The tablet may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and may contain a disintegrating agent such as starch, agar, alginic acid or a sodium salt or boiling mixture thereof and/ or an absorbent, coloring agent, flavoring agent, and in some cases a sweetening agent.

A pharmaceutical composition containing a compound of chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer may be administered as a single therapeutic agent or may be administered in combination with other applicable anticancer agents.

In accordance with yet another aspect of the present invention, there is provided a method for preventing or treating cancer, the method comprising administering a pharmaceutical composition comprising a compound of Chemical Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need of this.

Another object of the present invention is to provide the use of a compound of chemical 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 used for the prevention or treatment of cancer.

Hereinafter, the present invention will be described in detail with reference to examples and experimental examples.

However, the following examples and experimental examples are only intended to illustrate the present invention, and the content of the present invention is not limited to the following examples and experimental examples.

Analysis and purification conditions

The compounds synthesized in the examples of the present invention were purified or subjected to structural analysis using the following methods.

1. Median pressure liquid chromatography (MPLC) for purification.

CombiFlash Rf + UV from TELEDYNE ISCO was used as medium pressure liquid chromatography.

2. LC-MS for analysis (main ACQUITY UPLC H-class system). A device equipped with a QDA detector manufactured by Waters was used for a UPLC system (ACQUITY UPLC PDA detector) manufactured by Waters. The column used was ACQUITY UPLC BEHC18 (1.7 µm, 2.1 x 50 mm) from Waters, column temperature was 30°C.

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

Gradient condition (3 min at 10-100% B and flow rate = 0.6 ml/min)

3. Prep-150 LC system for purification (preparative liquid chromatography, UV spectrometry).

The Waters device was used for the Waters Prep 150 LC system (2545 Quaternary Gradient Module, 2998 Photodiode Array Detector, Fraction III Collector). The column used was XTERRA Prep RP18 OBD™ (10 µm, 30x300 mm) and the column temperature was room temperature.

Gradient condition (120 min at 3-100% B and flow rate = 40 ml/min).

4. SFC conditions for the separation of chiral compounds.

The preparative system SFC 80Q from Waters was used. The column used was CHIRALPAK AS (10 µm, 250x30 mm i.d.) from DAICEL, and the temperature

- 11 044405 the speakers were indoor. CO2 was used as the mobile phase and methanol was added to which 0.1% aqueous ammonia solution was added as a co-solvent and allowed to flow for 130 min.

5. NMR analysis

NMR analysis was performed using AVANCE III 400 or AVANCE III 400 HD from Bruker, and data were expressed in parts per million (δ) (ppm).

The commercially available reagents used were used without further purification. In the present invention, by room temperature is meant a temperature of about 20 to 25°C. A rotary evaporator was used for concentration under reduced pressure or distillation of the solvent.

Example 1. 2-(6-(6-((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3yl)-N-(5- methyl-1H-pyrazol-3-yl)furo[3,2-d]pyrimidin-4-amine.

The title compound was prepared by the method shown by the following Reaction Scheme 1.

Reaction scheme 1

Step 1. Preparation of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)furo[3,2-d]pyrimidin-4-amine.

After 2,4-dichlorofuro[3,2-d]pyrimidine (50 g, 264.55 mmol, 1 eq.), 5-methyl-1H-pyrazol3-amine (26.98 g, 277.78 mmol , 1.05 equiv.) and DIPEA (102.57 g, 793.65 mmol, 138.24 ml, 3 equiv.) were dissolved in DMSO (250 ml), the resulting solution was stirred at 60°C for 12 hours. Water was slowly added to the reaction mixture and the resulting solid was filtered. The solid was washed with water and then recovered to give the title compound 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)furo[3,2d]pyrimidin-4-amine (62 g).

MS (m/z): 250.1 [M+l]+.

Step 2. Preparation of 2-chloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)furo[3,2d]pyrimidin-4-amine.

After 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)furo[3,2-d]pyrimidin-4-amine (60 g, 240.33 mmol, 1 eq.) and TsOH (8.28 g, 48.07 mmol, 0.2 eq.) was dissolved in THF (600 ml), 3,4-dihydro2H-pyran (60.72 g, 721.86 mmol, 66 ml, 3 eq.) was added .) and the resulting mixture was stirred at 60°C for 15 hours. An aqueous solution of NaHCO ₃ (500 ml), EtOAc (500 ml) and water (1 L) was added to the reaction mixture, the organic layer was washed with brine (400 ml) after separation organic layer and dried using Na ₂ SO ₄ . The organic layer was filtered, concentrated in a vacuum concentrator and then purified using medium pressure chromatography (hexane/EtOAc = 4/1 to 2/1). After purification, the resulting product was concentrated under reduced pressure to obtain the target compound 2-chloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)furo[3,2 -d]pyrimidin-4-amine (60.66 g, 181.74 mmol, 75.62% yield).

MS (m/z): 334.1 [M+l] ⁺ .

¹ H NMR (400 MHz, CDCl3) δ=7.77 (d, J=2.0 Hz, 1H), 7.69 (s, 1H), 6.81 (d, J=2.2 Hz, 1H ), 6.76 (s, 1H), 5.20 (dd, J=2.8, 10.4 Hz, 1H), 4.12-4.02 (m, 1H), 3.681-3.618 (m, 1H), 2.40-2.32 (m, 4H), 2.14-2.04 (m, 1H), 1.89 (br dd, J=2.8, 13.6 Hz, 1H), 1.77-1.63 (m, 2H), 1.62-1.55 (m, 1H).

Step 3. Preparation of 2-(6-fluoropyridin-3-yl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazol-3-yl)furo[3,2-d ]pyrimidine-4-amine.

After 2-chloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)furo[3,2d]rpyrimidin-4-amine (20 g, 59.92 mmol, 1 eq.), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridine (16 g, 71.73 mmol, 1 ,20 eq.) and K ₂ CO ₃ (20.70 g, 149.80 mmol, 2.5 eq.) were dissolved in dioxane (400 ml) and water (20 ml), Pd(dppf)Cl ₂ was added to it .CH ₂ Cl ₂ (4.89 g, 5.99 mmol, 0.1 eq.). The reaction mixture was stirred under a nitrogen atmosphere at 90°C for 3 hours. After filtering the reaction mixture, the filtrate was concentrated and water and EtOAc were added to it.

The organic layer was collected and washed with brine (1.0 L) and then dried using Na ₂ SO ₄ . The organic layer was filtered, concentrated in a vacuum concentrator and then purified using medium pressure chromatography (hexane/EtOAc = 5/1 to 1/1). After purification, the resulting product was concentrated under reduced pressure to obtain the target compound 2-(6fluoropyridin-3-yl)-N-(5-methyl-1-(tetradiro-2H-pyran-2-yl)-1H-pyrazol-3-yl )furo[3,2-d]pyrimidine-4

- 12 044405 amine (22 g, 55.78 mmol, yield 93.09%).

MS (m/z): 395.4 [M+l]+.

¹ H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 9.10 (d, J=2.4 Hz, 1H), 8.78 (dt, J=2.4, 8 .4 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 7.30 (dd, J=2.8, 8.4 Hz, 1H), 7.11 (d, J =2.4 Hz, 1H), 6.64 (s, 1H), 5.35 (dd, J=2.4, 9.6 Hz, 1H), 3.91 (br d, J=10.8 Hz, 1H), 3.70-3.58 (m, 1H), 2.37 (s, 3H), 2.34-2.23 (m, 1H), 2.05-1.95 (m, 1H), 1.92-1.82 (m, 1H), 1.75-1.62 (m, 1H), 1.58-1.45 (m, 2H).

Step 4. Preparation of tert-butyl 3-(5-(4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3yl)amino)furo[3,2-d ]pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

After 2-(6-fluoropyridin-3-yl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3yl)furo[3,2-d ]pyrimidin-4-amine (1 g, 2.54 mmol, 1 eq.), tert-butyl-3,6-diazabicyclo[3.1.1]heptane-6carboxylate (700 mg, 3.53 mmol, 1.39 eq. .) and K ₂ CO ₃ (2 g, 14.47 mmol, 5.71 eq.) were dissolved in DMSO (10 ml), the resulting solution was stirred at 120°C for 12 hours. Water and the resulting solid were added to the reaction mixture the substance was filtered. Step 4 was repeated 21 times to obtain the target compound tert-butyl 3 -(5-(4-((5-methyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-3-yl)amino )furo[3,2d]pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (22.5 g, 37.82 mmol, yield 71.02 %).

MS (m/z): 573.1 [M+l] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ=10.29 (s, 1H), 9.08 (br s, 1H), 8.43 (br d, J=8.4 Hz, 1H), 8 .27 (br s, 1H), 7.04 (s, 1H), 6.74 (br d, J=8.8 Hz, 1H), 6.68 (s, 1H), 5.35 (br d , J=9.2 Hz, 1H), 4.21 (br d, J=5.2 Hz, 2H), 4.05 (br s, 2H), 3.92 (br d, J=10.4 Hz, 1H), 3.66 (br d, J=7.2 Hz, 1H), 3.48 (br d, J=11.2 Hz, 2H), 2.55 (br d, J=7, 2 Hz, 1H), 2.38 (s, 3H), 2.33 - 2.24 (m, 1H), 2.05-1.96 (m, 1H), 1.87 (br d, J= 12.0 Hz, 1H), 1.76-1.61 (m, 1H), 1.581.43 (m, 3H), 1.26 (s, 9H).

Step 5. Preparation of 2-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5-methyl-1Hpyrazol-3-yl)furo[3, 2-d]pyrimidin-4-amine dihydrochloride

After tert-butyl-3-(5-(4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3yl)amino)furo[3,2- d]pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (22 g, 36.98 mmol, 1 eq.) was dissolved in 4M HCl/MeOH ( 250 ml), the resulting solution was stirred at room temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, acetone (1 L) was added to it. The resulting product was filtered, recovered and then dried to obtain the target compound 2-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5-methyl-1Hpyrazol- 3-yl)furo[3,2-d]pyrimidin-4-amine dihydrochloride (22.4 g).

MS (m/z): 389.1 [M+l] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) 6=11.56 (br s, 1H), 10.61 (br s, 1H), 9.23 (br s, 1H), 9.03 (s, 1H), 8.76 (dd, J=2.0, 9.2 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 7.26 (br d, J=9.2 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 6.57 (s, 1H), 4.56 (br s, 2H), 4.19 (br s, 4H), 3, 01-2.95 (m, 1H), 2.39 (s, 3H), 1.94 (br dd, J=5.6, 10.0 Hz, 1H).

Step 6. Preparation of 2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3yl)pyridin-3-yl)-N-(5 -methyl-1H-pyrazol-3-yl)furo[3,2-d]pyrimidin-4-amine.

After 2-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5-methyl-1 H-pyrazol-3 yl)furo[ 3,2-d]pyrimidin-4-amine dihydrochloride (22.4 g, 48.55 mmol), 6-methoxypyridine-3-carbaldehyde (9.99 g, 72.83 mmol, 1.5 eq.) and TEA (39 .31 g, 388.43 mmol, 54.06 mL, 8 eq.) was dissolved in DMA (250 mL), NaBH(OAc) ₃ (30.87 g, 145.66 mmol, 3 eq.) was added and the resulting mixture stirred at 55°C for 5 hours. Water (1 L) and EtOAc (1.6 L) were added to the reaction mixture and the organic layer was recovered. The organic layer was washed with brine (800 ml) and then dried using Na ₂ SO ₄ . The organic layer was filtered, concentrated using a vacuum concentrator and then purified using RP-HPLC to give the title compound 2-(6-(6-((6-methoxypyridin-3yl)methyl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)pyridin-3-yl)-N-(5-methyl-1H-pyrazol-3-yl)furo[3,2d]pyrimidin-4-amine (11.7 g, 22.96 mmol, yield 47.29%).

MS (m/z): 510.4 [M+l] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) 6=12.11 (br s, 1H), 10.14 (br s, 1H), 9.13 (d, J=2.0 Hz, 1H), 8.46 (dd, J=2.0, 8.8 Hz, 1H), 8.26 (s, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.67 (dd , J=2.4, 8.8 Hz, 1H), 7.05 (s, 1H), 6.76 (dd, J=6.0, 8.8 Hz, 2H), 6.61 (br s , 1H), 3.82 (s, 3H), 3.75 (br d, J=12.0 Hz, 2H), 3.66 (br d, J=5.6 Hz, 2H), 3.61 -3.42 (m, 4H), 2.54-2.51 (m, 1H), 2.31 (s, 3H), l.56 (brd, J=8.4 Hz, 1H).

All exemplary compounds (compounds of Examples 1 to 37) were prepared by a method similar to Example 1, and the compound names, chemical structural formulas, NMR and LC-MS analysis results for each exemplary compound are summarized and shown in the following table. 1.

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Table 1

Illustrative strategic connection Structure Connection name ^X N NMR LCMS (m/z) 1 N-MH 2-(6-(6-((6-label sipyridin-3-yl) methyl)-3,6-diaza bicyclo [3.1.1] te ptan-3-yl)pyridin-3-yl)-A -(5-methyl-1H-pyrazol3-yl)furo[3,2-<7]pyrimidin-4-amine ^X H NMR (400 MHz, DMSO-d ₆ ) δ = 12.11 (br s, 1H), 10.14 (br s, 1H), 9, 13 (d, J = 2.0 Hz, 1H), 8.46 (dd, J = 2.0, 8.8 Hz, 1H), 8.26 (s, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.67 (dd , J = 2.4, 8.8 Hz, 1H), 7.05 (s, 1H), 6.76 (dd, J = 6.0, 8.8 Hz, 2H), 6.61 (br s , 1H), 3.82 (s, 3H), 3.75 (br d, J = 12.0 Hz, 2H), 3.66 (br d, J = 5.6 Hz, 2H), 3.61 - 3.42 (m, 4H), 2.54 - 2.51 (m, 1H), 2.31 (s, 3H), 1.56 (br d, J = 8.4 Hz, 1H) 510, 4 [M +H] ⁺ 2 _n -nh oY 2-(6-(6-((6-label sipyridin-3-yl) methyl)-3,6-diaza bicyclo [3.1.1] te ptan-3-yl)pyridin-3-yl)-A -(5-methyl-III-pyrazol3-yl)thieno[3,2-<7]pyrimidin-4-a min ^X H NMR (400 MHz, DMSO-d ₆ ) δ = 11.52 (s, 1H), 9.23 (d, J = 2.2 Hz, 1 H), 8.71 (dd, J = 9, 2, 2.3 Hz, 1H), 8.43 (d, J = 5.5 Hz, 2H), 8.07 (ddd, J = 8.3, 5.6, 2.4 Hz, 1H), 7.76 (d, J = 5.5 Hz, 1H), 7.02 (d, J = 9.3 Hz, 1H), 6.92 (d, J = 7.0 Hz, 1H), 6, 47 (s, 1H), 4.62 (dd, J = 23.4, 5.9 Hz, 2H), 4.48 - 4.42 (m, 2H), 4.26 (s, 2H), 4 .15 (s, 2H), 3.89 (s, 3H), 2.35 (s, 3 H) 526.3 [M +H] ⁺ 3 _ν -νη η ν'* ¹ **** 2-(6-(6-((6-label sipyridin-3-yl) methyl)-3,6-diaza bicyclo [3.1.1] te ptan-3-yl)pyridin-3-yl)-A -(5-methyl-III-pyrazol 3 -yl)quinazolin4-amine ^X H NMR (400 MHz, DMSO-d ₆ ) δ = 12.23 (br s, 1H), 10.29 (br s, 1H), 9. 24 (d, J = 2.0 Hz, 1H), 8.67 - 8.49 (m, 2H), 8.06 (s, 1H), 7.77 (br d, J = 2.0 Hz, 2H), 7.65 (br d, J = 8, 4 Hz, 1H), 7.52 - 7.41 (m, 1H), 6.84 - 6.6 8 (m, 3H), 3.81 (s, 3H), 3.75 (br d, 7 = 11.2 Hz, 2H), 3.64 (br d, J = 5.6 Hz, 2H), 3.60 - 3.45 (m, 4H), 2.53 - 520.3 [M +H] ⁺

- 14044405

2.51 (m, 1H), 2.35 (s, ZN), 1.55 (br d, /=8.4 Hz, 1H) 4 A?-c _F! cdbx ^N 44 ^ν >^4ζ ^ν 2-(6-(6-((6-label sipyridin-3-yl) methyl)-3,6-diaza bicyclo [3.1.1] re ptan-3-yl)pyridin-3-yl)-A- (5-trifluoromethyl)- Spirazol-3-yl)fu ro[3,2-b]pyrimi din-4-amine Ή NMR (400 MHz, DMSO-de) δ = 9.11 (d, J = 2.4 Hz, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.45 (d, J = 9.1 Hz, 1H), 8.07 (s, 1H), 7.95 (s, 2H), 7.68 (d, J = 8.7 Hz, 1H), 7.32 (d , J = 2.1 Hz, 1H), 7.25 (s, 2H), 6.86 (d, J = 9.0 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H ), 6.67 (s, 1H), 3.82 (s, 3H), 3.81-3.79 (m, 2H), 3.78 - 3.74 (m, 2H), 3.68 ( dd, J = 6.0, 1.8 Hz, 2H), 2.69 2.66 (m, 1H), 1.47 (d, J = 6.9 Hz, 1 H) 564, 3 [M +H] ⁺ 5 ν·ΝΗ__ ΜΗ' ⁴ ' A-(5-methyl-1R-p irazol-3-yl)-2-(6-(6-((5-methylthiazol-2-yl)methyl)-3,6-diazabicycle o[3.1.1] heptan-3yl)pyridin-3-yl)quinazolin-4-am in 'll NMR (400 MHz, DMSO-d6) δ = 10.34 (s, 1H), 9.23 (d, J = 2.2 Hz, 1 H), 8.64 - 8.51 (m, 2H ), 7.83 - 7.72 (m, 2H), 7.47 (ddd, J = 8.2, 6.0, 2.2 Hz, 1H), 7.35 (d, J = 1.2 Hz, 1H), 6.80 (d, J = 9.0 Hz, 1H), 6.73 (s, 1H), 3.81-3.73 (m, 6H), 3.60 (d, J = 11.7 Hz, 2H), 2.56 (dd, J = 11.6, 3.6 Hz, 1H), 2.41 (d, J = 1.0 Hz, ZN), 2.3 5 (s, ZN), 1.62 (d, J = 8.5 Hz, 1H) 510, 4 [M +H] ⁺ 6 n-nh cC-M xccr 2-(6-(3-((6-label sipyridin-3-yl) methyl)-3,6-diaza bicyclo[3.1.1]he ptan-6-yl)pyridin-3-yl)-A- (5-methyl-III-pyrazol3-yl)quinazolin4-amine Ή NMR (400 MHz, DMSO-de) δ = 11.91 (s, 1H), 10.32 (s, 1H), 9.24 (d, J = 2.1 Hz, 1H), 8.61 ( d, J = 8.3 Hz, 1H), 8.57 (dd, J = 8.9, 2.2 Hz, 1H), 7.78 (dd, J = 4.6, 1.1 Hz, 2H), 7.6 0 (d, J = 6.9 Hz, 1H), 7.48 (d, J = 6.2 Hz, 1H), 6.80 (d, J = 9.0 Hz, 1H ), 6.73 (s, 1H), 6.37 (s, 1H), 6.20 (dd, J = 6.9, 1.4 Hz, 1H), 4.53 (d, J = 6, 1 Hz, 1H), 4.00 (dd, J = 34.3, 12.5 Hz, 2H), 3.78 (d, J = 22.3 Hz, 2H), 3.7 3 (s, 2H ), 3.62 (dd, J = 13.2, 6.6 Hz, 2H), 2.63 (s, 1H), 2.35 (s, 3H), 1.64 (d, 7=6, 9 Hz, 1H) 520.4 [M +H] ⁺ 7 _N -NH hn'^^ aL XX' 2-(6-(6-((6-label sipyridin-3-yl) methyl)-3,6-diaza bicyclo[3.1.1]he ptan-3-yl)pyridin-3-yl)-A- (5th Ή NMR (400 MHz, DMSO-d6) δ 1 0.90 (s, 1H), 9.19 (dd, J = 22.3, 2.5 Hz, 1H), 8.67 (dd, J = 24 ,6, 9.5 Hz, 1H), 8.46 (dd, J = 36.6, 2.5 Hz, 1H), 8.14 - 8.02 (m, 1H), 7.05 (dd, J = 42.7, 9.4 Hz, 1H), 6.91 (dd, J = 8.6, 510, 3 [M +H] ⁺

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til-III-pyrazol3-yl)dihydro-5R-cyclopentaIn irimidin-4-ami and 7.2 Hz, 1H), 6.51 (d, J = 4.7 Hz, 1H), 4.64 (d, J = 6.1 Hz, 1H), 4.56 (d, J = 6, 2 Hz, 1H), 4.44 (d, J = 6.4 Hz, 2H), 4.26 - 4.05 (w, 6H), 3.88 (d, J = 6.8 Hz, ZN) , 3.13 (q, J = 7.8 Hz, 2 N), 2.88 (s, 2 H), 2.33 (d, J = 5.6 Hz, ZN), 2.16 (s, 2 H ) 8 n-nh HN ^Z ** ^S ' OlU UdU” A-(5-methyl-1 Η-π irazol-3-yl)-2-(6-(6-((6-trifluoromethyl)pyridin3-yl)methyl)-3,6diazabicyclo[3.1.1]heptane- 3-yl) pyridin-3-yl) chi nazolin-4-amine Ή NMR (400 MHz, DMSO-d6) δ 1 2.22 (s, 1H), 10.30 (s, 1H), 9.24 (d, J = 2.3 Hz, 1H), 8.75 ( d, J = 2.1 Hz, 1H), 8.62 - 8.54 (m, 2H), 8.06 (dd, J = 8.0, 2.1 Hz, 1H), 7.84 (d , J = 8.0 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.47 (ddd, J = 8.3, 6.1, 2.1 Hz, 1H), 6, 82 (d, J = 9.0 Hz, 1H), 6.73 (s, 1H), 3.7 9 - 3.59 (m, 8H), 2.58 (d, J = 7.0 Hz , 1H), 2.34 (s, 3H), 1.62 (d, J = 8.4 Hz, 1H) 558.5 [M+ H] ⁺ 9 Udu- 5-((3-(5-(4-((5-methyl-1H-pyrazol 3-yl)amino)quina zolin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[ 3.1.1 ]heptan-6-yl)met yl)picolinonitril Ή NMR (400 MHz, DMSO-d6) δ 1 2.22 (s, 1H), 10.30 (s, 1H), 9.23 (d, J = 2.3 Hz, 1H), 8.74 ( dd, 7 = 2,1,0, 9 Hz, 1H), 8.62 - 8.54 (m, 2H), 8.0 5 - 7.95 (m, 2H), 7.81 - 7.74 (m, 2H), 7.47 (ddd, J = 8.3, 6.2, 2.0 Hz, 1 H), 6.81 (d, J = 9.0 Hz, 1H), 6, 73 (s, 1H), 3.81 - 3.56 (m, 8H), 2.58 (d, J = 7.0 Hz, 1H), 2.34 (s, 3H), 1.61 (d , 7=8.4 Hz, 1H) 515.5 [M+ H] ⁺ 10 n-nh OL A-(5-methyl-1H-p irazol-3-yl)-2-(6-(6-((6-methylpyridin-3-yl)methyl)-3,6-diazabic clo[3.1. 1]heptan3-yl)pyridin-3yl)quinazolin-4amine Ή NMR (400 MHz, DMSO-d6) δ 1 2.22 (s, 1H), 10.30 (s, 1H), 9.23 (d, 7 = 2.3 Hz, 1H), 8.62 - 8.54 (m, 2H), 8.38 (d, 7 = 2.3 Hz, 1H), 7.81-7.74 (m, 2H), 7.63 (dd, J = 7.9, 2.3 Hz, 1H), 7.47 (ddd, 7 =8.3, 6.1, 2.1 Hz, 1H), 7.18 (d, 7 = 7.8 Hz, 1H), 6.8 1 (d, 7 = 9.0 Hz, 1H), 6.73 (s, 1H), 3.77 (d, 7 = 12.2 Hz, 2H), 3.69 (d, 7 = 5.9 Hz, 2H), 3.58 (d, J = 25.7 Hz, 4H), 2.43 (s, 3H), 2.41 (d, 7 = 3.5 Hz, 1H), 2.35 (s, 3H), 1.59 (d, 7 = 8.4 Hz, 1H) 504.5 [M+ H] ⁺ eleven ы-NH „4 ^: '^Fel&u 2-(6-(6-((3,5-dithoro-4-isopropoc sibenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyr idin-3-yl)-A- (5methyl-III-pyrazo l-3-yl)quinazoli n-4-amine Ή NMR (400 MHz, DMSO-d6) δ 1 2.19 (s, 1H), 10.30 (s, 1H), 9.23 (d, 7 = 2.3 Hz, 1H), 8.63 - 8.53 (m, 2H), 7.81 - 7.74 (m, 2H), 7.47 (ddd, 7 = 8.3, 6.1, 2.1 Hz, 1H), 7.15 - 7.08 (m, 2H), 6.80 (d, 7 = 9.0 Hz, 1H), 6.73 (s, 1H), 4.32 (hept, 7 = 6.1 Hz, 1 H) , 3.72 (d, 7 = 6.0 Hz, 4H), 3.53 (s, 2H), 3.33 (s, 2H), 2.57 (d, 7 = 6.9 G 583.5 [M+ H] ⁺

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ts, 1H), 2.34 (s, ZN), 1.59 (d, J = 8.4 Hz, 1H), 1.26 (d, J= 6.1 Hz, 6H) 12 n-nh hnAA~ '---CN 2-methoxy-5-((3-(5-(4-((5-methyl-1 R-pyrazol-3-yl) amino)quinazolin-2-yl)pyridin2-yl)-3,6-diazab icyclo[3.1.1]hep tan-6-yl)methyl)b enzonitrile Ή NMR (400 MHz, DMSO-d6) δ 1 2.21 (s, 1H), 10.30 (s, 1H), 9.23 (d, J = 2.3 Hz, 1H), 8.64 - 8.52 (m, 2H), 7.81 - 7.73 (m, 2H), 7.68 - 7.61 (m, 2H), 7.47 (ddd, J = 8.3, 6.1 , 2.1 Hz, 1H), 7.18 (d, J= 8.6 Hz, 1H), 6. 81 (d, J = 8.9 Hz, 1H), 6.73 (s, 1H), 3.89 (s, 3H), 3.75 (d, J = 12.1 Hz, 2 H), 3.68 (d, J = 5.9 Hz, 2H), 3.33 (s, 2H) , 2.58 - 2.53 (m, 1H), 2.35 (s, 3 H), 1.58 (d, 7=8.4 Hz, 1H) 544.5 [M+ H] ⁺ 13 _N .MH NH^ 0%. 2-(6-(6-((1 R-imidazol-5-yl)methyl)-3,6-diazabiclo[3.1.1]heptan3-yl)pyridin-3yl)-A-(5-methyl -1 R-pyrazol-3-yl) quinazoline-4-ami n Ή NMR (400 MHz, MeOD) δ = 9.19 (d, J = 2.1 Hz, 1H), 8.55 (dd, J = 9.0, 2.2 Hz, 1H), 8.26 ( d, J = 8.2 Hz, 1H), 7.84 - 7.75 (m, 3H), 7.54 - 7.47 (m, 1H), 7.25 (s, 1H), 6.80 (d, J = 9.0 Hz, 1H), 6.68 (s, 1H), 4.46 - 4.10 (m, 3H), 4.06 - 3.95 (m, 5H), 2, 39 (s, 3H) 479, 4 [M +H] ⁺ 14 ν·νη o5a 2-(6-(6-(4-methoxibenzyl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)pyridin-3-yl)-A-(5methyl-III-pyrazo l- 3-yl)quinazoli n-4-amine Ή NMR (400 MHz, DMSO-d ₆ ) δ = 10.54 (s, 1H), 9.25 (d, J = 2.2 Hz, 1 H), 8.64 (d, J = 8.2 Hz, 1H), 8.57 (dd, J = 8.9, 2.3 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.47 (ddd, J = 8.2, 5.8, 2.3 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6. 86 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 9.0 Hz, 1H), 6.74 (s, 1H), 3.76 (d, J = 2.5 Hz, 1H), 3.72 (s, 3H), 3.65 (d, J = 5.9 Hz, 2H), 3.57 (s, 2H), 3.48 (s, 2H), 2.54 (d, J = 2.7 Hz, 1H), 2.3 4 (s , 3H), 1.83 (s, 2H), 1.57 (d, J = 8.4 Hz, 1H) 519, 4 [M +H] ⁺ 15 Lo% 2-(6-(6-((6-isopropoxypyridin3-yl)methyl)-3,6diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-A -(5-methyl-III- pi razol-3-yl)quinase olin-4-amine Ή NMR (400 MHz, MeOD) δ = 9.20 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 7.4 Hz, 1H) , 8.09 (s, 1H), 7.83 - 7.73 (m, 2H), 7.68 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 7.0 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 5.20 (dt, J = 12.3, 6 , 1 Hz, 1H), 3.93 (d, J= 12.8 Hz, 4H), 3.76 (s, 4H), 2.38 (s, 3H), 1.32 (d, J = 6 ,2 Hz, 6H) 548, 4 [M +H] ⁺

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16 ν· ^ν η ©AT' 2-(6-(6-((5-chloro6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)AC5-methyl- 1 N-p irazol-3-yl)quin azolin-4-amine Ή NMR (400 MHz, DMSO-d ₆ ) δ = 10.47 (s, 1H), 9.23 (s, 1H), 8.59 (dd, J = 25.6, 8.5 Hz, 2H) , 8.08 (s, 1H), 7.86 (s, 1H), 7.77 (t, J = 7.3 Hz, 2H), 7.47 (t, J = 6.6 Hz, 1H) , 6.82 (d, J = 8.9 Hz, 1H), 6.72 (s, 1H), 3.92 (s, 3H), 3.77 (d, J = 11.4 Hz, 2H) , 3.70 (d, J = 5.3 Hz, 2H), 3.60 (d, J = 16.5 Hz, 2H), 3.53 (s, 2H), 2.57 - 2.52 ( m, 1H), 2.33 (s, 3H), 1.58 (d, J = 8, 1 Hz, 1H) 555.4 [M +H] ⁺ 17 ν·™ ojZ 2-(6-(6-((5-label sipyrazin-2-yl) methyl)-3,6-diaza bicyclo[3.1.1]he ptan-3-yl)pyrid in-3-yl)-A- (5-methyl-III-pyrazol3-yl)quinazolin4-amine Ή NMR (400 MHz, MeOD) δ = 9.18 (d, J = 1.8 Hz, 1H), 8.52 (dd, J = 8.9, 1.8 Hz, 1H), 8.23 ( d, J= 8.1 Hz, 1H), 8.13 (d, J = 2.8 Hz, 2H), 7.82 - 7.73 (m, 2H), 7.48 (t, J = 7 ,0 Hz, 1H), 6.75 (d, J = 9.0 Hz, 1H), 6.69 (s, 1H), 3.98 (d, J = 12.2 Hz, 2H), 3, 94 (s, 3H), 3.90 (d, J = 5.4 Hz, 2H), 3.75 (s, 2H), 3.67 (d, J = 11.9 Hz, 2 H), 2 .72 (s, 1H), 2.38 (s, 3H), 1.71 (d, J - 9.0 Hz, 1H) 521.4 [M +H] ⁺ 18 Ν' ^Ν Η DC5-methyl-1/7-p irazol-3-yl)-2-(6-(6-(quinolin-6yl-methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyr idin-3-yl)quinase olin-4-amine Ή NMR (400 MHz, DMSO-d ₆ ) δ = 11.97 (s, 1H), 10.31 (s, 1H), 9.26 (d, J = 2.1 Hz, 1H), 8.86 (dd, J = 4.1, 1.6 Hz, 1H), 8.64 - 8.55 (m, 2H), 8.34 (d, J = 7.6 Hz, 1H), 7.96 ( d, J = 8.7 Hz, 1H), 7.91 (s, 1H), 7.77 (dd, J = 10.3, 3.7 Hz, ZN), 7.53 - 7.44 ( m , 2H), 6.83 (d, J = 9.0 Hz, 1H), 6.74 (s, 1H), 3.82 (d, J = 11.4 Hz, 2H), 3.76 (d , J = 5.8 Hz, 4H), 3.61 (d, J = 8.8 Hz, 2H), 2.60 (dd, J = 12.9, 6.3 Hz, 1H), 2.35 (s, 3H), 1.62 (d, J = 8.4 Hz, 1H) 540.4 [M +H] ⁺ 19 n-nh ΝΗ^'' ^N ilL DC5-methyl-1 N-p irazol-3-yl)-2-( 6-(6-((4-methylthiazol-2-yl)methyl)-3,6-diazabicycle o[3.1.1]heptane- 3yl)pyridin-3-yl)quinazolin-4-am in Ή NMR (400 MHz, DMSO-d ₆ ) δ = 10.46 (s, 1H), 9.24 (d, J = 2.2 Hz, 1 H), 8.62 (d, J = 8.3 Hz, 1H), 8.57 (dd, J = 8.9, 2.3 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.47 (ddd, J = 8.2, 6.0, 2.2 Hz, 1H), 7.15 (d, J= 0.9 Hz, 1H), 6.81 (d, J = 9.0 Hz, 1H), 6.73 (s, 1H), 3.83 - 3.72 (m, 6H), 3.61 (d, J = 11, 510, 4 [M +H] ⁺

- 18 044405

4 Hz, 2H), 2.59 (dd, J = 13.5, 6.4 Hz, 1H), 2.34 (s, ZN), 2.30 (d, J = 0.7 Hz, ZN ), 1.62 (d, J = 8.6 Hz, 1H) 20 ν·νη αΖ , φχγ 2-(6-(6-((6-dimetylamino)pyridin n-3-yl)methyl)-3, 6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)- U-(5-methyl-1H-p irazol-3-yl)quin azolin-4-amine Ή NMR (400 MHz, DMSO-d ₆ ) δ = 11.49 (s, 1H), 9.63 (s, 1H), 9.19 (s, 1H), 8.75 (d, J = 7, 4 Hz, 1H), 8.55 (d, J = 8.9 Hz, 1H), 8.28 (s, 1H), 7.9 8 (d, J = 5.4 Hz, 2H), 7, 81 (d, J = 9.5 Hz, 1H), 7.68 (t, J = 6.6 Hz, 1H), 6.93 (dd, J = 17.3, 8.9 Hz, 2H), 6.67 (s, 1H), 4.59 (s, 2H), 4.47 (d, J = 5.6 Hz, 2H), 4.17 (d, J = 8.8 Hz, 2H), 3.99 (d, J = 12.8 Hz, 2H), 3.52 (d, J = 5.0 Hz, 1H), 3.12 (s, 6H), 2.36 (s, 3H), 2.07 - 2.01 (m, 1H) 533, 4 [M +H] ⁺ 21 _ν .νη eV . 4-((3-(5-(4-((5-methyl-1H-pyrazol 3-yl)amino)quina zolin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[ 3.1.1 ]heptan-6-yl)phen yl)methanesulfonamide Ή NMR (400 MHz, DMSO-d ₆ ) δ = 11.25 (s, 1H), 10.03 (s, 1H), 9.60 (s, 1H), 9.20 (d, J = 1, 8 Hz, 1H), 8.73 (s, 1H), 8.56 (dd, J = 9.1, 2.0 Hz, 1H), 7.94 (s, 2H), 7.64 (d, J = 6.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.27 (s, 2H), 6.93 (d, J = 9.1 Hz, 1H) , 6.6 7 (s, 1H), 4.64 (d, J = 5.5 Hz, 2H), 4.46 (d, J = 6.0 Hz, 2H), 4.15 (d, J = 10.1 Hz, 2H), 3.98 (d, J = 12.8 Hz, 2H), 3.05 (s, 3H), 2.35 (s, 3H), 2.04 (d, J = 7.8 Hz, 1H) 582, 4 [M +H] ⁺ 22 Ν' ^νη νη'^ ⁴ ^ 2-(6-(6-(4-fluorobenzyl)-3,6-diazabicylcyclo[3.1.1]hep tan-3-yl)pyridin-3-yl)-U-(5-metyl-III -pyrazol-3-yl)quinazolin-4amine Ή NMR (400 MHz, DMSO-d ₆ ) δ = 11.90 (s, 1H), 10.31 (s, 1H), 9.25 (d, J = 2.2 Hz, 1H), 8.65 - 8.52 (m, 2H), 7.78 (d, J = 6.0 Hz, 2H), 7.47 (d dd, J = 8.2, 5.9, 2.3 Hz, 1H ), 7.39 (dd, J = 8.3, 5.8 Hz, 2H), 7.13 (t, J = 8.8 Hz, 2H), 6.80 (d, J = 9.0 Hz , 1H), 6.74 (s, 1H), 3.76 (d, J = 13.7 Hz, 4 H), 3.60 (s, 4H), 2.58 (s, 1H), 2, 35 ( s,3H), 1.61 (d, 7=8.4 Hz, 1H) 507.5 [M +H] ⁺ 23 _ν .ΝΗ ΝΗ^ αΖ ' φ w 2-(6-(6-((6-fluoropiridin-3-yl)methyl yl)-3,6-diazabic iclo [3.1.1] hepta n-3-yl)pyridin- 3-yl)-U-(5-methyl -SH-pyrazole-Z-i Ή NMR (400 MHz, DMSO-d ₆ ) δ = 11.93 (s, 1H), 10.31 (s, 1H), 9.25 (d, J = 2.2 Hz, 1H), 8.63 - 8.53 (m, 2 H), 8.19 (s, 1H), 7.96 (td, J = 8.3, 2.4 Hz, 1H), 7.78 (t, J = 6, 1 Hz, 2H), 7.48 (ddd, J = 8.2, 5.8, 2.3 Hz, 1H), 508, 4 [M +H] ⁺

- 19 044405

l)quinazoline-4-a min 7.12 (dd, J = 8.4, 2.8 Hz, 1H), 6.81 (d, J = 9.0 Hz, 1H), 6.74 (s, 1H), 3.7 5 ( dd, J = 22.7, 8.8 Hz, 4H), 3.61 (s, 4H), 2.56 (d, J = 5.7 Hz, 1H), 2.34 (d, J = 9 ,2 Hz, ZN), 1.60 (d, J = 8.4 Hz, 1H) 24 Ν·ΝΗ 2-(6-(6-((6-ethox ipyridin-3-yl) methyl)-3,6-diaza bicyclo[3.1.1]he ptan-3-yl)pyridin-3-yl)-A- (5-methyl-III-pyrazol3-yl)quinazolin4-amine Ή NMR (400 MHz, DMSO-d ₆ ) δ = 12.02 (s, 1H), 10.35 (s, 1H), 9.27 (d, J = 2.1 Hz, 1H), 8.65 - 8.56 (m, 2H), 8.23 (s, 1H), 7.83 - 7.76 (m, 3H), 7.49 (ddd, J = 8.2, 6.0, 2 .2 Hz, 1H), 6.84 (t, J = 9.7 Hz, 2H), 6.73 (s, 1 H), 4.31 (q, J = 7.0 Hz, 2H), 4 .25 4.05 (m, 2H), 3.92 (s, 3H), 2.36 (s, 3H), 1.32 (t, J = 7.0 Hz, ZN) 534.5 [M +H] ⁺ 25 J&- - φχγ A-(5-methyl-1H-p irazol-3-yl)-2-(6-(6-((2-methylpyrimidin-5-yl)m ethyl)-3,6-diazabicylcyclo[3.1.1 ]hep tan-3-yl)pyridinium n-3-yl)quinazoli n-4-amine Ή NMR (400 MHz, DMSO-d ₆ ) δ = 12.10 (s, 1H), 10.66 (s, 1H), 9.25 (s, 1H), 8.87 (d, J = 6, 3 Hz, 1H), 8.68 - 8.56 (m, 2H), 7.84 (q, J = 8.4 Hz, 2H), 7.54 (dd, J = 10.5, 4.1 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.71 (s, 1H), 4.74 (s, 1H), 4.55 (s, 2H), 4 .02 (dd, J = 37.3, 15.8 Hz, 4H), 2.66 (s, 3H), 2.36 (s, 3H) 505.5 [M +H] ⁺ 26 αίν ^N «Г A-(5-methyl-1H-p irazol-3-yl)-2-(6-(6-((5-methylpyrazin-2-yl)methyl)-3,6-diazabic clo[3.1.1 ]heptan3-yl)pyridin-3yl)quinazolin-4amine Ή NMR (400 MHz, DMSO-d ₆ ) δ = 11.84 (s, 1H), 10.32 (d, J = 12.0 Hz, 1H), 9.25 (t, J = 4.0 Hz , 1H), 8.63 8.54 (m, 3H), 8.42 (s, 1H), 7.82 - 7.74 (m, 2H), 7.47 (ddd, J = 8.2, 5.9, 2.2 Hz, 1H), 6.81 (d, J = 9.0 Hz, 1H), 6.74 (s, 1H), 3.86 (d, J = 11.7 Hz, 2H), 3.75 (d, J = 5.7 Hz, 2H), 3.68 (s, 2H), 3.64 - 3.55 (m, 2H), 2.58 2.52 (m, 1H), 2.47 (s, 3H), 2.35 (s, 3H), 1.61 (d, 7=8.4 Hz, 1H) 505.5 [M +H] ⁺ 27 N-NH obi o - FmU 1-methyl-4-((3-(5(4-((5 -methyl-1Hpyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6-diazabic clo [3.1.1]heptan6-yl)methyl)pyridin-2(1H)-one Ή NMR (400 MHz, DMSO-d6) δ 1 2.21 (s, 1H), 10.31 (s, 1H), 9.14 (dd, J = 2.3, 0.8 Hz, 1H), 8.61 (d, 7=8, 3 Hz, 1H), 8.48 (dd, 7= 8.7, 2.3 Hz, 1H), 7.86 - 7.84 (m, 1H), 7 .81 - 7.7 6 (m, 2H), 7.48 (ddd, 7 = 8.3, 6.2, 2, 0 Hz, 1H), 7.18 (dd, J = 8.5, 2 ,4 Hz, 1H), 6.72 (s, 1H), 6.56 (ddd, 7= 13, 8, 8.6, 0.7 Hz, 2H), 4.40 (d, 7= 5, 8 Hz, 2H), 3.70 (s, 3H), 3.43 (s, 2H), 520.5 [M+ H] ⁺

- 20 044405

3.14 (d, J = 10.6 Hz, 2H), 2.73 (d, J = 10.4 Hz, 2H), 2.58 - 2.53 (w, 1H), 2.34 (s , ZN), 1.84 (d, J = 7.7 Hz, 1 N) 28 n-nh ΐ 2-(6-((25.57/-4-(( 6-methoxypyride in-3-yl)methyl)-2,5-dimethylpiper azin-1-yl)pyride in-3-yl)-A-( 5-methyl-1H-pyrazol 3-yl)quinazolin4-amine Ή NMR (400 MHz, DMSO-d6) δ 1 2.21 (s, 1H), 10.27 (s, 1H), 9.13 (d, J = 2.4 Hz, 1H), 8.59 ( d, J = 8.3 Hz, 1H), 8.47 (dd, J = 9.0, 2.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7, 79 - 7.70 (m, 3H), 7.46 (ddd, J= 8.3, 6.4, 1.8 Hz, 1H), 6.90 - 6.74 (m, 3H), 4, 58 (s, 1H), 4.17 - 4.07 (m, 1H), 3.85 (s, 3H), 3.83 (s, 1H), 3.61 (d, J= 13.5 Hz , 1H), 3.45 (d, J = 13.5 Hz, 1H), 3.30 (d, 7 = 3.7 Hz, lH), 3.10 (d, J = 6.8 Hz, 1H ), 2.77 (dd, J = 11.7, 4.2 Hz, 1H), 2.34 (s, 3H), 1.17 (d, J = 6.5 Hz, ZN), 1.01 - 0.99 (m, ZN) 536.5 [M+ H] ⁺ 29 N-NH HN**^ OuV II ^N 2-(6-(4-((6-label sipyridin-3-yl) methyl)-3,3-dimet ilpiperazin-1-i l)pyridin-3-yl) -A-(5-methyl-1Hpyrazol-3-yl)chi nazolin-4-amine Ή NMR (400 MHz, DMSO-d6) δ 1 2.21 (s, 1H), 10.28 (s, 1H), 9.12 (d, J = 2.4 Hz, 1H), 8.59 ( d, J = 8.3 Hz, 1H), 8.46 (dd, J = 9.0, 2.4 Hz, 1H), 8.08 (d, 7 = 2.3 Hz, 1H), 7, 81-7.71 (m, 2H), 7.67 (dd, 7 = 8.5, 2.4 Hz, 1 H), 7.46 (ddd, 7 = 8.2, 6.4, 1, 8 Hz, 1H), 6.96 (d, 7 = 9.1 Hz, 1H), 6.80 (d d, 7 = 8.5, 0.7 Hz, 1H), 6.71 (s, 1H ), 3.84 (s, 3H), 3.58 (d, 7 = 5.7 Hz, 2H), 3.48 (d, 7 = 15.3 Hz, 4H), 2.43 (t, 7 = 5.3 Hz, 2H), 2.33 (s, 3H), 1.15 (s, 6H) 536.5 [M+ H] ⁺ thirty n-nh hn' ^A '·' O(S ^qP 2-(6-(4-((6-meth sipyridin-3-yl) methyl)-1,4-diaze pan-1-yl)pyridin-3-yl)-A-(5-meth yl-III -pyrazol-3-yl)quinazolin-4amine Ή NMR (400 MHz, DMSO-d6) δ 1 2.20 (s, 1H), 10.26 (s, 1H), 9.16-9.10 (m, 1H), 8.58 (d, 7 = 8.3 Hz, 1H ), 8.47 (dd, 7 = 9.0, 2.4 Hz, 1H), 8.0 7 - 8.00 (m, 1H), 7.80 - 7.70 (m, 2 H), 7.62 (dd, 7 = 8.5, 2.4 Hz, 1H), 7.45 (ddd, 7 = 8.2, 6.5, 1.7 Hz, 1H) , 6.78 - 6.74 (m, 2H), 6.71 (s, 1H), 3.8 2 (s, 3H), 3.80 (d, 7 = 5.7 Hz, 2H), 3 .72 (t, 7 = 6.2 Hz, 2H), 3.56 (s, 2H), 2.71 (t, 7 = 5.0 Hz, 2H), 2.57 - 2.53 (m, 2H), 2.34 (s, 3H), 1.91 - 1.85 (m, 2H) 522.4 [M+ H] ⁺ 31 n-nh HN^ ⁴⁴ ' civ» Axcr 2-(6-((15.45)-5-((6-methoxypyridine in-3-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl) - Ή NMR (400 MHz, DMSO-d6) δ 1 2.21 (s, 1H), 10.26 (s, 1H), 9.14-9.10 (m, 1H), 8.58 (d, 7 = 8.3 Hz, 1H), 8.46 (dd, 7 = 8.9, 2.3 Hz, 1H), 8.0 9 - 8.04 (m, 1H), 7.80 - 7.71 (m, 2H), 7.66 (dd, 7 = 8.5, 2.4 Hz, 1H), 7 520.5 [M+ H] ⁺

- 21 044405

LC5-methyl-1 Η-η irazol-3-yl)quin azolin-4-amine .45 (ddd, J = 8.3, 6.4, 1.8 Hz, 1H), 6.75 (dd, J = 8.5, 0.7 Hz, 1H), 6.71 (s, 1H ), 6.63 (d, J = 8.9 Hz, 1H), 4.78 (s, 1H), 3.82 (s, ZH), 3.64 (s, 2H), 3.57 (d , J = 10.6 Hz, 2H), 3.40 (dd, J = 9.9, 2.2 Hz, 1H), 2.87 (dd, J = 9.5, 2.1 Hz, 1H) , 2.52 (d, J = 3.5 Hz, 1 N), 2.34 (s, ZN), 1.94 (d, J = 9.4 Hz, 1 N), 1.80 (d, 7 = 9.3 Hz, 1H) 32 n-nh 2-(6-((2^.55)-4-((6-methoxypyride in-3-yl)methyl)-2,5-dimethylpiper azin-1-yl)pyride in-3-yl)-^( 5-methyl-1H-pyrazol 3-yl)quinazolin4-amine Ή NMR (400 MHz, DMSO-d6) δ 1 2.21 (s, IH), 10.27 (s, IH), 9.13 (d, J = 2.4 Hz, IH), 8.59 ( d, J = 8.2 Hz, IH), 8.47 (dd, J = 9.0, 2.4 Hz, IH), 8.11 (d, J = 2.3 Hz, IH), 7, 79 - 7.70 (m, 3H), 7.46 (ddd, J = 8.3, 6.4, 1.8 Hz, IH), 6.90 - 6.71 (m, 3H), 4, 58 (s, IH), 4.16 - 4.09 (m, IH), 3.85 (s, 3H), 3.61 (d, J = 13.5 Hz, IH), 3.45 (d , J= 13.5 Hz, IH), 3.30 (d, 7 = 3.7 Hz, IH), 3.12 - 3.05 (m, IH), 2.7 7 (dd, 7 = 11 ,7, 4.2 Hz, IH), 2.34 (s, 3H), 2.30 (dd,7= 11.8, 1.9 Hz, IH), 1.17 (d, 7= 6, 6 Hz, ZN), 1.00 (d, 7 = 6.5 Hz, ZN) 536.5 [M+ H] ⁺ 33 -O (5)-2-(6-(4-((6-methoxypyridin-3 yl)methyl)-3-meth ilpiperazin-1-l)pyridin-3-yl) -^(5-methyl-Spirazol-3-yl)chi nazolin-4-amine Ή NMR (400 MHz, DMSO-d6) δ 1 2.20 (s, IH), 10.29 (s, IH), 9.14 (d, 7 = 2.4 Hz, IH), 8.59 ( d, 7 = 8.3 Hz, IH), 8.48 (dd, 7 = 9.0, 2.4 Hz, IH), 8.08 (d, 7 = 2.4 Hz, IH), 7, 81 - 7.72 (m, 2H), 7.66 (dd, 7 = 8.5, 2.4 Hz, 1 H), 7.46 (ddd, 7 = 8.3, 6.3, 1, 9 Hz, 1 H), 6.94 (d, 7 = 9.1 Hz, IH), 6.80 (d d, 7 = 8.4, 0.7 Hz, IH), 6.70 (s, IH ), 4.12 - 4.05 (m, IH), 4.04 - 3.96 (m, IH), 3.92 (d, 7 = 13.5 Hz, IH), 3.84 (s, 3H), 3.20 (d, 7 = 13.4 Hz, IH), 3, 18 - 3.11 (m, IH), 2.97 (dd, 7 = 12, 8, 8.8 Hz, IH ), 2.70 (dt, 7 = 11.7, 3.6 Hz, IH), 2.48 (dd, 7 = 6.0, 3.1 Hz, IH), 2.33 (s, 3H) , 2.16 (ddd, 7=11, 3.9,8,3.3 Hz, IH), 1.18 (d, 7= 6.1 Hz, ZN) 522.5 [M+ H] ⁺ 34 N-NH OX*. 2-(6-((1^,41?)-5-((6-methoxypyride in-3-yl)methyl)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)pyridin-3- yl)ACh5-methyl-1/7-p irazol-3-yl)quin Ή NMR (400 MHz, DMSO-d6) δ 1 2.18 (s, IH), 10.27 (s, IH), 9.15 - 9.10 (m, IH), 8.58 (d, 7 = 8.3 Hz, IH), 8.46 (dd, 7 = 8.9, 2.3 Hz, IH), 8.0 9 - 8.03 (m, IH), 7.81 - 7.71 (m, 2 H), 7.66 (dd, 7 = 8.5, 2.4 Hz, IH), 7.45 (ddd, 7 = 8.3, 6.4, 1.8 Hz, IH) , 6.78 - 6.59 (m, 3H), 4.78 (s, IH), 3.8 520.4 [M+ H] ⁺

- 22 044405

azoline-4-amine 2 (s, ZN), 3.64 (s, 2H), 3.57 (d, J = 10.3 Hz, 2H), 3.40 (dd, J = 9.9, 2.2 Hz, 1H ), 2.87 (dd, J = 9.4, 2.1 Hz, 1 N), 2.52 (d, J = 3.2 Hz, 1 H), 2.34 (s, ZN), 1, 94 (d, J = 9.3 Hz, 1H), 1.80 (d, 7 = 9.3 Hz, 1H) 35 N-MH ί 2-(6-((3^,55)-4-((6-methoxypyride in-3-yl)methyl)-3,5-dimethylpiper azin-1-yl)pyride in-3-yl)-A- (5-methyl-III-pyrazol 3 -yl)quinazolin4-amine Ή NMR (400 MHz, DMSO-d6) δ 1 2.21 (s, 1H), 10.29 (s, 1H), 9.13 (d, J = 2.4 Hz, 1H), 8.59 ( d, J = 8.3 Hz, 1H), 8.48 (dd, J = 9.0, 2.4 Hz, 1H), 8.15 (d, 7 = 2.4 Hz, 1H), 7, 80-7.73 (m, 2H), 7.69 (dd, J = 8.5, 2.5 Hz, 1 H), 7.46 (ddd, J = 8.2, 6.4, 1, 9 Hz, 1H), 6.97 (d, 7 = 9.1 Hz, 1H), 6.77 (d d, 7 = 8.5, 0.6 Hz, 1H), 6.70 (s, 1H ), 4.26 (d, 7= 11.1 Hz, 2H), 3.82 (s, 3 H), 3.76 (s, 2H), 2.75 (dd, 7= 12.9, 10 .2 Hz, 2H), 2.63 - 2.55 (m, 2H), 2.34 (s, 3H), 1.09 (d, J = 6.0 Hz, 6H) 536.5 [M+ H] ⁺ 36 Chhsg ί (I)-2-(6-(4-((6-methoxypyridin-3 yl)methyl)-3-meth ilpiperazin-1-l)pyridin-3-yl)-A-(5-methyl-1Hpyrazole -3-yl)chi nazolin-4-amine Ή NMR (400 MHz, DMSO-d6) δ 1 2.21 (s, 1H), 10.29 (s, 1H), 9.14 (d, J = 2.4 Hz, 1H), 8.59 ( d, J = 8.3 Hz, 1H), 8.48 (dd, J = 9.0, 2.4 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7, 81 - 7.73 (m, 2H), 7.66 (dd, J = 8.5, 2.4 Hz, 1 H), 7.46 (ddd, J = 8.3, 6.3, 1, 9 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.80 (d d, 7 = 8.4, 0.7 Hz, 1H), 6.71 (s, 1H ), 4.08 (dt, 7= 12.3, 3.0 Hz, 1H), 4.00 (d, J = 12.7 Hz, 1H), 3.92 (d, 7=13.5 Hz , 1H), 3.84 (s, 3H), 3.20 (d, J = 13.4 Hz, 1H), 3.15 (ddd, J = 12.8, 8, 2, 3.4 Hz, 1H), 2.97 (dd, 7 = 12.8, 8, 8 Hz, 1H), 2.74 - 2.66 (m, 1H), 2.5 0 - 2.46 (m, 1H), 2.33 (s, 3H), 2.16 (ddd, 7= 13.0, 10.4, 3.2 Hz, 1H), 1, 18 (d, 7= 6.1 Hz, ZN) 522.5 [M+ H] ⁺ 37 N-ΜΗ dX. 2-(6-(4-((6-label sipyridin-3-yl) methyl)-4,7-diaza spiro[2,5]octan7-yl)pyridin-3yl)-A-(5-methyl-1 I-pyrazol-Z-yl) quinazoline-4-ami And Ή NMR (400 MHz, DMSO-d6) δ 1 2.21 (s, 1H), 10.29 (s, 1H), 9.15 (d, J = 2.4 Hz, 1H), 8.59 ( d, J = 8.3 Hz, 1H), 8.49 (dd, J = 9.0, 2.4 Hz, 1H), 8.10 - 8.05 (m, 1H), 7.81 - 7 .73 (m, 2H), 7.62 (dd, J = 8.5, 2.4 Hz, 1H), 7.46 (ddd, 7= 8.3, 6.3, 1.9 Hz, 1H ), 6.93 (d, 7= 9.1 Hz, 1H), 6.78 (ddd, J = 8.4, 2.4, 0.7 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 3.83 (q, J = 5.8, 5.3 Hz, 6H), 3.70 - 3.65 (m, 2H), 3.57 (s, 2H), 2.84 - 2.78 (m, 2H), 2.33 (s, 534.5 [M+ H] ⁺

I________I__________________________________________ 3H),0.64(dt, 7 = 11.8, 1.9Hz,ZN)

Experimental Example 1: Evaluation of RET Enzyme Inhibition Ability

The following experiment was conducted to evaluate the RET enzyme inhibitory activity of the compound of the present invention.

The Example compound was reacted with purified human RET enzyme (658 end, SIGNALCHEM) to evaluate the ability to inhibit the enzyme by the following method. The reaction buffer was a composition of 40 mM Tris-HCl pH 7.4, 20 mM MgCl ₂ , 0.5 mg/ml BSA and 50 μM DTT, and all experimental materials were reacted with the reaction buffer. After human RET enzyme (658-end, 0.8 ng) was reacted with purified ATP (10 μM) and a defined substrate solution at 25°C for 1 h during the experiment, enzyme activity was confirmed using an in vitro ADP assay -Glo™ (Promega). Luminescence was measured by reacting enzyme activity reaction solution, ADP-Glo reaction solution and enzyme activity solution in a 2:2:1 ratio. The degree of inhibition of enzyme activity according to the concentration of each compound upon treatment was calculated based on the fluorescence of enzyme activity in the solvent control group in which the compound was not treated, in which case the concentration of each compound that inhibited the inhibition of enzyme activity by 50% was determined as the IC value ₅₀ (nM). The IC ₅₀ (nM) of each compound was determined using 3 data sets and obtained using Prism software (version 7.01, GraphPad). The results are shown in the following table. 2.

Experimental Example 2: Evaluation of inhibitory activity against proliferation of medullary thyroid cancer and lung cancer cells that express RET fusion genes.

To evaluate the inhibitory activity of the compound of the present invention on the proliferation of medullary thyroid cancer cells and the proliferation of lung cancer cells that express RET fusion genes, the following experiment was performed.

Among the lung cancer cell lines that express RET fusion genes, LC-2/ad cells

- 23 044405 was titrated after adding 10% FBS solution (HyClone) to RPMI:F12 (1:1) (Invitrogen), and F-12 (Invitrogen) with the addition of 10% FBS solution was used for TT cells. RPMI-1640 supplemented with 10% FBS and 5 ng/ml IL-3 (R&D Systems) was used for Ba/F3 cells. Transduced Ba/F3 cells were cultured by adding 1 μg/ml puromycin (Invitrogen) to the same medium. 24 hours before treatment of cells with the compound, 3000 to 5000 cells were aliquoted into each well of a 96-well white clear-bottom plate (Corning). The compound was diluted in DMSO (3-fold dilution, a total of 12 concentrations) and 0.5 μl of the compound was administered so that the final concentration was from 0.3 nM to 50 μM. To measure live cells 72 h after compound treatment, cells were kept at room temperature for 10 min using CellTiter-Glo luminescent cell viability enhancer (Promega) and then luminescence intensity was measured using a reader (SynergyNeo, Biotek). Each experiment was repeated in triplicate. The result was calculated using the ratio of cell growth (%) compared to control. The graph was generated using GraphPad Prism version 5.0 and the GI ₅₀ (nM) value was calculated. The results are shown in the following table. 2.

______________________Table 2______________________

Enzymatic Assay (IC50, nM) Cellular analysis (GI50, nM) Illusive expendable compound RET (WT) RET (V804M) CCDC6 -RET LC- 2/ad Ba/F3 (naive e) Ba/F3 CCDC6RET (WT) Ba/F3 KIF5BRET (WT) Ba/F3 KIF5BRET (V804M) TT 1 18 2.2 1.8 14 4896 59 19 19 88 2 12 4380 49 eleven 14 48 3 7 0.7 0.9 60 2301 51 13 3 thirty 4 >150 00 >15000 >15000 >15 000 5 18 1056 41 7 4 6 27 9223 166 67 70 7 10 6068 45 15 7 41 8 32 1979 51 12 23 9 thirty 822 62 23 23 10 10 920 39 9 10 eleven 119 12 38 2541 52 15 49 13 2449 14 10 2695 33 eleven 22 15 40 3097 75 24 thirty 16 17 18 19 20 21 22 23 24 25 26 27 28 29 thirty 31 60 eleven 34 40 14 20 15 14 7 7 123 34 25 4014 867 4603 1233 2784 1218 1301 4321 1651 973 6316 1127 1685 127 46 67 120 44 55 57 53 50 37 454 99 66 42 10 28 29 eleven 20 14 12 14 10 164 44 18 39 7 25 28 6 117 6 19 10 21 10 159 321 89 25 12 32 239 33 121 34 16 2591 65 19 20 35 328 36 59 4803 259 63 32 37 219 4648 305 107 50

In the enzyme assay column, RET (WT) is the unmutated form, RET (V804M) is the mutated form in which amino acid V at position 804 of RET is replaced by M, and CCDC6-RET is the form in which the RET gene (WT) and the CCDC6 gene is fused.

In the cell analysis column, LC-2/ad (with CCDC6-RET gene) is a lung cancer cell line, TT cell line (without RET gene (WT)) is a thyroid cancer cell line, Ba/F3 CCDC6-RET ( WT), Ba/F3 KIF5B-RET (WT) and Ba/F3 KIF5B-RET (V804M) are cells in which disease-associated traits (CCDC6-RET, KIF5B-RET and KIF5B-RET (V804M)) are introduced into Ba/F3 cells, and Ba/F3 (naive) represents a cell that is not

- 24 044405 transduced.

As shown in table. 2, by measuring the cell growth inhibitory activity of each exemplary compound against LC-2/ad cells, naive Ba/F3 cells, Ba/F3 CCDC6RET cells, Ba/F3 KIF5B-RET, Ba/F3 KIF5B -RET (V804M) and TT, it can be confirmed that the exemplary compound of the present invention excellently inhibits the proliferation of the Ba/F3 cell line and medullary thyroid cancer or lung cancer cell lines that express RET fusion genes.

Thus, as confirmed by experiments, the compound of the present invention can inhibit the proliferation of cancer cells and thus can be successfully used as a pharmaceutical composition for the prevention and treatment of cancer, such as medullary thyroid cancer or lung cancer.

Experimental Example 3: Evaluation of the Inhibitory Activity of the Compound of the Present Invention on Various Kinases

The following experiment was carried out to evaluate the inhibitory activity of the compound of the present invention against a larger number of enzymes. Specifically, for Examples 1 and 3, selected from the exemplary compounds of the present invention, enzyme (kinase) selectivity was measured using DiscoverX and the experiment was performed using the ScanMAX™ Kinase Assay Panel. In this case, the concentration of the drug treated with the enzyme was taken as 1 μM in DMSO, the adjusted percentage (% control) was determined in the same way as in the following equation 1, and the results are shown in the following table. 3.

Equation 1.

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

Here, the positive control refers to the compound showing an adjusted percentage of 0%, and the negative control shows an adjusted percentage of 100% with respect to DMSO. In addition, the selectivity of the enzyme of the present invention was determined to be active against the corresponding enzyme when the adjusted percentage was <35% (ie, less than 35%).

Table 3

Kinase Example P 1 Example r3 Kinase Example 1 Example 3 ABL1(H396P) unphosphorylated 10 2.5 RKGZ-autoinhibited 9.8 eleven ABY(H396P)phosphorylated 28 21 FRK 18 34 ABY(M351T)phosphorylated 16 15 GCN2 (kinase domain 2, S8O8G) 8 0.2 ABL1(Q252H)phosphorylated 15 17 ISK 4.1 3.2

-

Claims (11)

ABL1(T315I)- unphosphorylated 20 2.9 ICK 33 28 ABL1(T315I)- phosphorylated 19 3.2 ITK 2 1.6 ABL1(Y253F)phosphorylated 20 21 1AK1(domain JH1- catalytic) 15 9.7 ABC-phosphorylated thirty 15 1AK1(JH2-domain pseudokinase) 21 2.9 AMPK-alpha1 26 33 1AK2 (domain JH1- catalytic) 0.1 0 AURKA 4.1 2.2 1AKZ (domain JH1- catalytic) 0.55 1.9 AURKC 15 21 K1T(A829R) 2.8 eleven AXL 1.2 0 KIT(D816V) 32 6.5 BLK 1.4 0.05 KIT(V559D) 34 4.2 VTK 17 16 LCK 2.5 1.8 CSNK2A1 2.4 1.5 MARZK2 27 7.4 CSNK2A2 0 0.3 MEK2 24 17 DAPK3 19 34 MEKZ 27 4.9 DDR1 25 12 MEK5 9.9 2.2 DDR2 16 thirty MERTK 34 6.2 DLK 29 19 MST1 25 thirty EGFR(L747-E749del, A750Р) 16 17 PDGFRB 15 2.7 EGFR(L858R,T790M) 6.9 6.6 PLK4 1.3 1.2 EGFR(T790M) 8.1 16 RET 0 0 ERNV6 2.6 4.8 RET(M918T) 0.9 0.25 FGFR1 eleven 4.3 RET(V804L) 1.1 0.4 FGR 12 8.4 RET(V804M) 0 0 FLT3 1.2 0.55 RIOK3 13 thirty FLT3(D835H) 6.7 2.7 SNARK 22 17 FLT3(D835V) 1.3 0 SRC 0.7 0 FLT3(D835Y) 1.5 0.55 SYK 3.1 2.2 FLT3(ITD) 4.9 1.2 TRKA 0 0 FLT3(ITD,D835V) 0 0 TRKB 1.6 2.1 FLT3(ITD,F691L) 1.4 8.8 TRKC 0.45 1 FLT3(K663Q) 2.2 0.1 TUK2(domain JH1- catalytic) 0.2 5.3 FLT3(N841I) 0 0 YES eleven 3.8 FLT3(R834Q) 23 9.1 YSK4 6.2 5 As can be confirmed in Table. 3, it can be noted that the compound of the present invention has a value that is less than the adjusted percentage of 35% compared to ABL1(H396P)-unphosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(Q252H)- phosphorylated, ABL1(T315I)-unphosphorylated, ABL1(T315I)phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-phosphorylated, AMPK-alpha 1, AURKA, AURKC, AXL, BLK, BTK, CSNK2A1, CSNK2A2, DAPK3, DDR1, DDR2 , DLK, EGFR(L747E749del, A750P), EGFR(L858R,T790M), EGFR(T790M), EPHB6, FGFR1, FGR, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, FRK, GCN2(kinase domain 2, S808G), HCK, ICK, ITK, JAK1(JH1-catalytic domain), JAK1(JH2-pseudokinase domain), JAK2(JH1catalytic domain), JAK3(JH1-catalytic domain), KIT(A829P), KIT(D816V), KIT(V559D), LCK, MAP3K2, MEK2 , MEK3, MEK5, MERTK, MST1, PDGFRB, PLK4, RET, RET(M918T), RET(V804L), RET(V804M), RIOK3, SNARK, SRC, SYK, TRKA, TRKB, TRKC, TYK2(JH1-catalytic domain ), YES or YSK4 kinase. This suggests that the compound of the present invention exhibits suppressor activity against the above enzymes and is beneficial when used in diseases associated with the above enzymes. Therefore, the derivative compound of the present invention can be successfully used as a composition for treating or preventing a disease associated with the above enzymes. CLAIM 1. A compound of the following chemical formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof - 26 044405 [Chemical formula 1] where Θ' represents furan, thiophene, benzene or cyclopentene, R ¹ is straight or branched C ₁ -C ₃ -alkyl, where R ¹ is unsubstituted or substituted by at least one halogen, ring B is diazabicycloheptane, piperazine, diazepane or diazaspirooctane, where ring B is unsubstituted or substituted by at least one linear or branched C1-C6 alkyl, R ² is pyridinyl, thiazolyl, phenyl, imidazolyl, pyrazinyl, quinolinyl, pyrimidinyl or pyridonyl, wherein R ² is unsubstituted or substituted with at least one R ³ , and R ³ represents at least one substituent selected from the group consisting of linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ haloalkyl, linear or branched C ₁ -C ₆ alkoxy, halogen , C ₁ -C ₃ -alkanesulfonamido, amino, substituted with at least one linear or branched C ₁ -C ₃ -alkyl, and nitrile. 2. A compound, its isomer, its solvate, its hydrate or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane , piperazine, diazepane or 4,7-diazaspiro[2,5]octane. 3. A compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof according to claim 2, wherein ring B is linked to another adjacent group by two nitrogen atoms. 4. The compound, its isomer, its solvate, its hydrate or a pharmaceutically acceptable salt thereof according to claim 1, wherein in the case where R ² represents pyridinyl, thiazolyl, phenyl, pyrazinyl, pyrimidinyl or pyridonyl, R ² is substituted with at least one R ³ or when R ² is imidazolyl or quinoline, R ² is unsubstituted and R ³ represents at least one substituent selected from the group consisting of linear or branched C ₁ -C ₃ -alkyl, linear or branched C ₁ -C ₃ -haloalkyl, linear or branched C ₁ -C ₃ -alkoxy, halogen , C ₁ -C ₃ -alkanesulfonamido, amino, substituted with at least one linear or branched C ₁ -C ₃ -alkyl, and nitrile. 5. A compound, an isomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of chemical formula 1 is any compound selected from the following compounds: < 1 > 2-(6-(6-((6-methoxypyridin-3 -yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3 -yl)pyridin-3 -yl)-N (5 -methyl-1H-pyrazol-3-yl)furo[3,2-d]pyrimidin-4-amine; <2> 2-(6-(6-((6-methoxypyridin-3-yl)methyl)3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5 -methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin4-amine; <3> 2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)N-(5 -methyl-1H-pyrazol-3-yl)quinazolin-4-amine; <4> 2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5- (trifluoromethyl)-1H-pyrazol-3-yl)furo[3,2-d]pyrimidin-4-amine; <5> N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((5-methylthiazol-2-yl)methyl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <6> 2-(6-(3-((6-methoxypyridin-3yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyridin-3-yl)-N-(5- methyl-1H-pyrazol-3-yl)quinazolin-4amine; <7> 2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N (5 -methyl-1H-pyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine; <8> N-(5-methyl-1Hpyrazol-3-yl)-2-(6-(6-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,6-diazabicyclo [3.1.1 ]heptan-3 -yl)pyridin-3 -yl)quinazolin-4-amine; <9> 5-((3 -(5-(4-((5-methyl-1 H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin2-yl)-3,6-diazabicyclo[3.1 .1]heptan-6-yl)methyl)picolinonitrile; <10> N-(5-methyl-1H-pyrazol-3-yl)-2(6-(6-((6-methylpyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane -3-yl)pyridin-3-yl)quinazolin-4amine; <11> 2-(6-(6-(3,5-difluoro-4-isopropoxybenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3 yl)-N-(5- methyl-1H-pyrazol-3-yl)quinazolin-4-amine; < 12> 2-methoxy-5-((3-(5-(4-((5-methyl-1H-pyrazol-3yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl)methyl)benzonitrile; <13> 2-(6-(6-(( 1 H-imidazol-5 -yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3 -yl)pyridin-3 -yl)-N- (5-methyl-1Hpyrazol-3-yl)quinazolin-4-amine; < 14> 2-(6-(6-(4-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptan-3yl)pyridin-3-yl)-N-(5-methyl-1H-pyrazole-3 -yl) quinazolin-4-amine; <15> 2-(6-(6-((6-isopropoxypyridin-3 -yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3 -yl)pyridin-3 -yl)-N-( 5-methyl-1H-pyrazol-3 yl)quinazolin-4-amine; <16> 2-(6-(6-((5-chloro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl) -N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine; <17> 2-(6-(6-((5methoxypyrazin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5- methyl-1H-pyrazol3-yl)quinazolin-4-amine; <18> N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-(quinolin-6-ylmethyl)-3,6-diaza- 27 044405 bicyclo[3.1.1]heptane -3-yl)pyridin-3-yl)quinazolin-4-amine; <19> N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6((4-methylthiazol-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane -3-yl)pyridin-3-yl)quinazolin-4-amine; <20> 2-(6-(6-((6-(dimethylamino)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-( 5methyl-1H-pyrazol-3-yl)quinazolin-4-amine; <21> N-(4-((3 -(5 -(4-((5 -methyl-1 H-pyrazol-3 -yl)amino)quinazolin-2-yl)pyridin-2-yl)-3, 6-diazabicyclo[3.1.1]heptan-6-yl)methyl)phenyl)methanesulfonamide; <22> 2-(6-(6-(4-fluorobenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5-methyl-1H-pyrazole -3yl)quinazolin-4-amine; <23> 2-(6-(6-((6-fluoropyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3yl)pyridin-3-yl)-N-(5- methyl-1H-pyrazol-3-yl)quinazolin-4-amine; <24> 2-(6-(6-((6-ethoxypyridin-3yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5- methyl-1H-pyrazol-3-yl)quinazolin-4amine; <25> N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((2-methylpyrimidin-5-yl)methyl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <26> N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((5methylpyrazin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan- 3-yl)pyridin-3-yl)quinazolin-4-amine; <27> 1 methyl-4-((3-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3.6 -diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2(1H)-one; <28> 2-(6-((2S,5R)-4-((6-methoxypyridin-3-yl)methyl)-2,5-dimethylpiperazin-1-yl)pyridin-3-yl)-N-( 5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine; <29> 2-(6-(4((6-methoxypyridin-3 -yl)methyl)-3,3-dimethylpiperazin-1 -yl)pyridin-3 -ul)-N-(5 -methyl-1 H- pyrazol-3 yl)quinazolin-4-amine; <30> 2-(6-(4-((6-methoxypyridin-3-yl)methyl)-1,4-diazepan-1-yl)pyridin-3-yl)-N(5-methyl-1H-pyrazole -3-yl)quinazolin-4-amine; <31> 2-(6-((1S,4S)-5-((6-methoxypyridin-3-yl)methyl)-2,5diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl) -N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine; <32> 2(6-((2R,5S)-4-((6-methoxypyridin-3-yl)methyl)-2,5-dimethylpiperazin-1-yl)pyridin-3-yl)-N-(5 -methyl1H-pyrazol-3-yl)quinazolin-4-amine; <33> (S)-2-(6-(4-((6-methoxypyridin-3-yl)methyl)-3-methylpiperazin-1-yl)pyridin-3-yl)-N-(5-methyl- 1H-pyrazol-3-yl)quinazolin-4-amine; <34> 2-(6-((1R,4R)-5-((6methoxypyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl) -N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine; <35> 2-(6-((3R,5S)-4-((6-methoxypyridin-3-yl)methyl)-3,5-dimethylpiperazin-1-yl)pyridin-3-yl)-N-( 5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine; <36> (R)-2-(6-(4-((6methoxypyridin-3 -yl)methyl)-3 -methylpiperazin-1 -yl)pyridin-3 -yl)-N-(5-methyl-1 H -pyrazol-3-yl)quinazolin-4-amine and <37> 2-(6-(4-((6-methoxypyridin-3-yl)methyl)-4,7-diazaspiro[2,5]octane-7 -yl)pyridin-3yl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine. 6. A method for producing a compound of chemical formula 1, the method comprising obtaining a compound of chemical formula 3 from a compound of chemical formula 2; preparing a compound of chemical formula 4 from a compound of chemical formula 3; preparing a compound of chemical formula 5 from a compound of chemical formula 4; preparing a compound of chemical formula 6 from a compound of chemical formula 5; preparing a compound of chemical formula 7 from a compound of chemical formula 6 and preparing a compound of chemical formula 1 from a compound of chemical formula 7 [Chemical formula 2] G [Chemical formula 3] - 28 044405 where R ¹ , R ² O' and ring B are the same as defined in paragraph 1, G represents a leaving group, PG represents a protecting group and The B' ring has the same structure as the B ring, but is a form in which one nitrogen atom is protected by a protecting group. 7. A pharmaceutical composition containing a compound of chemical formula 1, an isomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient for the prevention or treatment of cancer. 8. The pharmaceutical composition according to claim 7, where the compound exhibits inhibitory activity against one or more protein kinases selected from the group consisting of ABL1(H396P)non-phosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(Q252H )-phosphorylated, ABL1 (T3151)-unphosphorylated, ABL1 (T3151)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-phosphorylated, AMPK-alpha 1, AURKA, AURKC, AXL, BLK, BTK, CSNK2A1, CSNK2A2, DAPK3, DDR1, DDR2, DLK, EGFR(L747-E749del, A750P), EGFR(L858R,T790M), EGFR(T790M), EPHB6, FGFR1, FGR, FLT3, FLT3(D835H), FLT3(D835V), - 29 044405 FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), PETZ-autoinhibited, FRK, CCNo(kinase domain 2,S808G), HCK, ICK, ITK, 1AK1(JH1-catalytic domain), 1AK1(Sh2-pseudokinase domain), 1AK2(JH1-catalytic domain), 1AKZ(JH1-catalytic domain), KIT(A829P), KIT( D816V), KIT(V559D), LCK, MARZK2, MEK2, MEKZ, MEK5, MERTK, MST1, PDGFRB, PLK4, RET, RET(M918T), RET(V804L), RET(V804M), RIOK3, SNARK, SRC, SYK , TRKA, TRKB, TRKC, ΤΥΚ2(λομβη JH1-catalytic), YES or YSK4. 9. Pharmaceutical composition according to π.7, where the compound exhibits RET enzyme inhibitory activity. 10. The pharmaceutical composition according to claim 7, wherein the cancer is one or more cancers selected from the group consisting of pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, medullary thyroid carcinoma, colon cancer, testicular cancer , myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myelogenous leukemia, acute lymphoblastic leukemia, basal cell carcinoma, epithelial ovarian cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, papilla cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, neuroglioma, renal pelvis 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, urothelial cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid tumors, gastrointestinal stromal cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumors colon, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell cancer, lung adenocarcinoma, lung cancer, squamous cell lung cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer and thymus cancer. 11. The pharmaceutical composition according to claim 7, wherein the cancer is a cancer that expresses a RET fusion gene. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2