KR20190114910A - Novel Sulfonamide Derivative as mutant Epidermal Growth Factor Receptor Inhibitor - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cancer having an EGFR mutation, comprising a compound represented by chemical formula I or the compound and a pharmaceutically acceptable carrier.

Description

Novel Sulfonamide Derivative as mutant Epidermal Growth Factor Receptor Inhibitor

The present invention relates to novel sulfonamide derivatives having an inhibitory effect on epidermal growth factor receptor mutations, and pharmaceutical compositions containing them as active ingredients.

Epidermal growth factor receptor (EGFR) is a protein consisting of a receptor moiety and tyrosine kinase moiety, and serves to transmit signals outside the cell into the cell through the cell membrane. EGFR plays an essential role in normal cellular regulation through intracellular signal transduction, but EGFR mutations that are characterized by overexpression of EGFR or ligand-independent tyrosine kinase activity also fail to modulate signaling by these receptors. It is known to induce cancer cell growth, differentiation, neovascularization, metastasis and expression of resistance by activating. In most solid cancer cells, abnormal overexpression of EGFR or frequent mutations have been reported, which is associated with poor prognosis. Among these, EGFR activating mutations such as L858R point mutation of exon 21 of the EGFR tyrosine kinase domain or in-frame deletion of exon 19 are known as important causes of non-small cell lung cancer. Therefore, studies are underway to develop anticancer agents targeting epithelial growth factor receptors in anticipation that blocking cancer cell signaling through the epidermal growth factor receptors will result in superior anticancer effects.

The first drug developed as an EGFR tyrosine kinase inhibitor in low molecular weight is gefitinib, a reversible inhibitor that selectively inhibits EGFR (Erb-B1) in the EGFR subtype. Another drug with this characteristic is Erlotinib, and this EGFR targeted therapy is mainly used in patients with EGFR activating mutations, mainly non-small cell lung cancer (NSCLC).

However, NSCLC patients with EGFR activating mutations administered gefitinib or erlotinib become resistant to drugs after about 8 to 16 months, of which about 60% are reported to be resistant to EGFR T790M mutations. (Helena A. Yu et al., Clin Cancer Res. 19 (8), 2240, 2013).

An irreversible inhibitor has been proposed to overcome resistance to existing EGFR inhibitors such as gefitinib or erlotinib. However, EGFR irreversible inhibitors also have high activity against EGFR WT (wild-type), which is also present in normal cells, causing serious side effects when doses to overcome resistance due to EGFR T790M mutations are administered. It shows the limitation of clinical application.

As an alternative, EGFR mutant selective inhibitors, osimertinib, olmutinib, naquotinib and Avitinib, and many other drugs are in development at the clinical stage. However, according to clinical results of Oshimtinib in patients with non-small cell lung cancer with EGFR resistance mutations, after about 10 months, the drug resistance is due to activation of other resistance mechanisms, of which a higher proportion of C797S mutations is more than 20%. It is known to appear. The C797S mutation is a point mutation in which cysteine 773 (Cys773), a covalent bond that forms irreversible inhibitors of EGFR, is converted to serine, resulting in a loss of reactivity to the drug as it fails to form a covalent bond with irreversible inhibitors to EGFR. .

As such, the development of EGFR-targeted therapeutics has shown a limitation in that it cannot maintain the drug for a certain period of time due to the expression of primary and secondary resistance. In particular, the study of EGFR C797S mutations, except for the reports of early preclinical studies, there is not even a substance under clinical research, and there is an urgent need for effective therapy.

Clin Cancer Res. 19 (8), 2240, 2013

One aspect of the invention is selective for cancer cell growth and resistance to drugs caused by mutation of the tyrosine kinase domain in epidermal growth factor receptor (EGFR) and for drugs having such resistance, and It is to provide a novel sulfonamide derivative that effectively inhibits and has fewer side effects.

Another aspect of the present invention to provide a pharmaceutical composition for inhibiting cancer cell growth comprising the novel sulfonamide derivative.

One aspect of the present invention provides a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the following formula (I).

[Formula I]

Another aspect of the present invention provides a method for treating cancer with an EGFR mutation comprising a sulfonamide derivative of Formula I, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Provided is a prophylactic or therapeutic pharmaceutical composition.

Compounds of the formula (I), solvates, stereoisomers or pharmaceutically acceptable salts thereof according to one aspect of the present invention are resistant to cancer and growth of cancer cells caused by mutation of tyrosine kinase domains in epithelial growth factor receptors. Or can effectively and effectively inhibit cancer with such resistance.

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

All technical terms used in the present invention, unless defined otherwise, are used in the meaning as commonly understood by those skilled in the art in the related field of the present invention. In addition, although a preferred method or sample is described herein, similar or equivalent things are included in the scope of the present invention. In addition, numerical values described in this specification are considered to include the meaning of "about", even if not specified. The contents of all publications that are incorporated herein by reference are incorporated by reference in their entirety.

One aspect provides the compounds, solvates, stereoisomers, or pharmaceutically acceptable salts thereof represented by Formula I:

[Formula I]

In Formula I,

Cy ₁ is C ₃ -C ₁₀ aryl or C ₃ -C ₁₀ heteroaryl, wherein the aryl or heteroaryl is halogen, hydroxy group, thiol group, cyano group, C ₁ -C ₆ alkyl group, and C ₁ -C ₆ alkoxy group May have one or more substituents selected from the group consisting of;

m is an integer from 0 to 5;

n is an integer from 1 to 4;

X is -NH- or -C-;

R ₁ and R ₂ are independently of each other a C ₁ -C ₆ alkyl group;

R ₃ is selected from hydrogen, halogen, hydroxy group, thiol group, cyano group, C ₁ -C ₆ haloalkyl group, and -C (O) OR ₆ , wherein R ₆ is C ₁ -C ₅ alkyl group;

R ₄ is selected from hydrogen, halogen, thiol group, cyano group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, and C ₁ -C ₆ haloalkyl group;

R ₅ is selected from hydrogen, halogen, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ hydroxyalkyl group;

Here, when R ₂ is X is -C-, X and R ₂ may be fused to form a 4- to 7-membered heteroaryl ring with the atoms to which they are bonded, or R ₂ is R ₁ or R ₅ Fused with to form a 5-7 membered heteroaryl or heterocycloalkyl ring with the atoms to which they are attached; And

Y is -Z- (CH ₂ ) _a -Q ₁ -Q ₂ ,

Wherein Z is absent or is selected from carbonyl (-CO-), amide (-CONH-), -S- and -O-,

A is an integer of 0 to 6,

Q ₁ is a C ₃ -C ₁₀ heterocycloalkyl group, or C ₆ -C ₁₀ heterobicycloalkyl, the heterocycloalkyl group or heterobicycloalkyl group is halogen, hydroxy group, thiol group, cyano group, C ₁ -C ₆ May have one or more substituents selected from the group consisting of alkyl groups,

Q ₂ is selected from hydrogen, a C ₁ -C ₆ alkyl group, and a C ₃ -C ₁₀ heterocycloalkyl group, wherein the heterocycloalkyl group consists of a halogen, a hydroxy group, a thiol group, a cyano group, and a C ₁ -C ₆ alkyl group It may have one or more substituents selected from the group.

The term "halogen" herein may be F, Cl, Br, or I.

As used herein, the term "alkyl" refers to a straight, or branched hydrocarbon moiety that may be substituted or unsubstituted unless otherwise noted. The alkyl group may include without limitation all possible isomers thereof, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, or isopropyl, isobutyl, and t-butyl.

As used herein, the term "alkoxy", unless stated otherwise, refers to a straight or branched hydrocarbon moiety that is substituted or unsubstituted, connected by oxygen. The alkoxy may include without limitation all possible isomers thereof, such as, for example, methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, and t-butoxy.

As used herein, the term “aryl” refers to an aromatic group which may be substituted or unsubstituted unless otherwise indicated, including, for example, C ₃ -C ₃₀ aryl, C ₃ -C ₂₀ aryl, or C ₃ -C ₁₀ aryl. And double bonds alternate (resonance) between adjacent carbon atoms or suitable heteroatoms. For example, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, or all possible isomers thereof may be included without limitation.

As used herein, the term “heteroaryl”, unless stated otherwise, refers to a monocyclic or bicyclic or more than one, including one or more heteroatoms selected from B, N, O, S, P (═O), Si, and P, or An aromatic group, which may be unsubstituted. Examples of monocyclic heteroaryls include pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxazozolyl, pyridine 1, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and similar groups, but is not limited to these. Examples of bicyclic heteroaryl include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, iso Quinolinyl, purinyl, puropyridinyl, oxochromen, dioxoisoindolin, pyrazolopyridinyl, pyrazolo [1,5-a] pyridinyl and the like, but are not limited to these.

The term "heterocycloalkyl" used herein is substituted or unsubstituted of a monocyclic including one or more heteroatoms selected from B, N, O, S, P (= 0), Si and P, unless stated otherwise. Cyclic alkyl, which may be used. Monoheterocycloalkyl can be C ₃ -C ₃₀ heterocycloalkyl, C ₃ -C ₂₀ heterocycloalkyl, or C ₃ -C ₁₀ heterocycloalkyl, for example piperidinyl, piperazinyl, Morpholinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl, tetrahydrofuryl, and the like, but are not limited to these.

As used herein, the term “heterobicycloalkyl”, unless otherwise indicated, is a substitution or non-substitution of a bicyclic comprising one or more heteroatoms selected from B, N, O, S, P (═O), Si and P Cyclic alkyl, which may be cyclic. The heterobicycloalkyl may be bridged heterobicycloalkyl or (Spiro) heterobicycloalkyl, for example C ₆ -C ₂₀ heterobicycloalkyl, or C ₆ -C ₁₀ heterobicyclo Alkyl, including 3,9-diazaspiro [5.5] undecanyl, 2,6-diazaspiro [3.3] heptanyl, 2,5-diazabicyclo [2.2.1 ] Heptanyl and similar groups include, but are not limited to these.

The numerical range indicated using the term “to” herein refers to a range including the numerical values described before and after the term “to” as the lower limit and the upper limit, respectively.

As used herein, the term “solvate” may refer to a compound of the present invention or a salt thereof that includes a stoichiometric or nonstoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents therein may be volatile, non-toxic, and / or solvents suitable for administration to humans.

As used herein, the term “stereoisomers” may refer to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula, but which is optically or sterically different, and specifically, diastereomers, enantiomers, geometric isomers, or shapes It may be an isomer.

As used herein, the term "derivative" refers to a compound obtained by substituting a part of the structure of the compound with another atom or group of atoms.

The compounds according to the invention can also be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, for example the salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, Pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, Salts derived from salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like.

Pharmaceutically acceptable salts of the compounds according to the invention are prepared by dissolving a compound of formula (I) in a water miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an aqueous acid solution of an inorganic acid. It can then be prepared by precipitation or crystallization. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.

In one embodiment, Cy ₁ in Formula I is C ₃ -C ₁₀ aryl or C ₃ -C ₁₀ heteroaryl; m is 0 or 1; n is an integer of 1 or 2; X is -NH- or -C-; R ₁ and R ₂ are independently of each other a C ₁ -C ₆ alkyl group; R ₃ is selected from hydrogen, halogen, cyano and a C ₁ -C ₆ haloalkyl group and —C (O) OR ₆ , wherein R ₆ is C ₁ -C ₃ alkyl group; R ₄ is selected from hydrogen, halogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, and a C ₁ -C ₆ haloalkyl group; R ₅ is selected from hydrogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ hydroxyalkyl group; Here, with the R ₂ when X is -C-, X and R ₂ are, or may form a heteroaryl ring of 5 to 7 members together and fused to atom to which they are attached, wherein R ₂ is R ₁ or R ₅ May be fused together with the atoms to which they are attached to form a 5-7 membered heteroaryl or heterocycloalkyl ring; And Y is -Z- (CH ₂ ) _a -Q ₁ -Q ₂ , Wherein Z is absent or is selected from carbonyl (-CO-), amide (-CONH-), and -S-, a is an integer from 0 to 3, and Q ₁ is C ₃ -C ₁₀ heterocycloalkyl group, or C ₆ -C ₁₀ heterobicycloalkyl group, the heterocycloalkyl group or heterobicycloalkyl group may have one or more C ₁ -C ₆ alkyl group as a substituent, wherein Q ₂ is hydrogen, C _{It is selected from a 1} -C ₆ alkyl group, and a C ₃ -C ₁₀ heterocycloalkyl group, the heterocycloalkyl group may have one or more C ₁ -C ₆ alkyl group as a substituent.

In one embodiment, Cy ₁ in Formula I is phenyl or pyrazole; m is 0 or 1; n is an integer of 1 or 2; R ₁ and R ₂ are independently of each other a C ₁ -C ₆ alkyl group; R ₃ is selected from hydrogen, halogen, cyano and a C ₁ -C ₆ haloalkyl group and —C (O) OR ₆ , wherein R ₆ is C ₁ -C ₃ alkyl group; Here, the R ₂ and X are the days when -C-, X and R ₂ are fused to, or may form a heteroaryl ring of 5 together with the atom to which they are attached, wherein R ₂ is fused with R ₁ or R ₅ Together with the atoms to which they are attached may form a five-membered heteroaryl or heterocycloalkyl ring; And Y is -Z- (CH ₂ ) _a -Q ₁ -Q ₂ , Wherein Z is absent or is selected from carbonyl (-CO-), amide (-CONH-), and -S-, a is an integer from 0 to 3, and Q ₁ is piperidinyl, Piperazinyl, pyrrolidinyl, morpholinyl, 3,9-diazaspiro [5.5] undecanyl, 2,6-diazaspiro [3.3] heptanyl, and 2,5-diazabicyclo [ 2.2.1] heptanyl, wherein piperazinyl may have one or more C ₁ -C ₆ alkyl groups as substituents, and Q ₂ is selected from hydrogen, C ₁ -C ₆ alkyl groups, and piperazinyl The piperazinyl may have one or more C ₁ -C ₆ alkyl groups as substituents.

In one embodiment, R ₂ may be a C ₁ -C ₆ alkyl group, for example, may be a methyl group.

In one embodiment, the compound of formula I may be selected from the group consisting of:

N- (2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2- (5-chloro-2-((2-methoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenylamino) pyrimidine-4 -Yl) amino) phenyl) -N -methylmethanesulfonylamide;

Isopropyl 2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -4-((2- ( N -methyl Methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate;

N- (2-((5-chloro-2-((3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((2-((3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl ) Amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((2,3-difluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino ) Pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((2-((2,3-difluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine- 4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((3-fluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) pyri) Midin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((2-methoxy-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) pyri) Midin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((3-methyl-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) -3- (trifluoromethyl) phenyl ) Amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((3,5-difluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) Amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((5-fluoro-2-methoxy-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) Phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-cyano-2-((3-fluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) Pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((2-((3-fluoro-4- (9-methyl-3.9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) -5- (trifluoro Methyl) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-bromo-2-((3-fluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) Pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((3-fluoro-4- (6-methyl-2,6-diazaspiro [3.3] heptan-2-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((2-methoxy-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N -methyl Methanesulfonamide;

N- (2-((5-chloro-2-((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide ;

N- (2-((5-chloro-2-((3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N Methylmethanesulfonamide;

N- (2-((5-chloro-2-((2,3-difluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl ) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((3-fluoro-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino ) Phenyl) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((5-fluoro-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino ) Phenyl) -N -methylmethanesulfonamide;

N - (2 - ((5- chloro-2 - ((2-methoxy -4 - ((1 S, 4 S) -5- methyl-2,5-diazabicyclo [2.2.1] heptane -2 -Yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N - (2 - ((5- chloro-2 - ((2-methoxy -4 - ((3 S, 5 R) -3,4,5- trimethyl-l-yl) phenyl) amino) Pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((4- (4-ethylpiperidin-1-carbonyl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl)- N -methylmethanesulfonamide;

4-((5-chloro-4-((2- ( N -methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxy- N- (1-methylpiperi Din-4-yl) benzamide;

4-((5-chloro-4-((2- ( N -methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxy- N- (2- (pyrroli Din-1-yl) ethyl) benzamide;

N- (2-((5-chloro-2-((2-methoxy-4- (morpholinomethyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide ;

N- (2-((5-chloro-2-((2-methoxy-4-((3-morpholinopropyl) thio) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4-yl) amino) -5- (hydroxymethyl) phenyl) -N -methylmethanesulfonamide;

N- (2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4-yl) amino) benzyl) -N -methylmethanesulfonamide;

N- (4-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4-yl) amino) -1-methyl-1 H -pyrazol-3-yl) -N -methylmethanesulfonamide;

2- (2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl) isothiazolidine-1,1-dioxide;

5-Chloro- N- (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -4- (1- (methylsulfonyl)- 1 H -indol-3-yl) pyrimidin-2-amine;

5-Chloro - N ² - (2- methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) - N ⁴ - (1- (methylsulfonyl ) -1 H -indol-7-yl) pyrimidine-2,4-diamine.

Another aspect provides a pharmaceutical composition for preventing or treating cancer with an EGFR mutation, comprising a compound, solvate, stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, according to one embodiment. to provide.

In one embodiment, the EGFR mutation provides a pharmaceutical composition, which is an activating EGFR mutation, a mutation that causes resistance to an EGFR inhibitor, or a combination thereof.

In one embodiment, the activating EGFR mutation may be del19, L858R, or a combination thereof.

In one embodiment, the mutation that causes resistance to the EGFR inhibitor may be T790M, C797S, or a combination thereof.

In one embodiment, the cancer having an EGFR mutation may be a cancer having a C797S mutation.

In one embodiment, the cancer is lung cancer, liver cancer, esophageal cancer, gastric cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethra It may be selected from the group consisting of cancer, bladder cancer, testicular cancer, hematologic cancer, lymphoma, skin cancer, psoriasis and fibroadenoma.

In one embodiment, the cancer may be non-small cell lung cancer.

In one embodiment, the pharmaceutical composition may comprise conventional pharmaceutically acceptable carriers, excipients or additives. The pharmaceutical compositions of the present invention may be formulated according to conventional methods and may be formulated in various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions or parenteral such as intramuscular, intravenous or subcutaneous administration. It may be prepared in a dosage form.

When the pharmaceutical composition according to one embodiment is prepared in the form of an oral dosage form, examples of the additive or carrier to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid and stearic acid. Magnesium, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents and the like. When the pharmaceutical composition of the present invention is prepared in the form of injectables, the additive or carrier may include water, saline, aqueous glucose solution, pseudoglucose solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid, fatty acid ester , Glycerides, surfactants, suspending agents, emulsifiers and the like.

According to one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used to inhibit cancer cell growth and drug resistance caused by mutation of tyrosine kinase domain in epithelial growth factor receptor (EGFR), or such resistance. Selectively and effectively inhibit having cancer. Thus, one aspect is directed to an individual in need of treatment of a cancer caused by an EGFR mutation, including administering to a subject a compound of the invention or a pharmaceutical composition comprising the same in a therapeutically effective amount or such a dose (e.g., , Patient).

The dosage of the pharmaceutical composition is an amount effective for treating or preventing an individual or a patient, and may be orally or parenterally administered as desired. Upon oral administration, 0.01 to 1000 per kg of body weight per day based on the active ingredient mg, more specifically 0.1 to 300 mg, to be administered in an amount of 0.01 to 100 mg per kg body weight per day, more specifically 0.1 to 50 mg based on the active ingredient during parenteral administration It may be administered in divided doses of 1 to several times. Dosages for a particular individual or patient should be determined in light of several relevant factors such as the patient's weight, age, sex, health condition, diet, time of administration, mode of administration, severity of the disease and can be appropriately added or subtracted by a specialist. It is to be understood that such doses are not intended to limit the scope of the invention in any aspect. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian may use a dose of a compound of the invention for use in a pharmaceutical composition, starting at a lower level than required to achieve the desired therapeutic effect, and gradually increasing the dosage until the desired effect is achieved. Can be increased.

As used herein, the term “treating” or “treatment” refers to inhibiting a disease, eg, inhibiting a disease, condition or disorder in an individual experiencing or exhibiting the pathology or indication of the disease, condition or disorder, ie Preventing further development of the pathology and / or signs, or ameliorating the disease, eg, improving a disease, condition or disorder in an individual experiencing or exhibiting the pathology or sign of the disease, condition or disorder, ie Reversing pathology and / or signs, such as reducing disease severity.

As used herein, the term "preventing" or "prevention" refers to preventing a disease, eg, a disease in an individual who may be inclined to a disease, condition or disorder but has not yet experienced or exhibits the pathology or signs of the disease, To prevent a condition or disorder.

As used herein, the term “individual” or “patient” refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, and humans. .

Pharmaceutical compositions according to one embodiment include within their scope pharmaceutical compositions comprising, as active ingredient, a therapeutically effective amount of at least one of the compounds according to one embodiment, alone or in combination with a pharmaceutical carrier. Optionally, the compound according to one embodiment may be used alone, in combination with a compound according to another embodiment, or in combination with one or more other therapeutic agents, for example anticancer agents or other pharmaceutically active substances.

The compound of formula (I) or a pharmaceutically acceptable salt thereof according to one embodiment may enhance the therapeutic effect of the anticancer agent by co-administration with other anticancer agents.

Another aspect provides a compound library comprising at least one of the compounds according to the invention, salts, isomers, hydrates and solvates thereof.

Another aspect includes a method of preventing or treating cancer comprising administering to a subject a pharmaceutical composition comprising a compound, solvate, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof; And the pharmaceutical use of a compound, solvate, stereoisomer or pharmaceutically acceptable salt thereof according to one embodiment for the prevention or treatment of cancer; There is provided a medicinal use of a compound, solvate, stereoisomer or pharmaceutically acceptable salt thereof according to one embodiment for the preparation of a cancer treatment.

Hereinafter, the manufacturing method of the compound which concerns on this invention is demonstrated in detail.

The compounds of formula (I) according to the present invention may be prepared using chemical transformations well known to those skilled in the organic / medical chemistry art according to the methods representatively shown in Scheme 1 below.

Scheme 1

In Scheme 1,

Cy ₁ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , m, n, X and Y are as defined in formula (I) above.

In more detail with reference to Scheme 1, it is possible to obtain compound (iii) substituted with chloride at position 4 of pyrimidine using compound (ii) from commercially available pyrimidine compound (i). This entails stirring at a temperature ranging from room temperature to 100 ° C. in a solvent such as butanol or N, N-dimethylformamide using a base of suitable strength such as N , N -diisopropylethylamine or potassium carbonate. do. In this case, the compound (ii) used in the reaction can be obtained by the same method as in Scheme 2 below.

Or as a synthesis of another route for synthesizing compound (iii), a compound (ii ') commercially available from commercially available pyrimidine compound (i) is prepared by using a Lewis acid such as AlCl ₃ with 1,2-di The compound (iii ') in which the chloride at position 4 of the pyrimidine is substituted may be obtained by reacting in a solvent such as methoxyethane at a temperature ranging from room temperature to 100 ° C. Compound (iii ') prepared is then used in a solvent such as N, N -dimethylformamide under basic conditions such as sodium hydride using a commercially available sulfonyl chloride R ₂ S (O) ₂ Cl By reacting at a temperature in the range, the compound (iii) in which the sulfone group is substituted can be obtained.

The prepared compound (iii) and amine compound (iv) are reacted in an alcohol solvent such as 2-butanol in the presence of an inorganic acid such as hydrochloric acid or an organic acid such as p -toluenesulfonic acid or trifluoroacetic acid at a temperature ranging from 70 ° C. to reflux. Or 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl biphenyl (Xphos) in the presence of a palladium catalyst such as tris (dibenzylideneacetone) dipalladium (0) In the presence of the same ligand and an inorganic base such as cesium carbonate or potassium carbonate, the halogen at the pyrimidine 2-position is replaced with an amine in a temperature range of about 100 ° C. in an organic solvent such as 2-butanol or 1,4-dioxane. The compounds of formula I of the present invention can be obtained. At this time, the amine compound (iv) used for the reaction can be obtained by the same method as in Scheme 3 below.

Intermediates used in the above schemes may require additional reaction steps to convert to the compounds of the present invention. Examples thereof are provided in the following schemes.

Scheme 2

Scheme 2 is a scheme for preparing compound (ii) intermediate,

In Scheme 2,

Cy ₁ , R ₁ , R ₂ , R _5, m and X are as defined in Formula I above, X 'is trityl, tert-butyldimethylsilane, tert-butyldiphenylsilane or tert-butylcarbamate X or NO ₂ substituted with the same protecting group and X 'is halogen.

In more detail with reference to Scheme 2, a sulfonyl chloride R ₂ S (O) ₂ Cl commercially available from a commercially available amine compound (v) can be used in a range of room temperature to 100 ° C. under a solvent such as pyridine. It is reacted at temperature, and the compound (vi) which the sulfone group is substituted by amine can be obtained.

Compound (vi) prepared was prepared at a temperature ranging from room temperature to 100 ° C. in a solvent such as N, N -dimethylformamide under basic conditions such as commercially available R ₁ substituted iodide R ₁ I and sodium hydride. The reaction can yield compound (vii) in which R ₁ is substituted for amine.

Or as a synthesis of another route for synthesizing compound (vii), the sulfonamide compound (viii) in which R ₁ and R ₂ are substituted from commercially available compound (v ') under basic conditions such as cesium carbonate or sodium hydride React with a commercially available compound (v '') or sulfonyl chloride R ₂ S (O) _{2 in a} solvent such as acetonitrile or N, N -dimethylformamide at temperatures ranging from room temperature to 100 ° C. Cl may be reacted at a temperature ranging from room temperature to 100 ° C. in a solvent such as N, N-dimethylformamide under basic conditions such as sodium hydride to obtain compound (vii) in which sulfonamide is substituted. The sulfonamide compound (viii) used in the reaction may be a commercially available or commercially available amine compound substituted with R ₁ and a sulfonyl chloride compound substituted with R ₂ in 1,8-diazabicyclo [5.4. .0] at room temperature in a solvent such as pyridine or dichloromethane at base conditions of suitable strength such as undec-7-ene and 4-dimethylaminopyridine, potassium carbonate, triethylamine or N , N -diisopropylethylamine Compound (viii) can be prepared and used by reacting at a temperature in the range of from 50 ° C.

In the prepared compound (vii), when X 'is a nitro group, hydrogenation reaction using palladium / carbon as a catalyst or reduction reaction via iron is converted to amine, or tetrahydrofuran when X' is X having a protecting group or Compound (ii) can be obtained by reacting in an organic solvent such as methylene chloride under acidic conditions such as tetrabutylammonium fluoride or trifluoroacetic acid or hydrochloric acid to obtain a deprotection reaction.

Scheme 3

Scheme 3 is a scheme for preparing compound (iv) intermediate,

In Scheme 3,

R ₄ , n, and Y are as defined in Formula I above, X '' is halogen, R is H or substituted or unsubstituted alkyl, and when R is alkyl, two R can form a fused ring have.

In more detail with reference to Scheme 3, YH commercially available from commercially available halogen-substituted nitro compound (ix) is subjected to normal temperature to 100 ° C. in a solvent such as acetonitrile under basic conditions such as potassium carbonate. Substitution reaction is carried out at a temperature in the range of to obtain compound (x) in which the halogen of compound (ix) is substituted with Y. Alternatively, compound (x) can be obtained by coupling compound (ix) with boronic acid or boronate ester YB (OR) ₂ under Suzuki conditions by a synthesis method under other conditions. Typically this reaction involves the reaction of a halogen compound with boronic acid or ester with a base such as potassium carbonate and a catalyst, such as 1,1 ′ ′-bis (diphenylphosphino) ferrocene, in a solvent such as dioxane or N, N -dimethylformamide. ] Dichloropalladium (II), dichloromethane complex or tetrakis (triphenylphosphine) palladium in the presence of heating at a temperature around 80 ℃ to 100 ℃. The boronic acid or boronate ester YB (OR) ₂ used at this time is commercially available or can be obtained by coupling a boronate ester dimer from a halogen compound substituted with Y.

Compound (iv) can be obtained by converting the nitro group of the prepared compound (x) into an amine through a hydrogenation reaction using palladium / carbon as a catalyst or a reduction reaction via iron.

A pharmaceutical composition comprising as an active ingredient a compound of formula (I), a solvate, a stereoisomer and a pharmaceutically acceptable salt thereof synthesized by this preparation method is caused by a mutation of the tyrosine kinase domain in the epidermal growth factor receptor Growth of cancer cells and resistance to drugs, or to treat cancer with such resistance.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited by the following examples.

Example 1: N -(2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine- 4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Step 1) N Preparation of-(2-nitrophenyl) methanesulfonamide

4 g (29.0 mmol) of 2-nitroaniline was diluted with 10 mL of pyridine, and 3.71 mL (47.9 mmol) of methanesulfonyl chloride were slowly added at 0 ° C, and stirred at room temperature for 17 hours. When the reaction was completed, the resultant reaction mixture was slowly added dropwise to ice water, followed by stirring. The resulting mixture was filtered under reduced pressure, and the solid obtained was diluted with 100 ml of a tetrahydrofuran: 1N sodium hydroxide aqueous solution (2: 3 (volume ratio)) mixed solvent and stirred at room temperature for 1 hour. The resulting mixture was neutralized with 2N aqueous hydrochloric acid solution and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to yield 5.15 g (yield: 82%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.77 (s, 1H), 8.29 (d, 1H), 7.90 (d, 1H), 7.69 (t, 1H), 7.25 (t, 1H), 3.16 (s, 3H).

Step 2) N -methyl- N Preparation of-(2-nitrophenyl) methanesulfonamide

3.32 g (15.3 mmol) of the compound prepared in step 1) was diluted with 50 ml of N and N -dimethylformamide, and 1.23 g (18.4 mmol) of 60% sodium hydride was slowly added at 0 ° C., followed by stirring at room temperature for 30 minutes. I was. 1.43 mL (23.0 mmol) of methyl iodide was slowly added thereto at 0 ° C., followed by stirring at room temperature for 2 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was added with 20 ml of a mixed solvent of dichloromethane and n-hexane (1: 5 (volume ratio)), stirred for 30 minutes, and the resulting solid was filtered under reduced pressure to yield 3.24 g of the title compound (yield: 91% )

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.93 (d, 1H), 7.67-7.52 (m, 3H), 3.35 (s, 3H), 3.01 (s, 3H).

Step 3) N -(2-aminophenyl)- N Preparation of Methylmethanesulfonamide

3.24 g (14.3 mmol) of the compound prepared in step 2) was diluted with 50 mL of ethyl acetate, 650 mg (10 wt%) of palladium / carbon was added thereto, and the mixture was stirred at room temperature under hydrogen gas for 16 hours. After the reaction was completed, the reaction mixture was washed with a celite-filled filter with ethyl acetate, filtered under reduced pressure, and the resulting filtrate was distilled under reduced pressure to obtain 2.77 g (yield: 98%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.18-7.13 (m, 2H), 6.83-6.74 (m, 2H), 4.23 (s, 2H), 3.24 (s, 3H), 2.97 (s, 3H).

Step 4) N -(2-((2,5-Dichloropyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

2.77 g (13.8 mmol) of the compound prepared in step 3) and 1.74 mL (15.2 mmol) of 2,4,5-trichloropyrimidine were diluted in 22 mL of n-butanol and 4.8 N , N -diisopropylethylamine ML (27.6 mmol) was added and the mixture was stirred at 110 ° C. for 5 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: ethyl acetate = 20: 1 (volume ratio)) to give 3.21 g (yield: 67%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.70 (s, 1H), 8.34 (d, 1H), 8.23 (s, 1H), 7.47 (t, 1H), 7.35 (d, 1H), 7.22 (t, 1H), 3.29 (s, 3H), 2.99 (s, 3H).

Step 5) Preparation of 1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazin

8.5 g (49.7 mmol) of 5-fluoro-2-nitroanisole and 10.9 g (49.7 mmol) of 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were diluted in 80 ml of acetonitrile. 21 g (149.0 mmol) of potassium carbonate was added, followed by stirring at 80 ° C. for 15 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and distilled under reduced pressure. The obtained residue was diluted with dichloromethane and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (dichloromethane: methanol = 5: 1 (volume ratio)) to give 11.4 g (yield: 69%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.99 (d, 1H), 6.41 (d, 1H), 6.30 (s, 1H), 3.94 (s, 3H), 3.92 (m, 2H), 2.96 (t, 2H), 2.62-2.45 (m, 9H), 2.29 (s, 3H), 1.96 (d, 2H), 1.59 (m, 2H).

Step 6) Preparation of 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline

11.4 g (34.1 mmol) of the compound prepared in step 5) was diluted with 120 mL of methanol, and then 1.2 g (10 wt%) of palladium / carbon was added thereto, followed by stirring at room temperature under hydrogen gas for 14 hours. After the reaction was completed, the reaction mixture was washed with a celite-filled filter with ethyl acetate, filtered under reduced pressure, and the resulting filtrate was distilled under reduced pressure to obtain 10 g (yield: 96%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.64 (d, 1H), 6.53 (s, 1H), 6.42 (d, 1H), 3.84 (s, 3H), 3.53 (d, 4H), 2.66-2.50 ( m, 11H), 2.31 (s, 3H), 1.95-1.70 (m, 4H).

Step 7) N -(2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine- 4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

2 g (5.76 mmol) of the compound prepared in Step 4) and 1.75 g (5.76 mmol) of the compound prepared in Step 6) were diluted with 20 mL of 2-butanol, and 1.31 g (6.91 mmol) of p-toluenesulfonic acid was added thereto. After addition, it sealed and stirred at 90 degreeC for 3 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (dichloromethane: 7N ammonia methanol solution = 100: 3 (volume ratio)) to obtain 1.10 g of the title compound (final). Step yield: 31%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.27 (m, 2H), 8.12-8.10 (m, 2H), 7.58 (d, 1H), 7.36 (d, 1H), 7.24 (t, 1H), 7.17 (m, 1H), 6.61 (s, 1H), 6.46 (d, 1H), 3.75 (s, 3H), 3.69 (m, 2H), 3.30 (m, 4H), 3.18 (s, 3H), 3.10 (s, 3H), 2.66 (m, 3H), 2.30 (m, 4H), 2.14 (s, 3H), 1.85 (m, 2H), 1.51 (m, 2H); MS (ESI < + >): m / z = 615.3 [M + H] ⁺ .

Example 2: N -(2- (5-chloro-2-((2-methoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenylamino) pyrimidine-4- 1) amino) phenyl)- N Preparation of Methylmethanesulfonylamide

Except for using 1-methyl-4-piperazin-4-yl-piperidine hydrochloride instead of 1-methyl-4-piperidin-4-yl-piperazine hydrochloride in step 5) of Example 1 above , 45 mg (final step yield: 42%) of the title compound were obtained in the same manner as the Example 1 above.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.25 (d, 1H), 8.06 (s, 2H), 7.55 (d, 1H), 7.34 (d, 2H), 7.25 (m, 1H), 7.15 ( m, 1H), 6.58 (d, 1H), 6.40 (d, 1H), 3.72 (s, 3H), 3.40 (m, 4H), 3.15 (s, 3H), 3.10 (m, 2H), 3.09 (s , 3H), 2.78 (m, 2H), 2.59 (m, 4H), 2.48 (m, 1H), 2.10 (s, 3H), 1.77 (m, 2H), 1.45 (m, 2H); MS (ESI < + >): m / z = 615.3 [M + H] ⁺ .

Example 3: isopropyl 2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -4-((2- ( N Preparation of -methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate

Step 1) Preparation of 2,4-Dichloropyrimidine-5-carbonylchloride

5.01 g (32.1 mmol) of 2,4-dihydroxypyrimidine-5-carboxylic acid and 2.34 g (112 mmol) of phosphorus pentachloride were diluted with 25 ml of phosphorus (V) oxychloride and stirred at 110 ° C. for 22 hours. . When the reaction was completed, the resultant reaction mixture was distilled under reduced pressure, and the residue obtained was diluted with 100 ml of ethyl acetate and stirred for 30 minutes. The obtained solid was washed with ethyl acetate and filtered under reduced pressure to obtain 9.75 g (yield: 100%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.24 (s, 1H).

Step 2) Preparation of Isopropyl 2,4-Dichloropyrimidine-5-carboxylate

9.75 g (46.1 mmol) of the compound prepared in step 1) was diluted with 100 mL of dichloromethane, 4.05 mL (43.0 mmol) of isopropyl alcohol and 9.64 mL (55.3 mmol) of N , N -diisopropylethylamine were added to- Slowly added at 78 ° C and stirred at room temperature for 3 hours. Upon completion of the reaction, the resulting mixture was diluted with dichloromethane and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was separated by column chromatography (n-hexane: ethyl acetate (5: 1 (volume ratio)) to give 1.75 g (yield: 16%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.98 (s, 1H), 5.29 (m, 1H), 1.40 (d, 9H).

Step 3) Isopropyl 2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -4-((2- ( N Preparation of -methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate

30 mg of the title compound was carried out in the same manner as in Example 1, except that the compound prepared in Step 2) was used instead of 2,4,5-trichloropyrimidine in Step 4 of Example 1 (Final step yield: 18%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 10.89 (br, 1H), 8,79 (s, 1H), 8.54 (m, 1H), 8.06 (m, 1H), 7.53 (s, 1H), 7.46 (d, 1H), 7.34 (t, 1H), 7.16 (m, 1H), 6.56 (d, 1H), 6.48 (m, 1H), 5.28 (m, 1H), 3.88 (s, 3H), 3.70 (m, 2H), 3.29 (s, 3H), 3.10 (s, 3H), 2.75 (m, 2H), 2.69 (m, 4H), 2.53 (m, 4H), 2.39 (m, 1H), 2.33 ( s, 3H), 1.98 (m, 2H), 1.75 (m, 2H), 1.38 (d, 6H); MS (ESI < + >): m / z = 667.3 [M + H] ⁺ .

Example 4: N -(2-((5-chloro-2-((3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine- 4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

The same process as in Example 1 was performed except that 3,4-difluoronitrobenzene was used instead of 5-fluoro-2-nitroanisole in step 5) of Example 1 52 mg (final step yield: 62%) were obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 8.39 (s, 1H), 8.29-8.21 (m, 2H), 7.66-7.55 (m, 2H), 7.42 (m, 1H ), 7.30-7.19 (m, 2H), 6.92 (m, 1H), 3.33 (m, 4H), 3.19 (s, 3H), 3.10 (s, 3H), 2.59 (m, 4H), 2.35 (m, 5H), 2.17 (s, 3H), 1.82 (m, 2H), 1.54 (m, 2H); MS (ESI < + >): m / z = 603.2 [M + H] ⁺ .

Example 5: N -(2-((2-((3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) Amino) phenyl)- N Preparation of Methylmethanesulfonamide

2,4-dichloropyrimidine is used instead of 2,4,5-trichloropyrimidine in step 4) of Example 1, and 5-fluoro-2-nitro in step 5) of Example 1 Except for using 3,4-trifluoronitrobenzene instead of anisole, the same process as in Example 1 was carried out to obtain 40 mg of the title compound (final step yield: 44%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 8.43 (s, 1H), 8.03-8.01 (m, 2H), 7.66 (d, 1H), 7.54 (d, 1H), 7.36 (m, 1H), 7.27-7.17 (m, 2H), 6.89 (m, 1H), 6.37 (d, 1H), 3.34 (m, 4H), 3.15 (s, 3H), 3.06 (s, 3H) , 2.58 (m, 4H), 2.38 (m, 5H), 2.19 (s, 3H), 1.82 (m, 2H), 1.54 (m, 2H); MS (ESI < + >): m / z = 569.3 [M + H] ⁺ .

Example 6: N -(2-((5-chloro-2-((2,3-difluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) Pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

The same process as in Example 1 was performed except that 2,3,4-trifluoronitrobenzene was used instead of 5-fluoro-2-nitroanisole in step 5) of Example 1. 31 mg (final step yield: 29%) of the title compound were obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.09 (s, 1H), 8.34 (m, 1H), 8.22 (m, 1H), 8.15 (s, 1H), 7.58 (m, 1H), 7.15 ( m, 3H), 6.81 (m, 1H), 3.22 (m, 4H), 3.18 (s, 3H), 3.09 (s, 3H), 2.68 (m, 4H), 2.37 (m, 4H), 2.28 (m , 1H), 2.17 (s, 3H), 1.85 (m, 2H), 1.56 (m, 2H); MS (ESI < + >): m / z = 621.2 [M + H] ⁺ .

Example 7: N -(2-((2-((2,3-difluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine-4 -Yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

2,4-dichloropyrimidine is used instead of 2,4,5-trichloropyrimidine in step 4) of Example 1, and 5-fluoro-2-nitro in step 5) of Example 1 Except for using 2,3,4-trifluoronitrobenzene instead of anisole, the same process as in Example 1 was carried out to obtain 31 mg (final step yield: 33%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.32 (s, 1H), 8.07 (d, 1H), 7.95 (d, 1H), 7.49 (d, 1H), 7.20 ( m, 2H), 7.20 (m, 1H), 6.77 (t, 1H), 6.38 (d, 1H), 3.34 (m, 4H), 3.13 (s, 3H), 3.04 (s, 3H), 2.68 (m , 4H), 2.30 (m, 1H), 2.23 (s, 3H), 1.98 (m, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.17 (m, 2H); MS (ESI < + >): m / z = 587.3 [M + H] ⁺ .

Example 8: N -(2-((5-chloro-2-((3-fluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Step 1) Preparation of tert-butyl 9-methyl-3,9-diazaspiro [5.5] undecane-3-carboxylate

2 g (6.88 mmol) of tert-butyl 3,9-diazaspiro [5.5] undecane-3-carboxylate were diluted in 20 ml of methanol, and 2 ml of formaldehyde was added thereto, followed by stirring at room temperature for 1 hour. After cooling the reaction mixture to 0 ° C., 390 mg (10.32 mmol) of sodium borohydride was added in small portions and stirred at room temperature for 1 hour. Upon completion of the reaction, the resulting reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain 1.45 g (yield: 78%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 3.37 (m, 4H), 2.38 (m, 4H), 2.29 (s, 3H), 1.55 (m, 4H), 1.46 (s, 9H), 1.43 (m, 4H).

Step 2) Preparation of 3-methyl-3,9-diazaspiro [5.5] Undecane.

1.45 g (5.40 mmol) of the compound prepared in step 1) was diluted with 10 mL of dichloromethane, 5 mL of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, the resulting reaction mixture was distilled under reduced pressure, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain 1.05 g (yield: 100%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 2.89 (m, 4H), 2.41 (m, 4H), 2.29 (s, 3H), 1.58-1.50 (m, 8H).

Step 3) N -(2-((5-chloro-2-((3-fluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Example 5 in step 5) instead of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride and 3,4-difluoronitrobenzene Except for using the compound prepared in Step 2), the same process as in Example 1 was carried out to obtain 6 mg (final step yield: 7%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.37 (s, 1H), 8.27 (m, 1H), 8.20 (s, 1H), 7.63 (m, 1H), 7.54 ( d, 1H), 7.40 (t, 1H), 7.29-7.22 (m, 2H), 6.92 (t, 1H), 3.18 (s, 3H), 3.08 (s, 3H), 2.87 (m, 4H), 2.26 (m, 4H), 2.14 (s, 3H), 1.53 (m, 4H), 1.46 (m, 4H); MS (ESI < + >): m / z = 588.2 [M + H] ⁺ .

Example 9: N -(2-((5-chloro-2-((2-methoxy-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Except for using the compound prepared in step 2) of Example 8 instead of 1-methyl-4-piperidin-4-yl-piperazine hydrochloride in step 5) of Example 1, The same procedure as in 1 was carried out to obtain 5 mg of the title compound (final step yield: 49%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.44 (d, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 8.04 (d, 1H), 7.41 (t, 1H), 7.36 (d, 1H), 7.22 (m, 1H), 7.17 (t, 1H), 6.57 (m, 1H), 6.48 (m, 1H), 3.87 (s, 3H), 3.30 (s, 3H), 3.12 (m, 4H ), 3.01 (s, 3H), 2.41 (m, 4H), 2.31 (s, 3H), 1.67 (m, 4H), 1.62 (m, 4H); MS (ESI < + >): m / z = 600.2 [M + H] ⁺ .

Example 10: N -(2-((5-chloro-2-((3-methyl-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) pyrimidine- 4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

2-fluoro-5-nitrotoluene instead of 3,4-difluoronitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride in step 5) of Example 1 Except for using the compound prepared in Example 2 step 2), to obtain the title compound 7 mg (final step yield: 15%) in the same manner as in Example 1.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.45 (d, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7.39-7.25 (m, 4H), 7.17 (t, 1H), 6.99 ( d, 1H), 6.81 (s, 1H), 3.30 (s, 3H), 3.01 (s, 3H), 2.82 (m, 4H), 2.44 (m, 4H), 2.33 (s, 3H), 2.28 (s , 3H), 1.66-1.62 (m, 8H); MS (ESI < + >): m / z = 584.2 [M + H] ⁺ .

Example 11: N -(2-((5-chloro-2-((4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) -3- (trifluoromethyl) phenyl) Amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

2-fluoro-5-nitrobenzotrile instead of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride in step 5) of Example 1 Except for using fluoride and the compound prepared in step 2) of Example 8, the same process as in Example 1 was carried out to obtain 24 mg of the title compound (final step yield: 48%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 8.41 (s, 1H), 8.27 (d, 2H), 8.24 (s, 1H), 7.87 (d, 1H), 7.84 ( d, 1H), 7.48 (d, 1H), 7.38 (t, 1H), 7.25 (t, 1H), 3.15 (s, 3H), 3.09 (s, 3H), 2.75 (m, 4H), 2.30 (m , 4H), 2.26 (s, 3H), 1.52 (m, 8H); MS (ESI < + >): m / z = 638.2 [M + H] ⁺ .

Example 12: N -(2-((5-chloro-2-((3,5-difluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino ) Pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

1,2,3-trifluoro-5 instead of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride in step 5) of Example 1 Except for using nitrobenzene and the compound prepared in step 2) of Example 8, the same procedure as in Example 1 was carried out to obtain 10 mg (final step yield: 11%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.66 (s, 1H), 9.25 (s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 8.18 (d, 1H), 7.65 ( d, 1H), 7.47 (m, 1H), 7.33 (m, 2H), 3.34 (m, 4H), 3.19 (s, 3H), 3.09 (s, 3H), 2.99 (m, 4H), 2.74 (s , 3H), 1.65 (m, 4H), 1.56 (m, 4H); MS (ESI < + >): m / z = 606.2 [M + H] ⁺ .

Example 13: N -(2-((5-chloro-2-((5-fluoro-2-methoxy-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl ) Amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Step 1) Preparation of 1,2-difluoro-4-methoxy-5-nitrobenzene

1 g (5.71 mmol) of 4,5-difluoro-2-nitrophenol and 531 μl (8.57 mmol) of methyl iodide were diluted in 10 mL of N , N -dimethylformamide and 1.18 g of potassium carbonate (8.57) mmol) was added and stirred at room temperature for 15 hours. When the reaction was completed, the resultant reaction mixture was slowly added dropwise to ice water, followed by stirring. The resulting solid was washed with distilled water, filtered under reduced pressure, and dried under reduced pressure to obtain 900 mg (yield: 83%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.85 (q, 1H), 6.93 (q, 1H), 3.95 (s, 3H).

Step 2) N -(2-((5-chloro-2-((5-fluoro-2-methoxy-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl ) Amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Example 5 and the compound prepared in step 1) instead of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride in step 5) of Example 1 Except for using the compound prepared in Step 2) of Example 8, the same process as in Example 1 was carried out to obtain 60 mg of the title compound (final step yield: 34%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.38 (s, 1H), 8.23 (m, 1H), 8.19 (d, 1H), 8.05 (d, 1H), 7.62 (m, 2H), 7.31 ( t, 1H), 7.27 (t, 1H), 6.72 (d, 1H), 3.81 (s, 3H), 3.19 (s, 3H), 3.10 (s, 3H), 2.97 (m, 4H), 2.28 (m , 4H), 2.17 (s, 3H), 1.57 (m, 4H), 1.50 (m, 4H); MS (ESI < + >): m / z = 618.2 [M + H] ⁺ .

Example 14: N -(2-((5-cyano-2-((3-fluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) pyri) Midin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

2,4-dichloro-5-cyanopyrimidine in place of 2,4,5-trichloropyrimidine in step 4) of Example 1, and 5-fluoro-2-nitro in step 5) Except for using 3,4-difluoronitrobenzene and the compound prepared in step 2) of Example 8 above in place of anisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride The same process as in Example 1 was carried out to obtain 3 mg (7% of final step yield) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.34 (d, 2H), 8.21 (d, 1H), 7.52 (d, 1H), 7.44 (m, 2H), 7.24 (m, 1H), 6.95 (m, 1H), 6.89 (m, 1H), 3.28 (s, 3H), 3.03 (s, 3H), 2.99 (m, 4H), 2.55 (m, 4H), 2.40 (s, 3H), 1.70 (m, 4H ), 1.68 (m, 4 H); MS (ESI < + >): m / z = 579.3 [M + H] ⁺ .

Example 15: N -(2-((2-((3-fluoro-4- (9-methyl-3.9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) -5- (trifluoromethyl ) Pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

2,4-dichloro-5- (trifluoromethyl) pyrimidine in place of 2,4,5-trichloropyrimidine in step 4) of Example 1, and 5-fluoro- in step 5) Instead of 2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride, 3,4-difluoronitrobenzene and the compound prepared in step 2) of Example 8 were used. Except for, the same process as in Example 1 was carried out to give 5 mg (final step yield: 3%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.33 (s, 1H), 8.28 (s, 1H), 7.95 (m, 1H), 7.50 (m, 1H), 7.28 (m, 1H), 7.15- 6.97 (m, 4H), 3.12 (s, 3H), 3.04 (s, 3H), 2.97 (m, 4H), 2.27 (m, 4H), 2.15 (s, 3H), 1.57 (m, 4H), 1.49 (m, 4H); MS (ESI < + >): m / z = 622.3 [M + H] ⁺ .

Example 16: N -(2-((5-bromo-2-((3-fluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) pyri) Midin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

5-bromo-2,4-dichloropyrimidine in place of 2,4,5-trichloropyrimidine in step 4) of Example 1, and 5-fluoro-2-nitro in step 5) Except for using 3, 4-difluoronitrobenzene and the compound prepared in step 2) of Example 8 above instead of anisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride Was prepared in the same manner as in Example 1 to obtain 49 mg of the title compound (final step yield: 43%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.29 (m, 1H), 8.31-8.28 (m, 1H), 8.27 (s, 1H), 7.63 (m, 1H), 7.54 (m, 1H), 7.42 (m, 1H), 7.30 -7.19 (m, 2H), 6.93 (m, 1H), 3.19 (s, 3H), 3.11 (s, 3H), 2.88 (m, 4H) , 2.26 (m, 4H), 2.15 (s, 3H), 1.54 (m, 4H), 1.47 (m, 4H); MS (ESI < + >): m / z = 632.2 [M + H] ⁺ .

Example 17: N -(2-((5-chloro-2-((3-fluoro-4- (6-methyl-2,6-diazaspiro [3.3] heptan-2-yl) phenyl) amino) pyrimidine- 4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Step 1) Tert-butyl Preparation of 6- (2-fluoro-4-nitrophenyl) -2,6-diazaspiro [3.3] heptan-2-carboxylate

300 mg (1.88 mmol) of 3,4-difluoronitrobenzene and 301 μl (2.26 mmol) of methyl iodide were diluted in 6 mL of N , N -dimethylformamide and 521 mg (3.77 mmol) of potassium carbonate. After the addition, the mixture was stirred at 70 ° C for 3 hours. Upon completion of the reaction, the resultant reaction mixture was cooled to room temperature, slowly added dropwise to ice water, and stirred. The resulting solid was washed with distilled water, filtered under reduced pressure, and dried under reduced pressure to obtain 500 mg (yield: 79%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.94 (d, 1H), 7.83 (d, 1H), 6.33 (t, 1H), 4.28 (s, 4H), 4.12 (s, 4H), 1.44 (s, 9H).

Step 2) Preparation of tert-butyl 6- (4-amino-2-fluorophenyl) -2,6-diazaspiro [3.3] heptan-2-carboxylate

500 mg (1.48 mmol) of the compound prepared in step 1) was diluted with 10 ml of methanol, and then 100 mg (10 wt%) of palladium / carbon was added thereto, followed by stirring under hydrogen gas for 16 hours. Upon completion of the reaction, the resulting reaction mixture was washed with celite-filled filter with methanol, filtered under reduced pressure and distilled under reduced pressure to obtain 400 mg (yield: 88%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.41-6.29 (m, 3H), 4.06 (s, 4H), 3.91 (s, 4H), 1.47 (s, 9H).

Step 3) tert-butyl 6- (4-((5-chloro-4-((2- ( N Preparation of -methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -2-fluorophenyl) -2,6-diazaspiro [3.3] heptan-2-carboxylate

120 mg (0.39 mmol) of the compound prepared in Step 2) and 150 mg (0.4328 mmol) of the compound prepared in Step 4) of Example 1 were diluted in 5 ml of 1,4-dioxane and 2-dicyclohexylphosphino 25 mg (0.04 mmol) of -2 ', 4', 6'-triisopropylbiphenyl and 119 mg (0.86 mmol) of cesium carbonate were stirred at room temperature for 5 minutes, followed by tris (dibenzylideneacetone) dipalladium. (O) 40 mg (0.04 mmol) was added thereto and stirred at 100 ° C. for 3 hours. After the reaction was completed, the resulting reaction mixture was cooled to room temperature and filtered through a celite-filled filter, and then the filtrate was diluted with a chloroform: 2-propanol (3: 1 (volume ratio)) mixed solvent and washed with water. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was separated by column chromatography (n-hexane: ethyl acetate = 1: 1: volume ratio) to obtain 90 mg (yield: 34%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 8.34 (d, 1H), 8.05 (s, 1H), 7.45 (d, 1H), 7.36 (d, 1H), 7.33 (m, 1H), 7.20 (d, 1H), 6.91 (d, 1H), 6.89 (s, 1H), 6.38 (d, 1H), 4.10 (s, 4H), 4.01 (s, 4H), 3.27 (s, 3H ), 2.98 (s, 3 H), 1.45 (s, 9 H).

Step 4) N -(2-((5-chloro-2-((2-methoxy-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

90 mg (0.15 mmol) of the compound prepared in step 3) was diluted with 1.5 mL of dichloromethane and 2.5 mL of trifluoroacetic acid were added, followed by stirring at room temperature for 2 hours. When the reaction was completed, the resultant reaction mixture was distilled under reduced pressure, and the obtained residue was diluted with a chloroform: 2-propanol (3: 1 (volume ratio)) mixed solvent and washed with a saturated aqueous sodium bicarbonate solution. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was dissolved in 5 ml of methanol, 65 mg (2.17 mmol) of formaldehyde was added and stirred at room temperature for 1 hour. 98 mg (2.58 mmol) of sodium borohydride was added thereto at 0 ° C., followed by stirring at room temperature for 3 hours. Upon completion of the reaction, the resulting reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain 26 mg (final step yield: 34%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.35 (s, 1H), 8.29 (d, 1H), 8.18 (s, 1H), 7.63 (d, 1H), 7.49 ( d, 1H), 7.41 (m, 1H), 7.25 (d, 1H), 7.13 (d, 1H), 6.43 (t, 1H), 3.86 (s, 4H), 3.24 (s, 4H), 3.19 (s , 3H), 3.09 (s, 3H), 2.26 (s, 3H); MS (ESI < + >): m / z = 532.2 [M + H] ⁺ .

Example 18: N -(2-((5-chloro-2-((2-methoxy-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Step 1) Tert-Butyl 4- (3-methoxy-4-nitrophenyl) -3,6-dihydropyridine-1 (2 H ) -Manufacture of Carboxylate

4-methoxy-aniline 3.31 g (14.3 mmol) and N-tert-butyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester 4.2 g (13.6 mmol) N Dilute to N -dimethylformamide and add 5.64 g (40.8 mmol) of potassium carbonate and 630 mg (0.86 mmol) of [1,1 ′ '-bis (diphenylphosphino) ferrocene] dichloropalladium (II). After that, the mixture was stirred at 87 ° C for 17 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (n-hexane: ethyl acetate = 1: 3 (volume ratio)) to obtain 500 mg of the title compound (yield: 11). %) Was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.87 (d, 1H), 7.29 (s, 1H), 7.16 (d, 1H), 6.40 (brm, 1H), 4.03 (m, 2H), 3.95 ( s, 3H), 3.61-3.45 (m, 2H), 2.50 (m, 2H), 1.42 (s, 9H).

Step 2) Preparation of tert-butyl 4- (4-amino-3-methoxyphenyl) piperidine-1-carboxylate

500 mg (1.50 mmol) of the compound prepared in step 1) was diluted with 5 ml of methanol, and then 100 mg (10 wt%) of palladium / carbon was added thereto, followed by stirring under hydrogen gas for 16 hours. Upon completion of the reaction, the resulting reaction mixture was washed with celite filled filter with methanol, filtered under reduced pressure and distilled under reduced pressure. The resulting residue was separated by column chromatography (n-hexane: ethyl acetate = 4: 1 (volume ratio)) to give 310 mg (yield: 68%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.67-6.55 (m, 3H), 4.20 (brm, 2H), 3.84 (s, 3H), 3.69 (m, 2H), 2.77 (m, 2H), 2.53 ( m, 1H), 1.70 (m, 2H), 1.58 (m, 2H), 1.47 (s, 9H).

Step 3) N -(2-((5-chloro-2-((2-methoxy-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

The compound prepared in step 2) was used instead of 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline in step 7) of Example 1 Except that, to give the title compound 14 mg (final step yield: 10%) in the same manner as in step 7).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 8.22 (d, 1H), 8.14 (s, 2H), 7.59 (d, 2H), 7.27 (t, 1H), 7.19 ( m, 1H), 6.88 (d, 1H), 6.72 (d, 1H), 3.77 (s, 3H), 3.16 (s, 3H), 3.08 (s, 3H), 3.02 (m, 2H), 2.60-2.49 (m, 3 H), 1.59-1.49 (m, 4 H); MS (ESI < + >): m / z = 517.2 [M + H] ⁺ .

Example 19: N -(2-((5-chloro-2-((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Example 5 in step 5) instead of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride and 1-fluoro-4-nitrobenzene Except for using 1-methylpiperazine, the same process as in Example 1 was carried out to obtain 24 mg of the title compound (final step yield: 16%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.19 (s, 1H), 8.36-8.31 (m, 2H), 8.14 (s, 1H), 7.61 (d, 1H), 7.42-7.35 (m, 3H ), 7.21 (t, 1H), 6.84-6.81 (m, 2H), 3.17 (s, 3H), 3.09 (s, 3H), 3.04 (m, 4H), 2.44 (m, 4H), 2.21 (s, 3H); MS (ESI < + >): m / z = 502.2 [M + H] ⁺ .

Example 20: N -(2-((5-chloro-2-((3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Example 5 in step 5) instead of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride and 3,4-difluoronitrobenzene Except for using 1-methylpiperazine, the same process as in Example 1 was carried out to obtain 120 mg (final step yield: 47%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.37 (s, 1H), 8.27-8.20 (m, 2H), 7.64-7.55 (m, 2H), 7.40 (t, 1H ), 7.28-7.18 (m, 2H), 6.89 (t, 1H), 3.70 (s, 3H), 3.08 (s, 3H), 2.92 (m, 4H), 2.48 (m, 4H), 2.22 (s, 3H); MS (ESI < + >): m / z = 520.2 [M + H] ⁺ .

Example 21: N -(2-((5-chloro-2-((2,3-difluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) - N Preparation of Methylmethanesulfonamide

1,2,3-trifluoro-4 instead of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride in step 5) of Example 1 above Aside from using nitrobenzene and 1-methylpiperazine, the same process as in Example 1 was carried out to give 100 mg (final step yield: 65%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.11 (s, 1H), 8.34 (m, 1H), 8.20 (m, 1H), 8.16 (s, 1H), 7.59 (t, 1H), 7.18 ( m, 3H), 6.82 (t, 1H), 3.44 (m, 4H), 3.18 (s, 3H), 3.10 (s, 3H), 3.04 (m, 4H), 2.24 (s, 3H); MS (ESI < + >): m / z = 538.2 [M + H] ⁺ .

Example 22: N -(2-((5-chloro-2-((3-fluoro-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) Phenyl)- N Preparation of Methylmethanesulfonamide

Step 1) Preparation of 1,2-difluoro-3-methoxy-4-nitrobenzene

1 g (5.65 mmol) of 2,3,4-trifluoronitrobenzene and 0.23 ml (5.65 mmol) of methanol were diluted with 10 ml of toluene, and potassium hydroxide 320 mg (5.65 mmol) was added thereto, followed by stirring at room temperature for 4 hours. I was. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was separated by column chromatography (n-hexane: ethyl acetate = 4: 1 (volume ratio)) to give 770 mg (yield: 72%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.88 (m, 1H), 7.43 (m, 1H), 4.04 (s, 3H).

Step 2) N -(2-((5-chloro-2-((3-fluoro-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) Phenyl)- N Preparation of Methylmethanesulfonamide

The compound prepared in step 1) and 1- in place of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride in step 5) of Example 1 Except for using methyl piperazine, the same process as in Example 1 was carried out to obtain 89 mg (final step yield: 49%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 8.32 (s, 1H), 8.24 (m, 1H), 8.14 (s, 1H), 7.5 (m, 1H), 7.30- 7.15 (m, 3H), 6.69 (t, 1H), 3.75 (s, 3H), 3.17 (s, 3H), 3.09 (s, 3H), 2.99 (m, 4H), 2.49 (m, 4H), 2.25 (s, 3H); MS (ESI < + >): m / z = 550.2 [M + H] ⁺ .

Example 23: N -(2-((5-chloro-2-((5-fluoro-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) Phenyl)- N Preparation of Methylmethanesulfonamide

Prepared in step 1) of Example 13 instead of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride in step 5) of Example 1 Except for using the compound and the compound prepared in step 2) of Example 8, the same process as in Example 1 was carried out to obtain 110 mg (final step yield: 70%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 8.22 (m, 2H), 8.09 (s, 1H), 7.60 (m, 2H), 7.32 (m, 1H), 7.26 ( m, 1H), 6.65 (d, 1H), 3.80 (s, 3H), 3.44 (m, 4H), 3.25 (s, 3H), 3.18 (s, 3H), 3.09 (m, 4H), 2.23 (s , 3H); MS (ESI < + >): m / z = 550.2 [M + H] ⁺ .

Example 24: N - (2 - ( (5- chloro-2 - ((2-methoxy -4 - ((1 S, 4 S) -5- methyl-2,5-diazabicyclo [2.2. ] Heptan-2-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide

Step 1) tert-butyl (1 S ,4 S ) -5-benzyl-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

Dilute 500 mg (1.43 mmol) of (1 S , 4 S ) -2,5-diazabicyclo [2.2.1] heptane dibromide in 5 ml of dichloromethane, add 0.8 ml (5.72 mmol) of triethylamine, and add 10 ml. Stirred for a minute. 0.36 mL (1.57 mmol) of di-tert-butyl dicarbonate was added thereto, followed by stirring at room temperature for 3 hours. Upon completion of the reaction, the resulting reaction mixture was diluted with dichloromethane and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain 700 mg (yield: 100%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.37-7.25 (m, 5H), 4.32 (m, 1H), 3.76-3.46 (m, 4H), 3.19-2.57 (m, 4H), 1.89 (m, 1H ), 1.48 (s, 9 H).

Step 2) tert-butyl (1 S ,4 S ), 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

700 mg (2.43 mml) of the compound prepared in step 1) was diluted with 7 ml of ethanol, 650 mg (10 wt%) of palladium / carbon and 1 ml of acetic acid were added, followed by stirring at room temperature under hydrogen gas for 16 hours. When the reaction was completed, the resultant reaction mixture was washed with a celite-filled filter with ethyl acetate, filtered under reduced pressure, and the resulting filtrate was distilled under reduced pressure to obtain 570 mg (yield: 100%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 4.52 (m, 1H), 4.21 (m, 1H), 3.35 (m, 2H), 3.24 (m, 2H), 1.93 (m, 2H), 1.47 (s, 9H).

Step 3) tert-butyl (1 S ,4 S Preparation of) -5- (3-methoxy-4-nitrophenyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

200 mg (1.01 mmol) of the compound prepared in step 2) and 173 mg (1.01 mmol) of 5-fluoro nitroanisole were diluted in 2 ml of dimethyl sulfoxide and stirred at 90 ° C. for 16 hours. Upon completion of the reaction, the resulting reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was separated by column chromatography (n-hexane: ethyl acetate = 4: 1 (volume ratio)) to give 153 mg (yield: 87%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.05 (d, 1H), 6.14 (d, 1H), 5.97 (s, 1H), 4.66 (m, 1H), 4.52 (s, 1H), 3.96 (s, 3H), 3.60-3.26 (m, 4H), 2.02 (m, 2H), 1.46 (m, 9H).

Step 4) N -(2-((2-((4-((1 S ,4 S ) -2,5-diazabicyclo [2.2.1] heptan-2-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

In Example 6, the compound prepared in Step 3) instead of 1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazin Except for using, Step 6) and Step 7) of Example 1 were carried out sequentially to obtain 22 mg (yield: 32%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.31 (m, 1H), 8.23 (s, 1H), 8.06 (m, 2H), 7.58 (d, 1H), 7.25-7.10 (m, 3H), 6.21 ( s, 1H), 6.10 (d, 1H), 4.34 (s, 1H), 3.72 (s, 3H), 3.60 (s, 1H), 3.51 (m, 1H), 3.17 (s, 3H), 3.09 (s , 3H), 2.92-2.86 (m, 2H), 1.79 (m, 2H), 1.64 (m, 1H).

Step 5) N -(2-((5-chloro-2-((2-methoxy-4-((1 S ,4 S ) -5-methyl-2,5-diaza bicyclo [2.2.1] heptan-2-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of -methyl methanesulfonamide

22 mg (0.04 mmol) of the compound prepared in step 4) was diluted with 1 mL of methanol, 0.5 mL of formaldehyde was added thereto, followed by stirring at room temperature for 30 minutes. 3 mg (0.08 mmol) of sodium borohydride was slowly added thereto at 0 ° C., followed by stirring at room temperature for 1 hour. Upon completion of the reaction, the resulting reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 10: 1 (volume ratio)) to obtain 10 mg of the title compound (final step yield: 46%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.48 (d, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.91 (d, 1H), 7.40-7.32 (m, 2H), 7.19- 7.09 (m, 2H), 6.15-6.10 (m, 2H), 4.20 (s, 1H), 3.86 (s, 3H), 3.54 (s, 1H), 3.43 (m, 2H), 3.29 (s, 3H) , 3.03 (m, 1H), 3.01 (s, 3H), 2.71 (d, 1H), 2.42 (s, 3H), 2.05-1.93 (m, 2H); MS (ESI < + >): m / z = 544.2 [M + H] ⁺ .

Example 25: N -(2-((5-chloro-2-((2-methoxy-4-((3 S , 5 R ) -3,4,5-trimethylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Step 1) (3 S , 5 R ) -1- (3-methoxy-4-nitrophenyl) -3,5-dimethylpeperazine

시스-2,6-다이메틸피페라진 1 g (8.76 mmol)과 5-플루오로-2-나이트로아니솔 1.36 g (7.96 mmol)을 다이메틸설폭사이드 10 ㎖에 묽히고 90 ℃에서 2 시간 교반시켰다. 반응이 완결되면 결과의 반응혼합물을 에틸 아세테이트에 묽힌 후 포화 중탄산나트륨수용액으로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 표제화합물 1.75 g (수율: 75 %)을 얻었다.

1 g (8.76 mmol) of cis-2,6-dimethylpiperazine and 1.36 g (7.96 mmol) of 5-fluoro-2-nitroanisole are diluted in 10 ml of dimethylsulfoxide and stirred at 90 ° C. for 2 hours. I was. Upon completion of the reaction, the resulting reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain 1.75 g (yield: 75%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ8.02 (d, 1H), 6.42 (d, 1H), 6.30 (s, 1H), 3.97 (s, 3H), 3.66 (d, 2H), 2.79 (t , 2H), 2.36 (m, 2H), 1.22 (d, 6H).

Step 2) (2 S , 6 R ) -4- (3-methoxy-4-nitrophenyl) -1,2,6-trimethylpiperazine

상기 단계 1)에서 제조된 화합물 200 mg (0.75 mmol)을 메탄올 2 ㎖에 묽히고 포름알데하이드 340 mg (11.3 mmol)을 가하고 상온에서 30 분간 교반시켰다. 여기에 수소화붕소나트륨 200 mg (5.28 mmol)을 0 ℃에서 천천히 가한 후 상온에서 3 시간 교반시켰다. 반응이 완결된 후 결과의 반응혼합물을 에틸 아세테이트에 묽힌 후 포화 중탄산나트륨수용액으로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하였다. 결과로 얻어진 잔사를 컬럼 크로마토그래피 (다이클로로메탄 : 메탄올 = 40 : 1(부피비))로 분리하여 표제화합물 99 mg (수율: 47 %)을 얻었다.

200 mg (0.75 mmol) of the compound prepared in step 1) was diluted with 2 ml of methanol, 340 mg (11.3 mmol) of formaldehyde was added thereto, and stirred at room temperature for 30 minutes. 200 mg (5.28 mmol) of sodium borohydride was slowly added thereto at 0 ° C., followed by stirring at room temperature for 3 hours. After the reaction was completed, the resulting reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 40: 1 (volume ratio)) to obtain 99 mg (yield: 47%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.02 (d, 1H), 6.42 (d, 1H), 6.30 (s, 1H), 3.97 (s, 3H), 3.65 (m, 2H), 2.79 (m, 2H), 2.35 (m, 2H), 2.30 (s, 3H), 1.21 (d, 6H).

Step 3) N -(2-((5-chloro-2-((2-methoxy-4-((3S, 5R) -3,4,5-trimethylpiperazin-1-yl) phenyl) amino) pyrimidine- 4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Example 6 above using the compound of step 2) in place of 1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazin Except that, the steps 6) and 7) of Example 1 were carried out sequentially to obtain 22 mg of the title compound (final step yield: 25%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.26-8.24 (m, 2H), 8.09 (m, 2H), 7.57 (d, 1H), 7.31 (d, 1H), 7.22 (t, 1H), 7.17 (t, 1H), 6.61 (s, 1H), 6.43 (d, 1H), 3.75 (s, 3H), 3.54 (m, 2H), 3.17 (s, 3H), 3.09 (s, 3H), 2.38 (t, 2H), 2.34 (m, 2H), 2.20 (s, 3H), 1.08 (d, 6H); MS (ESI < + >): m / z = 560.2 [M + H] ⁺ .

Example 26: N -(2-((5-chloro-2-((4- (4-ethylpiperidin-1-carbonyl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Step 1) 4-((5-chloro-4-((2- N Preparation of -methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxybenzoic acid

500 mg (1.44 mmol) of the compound prepared in step 4) of Example 1 and 240 mg (1.44 mmol) of 4-amino-3-methoxybenzoic acid were diluted in 2 mL of 2-butanol and 0.07 mL of trifluoroacetic acid ( 4.32 mmol) was added, followed by stirring at 100 ° C. for 16 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, the resulting solid was washed with 2-butanol, filtered under reduced pressure and dried under reduced pressure to give 530 mg (yield: 76%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.01 (s, 1H), 8.76 (s, 1H), 8.36 (s, 1H), 8.00-7.90 (m, 2H), 7.65 (m, 1H), 7.49-7.34 (m, 4H), 3.88 (s, 3H), 3.13 (s, 3H), 3.05 (s, 3H).

Step 2) N -(2-((5-chloro-2-((4- (4-ethylpiperidin-1-carbonyl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

80 mg (0.17 mmol) of the compound prepared in step 1) and 19 mg (0.17 mmol) of 1-ethyl piperazine were diluted in 2.4 mL of N, N -dimethylformamide, and N , N -diisopropylethylamine 65 mg (0.51 mmol) and 95 mg (0.26 of 1- [bis (dimethylamino) methylene] -1 H -1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate mmol) was added, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the mixture was diluted with chloroform: 2-propanol (10: 1 (volume ratio)) mixed solvent and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (dichloromethane: methanol = 9: 1 (volume ratio)) to give 60 mg of the title compound (final step yield: 61%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.40 (s, 1H), 8.18-8.14 (m, 3H), 7.88 (m, 1H), 7.60 (m, 1H), 7.36 (m, 1H), 7.23 (m, 1H), 7.01 (d, 1H), 6.86 (m, 1H), 3.82 (s, 3H), 3.58 (m, 4H), 3.16 (s, 3H), 3.07 (s, 3H), 2.38 2.31 (m, 6 H), 0.99 (t, 3 H); MS (ESI < + >): m / z = 574.2 [M + H] ⁺ .

Example 27: 4-((5-chloro-4-((2- ( N -Methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxy- N Preparation of-(1-methylpiperidin-4-yl) benzamide

Except for using 4-amino-1-methylpiperidine instead of 1-ethyl piperazine in step 2) of Example 24, the same process as in Example 24 was carried out to obtain 36 mg of the title compound (final step) Yield: 37%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.19 (s, 1H), 8.19-8.11 (m, 3H), 7.99 (d, 1H), 7.62 (dd, 1H), 7.46 (d, 1H), 7.42-7.25 (m, 2H), 7.25 (m, 1H), 3.88 (s, 3H), 3.74 (m, 1H), 3.17 (s, 3H), 3.08 (s, 3H) , 2.85 (m, 2H), 2.24 (s, 3H), 2.07 (m, 2H), 1.67 (m, 2H), 1.58 (m, 2H); MS (ESI < + >): m / z = 574.2 [M + H] ⁺ .

Example 28: 4-((5-chloro-4-((2- ( N -Methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxy- N Preparation of-(2- (pyrrolidin-1-yl) ethyl) benzamide

Step 1) Preparation of 2-((tert-butoxycarbonyl) amino) ethyl4-methylbenzenesulfonate

1 g (6.20 mmol) of 2- (tert-butoxycarbonylamino) -1-ethanol and 151 mg (1.20 mmol) of 4-dimethylaminopyridine are diluted in 20 ml of tetrahydrofuran and 1.73 ml of triethylamine ( 12.4 mmol) and 1.3 g (6.82 mmol) of p -toluenesulfonylchloride were slowly added at 0 ° C., followed by stirring at room temperature for 16 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (n-hexane: ethyl acetate = 1: 1: volume ratio) to obtain 900 mg (yield: 46%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.78 (d, 2H), 7.34 (d, 2H), 4.83 (s, 1H), 4.06 (m, 2H), 3.37 (m, 2H), 2.44 (s, 3H), 1.40 (s, 9H).

Step 2) Preparation of tert-butyl (2- (pyrrolidin-1-yl) ethyl) carbamate

150 mg (0.48 mmol) of the compound prepared in step 1) and 68 mg (0.96 mmol) of pyrrolidine were diluted in 3 ml of acetonitrile and 99 mg (0.72 mmol) of potassium carbonate was added thereto, followed by 16 at 90 ° C. Stirred for time. When the reaction was completed, the resulting reaction mixture was cooled to room temperature, diluted with dichloromethane and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (dichloromethane: methanol = 9: 1 (volume ratio)) to give 66 mg of the title compound (yield: 64%). )

¹ H-NMR (300 MHz, CDCl ₃ ) δ 5.11 (s, 1H), 3.27 (m, 2H), 2.65-2.58 (m, 6H), 1.75 (m, 4H), 1.45 (s, 9H).

Step 3) 4-((5-chloro-4-((2- ( N -Methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxy- N Preparation of-(2- (pyrrolidin-1-yl) ethyl) benzamide

66 mg (0.31 mmol) of the compound prepared in step 2) was diluted with 1 ml of dichloromethane and 1 ml of trifluoroacetic acid was added, followed by stirring at room temperature for 4 hours. After the reaction was completed, the resultant reaction mixture was distilled under reduced pressure, and the residue obtained in the same manner as in Example 26 was used except that the residue obtained in place of 1-ethyl piperazine in step 2) of Example 26 was used. 30 mg (final step yield: 43%) were obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.46 (m, 2H), 8.25 (s, 1H), 8.21-8.15 (m, 2H), 8.03 (d, 1H), 7.64 (m, 1H), 7.50 (d, 1H), 7.45-7.37 (m, 2H), 7.27 (m, 1H), 3.90 (s, 3H), 3.40 (m, 4H), 3.19 (s, 3H), 3.10 (s, 3H) , 2.84 (m, 4 H), 1.78 (m, 4 H); MS (ESI < + >): m / z = 574.2 [M + H] ⁺ .

Example 29: N -(2-((5-chloro-2-((2-methoxy-4- (morpholinomethyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Step 1) Preparation of Methyl 3-methoxy-4-nitrobenzoate

3 g (16.4 mmol) of 3-hydroxy-4-nitrobenzoic acid and 4.53 g (32.8 mmol) of potassium carbonate were diluted in 20 ml of N , N -dimethylformamide, and 531 µl of methyl iodide (at 0 ° C) 8.57 mmol) and stirred at room temperature for 15 hours. When the reaction was completed, the resultant reaction mixture was slowly added dropwise to ice water, followed by stirring. The resulting solid was washed with distilled water, filtered under reduced pressure and dried under reduced pressure to give 2.8 g (yield: 81%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.84 (d, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 4.01 (s, 3H), 3.96 (s, 3H).

Step 2) Preparation of (3-methoxy-4-nitrophenyl) methanol

1.5 g (4.74 mmol) of the compound prepared in step 1) was diluted with 15 ml of tetrahydrofuran, and 7.1 ml (7.10 mmol) of 1.0M lithium aluminum hydride tetrahydrofuran solution was slowly added at -78 ° C, and then 15 hours at room temperature. Stirred. When the reaction was completed, the resulting reaction mixture was slowly added dropwise to ice water and stirred. The resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 15: 1 (volume ratio)) to give 720 mg (yield: 83%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.84 (d, 1H), 7.14 (s, 1H), 6.95 (d, 1H), 4.77 (s, 2H), 4.02 (s, 3H).

Step 3) Preparation of 3-methoxy-4-nitrobenzaldehyde

720 mg (4.26 mmol) of the compound prepared in step 2) was diluted with 15 mL of dichloromethane, and 1.85 g (2.13 mmol) of manganese dioxide was added thereto, followed by stirring at room temperature for 15 hours. Upon completion of the reaction, the resulting reaction mixture was filtered through a celite packed filter and the resulting filtrate was distilled off under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 15: 1 (volume ratio)) to give 235 mg (yield: 30%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 10.08 (s, 1H), 8.07 (d, 1H), 7.81 (s, 1H), 7.65 (d, 1H), 4.09 (s, 3H).

Step 4) Preparation of 4- (3-methoxy-4-nitrobenzyl) morpholine

235 mg (1.30 mmol) of the compound prepared in step 3) and 113 mg (1.30 mmol) of morpholine were diluted in 15 ml of tetrahydrofuran and 20 µl of acetic acid was added thereto. 551 mg (2.6 mmol) of sodium triacetoxyborohydride were slowly added at 0 ° C., followed by stirring at room temperature for 15 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was separated by column chromatography (n-hexane: ethyl acetate = 1: 1: volume ratio) to obtain 110 mg (yield: 34%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.84 (d, 1H), 7.28 (s, 1H), 7.06 (d, 1H), 3.91 (s, 3H), 3.50 (m, 6H), 2.40 ( m, 4H).

 Step 5) N -(2-((5-chloro-2-((2-methoxy-4- (morpholinomethyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

In Example 6 Step 6), instead of 1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine, the compound prepared in Step 4) was used. Except for, step 6) and 7) of Example 1 were carried out sequentially to obtain 3.5 mg (final step yield: 3%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.30 (s, 1H), 8.14 (m, 2H), 8.10 (m, 1H), 7.58 (d, 1H), 7.55 (d, 1H), 7.30 ( m, 1H), 7.22 (m, 1H), 6.90 (s, 1H), 6.80 (d, 1H), 3.91 (s, 3H), 3.50 (m, 6H), 3.16 (s, 3H), 2.40 (m , 4H), 3.08 (s, 3H); MS (ESI < + >): m / z = 533.2 [M + H] ⁺ .

Example 30: N -(2-((5-chloro-2-((2-methoxy-4-((3-morpholinopropyl) thio) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

Step 1) Preparation of 4- (3-chloropropyl) morpholine

5 g (57.4 mmol) of morpholine and 11 mL (114.6 mmol) of 1-bromo-3-chloropropane were diluted in 50 mL of toluene, followed by stirring at 70 ° C for 2 hours. When the reaction was completed, the reaction mixture was cooled to room temperature, the insoluble material was removed by filtration under reduced pressure, and the filtrate was distilled under reduced pressure to obtain 4 g (yield: 43%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 3.67 (q, 2H), 3.57 (m, 4H), 2.37 (m, 2H), 2.31 (m, 4H), 1.86 (m, 2H).

Step 2) Preparation of 3-morpholinopropane-1-thiol

4 g (24.4 mmol) of the compound prepared in step 1) and 2.78 g (36.6 mmol) of thiourea were diluted in 40 ml of an aqueous 95% ethanol solution, followed by dropwise addition of 2 g (12.2 mmol) of potassium iodide. It stirred at 15 degreeC. An aqueous solution of 1.46 g of sodium hydroxide dissolved in 15 ml of distilled water was added dropwise thereto, followed by stirring at 100 ° C for 15 hours. When the reaction was completed, the reaction mixture was cooled to room temperature and distilled under reduced pressure. The obtained residue was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain 1.7 g (yield: 44%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 3.80 (q, 2H), 3.507 (m, 4H), 2.27 (m, 2H), 2.25 (m, 4H), 1.75 (m, 2H).

Step 3) Preparation of 4- (3-((3-methoxy-4-nitrophenyl) thio) propyl) morpholine

226 mg (1.40 mmol) of the compound prepared in step 2) and 200 mg (1.17 mmol) of 5-fluoro-2-nitroanisole were diluted in 10 ml of N , N -dimethylformamide, and cesium carbonate 762. mg (2.34 mmol) was added dropwise and stirred at 80 ° C. for 5 hours. After the reaction was completed, the resultant reaction mixture was cooled to room temperature, and the resultant reaction mixture was slowly added dropwise to ice water, followed by stirring. The resulting solid was washed with distilled water, filtered under reduced pressure, and dried under reduced pressure to obtain 150 mg (yield: 41%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.84 (d, 2H), 6.88 (d, 2H), 4.11 (s, 3H), 3.71 (m, 4H), 3.05 (t, 2H), 2.46 (t, 2H), 2.41 (m, 4H), 1.87 (m, 2H).

Step 4) N -(2-((5-chloro-2-((2-methoxy-4-((3-morpholinopropyl) thio) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N Preparation of Methylmethanesulfonamide

In Example 6 Step 6), instead of 1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine, the compound prepared in Step 3) was used. Except for, step 6) and 7) of Example 1 were carried out sequentially to give 65 mg (final step yield: 46%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 8.14 (m, 3H), 7.68 (d, 1H), 7.58 (d, 1H), 7.33 (t, 1H), 7.22 ( t, 1H), 6.98 (s, 1H), 6.84 (d, 1H), 3.97 (s, 3H), 3.52 (m, 4H), 3.16 (s, 3H), 3.08 (s, 3H), 2.95 (t , 2H), 2.35 (t, 2H), 2.28 (m, 4H), 1.69 (m, 2H); MS (ESI < + >): m / z = 593.2 [M + H] ⁺ .

Example 31: N -(2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine- 4-yl) amino) -5- (hydroxymethyl) phenyl)- N Preparation of Methylmethanesulfonamide

Step 1) Methyl 3- ( N Preparation of -methylmethylsulfonamido) -4-nitrobenzoate

3.5 g (17.6 mmol) of methyl 3-fluoro-4-nitrobenzoate and 1.9 g (17.6 mmol) of N -methylmethanesulfonamide were diluted in 70 ml of acetonitrile and 8.6 g (26.4 mmol) of cesium carbonate was added. After that, the mixture was stirred at 60 ° C for 16 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (n-hexane: ethyl acetate = 2: 1 (volume ratio)) to give 3.96 g (yield: 78) of the title compound. %) Was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.27 (d, 1H), 8.11-8.09 (m, 2H), 3.92 (s, 3H), 3.30 (s, 3H), 3.08 (s, 3H).

Step 2) methyl 4-amino-3- ( N Preparation of -methylmethylsulfonamido) benzoate

After diluting 1 g (3.47 mmol) of the compound prepared in step 1) in 30 ml of methanol, 200 mg (10 wt%) of palladium / carbon was added thereto, followed by stirring for 4 hours under hydrogen gas. After completion of the reaction, the resultant reaction mixture was washed with celite-filled filter with methanol, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (n-hexane: ethyl acetate = 1: 1 (volume ratio)). 710 mg (yield 79%) of compound were obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.74 (d, 1H), 7.62 (dd, 1H), 6.75 (d, 1H), 6.04 (s, 2H), 3.75 (s, 3H), 3.07 ( s, 6H);

Step 3) Methyl 4-((2,5-dichloropyrimidin-4-yl) amino) -3- ( N Preparation of -methylmethyl sulfonamido) benzoate

704 mg (2.73 mmol) of the compound prepared in step 2) and 500 mg (2.73 mmol) of 2,4,5-trichloropyrimidine were diluted in 10 ml of N, N -dimethylformamide, and tert-butoxy 918 mg (8.18 mmol) of potassium was slowly added at 0 ° C. and stirred at room temperature for 4 hours. When the reaction is complete after mukhin the reaction and the resulting mixture taken up in ethyl acetate and washed with 1 N hydrochloric acid solution and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was separated by column chromatography (n-hexane: ethyl acetate = 1: 1: volume ratio) to give 400 mg (yield: 36%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.10 (s, 1H), 8.52 (s, 1H), 8.14 (m, 2H), 8.02 (m, 1H), 3.98 (s, 3H), 3.24 ( s, 3H), 3.07 (s, 3H).

Step 4)  N -(2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine- 4-yl) amino) -5- (hydroxymethyl) phenyl)- N Preparation of Methylmethanesulfonamide

100 mg (0.25 mmol) of the compound prepared in step 3) was diluted with 3 ml of tetrahydrofuran, and 0.75 ml of 1.0 M lithium aluminum hydride tetrahydrofuran solution was slowly added at 0 ° C., followed by stirring at room temperature for 3 hours. When the reaction was completed, the resultant reaction mixture was slowly added dropwise to an aqueous sodium potassium tartrate solution, followed by stirring. The resulting mixture was diluted in ethyl acetate and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. 50 mg (0.13 mmol) of the resulting residue and 40 mg (0.13 mmol) of the compound prepared in Step 6) of Example 1 were diluted with 1 mL of 2-butanol and 0.03 mL (0.39 mmol) of trifluoroacetic acid was added. After that, the mixture was stirred at 100 ° C for 16 hours. Upon completion of the reaction, the resulting reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (dichloromethane: methanol = 8: 1 (volume ratio)) to give 10 mg of the title compound (final step yield: 12%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.21 (s, 1H), 8.16 (m, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.47 (d, 1H), 7.35 ( m, 1H), 7.17 (m, 1H), 6.60 (m, 1H), 6.42 (m, 1H), 5.19 (s, 1H), 4.48 (s, 2H), 3.77 (s, 3H), 3.75-3.68 (m, 2H), 3.30 (m, 4H), 3.15 (s, 3H), 3.09 (s, 3H), 2.69-2.62 (m, 5H), 2.22 (s, 3H), 1.87 (m, 2H), 1.53 (m, 2 H), 1.49 (m, 2 H); MS (ESI < + >): m / z = 645.3 [M + H] ⁺ .

Example 32: N -(2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine- 4-yl) amino) benzyl)- N Preparation of Methylmethanesulfonamide

Step 1) N -methyl- N Preparation of-(2-nitrobenzyl) methanesulfonamide

2-nitro-benzyl bromide and 700 mg (3.24 mmol) and N - methyl methane-sulfonamide 388 mg (3.56 mmol) N, N - dimethylformamide Higo diluted ㎖ amide 7 by the addition of potassium carbonate and 672 mg (4.86 mmol) Then, it stirred at 50 degreeC for 4 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (n-hexane: ethyl acetate = 4: 1 (volume ratio)) to give the title compound (420 mg (yield: 74). %) Was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.05 (dd, 1H), 7.81 (dd, 1H), 7.68 (dd, 1H), 7.59 (dd, 1H), 4.62 (s, 2H), 3.03 ( s, 3H), 2.75 (s, 3H).

Step 2) N -(2-aminobenzyl)- N Preparation of Methylmethanesulfonamide

420 mg (2.09 mmol) of the compound prepared in step 1) and 45 mg (0.83 mmol) of ammonium chloride were diluted in 4 ml of ethanol and 4 ml of water, and 351 mg (6.29 mmol) of iron was added thereto, followed by 2 hours at 80 ° C. Stirred. After the reaction was completed, the resultant reaction mixture was cooled to room temperature, filtered through a celite-filled filter, and the filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was separated by column chromatography (n-hexane: ethyl acetate = 2: 1 (volume ratio)) to give 310 mg (yield: 74%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.04-7.01 (m, 2H), 6.66 (dd, 1H), 6.55 (m, 1H), 5.02 (s, 2H), 4.07 (s, 2H), 2.99 (s, 3 H), 2.61 (s, 3 H).

Step 3) N -(2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine-4 -Yl) amino) benzyl)- N Preparation of Methylmethanesulfonamide

Step in Example 14) from N - (2- amino-phenyl) -N- methyl-methane sulfonamide instead of the step 2) of Example 1, except for using the compound prepared in 4-7 Was performed sequentially to give 15 mg (final step yield: 15%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.60 (s, 1H), 8.02 (s, 1H), 7.52-7.50 (m, 2H), 7.45-7.30 (m, 4H), 6.53 (m, 1H ), 6.19 (m, 1H), 4.20 (s, 2H), 3.74 (s, 3H), 3.60 (m, 2H), 3.30 (m, 2H), 2.91 (s, 3H), 2.60 (s, 3H) , 2.56 (m, 4H), 2.30 (m, 5H), 2.15 (s, 3H), 1.82 (m, 2H), 1.51 (m, 2H); MS (ESI < + >): m / z = 629.3 [M + H] ⁺ .

Example 33: N -(4-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine- 4-yl) amino) -1-methyl-1 H Pyrazol-3-yl) N Preparation of Methylmethanesulfonamide

Step 1) Methyl 1-methyl-4-nitro-1 H Preparation of Pyrazole-3-carboxylate

2 g (19.1 mmol) of 4-nitro-1 H -pyrazole-3-carboxylic acid are diluted in 40 ml of N, N -dimethylformamide, 5.8 g (42 mmol) of potassium carbonate and 3.9 ml of methyl iodide. (42 mmol) was added at room temperature, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was added with 15 ml of a mixed solvent of dichloromethane and methanol (1: 5 (volume ratio)), stirred for 30 minutes, and the resulting solid was filtered under reduced pressure to yield 1.77 g (yield: 50%) of the title compound. Got.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H).

Step 2) 1-Methyl-4-nitro-1 H Preparation of Pyrazole-3-carboxylic Acid

1.77 g (9.56 mmol) of the compound prepared in step 1) was diluted with 20 ml of a mixed solvent of tetrahydrofuran: methanol (3: 2 (volume ratio)), and 458 mg (19.1 mmol) of lithium hydroxide was diluted with 5 ml of distilled water. Was added at 0 ° C., and the mixture was stirred at room temperature for 2.5 hours. When the reaction was completed, the resultant reaction mixture was distilled under reduced pressure, 10 ml of distilled water was added, and acidified (pH 2) with hydrochloric acid (35% aqueous solution) at 0 ° C., followed by stirring. The resulting solid was dried under reduced pressure to give 1.25 g (yield 76%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.68 (s, 1H), 3.83 (s, 3H).

Step 3) 1-Methyl-4-nitro-1 H Preparation of Pyrazol-3-amine

1.25 g (7.31 mmol) of the compound prepared in step 2) was diluted with 12 ml of tert-butanol and 19 ml of 1,4-dioxane, 1.53 ml (10.9 mmol) of triethylamine and 2.34 ml of diphenylphosphoryl azide. (10.9 mmol) was added, followed by stirring under reflux for 12 hours. When the reaction was completed, the resultant reaction mixture was cooled to room temperature and distilled under reduced pressure, and the residue obtained was diluted with a chloroform: 2-propanol (3: 1 (volume ratio)) mixed solvent and washed twice with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The obtained residue was diluted with 12 ml of dichloromethane and 6 ml of trifluoroacetic acid was added, followed by stirring at room temperature for 2 hours. After the reaction was completed, the resulting reaction mixture was distilled under reduced pressure, diluted with a chloroform: 2-propanol (3: 1 (volume ratio)) mixed solvent, and washed with a saturated aqueous sodium bicarbonate solution. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was added with dichloromethane and n-hexane (1: 5 (volume ratio)) and stirred for 30 minutes, and then the solid was filtered to give a title. 373 mg (yield 36%) of compound were obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.46 (s, 1H), 6.24 (s, 2H), 3.66 (s, 3H).

Step 4) N -(1-methyl-4-nitro-1 H Preparation of Pyrazol-3-yl) methanesulfonamide

373 mg (2.62 mmol) of the compound prepared in step 3) was diluted with 8 ml of pyridine, and 705 μl (7.87 mmol) of methanesulfonyl chloride was slowly added at 0 ° C., followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the resulting reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure. The resulting residue was diluted with 10 ml of a tetrahydrofuran: 1N aqueous sodium hydroxide aqueous solution (2: 3 (volume ratio)) mixed solvent and stirred for 1 hour. The resulting mixture was neutralized with 2N aqueous hydrochloric acid solution and extracted with chloroform: 2-propanol (3: 1 (volume ratio)) mixed solvent. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (n-hexane: ethyl acetate = 1: 2 (volume ratio)) to give 130 mg of the title compound (yield: 22). %) Was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 8.80 (s, 1H), 3.84 (s, 3H), 3.24 (s, 3H).

Step 5) N -methyl- N -(1-methyl-4-nitro-1 H Preparation of Pyrazol-3-yl) methanesulfonamide

130 mg (0.59 mmol) of the compound prepared in step 4) was diluted with 5 ml of N, N -dimethylformamide, 28 mg (0.71 mmol) of sodium hydroxide (60%) was added slowly at 0 ° C., and then at room temperature. Stirred for 30 minutes. 55 μl (0.89 mmol) of methyl iodide was slowly added to the reaction solution at 0 ° C., followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (dichloromethane: methanol = 15: 1 (volume ratio)) to give 88 mg of the title compound (yield: 64%). )

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.86 (s, 1H), 3.94 (s, 3H), 3.14 (s, 6H).

Step 6) N -(4-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine- 4-yl) amino) -1-methyl-1 H Pyrazol-3-yl) N Preparation of Methylmethanesulfonamide

Except for using the compound prepared in step 5) instead of N -methyl- N- (2-nitrophenyl) methane sulfonamide in step 3) of Example 1, in step 3 of Example 1 Sequentially following the same procedure as in step 7, 36 mg (final step yield: 34%) of the title compound were obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.13 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.63 (s, 1H), 7.31 (d, 1H), 6.64 ( s, 1H), 6.51 (d, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.26 (s, 3H), 3.01 (s, 3H), 2.70 (m, 4H), 2.62 (m , 3H), 2.48 (m, 2H), 2.43 (m, 4H), 2.14 (s, 3H), 1.98 (m, 2H), 1.52 (m, 2H); MS (ESI < + >): m / z = 619.2 [M + H] ⁺ .

Example 34: 2- (2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) Preparation of amino) pyrimidin-4-yl) amino) phenyl) isothiazolidine-1,1-dioxide

Step 1) Preparation of 2- (2-nitrophenyl) isothiazolidine 1,1-dioxide

300 mg (2.13 mmol) of 2-fluoronitrobenzene was diluted in 15 ml of N, N -dimethylformamide, and 102 mg (2.55 mmol) of 60% sodium hydride was slowly added at 0 ° C, followed by stirring for 30 minutes. . 309 mg (2.55 mmol) of 1,3-propanesultam was slowly added to the reaction solution at 0 ° C, and the mixture was stirred at room temperature for 12 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain 480 mg (yield: 93%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.96 (d, 1H), 7.77 (m, 1H), 7.64 (m, 2H), 3.75 (t, 2H), 3.38 (m, 2H), 2.44 ( m, 2H).

Step 2) 2- (2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino Preparation of Pyrimidin-4-yl) amino) phenyl) isothiazol 1,1-dioxide

Step 3) of Example 1, except that the compound prepared in Step 1) is used instead of N -methyl- N- (2-nitrophenyl) methanesulfonamide in Step 3) of Example 1 To give 112 mg (final step yield: 64%) of the title compound in the same manner as in step 7).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 8.30 (d, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.43 (d, 1H), 7.34 ( d, 1H), 7.24 (m, 1H), 7.15 (m, 1H), 6.62 (s, 1H), 6.46 (d, 1H), 3.75 (s, 3H), 3.70 (m, 2H), 3.63 (m , 2H), 3.53 (m, 3H), 2.66 (m, 4H), 2.47 (m, 2H), 2.39 (m, 4H), 2.18 (s, 3H), 1.84 (m, 2H), 1.50 (m, 2H), 1.24 (m, 2H); MS (ESI < + >): m / z = 627.2 [M + H] ⁺ .

Example 35 5-chloro- N -(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -4- (1- (methylsulfonyl) -1 H Preparation of Indo-3-yl) pyrimidin-2-amine

Step 1) 3- (2,5-Dichloropyrimidin-4-yl) -1- (methylsulfonyl) -1 H Production of indole

300 mg (1.14 mmol) of 3- (2,5-dichloropyrimidin-4-yl) -1 H -indole (see manufacturing method WO201301148) was diluted in 5 ml of N, N -dimethylformamide, 60% 68 mg (0.71 mmol) of sodium hydride were added slowly at 0 ° C. and stirred for 30 minutes. 97 μl (1.25 mmol) of methanesulfonyl chloride was slowly added to the reaction solution at 0 ° C., followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure to obtain 190 mg (yield: 49%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.96 (d, 1H), 8.62 (d, 1H), 8.44 (m, 1H), 7.97 (m, 1H), 7.52 (m, 2H).

Step 2) 5-chloro- N -(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -4- (1- (methylsulfonyl) -1 H Preparation of Indo-3-yl) pyrimidin-2-amine

The compound prepared in step 1) instead of N- (2-((2,5-dichloropyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide in step 7) of Example 1 Except for the use, the procedure was carried out in the same manner as in Step 7) of Example 1 to obtain 50 mg of the title compound (final step yield: 28%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (s, 1H), 8.47 (d, 2H), 8.23 (s, 1H), 7.87 (d, 1H), 7.43 (t, 1H), 7.28 ( d, 1H), 7.23 (m, 1H), 6.66 (s, 1H), 6.49 (m, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 3.59 (m, 3H), 2.69 (m , 4H), 2.41 (m, 4H), 2.21 (s, 3H), 1.98 (m, 2H), 1.55 (m, 2H), 1.24 (m, 2H); MS (ESI < + >): m / z = 610.2 [M + H] ⁺ .

Example 36 5-chloro- N ² -(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl)- N ⁴ -(1- (methylsulfonyl) -1 H Preparation of Indo-7-yl) pyrimidine-2,4-diamine

Step 1) 1- (methylsulfonyl) -7-nitro-1 H Production of indole

500 mg (3.08 mmol) of 7-nitroindole was diluted in 10 mL of N, N -dimethylformamide, and 185 mg (4.63 mmol) of 60% sodium hydride was slowly added at 0 ° C., followed by stirring for 30 minutes. A solution of 389 mg (3.39 mmol) of methanesulfonyl chloride in 5 ml of N, N -dimethylformamide was slowly added to the reaction solution at 0 ° C., followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (n-hexane: ethyl acetate = 2: 1 (volume ratio)) to give 430 mg of the title compound (yield: 58). %) Was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.83 (d, 1H), 7.75 (d, 1H), 7.61 (d, 1H), 7.36 (t, 1H), 6.81 (d, 1H), 3.67 (s, 3H).

Step 2) 1- (methylsulfonyl) -1 H Preparation of Indole-7-amine

430 mg (1.79 mmol) of the compound prepared in step 1) was diluted with 15 ml of ethyl acetate, and 10 wt% 60 mg was added thereto, followed by stirring for 4 hours under hydrogen gas. When the reaction was completed, the resultant reaction mixture was washed with a celite-filled filter with ethyl acetate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (n-hexane: ethyl acetate = 4: 1 (volume ratio)). 280 mg (yield 74%) of the title compound were obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.48 (s, 1H), 7.07 (m, 2H), 6.63 (m, 2H), 4.75 (s, 2H), 3.41 (s, 3H).

Step 3) N -(2,5-dichloropyrimidin-4-yl) -1- (methylsulfonyl) -1 H Preparation of Indole-7-amine

280 mg (1.33 mmol) of the compound prepared in step 2) and 269 mg (1.46 mmol) of 2,4,5-trichloropyrimidine were diluted in 5 ml of N, N -dimethylformamide and 368 mg of potassium carbonate ( 2.66 mmol) was added, followed by stirring at 70 ° C. for 12 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue obtained by filtration under reduced pressure and distillation under reduced pressure was separated by column chromatography (n-hexane: ethyl acetate = 2: 1 (volume ratio)) to give 160 mg of the title compound (yield: 34). %) Was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.98 (s, 1H), 8.26 (s, 1H), 7.74 (d, 1H), 7.52 (d, 2H), 7.38 (t, 1H), 6.72 (d, 1H), 3.22 (s, 3 H).

Step 4) 5-chloro- N ² -(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl)- N ⁴ -(1- (methylsulfonyl) -1 H Preparation of Indo-7-yl) pyrimidine-2,4-diamine

The compound prepared in step 3), instead of N- (2-((2,5-dichloropyrimidin-4-yl) amino) phenyl) -N -methylmethane sulfonamide in step 7) of Example 1 Aside from using, the same procedure as in Step 7) of Example 1 gave 12 mg (17% of final step yield) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 8.40 (s, 1H), 7.92 (d, 2H), 7.84 (d, 2H), 7.67 (m, 2H), 7.19 ( d, 1H), 6.84 (d, 1H), 6.45 (m, 1H), 4.12 (s, 3H), 3.99 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 2.84 (m , 3H), 2.69 (m, 6H), 2.15 (m, 2H), 1.82 (m, 2H), 1.57 (m, 2H); MS (ESI < + >): m / z = 625.2 [M + H] ⁺ .

Experimental Example 1: Ba / F3 EGFR del19 / T790M / C797S cell growth inhibition test

In this Experimental Example, the effect of the compounds obtained in Examples 1 to 36 to the activity of the cells expressing the EGFR del19 / T790M / C797S variant. To this end, Ba / F3 cell line (Crown bio) having a EGFR del19 / T790M / C797S mutation was confirmed, the cell growth inhibition effect of the addition of the compound as follows. Cell growth conditions, on the other hand, were RPMI Medium 1640 (1 ×) medium containing 10% FBS and 1% penicillin / straptomycin (Gibco BRL).

Specifically, the cell line stored in the liquid nitrogen tank was taken out and rapidly dissolved at 37 ° C., and then centrifuged to remove the cryopreservation medium. The recovered cell pellets were mixed well in the culture medium and placed in a culture flask and passaged under 37 ° C. and 5% carbon dioxide conditions to stabilize the cells by logarithmic growth. Cells were then taken from the flask, centrifuged to remove culture medium, washed with DPBS (Dulbecco's Phosphate Buffered Saline), centrifuged to remove DPBS and diluted to 1 × 10 ⁵ cells / ml with culture medium. . The diluted cells were dispensed at 100 μl per well in 96-well plates. The compounds prepared in the above examples were dissolved in 99.5% dimethyl sulfoxide (hereinafter DMSO, cell culture grade) to 10 mM each. Each compound-containing DMSO solution was diluted in a culture medium at a concentration of 30 μM and then diluted 10 times stepwise to prepare a solution diluted to 0.3 nM (wherein the final DMSO concentration was 1% or less).

50 µl of the test solution of each compound was added to a 96-well plate from which cells were dispensed, and the final concentration of 10 µM to 0.1 nM was added to 150 µl per well. The cells treated with the test solution were incubated for 72 hours under 37 ° C. and 5% carbon dioxide conditions. The cells were then incubated in a 96-well plate for 30 minutes at room temperature, and then 50 μl of CellTiter-Glo ^® Luminescent Cell Assay Reagent (CTG, Promega) was dispensed per well. After stabilizing the luminescence signal for 10 minutes, the luminescence intensity was measured with a microplate reader.

Based on the measured values, the initial cell density value was subtracted from the final cell density value of the wells that were not treated with the test substance, and the value of GI _{50 was} determined at the concentration at which each compound inhibited cell growth by 50%. Was calculated. The GI ₅₀ value of each compound was determined by nonlinear regression of GraphPadprism; log [inhibitor] vs. It was calculated using normalized response analysis, and the results are shown in Table 1 below.

Experimental Example 2: Evaluation of EGFR Enzyme Inhibitory Activity

In this experimental example, it was intended to confirm whether the compound obtained in Example 1 exhibits EGFR normal (WT) or mutant (T790M / L858R, del19 / T790M / C797S) inhibitory activity. To this end, the evaluation of enzyme inhibition activity was evaluated by Reaction Biology (MA, USA), a simple test method is described as follows.

Each enzyme human EGFR WT, EGFR T790M / L858R or EGFR del19 / T790M / C797S was mixed with 0.2 mg / ml of poly [Glu: Tyr] (4: 1) substrate and 10 μM of ATP together with the compound for phosphorylation of the substrate. Measured.

Specifically, the compounds prepared in the Examples were made with 10 mM DMSO solution, from which they were diluted 1/10 multiples up to 0.1 nM. Add substrate to kinase solution (20 mM Hepes (pH7.5), 10 mM MgCl ₂ , 1 mM EGTA, 0.02% Brij35. 0.2 mg / ml BSA, 0.1 mM Na ₃ VO ₄ , 2 mM DTT, 1% DMSO) And the enzymes were mixed lightly after each addition. To the mixed solution was added a compound prepared using Acoustic Technology (Echo550; nanoiter range) and reacted for 20 minutes at room temperature. Thereafter, ³³ P-ATP was further added, followed by reaction at room temperature for 2 hours. After measuring the kinase activity permeated through the filter IC ₅₀ was calculated using Graphpad Prism Sigmoidal dose-response (variable slop), the results are shown in Table 2 below.

Claims (14)

Compounds, solvates, stereoisomers or pharmaceutically acceptable salts thereof represented by the formula (I)
[Formula I]

In Formula I,
Cy ₁ is C ₃ -C ₁₀ aryl or C ₃ -C ₁₀ heteroaryl, wherein the aryl or heteroaryl is halogen, hydroxy group, thiol group, cyano group, C ₁ -C ₆ alkyl group, and C ₁ -C ₆ alkoxy group May have one or more substituents selected from the group consisting of;
m is an integer from 0 to 5;
n is an integer from 1 to 4;
X is -NH- or -C-;
R ₁ and R ₂ are independently of each other a C ₁ -C ₆ alkyl group;
R ₃ is selected from hydrogen, halogen, hydroxy group, thiol group, cyano group, C ₁ -C ₆ roalkyl group, and -C (O) OR ₆ , wherein R ₆ is C ₁ -C ₅ alkyl group;
R ₄ is selected from hydrogen, halogen, thiol group, cyano group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, and C ₁ -C ₆ haloalkyl group;
R ₅ is selected from hydrogen, halogen, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ hydroxyalkyl group;
Here, when R ₂ is X is -C-, X and R ₂ may be fused to form a 4- to 7-membered heteroaryl ring with the atoms to which they are bonded, or R ₂ is R ₁ or R ₅ Fused with to form a 5-7 membered heteroaryl or heterocycloalkyl ring with the atoms to which they are attached; And
Y is -Z- (CH ₂ ) _a -Q ₁ -Q ₂ ,
Wherein Z is absent or is selected from carbonyl (-CO-), amide (-CONH-), -S- and -O-,
A is an integer of 0 to 6,
Q ₁ is a C ₃ -C ₁₀ heterocycloalkyl group, or C ₆ -C ₁₀ heterobicycloalkyl, the heterocycloalkyl group or heterobicycloalkyl group is halogen, hydroxy group, thiol group, cyano group, C ₁ -C ₆ May have one or more substituents selected from the group consisting of alkyl groups,
Q ₂ is selected from hydrogen, a C ₁ -C ₆ alkyl group, and a C ₃ -C ₁₀ heterocycloalkyl group, wherein the heterocycloalkyl group consists of a halogen, a hydroxy group, a thiol group, a cyano group, and a C ₁ -C ₆ alkyl group It may have one or more substituents selected from the group. The compound of claim 1, wherein Cy ₁ is C ₃ -C ₁₀ aryl or C ₃ -C ₁₀ heteroaryl;
m is 0 or 1;
n is an integer of 1 or 2;
X is -NH- or -C-;
R ₁ and R ₂ are independently of each other a C ₁ -C ₆ alkyl group;
R ₃ is selected from hydrogen, halogen, cyano and a C ₁ -C ₆ haloalkyl group and —C (O) OR ₆ , wherein R ₆ is C ₁ -C ₃ alkyl group;
R ₄ is selected from hydrogen, halogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, and a C ₁ -C ₆ haloalkyl group;
R ₅ is selected from hydrogen, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ hydroxyalkyl group;
Here, with the R ₂ when X is -C-, X and R ₂ are, or may form a heteroaryl ring of 5 to 7 members together and fused to atom to which they are attached, wherein R ₂ is R ₁ or R ₅ May be fused together with the atoms to which they are attached to form a 5-7 membered heteroaryl or heterocycloalkyl ring; And
Y is -Z- (CH ₂ ) _a -Q ₁ -Q ₂ ,
Wherein Z is absent or is selected from carbonyl (-CO-), amide (-CONH-), and -S-,
A is an integer of 0 to 3,
Q ₁ is a C ₃ -C ₁₀ heterocycloalkyl group, or a C ₆ -C ₁₀ heterobicycloalkyl group, wherein the heterocycloalkyl group or heterobicycloalkyl group may have at least one C ₁ -C ₆ alkyl group as a substituent ,
Q ₂ is selected from hydrogen, a C ₁ -C ₆ alkyl group, and a C ₃ -C ₁₀ heterocycloalkyl group, wherein the heterocycloalkyl group may have at least one C ₁ -C ₆ alkyl group as a substituent, Solvates, stereoisomers or pharmaceutically acceptable salts thereof. The compound of claim 1, wherein Cy ₁ is phenyl or pyrazole;
m is 0 or 1;
n is an integer of 1 or 2;
R ₁ and R ₂ are independently of each other a C ₁ -C ₆ alkyl group;
R ₃ is selected from hydrogen, halogen, cyano and a C ₁ -C ₆ haloalkyl group and —C (O) OR ₆ , wherein R ₆ is C ₁ -C ₃ alkyl group;
Here, the R ₂ and X are the days when -C-, X and R ₂ are fused to, or may form a heteroaryl ring of 5 together with the atom to which they are attached, wherein R ₂ is fused with R ₁ or R ₅ Together with the atoms to which they are attached may form a five-membered heteroaryl or heterocycloalkyl ring; And
Y is -Z- (CH ₂ ) _a -Q ₁ -Q ₂ ,
Wherein Z is absent or is selected from carbonyl (-CO-), amide (-CONH-), and -S-,
A is an integer of 0 to 3,
Q ₁ is piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 3,9-diazaspiro [5.5] undecanyl, 2,6-diazaspiro [3.3] heptanyl, and 2,5-diazabicyclo [2.2.1] heptanyl, and the piperazinyl may have one or more C ₁ -C ₆ alkyl groups as substituents,
Q ₂ is selected from hydrogen, C ₁ -C ₆ alkyl group, and piperazinyl, wherein piperazinyl may have one or more C ₁ -C ₆ alkyl groups as substituents, compounds, solvates, stereoisomers or Pharmaceutically acceptable salts thereof. The compound, solvate, stereoisomer or pharmaceutically acceptable salt thereof of any one of claims 1 to 3, wherein R ₂ is a C ₁ -C ₆ alkyl group. The compound, solvate, stereoisomer or pharmaceutically acceptable salt thereof of claim 4, wherein R ₂ is a methyl group. The compound, solvate, stereoisomer or pharmaceutically acceptable salt thereof of claim 1, selected from the group consisting of:
N- (2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2- (5-chloro-2-((2-methoxy-4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) phenylamino) pyrimidine-4 -Yl) amino) phenyl) -N -methylmethanesulfonylamide;
Isopropyl 2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -4-((2- ( N -methyl Methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate;
N- (2-((5-chloro-2-((3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((2-((3-fluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl ) Amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((2,3-difluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino ) Pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((2-((2,3-difluoro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine- 4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((3-fluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) pyri) Midin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((2-methoxy-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) pyri) Midin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((3-methyl-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) -3- (trifluoromethyl) phenyl ) Amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((3,5-difluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) Amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((5-fluoro-2-methoxy-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) Phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-cyano-2-((3-fluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) Pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((2-((3-fluoro-4- (9-methyl-3.9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) -5- (trifluoro Methyl) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-bromo-2-((3-fluoro-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl) amino) Pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((3-fluoro-4- (6-methyl-2,6-diazaspiro [3.3] heptan-2-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((2-methoxy-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N -methyl Methanesulfonamide;
N- (2-((5-chloro-2-((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide ;
N- (2-((5-chloro-2-((3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N Methylmethanesulfonamide;
N- (2-((5-chloro-2-((2,3-difluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl ) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((3-fluoro-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino ) Phenyl) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((5-fluoro-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino ) Phenyl) -N -methylmethanesulfonamide;
N - (2 - ((5- chloro-2 - ((2-methoxy -4 - ((1 S, 4 S) -5- methyl-2,5-diazabicyclo [2.2.1] heptane -2 -Yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N - (2 - ((5- chloro-2 - ((2-methoxy -4 - ((3 S, 5 R) -3,4,5- trimethyl-l-yl) phenyl) amino) Pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((4- (4-ethylpiperidin-1-carbonyl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl)- N -methylmethanesulfonamide;
4-((5-chloro-4-((2- ( N -methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxy- N- (1-methylpiperi Din-4-yl) benzamide;
4-((5-chloro-4-((2- ( N -methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxy- N- (2- (pyrroli Din-1-yl) ethyl) benzamide;
N- (2-((5-chloro-2-((2-methoxy-4- (morpholinomethyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide ;
N- (2-((5-chloro-2-((2-methoxy-4-((3-morpholinopropyl) thio) phenyl) amino) pyrimidin-4-yl) amino) phenyl)- N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4-yl) amino) -5- (hydroxymethyl) phenyl) -N -methylmethanesulfonamide;
N- (2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4-yl) amino) benzyl) -N -methylmethanesulfonamide;
N- (4-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4-yl) amino) -1-methyl-1 H -pyrazol-3-yl) -N -methylmethanesulfonamide;
2- (2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine -4-yl) amino) phenyl) isothiazolidine-1,1-dioxide;
5-Chloro- N- (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -4- (1- (methylsulfonyl)- 1 H -indol-3-yl) pyrimidin-2-amine;
5-Chloro - N ² - (2- methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) - N ⁴ - (1- (methylsulfonyl ) -1 H -indol-7-yl) pyrimidine-2,4-diamine. A pharmaceutical composition for preventing or treating cancer with an EGFR mutation, comprising the compound of claim 1, a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 7, wherein the EGFR mutation is an activating EGFR mutation, a mutation that causes resistance to an EGFR inhibitor, or a combination thereof. The pharmaceutical composition of claim 8, wherein the activating EGFR mutation is del19, L858R, or a combination thereof. The pharmaceutical composition of claim 8, wherein the mutation causing resistance to the EGFR inhibitor is T790M, C797S, or a combination thereof. The pharmaceutical composition of claim 7, wherein the cancer with the EGFR mutation is a cancer with the C797S mutation. The method of claim 7, wherein the cancer is lung cancer, liver cancer, esophageal cancer, gastric cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethra A pharmaceutical composition selected from the group consisting of cancer, bladder cancer, testicular cancer, hematologic cancer, lymphoma, skin cancer, psoriasis and fibroadenoma. The pharmaceutical composition of claim 7, wherein the cancer is non-small cell lung cancer. The pharmaceutical composition of claim 7 formulated in a pharmaceutically acceptable form comprising tablets, pills, powders, capsules, syrups, emulsions or microemulsions.