WO2019177375A1 - 2, 4, 5-substituted pyrimidine derivatives, method for preparing same, and pharmaceutical composition for preventing or treating cancer comprising same as active ingredient - Google Patents

Abstract

The present invention relates to 2, 4, 5-substituted pyrimidine derivatives, a method for preparing same, and a pharmaceutical composition for preventing or treating cancer comprising same as an active ingredient. Since the compound exhibits a high inhibitory ability against the epidermal growth factor receptor (EGFR) wild type or mutation, the compound can be effectively used for the treatment of cancer expressing the EGFR wild type or EGFR mutation. The compound has an excellent ability to inhibit the proliferation of lung cancer cell lines and can be particularly useful for the treatment of lung cancer.

Description

 【Specification】

 [Name of invention]

 2, 4,5-substituted pyrimidine derivatives, gymnastic methods thereof and pharmaceutical compositions for the prevention or treatment of cancer comprising the same as active ingredients

Technical Field

 2,4,5-substituted pyrimidine derivatives, a preparation method thereof and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.

Background Art

The incidence of cancer is related to various environmental factors, including chemicals, radiation, and viruses, as well as changes in oncogenes, tumor suppressor genes, and genes involved in apoptosis and DNA repair. Understanding this mechanism has enabled new chemotherapy targeted chemotherapy. Targeted therapies are generally designed to target the molecules that are characteristic of cancer cells and to have an effect. The molecular targets are the si gnal transduct ion pathway and angiogens of cancer cells. Genes involved in cell matrix, cell cycle regulators, and apoptosis. Currently used as important target therapeutics in therapy include ¹ signaling pathway inhibitors, including tyrosine kinase inhibitors' and angiogenesis inhibitors ¹ . Protein tyrosine kinase has been shown to play an important role in many malignant tumors. In particular, epidermal growth factor receptor (EGFR), a receptor tyrosine kinase of the erbB family, is a non-small cell lung cancer. Abnormally active in many epithelial cell tumors, including species (NSCLC), breast cancer, glioma, squamous cell carcinoma of the head and neck, colorectal cancer, rectal carcinoma, head and neck cancer, gastric cancer and prostate cancer, and the EGFR-tyrosine kinase It is known that activation leads to continuous cell proliferation, invasion of surrounding tissues, distant metastasis, angiogenesis and increased cell survival. Specifically, the EGFR is one of the ErbB tyrosine kinase receptors family (EGFR, HER-2, ErbB-3, ErbB-4), and the extra race 11 uar ligand-binding domain. It is a transmembrane tyrosine kinase (t ransmembr ane tyrosine kinase) with an intrace 1 lu lar domain including the tyros ine kinase domain. When a ligand binds to a homodimer or heterodimer receptor, Tyrosine kinase in the body is activated and the signal stimulated by EGFR is the phosphatidyl inosi tol 3-kinase (PI3K) / AKT / inT0R, RAS / RAF / MAPK, JAK / STAT signaling pathway. (Nat Rev Cancer 2007: 7: 169-81).

EGFR is particularly overexpressed in more than half of non-sma 11 cell 1 ungcancers (NSCLCs), and many studies have been conducted as targets for treatment. EGFR tyrosine kinase inhibitors (TKIs) have been developed to inhibit EGFR tyrosine kinase activity. Representative agents include zephytinib (IRESSAä), erlotinib (TARCEVAä) and lapatinib (TYKERBä, TYVERBä). On the other hand, it was reported that the activating mutation of EGFR in 2004 correlated with the response to zephytinib therapy in non-small cell lung cancer (NSCLC: non-sma 11 -cel 11 ungcancer) (Science [2004] Vo 1.304, 1497). -500 and New England Journal of Medicine [2004] Vo 1. 350, 2129-39).

 Specifically, the EGFR mutation is classified into a sensitizing mutation and a resi stant mutation. Deletion of exon 19 and L858R point mutation of exon 21 are the most important susceptibility mutations. It accounts for about 85 to 90%, and exon 19 del mutations are known to be more susceptible to TKI. In contrast, the T790M point mutation of exon 20 is the most important resistance mutation and is known to be found in more than 50% of acquired resistant patients (Clin Cancer Res 2006; 12: 6494-6501.). The somatic mutations identified thus far include point mutations in exon 19 or insertion into exon 20, as well as point mutations in which a single nucleic acid residue is modified in the expressed protein (eg, L858R, G719S, G719C, G719A,

L861Q) (Fukuoka et al. JC0 2003; Kris et al JAMA 2003 and Shepherd et al NEJM 2004).

Despite the initial clinical effects of zefitinib / erlotinib in NSCLC patients with EGFR mutations, most patients eventually develop advanced cancer during therapy with these agents. Early studies of relapsed samples identified a secondary EGFR mutation, T790M, which makes zefitinib and erlotinib ineffective inhibitors of EGFR kinase activity (Kobayashi et al NEJM 2005 and Pao et al PL0S Medicine 2005). Subsequent studies have demonstrated that EGFR T790M mutations were found in approximately 50% (24/48) of patient-derived tumors that acquired resistance to zephytinib or erlotinib (Kosaka et al CCR 2006; Balak et a 1 CCR). 2006 and Engelman et al Science 2007). This secondary genetic modification is caused at a position similar to a 'gatekeeper' residue and its associated secondary allele in a patient treated with a kinase inhibitor (eg, T315I in ABL in imatinib resistant CML). It has long been known that the EGFR mutations EGFR_dell9 or EGFR_L858R are the major causes of non-small cell lung cancer and head and neck cancer, and their therapeutic drugs, Iresa and Taceva, have been developed and are currently used in clinical practice. However, when these drugs were used in patients, acqui red resistance to EGFR secondary mutations based on the structure of the drug was observed, which was found to be a major cause of drug resistance. If EGFR first generation inhibitors are used for an average of about 10 months, the acquisition resistance of the T790M mutation located in the gatekeeper of the EGFR kinase may occur, preventing the EGFR first generation inhibitors from taking effect. In other words, EGFR_deU9_T790M or EGFR_L858R_T790M double mutations occur, preventing the existing therapeutic from showing efficacy.

[Detailed Description of the Invention]

 [Technical problem]

 It is an object of the present invention to provide 2, 4, 5-substituted pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof. Another object of the present invention is to provide a method for preparing the 2,4,5-substituted pyrimidine derivatives. Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer containing the 2,4,5-substituted pyrimidine, derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient. To provide. Another object of the present invention to provide a health functional food composition for the prevention or improvement of cancer containing the 2,4,5-substituted pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient. It is.

Technical Solution

 In order to achieve the above object,

 According to one aspect of the present invention, there is provided a compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:

[Formula 1] 2019/177375 1 »（： 1 ^ 112019/002915

 4

 (In Formula 1,

요¹은 비치환 또는 치환된

， 0 및 £로 이 루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5 내지 15원자의 헤테로아릴이고 ,

/ \

¹ is unsubstituted or substituted

Unsubstituted or substituted 5 to 15 membered heteroaryl containing one or more heteroatoms selected from the group consisting of 0 and £,

Cycloalkyl, or 0 and at least one selected being the one or more heteroatoms from the group comprising unsubstituted or substituted 3 to 10 membered heterocycloalkyl or heterocycloalkyl of 3 to 10 atoms of atoms consisting of (:卜₃ alkyl ，

The substituted aryl, heteroaryl, cycloalkyl, and heterocycloalkyl _ ((= 0), !? ^5, - ^5, - I, - to ^6, halogen, a linear or branched-alkyl and straight- or ₅ It can be optionally substituted with one or more selected from the group consisting of _5-alkoxy, cat ^5, I ^6, and ^ is a linear or branched independently (-branched ₅ alkyl or four犯¾ ^{9, Requirement,} and John ⁹ is independently hydrogen or straight or branched- ₅ alkyl; is hydrogen or straight or branched (: ^ ^ ₅ alkoxy; John ³ is internal ^{10 1} or -A ² ,

Wherein, 요, ^{11 11} and ^{12 12} are independently hydrogen or alkyl of straight or branched chain, wherein one or more substituents may be substituted with one or more amines substituted with the alkylshon unsubstituted or straight or branched ^ _-5 alkyl. And

Or groups ^{1 ()} and ¹¹ , together with the atoms to which they are attached, form a 3 to 10 membered unsubstituted or substituted heterocycloalkyl comprising at least one hetero atom selected from the group consisting of 0 and 3; Wherein said substituted heterocycloalkyl may be substituted with at least one substituted with one or more linear or branched- ₅ alkyl and unsubstituted or straight or branched- ₅ alkyl. And it may be substituted with one or more selected from the group consisting of 5 to 10 atoms of heterocycloalkyl containing one or more hetero atoms selected from the group consisting of S). According to another aspect of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of cancer, containing the compound represented by the formula (1), its optical isomer or pharmaceutically acceptable salt thereof as an active ingredient. According to another aspect of the present invention, there is provided a health functional food for preventing or improving cancer containing the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. According to another aspect of the invention, the cancer comprising the step of administering a pharmaceutical composition or nutraceutical composition containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof Prophylactic or therapeutic methods are provided. According to another aspect of the present invention, there is provided a use of a pharmaceutical composition or nutraceutical composition containing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer.

Advantageous Effects

 Since the 2,4,5-substituted pyrimidine derivatives according to the present invention exhibit a high inhibitory effect against EGFR (epidermal growth factor receptor) wild type or mutation, it can be usefully used for the treatment of cancer expressing EGFR wild type or EGFR mutation. It is excellent in inhibiting lung cancer cell line proliferation, and in particular, it can be usefully used for the treatment of lung cancer.

[Best form for implementation of the invention]

 Hereinafter, the present invention will be described in detail. One aspect of the present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1] 02019/177375 1 »(^ 1 {2019/002915

 6

0 및 으로 이 루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 하나 이상 포함하는 비치환 또는 치환된 5 내지 15원자의 헤테로아릴이고，

An unsubstituted or substituted 5 to 15 membered heteroaryl containing one or more heteroatoms selected from the group consisting of 0 and

Where, is unsubstituted or substituted (: _6-14 aryl, straight or branched _-10 alkyl, straight or branched -alkoxy- ₃ alkyl, unsubstituted or substituted ◦cycloalkyl or 0 and Unsubstituted or substituted 3 to 10 membered heterocycloalkyl or 3 to 10 membered heterocycloalkyl containing from one or more heteroatoms selected from the group 0 _1-3 alkyl,

The substituted aryl, heteroaryl, cycloalkyl and heterocyclo alkyl may be selected from _ (: (= 0) ·! ⁵ , ^-5 ,-· (= 0) 1 -¾ ⁷ , halogen, straight or branched chain- ₅ alkyl and linear or branched and may be substituted with one or more selected from the group ^(consisting of wi alkoxy chain, all ^5, and seedlings ⁷ is a linear or branched independently - a _5-alkyl or naemyo ¾ ^9, seedlings ⁸ And ^ is independently hydrogen or straight or branched -5 alkyl;

And ^{12 10 one} or -0 seedlings, - A ^3, -, are hydrogen or linear or branched (^ ₁₀ alkoxy

Wherein, yo ¹ o, yo ¹¹ and yo ¹² are independently hydrogen or alkyl of straight or branched chain, wherein said alkyl is unsubstituted or substituted with one or more amines substituted with one or more of _-5 alkyl of straight or branched chain. Can,

Or ¹⁾ and ^{11 )} together with the N atom to which they are attached form a 3-10 membered unsubstituted or substituted heterocycloalkyl comprising at least one hetero atom selected from the group consisting of 0 and Wherein said substituted heterocycloalkyl is zero or one substituted with one or more linear or branched- ₅ alkyl and unsubstituted or straight or branched ^ _-5 alkyl. 2019/177375 1 »（： 1 ^ 112019/002915

 It may be substituted with one or more selected from the group consisting of 5 to 10 atoms of heterocycloalkyl containing one or more hetero atoms selected from the group consisting of 7 and. The compound represented by Formula 1 may be a compound represented by Formula 13 below.

 [Formula 1

 (In the above formula,

Is unsubstituted or substituted aryl, unsubstituted or substituted 5 to 15 membered heteroaryl containing one or more heteroatoms selected from the group consisting of- ⁴ or 0 and

Wherein is at least one hetero atom selected from the group consisting of unsubstituted or substituted (: _6-14 aryl, linear or branched ^ _-10 alkoxy- ₃ alkyl, unsubstituted or substituted- ₁₀ cycloalkyl or 0 and Unsubstituted or substituted 3 to 10 membered heterocycloalkyl or 3 to 10 membered heterocycloalkyl- ₃ alkyl containing one or more

The substituted aryl, heteroaryl, cycloalkyl and heterocyclo alkyl may be selected from-(: (= 0 ⁵ ,-的 八⁵ ,-·, ⑴ ⁷ , halogen, straight or branched- ₅ alkyl and straight or branched chain. _May be substituted with one or more selected from the group consisting of ₅ alkoxy, V ⁵ , Y ⁶ and are independently linear or branched 0 ^ ₅ alkyl or ⁹ in, V ⁸ and ⁹ are independently hydrogen Or straight or branched (^ _-5 alkyl; is hydrogen or straight or branched (: ^ ₀ alkoxy; is in ¹¹ or -0 ² ,

Wherein. And ¹ are independently hydrogen, straight or branched chain, 0 _1-5 alkyl or ¹ %-; _? Alkyl, ² is hydrogen or ¹ %- _:? Alkyl, wherein ³ , ⁴ , V ¹⁵ and ⁶ are independently hydrogen or linear or branched _-5 alkyl, and ¹ and ¹ are unsubstituted or substituted 5-8 membered heterocyclo together with the atoms to which they are attached Alkyl may be formed, wherein the heterocycloalkyl may further include one or more, wherein the substituted heterocycloalkyl may be linear or branched- ₅ alkyl and non- 2019/177375 1 »（： 1 ^ 1 {2019/002915

To be substituted with one or more selected from the group consisting of 5 to 10 atoms of heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of 0 and one or more substituted with one or more substituted by one or _five alkyl, linear or branched chain. Can be. In Chemical Formula 1 ₃ ,

The unsubstituted or substituted 5 to 10 membered heteroaryl containing at least one heteroatom selected from the group consisting of: unsubstituted or substituted ( _6-10 aryl, -0 or 0 and £); Wherein, is an unsubstituted or substituted -aryl, straight or branched chain

^ _-5 alkoxy- ₃ alkyl, unsubstituted or substituted- ₇ cycloalkyl or unsubstituted or substituted 3 to 7 membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of I 0 and on or 3 to 7 membered heterocycloalkyl (ᅱ alkyl,

The substituted aryl, heteroaryl, cycloalkyl and heterocyclo alkyl may be selected from-(: (= 0) a,-八⁵ ,-■ 的⁵ , -P (= 0) Y ⁶ Y ⁷ , straight or branched chain May be substituted with one or more substituents selected from the group consisting of _-3 alkyl and straight or branched _-3 alkoxy, and 먕 and are independently straight or branched ( _-3 alkyl or ^-9 , V ⁸ And I ⁹ is independently hydrogen or straight or branched ( _-3 alkyl); Is hydrogen or straight or branched- ₅ alkoxy; Is my ¹¹ or -0 ² ，

Wherein. And ¹ are independently hydrogen, linear or branched 0 _1-3 alkyl or ¹ ; ¹⁴ (： 卜₃ alkyl, ² is hydrogen or alkyl, and V ¹³ , ⁴ , V ¹⁵ and ⁶ are independent Or hydrogen or a straight or branched chain ( _-3 alkyl), or and may form an unsubstituted or substituted 5 to 8 membered heterocycloalkyl together with the atoms to which they are attached, wherein the heterocycloalkyl And may further include one or more silver, wherein the substituted heterocycloalkyl is selected from the group consisting of 0 and one or more substituted with one or more linear or branched alkyl and unsubstituted or linear or branched (^ _-3 alkyl). It may be substituted with one or more selected from the group consisting of 5 or 6 membered heterocycloalkyl containing one or more heteroatoms selected. In addition, in the formula 1å1,

Is unsubstituted or substituted phenyl,-· ^-4 or unsubstituted or substituted indolinyl,

Wherein at least one hetero atom selected from the group consisting of unsubstituted or substituted phenyl, straight or branched chain 0 _1-3 alkoxy ^ _-2 alkyl, unsubstituted or substituted (： _3-5 cycloalkyl or 0 and One 2019/177375 1 »（： 1 ^ 1 {2019/002915

It is an unsubstituted or substituted 5 or 6 membered heterocycloalkyl or 5 or 6 membered heterocycloalkylmethyl containing at least,

The substituted phenyl, indolinyl, cycloalkyl, and heterocycloalkyls may be selected from _ (： (= 0 川⁵ ,-介⁵ ,-애 ^^, ⁵ , (= 0 作⁷ , methyl, ethyl, methoxy and ethoxy It may be substituted with one or more substituents selected from the group consisting of, V ⁶ And is independently 0 _1-3 alkyl or ⁹ in a straight or branched chain, room and ^ is independently hydrogen or a straight or branched chain _-3 alkyl; Is hydrogen or straight or branched _-3 alkoxy; Is my ¹¹ or -0 ² ，

Here,. And ¹ are independently hydrogen, straight or from 0 _1-3 ¹⁴ alkyl or ethyl branched, ² is hydrogen or ^{ethyl. 16,} the ^3, 4, and ⁶ V ¹⁵ are independently hydrogen or straight or branched Or- ₃ alkyl of the chain,. And ¹ together with the four atoms to which they are attached may form an unsubstituted or substituted piperazine or piperidine, wherein the substituted piperazine and piperidine are methyl, ethyl and non- It may be substituted with one or more selected from the group consisting of piperazinyl substituted with one or more _-3 alkyl of a ring or a straight or branched chain.

ego ; 2019/177375 1 »（： 1 ^ gravy 2019/002915

 10 is hydrogen or methoxy;

본 발명에 따른 상기 화학식 로 표시되는 화합물의 예로는 하 기의 화합물들을 들 수 있다:

Examples of the compound represented by the above formula according to the present invention include the following compounds:

 <13-1>-(5-（(5- （3,6-dihydro-e-pyran-4-yl) -4-（(2- (isopropylsulfonyl) phenyl) amino) pyrimidine-2 -Yl) amino) -4 -methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

 <-2 ñ-（5-（（5- （3,6-dihydro _21-pyran- 4-yl) -4-（(2- (isoprosulsulfonyl) phenyl) amino) pyrimidin-2-yl ） Amino） -2-((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

 <1 3 ñ-(5-（（5- （3,6-dihydropyran-4-yl) -4-（(2- (dimethyl phosphpoly) phenyl) amino) pyrimidin-2-yl) amino） 2-((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, 2,2,2-trifluoroacetate;

 <比 -4 ñ-（5-（（5- （3,6-dihydropyran-411） -4-（(2-vs-dimethylsulfamoyl) phenyl) amino） pyrimidin-2-yl) amino ) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide, 2,2,2-trifluoroacetate;

 <13-5> （5-（（5- （3,6-Dihydro-ethoxypyran-4-yl)-4-（(2-tetra-dimethylsulfamoyl) phenyl) amino) pyrimidine- 2 -yl) amino)-2-((2- (dimethylamino) ethyl) (methyl) amino) -4 -methoxyphenyl) acrylamide, 2,2,2-trifluoroacetic acid salt;

 <18-6> 1 （5-（（5- （3,6-dihydro-la-pyran-4-yl)） 4-(（2,4-dimethoxyphenyl) amino） pyrimidine-2 Sun) amino)-2-((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, 2, 2, 2-trifluoroacetic acid salt;

<13-7> （5-（（5- （3,6-dihydro-211-pyran-4-group) -4-（(2- (methylsulfon ⁰ ] ・ mido) phenyl) ⁰ ] mino ） Pyrimidine-2-yl) ⁰ ] -mino) -2- (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, 2, 2, 2-trifluoro Furnace acetate;

<13-8 ñ (seed)--(5-（（5- （3,6-dihydro _ _ pyran-4 -yl) -4-（((tetrahydrofuran-2-yl) methyl) Amino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, 2, 2, 2-tri 2019/177375 1 »（： 1 ^ 1 {2019/002915

 11 fluoroacetic acid salt;

 <1 9 （（3-（（5- （3,6-dihydropyran-4-yl) -4-（(2-gawa-dimethylsulfamoyl) phenyl) amino） pyrimidin-2-yl) amino )-5- (4-methylpiperazin-1-yl) phenyl) acrylamide, 2,2,2-trifluoroacetic acid salt;

 <13-10 （（5-（（5- （3,6-dihydro_2_2pyran-4-yl) -4-（(2- (isopropylsulfony) phenyl) amino) pyrimidine-2 Sun) amino) -4-methoxy-2-(4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt ;

<13-11 2- 2-（（2-（（5-acrylamido-4-(（2- (dimethylamino) ethyl） (methyl) amino） -2-methoxyphenyl) amino） -2-5- （ 3,6-dihydro-211-pyran-4-yl) pyrimidin- ₄ -yl) amino)-methylbenzoamide 2,2,2-trifluoroacetic acid salt;

<13-12 (5-（（5- （3,6-dihydro-2 ^ 1-pyran-4-yl) -4- （1-methyl-in-indole-3-yl) pyrimidine-2 -yl) amino) - 4-methoxy-2- (4-methyl _piperazinyl, cinnabar-yl) phenyl) acrylamide;

<13-13>-(5-（（5- （3,6-dihydro-2 [amppyran-4-yl) -4--4-l-methyl-one indole-3-yl) pyrimidine-2 -Yl) amino)-2-((2- (dimethylamino) ethyl) (methyl) 0gmino) _-4 -methoxyphenyl) acrylamide;

 <13-14> （5-（（5- （3,6-dihydro _2｝ 卜 pyran-4-yl) -4- （1-methyl-in-indole-3-yl) pyrimidine-2-day ） Amino） -4-methoxy-2- （4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide 2,2,2-trifluoroacetate:

 <13-15 ᅡ ᅡ （5-（（5- （3,6-dihydro-e_pyran-4 4-yl) -4- （1-methyl-in-indole _3-yl) pyrimidine-2 2-day ) Amino)-(2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide 2,2,2-trifluoroacetate:

 <13-16 ñ (5-（（5- （3,6-dihydro-e-pyran-4-yl) -4- (in-indole-3-yl) pyrimidin-2-yl) amino)- 2-((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide 2,2,2- and trifluoroacetic acid salt;

 <13-17 （5-（（5- （3,6-dihydro-la-pyran-4-yl) -4-（(2-methoxyethyl) amino） pyrimidin 1- 2-yl) amino） 一2-((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide 2,2,2-trifluoroacetic acid salt:

 <13-18 1 1 （5-（（4- (cyclopropylamino)-5- （3,6-dihydro-sea-pyran-4-yl) pyrimidin-2-yl) amino） -2- ((2_ (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide;

<13-19--（5-（（5- （3,6-dihydro-la _pyran- 4-yl) -4-（(1-methylpyridin-4-yl) amino） pyrimidine- 2 -yl) amino)-2-((2- (dimethylamino) ethyl) (methyl) amino) -4 -methoxyphenyl) acrylamide 2,2,2-trifluoroacetate. The compound represented is shown in Scheme 13 below.

Compound represented by the formula (73) and compound represented by the formula (8) 2019/177375 1 »（： 1 ^ 1 {2019/002915

 12 reactions to prepare a compound represented by formula 53 (step 1);

 Preparing a compound represented by Chemical Formula 43 by reacting the compound represented by Chemical Formula 53 with the compound represented by Chemical Formula 63 (step 2);

 Reacting the compound represented by Chemical Formula 43 to prepare a compound represented by Chemical Formula 2 (step 3); and

 It may be prepared by a method for preparing a compound represented by the formula (13) comprising the step (step 4) of preparing a compound represented by the formula (13) by reacting the compound represented by the formula (23) and the compound represented by the formula (33).

 Scheme 13

(In Scheme 13,, X ² and are as defined in Formula 13; And

X ¹ , X ² and X ³ are independently halogen. Hereinafter, a method for preparing a compound represented by the above formula according to the present invention will be described in detail. Step 1 of Scheme 1å1 is a step of preparing a compound represented by Chemical Formula 5 by reacting a compound represented by Chemical Formula 73 with a compound represented by Chemical Formula 83. Specifically, halogen of the compound represented by Chemical Formula 7å1 and Chemical Formula 83 The primary amine of the compound represented by the reaction is a step of preparing a compound represented by the formula (53).

 Step 1 reaction of Scheme 13 is not particularly limited as long as it is a condition capable of combining amine and commonly known halogen and amine.

크 !!을 통하여 반응을 진행하였으며， 염기 및 금속 리간드 존재하에 반응을 수행하였으며， 상기 염기는 2019/177375 1»（：1^1{2019/002915 In the present invention

The reaction proceeded through !!, the reaction was performed in the presence of a base and a metal ligand, and the base 2019/177375 1 »（： 1 ^ 1 {2019/002915

통상적으로 사용하는 염기라면 한정되지 않고， -다이메틸아미노피리딘（아ᅵ쇼!⁵） , 피리딘， 트라이에틸아민， ， -다이 이소프로필에틸아민 , 1，8 -디아자비사이클로 [5.4.0]_7 -운데센 에） 등 의 유기염기 또는 소둠카보네이트， 소둠바이카보네이트 , 수산화나트륨， 수산화칼륨， 내 등의 무기염기가 있으며 ， 이를 단독 또는 혼합하여 ， 당량 또는 과량으로 사용할 수 있다. 또한, 상기 금속 리간드는 팔라 둠 , 니켈， 구리 리간드 등을 사용할 수 있다 . 본 발명의 일 실시예에 서는 팔라듐 리간드로서 ?（1₂（（比3）₃를 사용하였으나， 이는 일례일 뿐 , 이에 한정되는 것은 아니다. 13

It is not limited as long as it is a base commonly used, -dimethylaminopyridine (show! ⁵ ) organic bases such as pyridine, triethylamine, -diisopropylethylamine, 1,8-diazabicyclo [5.4.0] _7-undecene), sodomium carbonate, sodium bicarbonate, sodium hydroxide, There are inorganic bases, such as potassium hydroxide and the like, which can be used alone or in combination, equivalent or excess. In addition, as the metal ligand, palladium, nickel, copper ligand, or the like may be used. In one embodiment of the present invention,? (1 ₂ ((比 3) ₃ ) was used as the palladium ligand, but this is only an example, but is not limited thereto.

 The reaction solvent is a lower alcohol containing isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (Ya00, Dimethylsulphoxide (¾ 格 0), Methylene chloride, Dichloroethane, Water, Acetonazenesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Ethyl acetate, Phenyl acetate, Phenyl Propionate, Phenylbutyrate, Citrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate, Naphthalene-2-sulfonate, Mandel Latex, acetonitrile and the like, which may be used alone or in combination. Step 2 of Scheme 13 is a step of preparing a compound represented by Chemical Formula 43 by reacting a compound represented by Chemical Formula 53 with a compound represented by Chemical Formula 6, specifically, halogen and Chemical Formula 6 of the compound represented by Chemical Formula 53. Hydrogen of the compound represented by C is reacted to prepare a compound represented by Chemical Formula 43.

 The step 2 reaction of the above scheme is not particularly limited as long as the halogen and hydrogen are substituted.

The reaction solvent is a lower alcohol containing isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran (large; Dioxane; Ether solvents containing ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (10, dimethyl sulfoxide (01 0), methylene chloride, dichloroethane, water, acetonasulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, ethyl acetate, phenylacetate, phenylpropione Yate, Phenylbutyrate, Citrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate, Naphthalene-2-sulfonate, Mandelate , Acetonitrile, etc., which may be used alone or in combination. Step 3 of Scheme 13 is a step of preparing a compound represented by Chemical Formula 23 by reacting a compound represented by Chemical Formula 43, specifically, 2019/177375 1 »（： 1 ^ 1 {2019/002915

14 A nitro of a compound represented by the formula (43) is hydrogenated in the presence of a catalyst to form a primary amine, thereby preparing a compound represented by the formula (23). The reaction of Step 3 of Scheme 13 is not limited as long as the hydrogenation may occur, and the catalyst may be used without limitation if the catalyst is also a commonly used catalyst. In the present invention, 311 uses ₂ · 2¾0, but is not limited thereto. It is not.

로 표시되는 화합물이 제조되는 단계이다. The reaction solvent is a lower alcohol containing isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran pear); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (^, Dimethylsulphoxide (E)), Methylene chloride, Dichloroethane, Water, Acetonasesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Ethyl acetate, Phenyl acetate, Phenylpropionate Phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 -sulfonate, naphthalene-2 -sulfonate, mandelate, aceto Nitriles and the like, which may be used alone or in combination. Step 4 of Scheme 13 is a step of preparing a compound represented by Chemical Formula 13 by reacting the compound represented by Chemical Formula 23 with the compound represented by Chemical Formula 33, specifically, with the primary amine of the compound represented by Chemical Formula 23; Halogen of the compound represented by Formula 33 reacts to form an amine bond.

The compound represented by step is prepared.

Step 4 The reaction of Scheme 13 is If conditions capable of forming a bond to a halogen with an ^amine, Nu bond are not particularly limited.

In the present invention, the base conditions were used, and as the base

Imethylaminopyridine show! ⁵ ) organic bases such as pyridine, triethylamine, -diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene 81]) or sodium carbonate, sodium bicarbonate, hydroxide There are inorganic bases such as sodium, potassium hydroxide, and kerosene, which may be used alone or in mixtures and used in equivalent or excessive amounts.

The reaction solvent is a lower alcohol containing isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Dimethyl formamide (A), Dimethyl sulfoxide (! ), Methylene chloride, dichloroethane, water, acetonizensulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, ethyl acetate, phenylacetate, phenylpropionate, phenylbutyrate, cyclate, lactate, hydroxy Butyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 -sulfonate, naphthalene-2 -sulfonate, mandelate, acetonitrile, etc., which may be used alone or in combination Can be. 2019/177375 1 »（： 1 ^ 1 {2019/002915

 15

The compound represented by Formula 1 may be a compound represented by Formula 113 below.

 [Formula 113]

 (In the above formula,

Is an unsubstituted or substituted 5 to 15 membered heteroaryl containing at least one hetero atom selected from the group consisting of -fold ⁴ or 0 and

2 ⁴ 0 _1-1 straight or branched chain ᄋ alkyl, unsubstituted or 0 _6-14 O reel or 0, and unsubstituted or substituted, which contain one or more heteroatoms selected from the group consisting of substituted 3 to 10 Heterocycloalkyl- ₃ alkyl of the atom,

The substituted aryl, heteroaryl, and heterocycloalkyl may be -30 ₂ 2 ^5- ? (= 0) å ⁶ å ⁷ ,-ᄄ), straight or branched chain ( _-5 alkyl and straight or branched chain _5). It may be substituted with one or more substituents selected from the group consisting of alkoxy, 1, 1 \ I ¹ and are independently a straight or branched chain of ( _-5 alkyl or unsubstituted or linear or branched ( _-5 alkyl) One or more substituted amines; Hydrogen or straight or branched chain (: alkoxy; 3 is 2¾ ¹⁰ or- ^{1 1} ,

Wherein, ⁹ , and independently independently hydrogen or straight or branched-chain ₅ alkyl, wherein said alkyl may be substituted one or more by unsubstituted or straight-chain or branched (amine) alkyl groups at least one substituted with (ᅭ ₅ alkyl), Or 냔 and ¹ () together with the atoms to which they are attached may form an unsubstituted or substituted heterocycloalkyl of 3 to 10 atoms comprising one or more hetero atoms selected from the group consisting of 0 and 3, Substituted heterocycloalkyl is a straight or branched chain of- ₅ alkyl, and 3 to 10 atoms of unsubstituted or straight or branched chain 0 _1-5 alkyl containing one or more hetero atoms selected from the group consisting of 0 and. In groups consisting of one or more substituted heterocycloalkyls 2019/177375 1 »（： 1/10 公 019/002915

 16 may be substituted with one or more selected).

Unsubstituted or substituted 3 to 8 membered heterocyclo alkyl 1-3 alkyl containing one or more,

The substituted aryl, heteroaryl, and heterocycloalkyl are-,-? (= 0) 1 ⁶ 1 ⁷ , -0: = 0) E 2 ⁸ , one or more substituents selected from the group consisting of straight or branched _-3 alkyl and straight or branched _-3 alkoxy, , 1 \ 1 \ I ¹ and are independently straight or branched ^ _-3 alkyl or unsubstituted or straight or branched (^ _-3 alkyl substituted with one or more amines; 2 is hydrogen or straight or branched Chain is _-5 alkoxy; is ^-10 or ^-11 ,

Wherein 1 \ ¹ o and ¹¹ are independently hydrogen or straight or branched _-3 alkyl, wherein said alkyl may be substituted one or more with amines substituted one or more by unsubstituted or straight or branched _-3 alkyl Or ₂ ⁹ and。 together with the atoms to which they are attached may form an unsubstituted or substituted heterocycloalkyl of 3 to 8 atoms comprising one or more hetero atoms selected from the group consisting of 0 and , the substituted heterocycloalkyl is a straight-chain or branched-one ₃ Al _kilo-5 alkyl, and 0, and 3 to 8 which is unsubstituted or straight or branched chain of atoms including one or more heteroatoms selected from the group consisting of It may be substituted with one or more selected from the group consisting of at least substituted heterocycloalkyl. In the above formula,

¹ is an unsubstituted or substituted 5 to 9 membered heteroaryl containing one or more-■ -å ⁴ or ^ atoms,

^ Is an unsubstituted or substituted 5 or 6 membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of straight or branched chain (^ _-3 alkyl, unsubstituted or substituted phenyl or 0 and _-3 alkyl,

The substituted phenyl, heteroaryl, and heterocycloalkyl may be one or more substituents selected from the group consisting of-, (= 0) 2¾ ⁷ , -0: = 0), methyl, ethyl, methoxy and ethoxy. Can be substituted, 1 \ 1 \ I ¹ 2019/177375 1 »（： 1 ^ 1 {2019/002915

17 and are independently straight or branched ( _-3 alkyl or unsubstituted or amine substituted with one or more methyl; hydrogen or straight or branched (^ _-3 alkoxy); 3 is ^-10 or-的¹¹ ego,

Wherein å ⁹ ,. And ¹ are independently hydrogen or a straight or branched chain (^ _-3 alkyl), wherein the alkyl may be substituted one or more with an amine unsubstituted or substituted with one or more methyl,

Or ⁹ and. May together with the ^ atom to which they are attached form an unsubstituted or substituted piperidine or piperazine, wherein the substituted piperidine and piperazine are methyl, ethyl and unsubstituted or straight or branched It may be substituted with one or more selected from the group consisting of piperazinyl or morpholinyl substituted at least one with 0 _1-3 alkyl of the chain.

2019/177375 1»（：1^1{2019/002915

2019/177375 1 »（： 1 ^ 1 {2019/002915

 18

Examples of the compound represented by Formula 113 according to the present invention include the following compounds:

 <113-1 (5-（（4-（(2- (isopropylsulfonyl) phenyl) amino) -5-morpholinopyrimidin-2-yl) amino) -4-methoxy-2- （ 4-methylpiperazin-1-yl) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt;

 <113-2 ñ-(2-（(2- (dimethylamino) ethyl) (methyl) amino)-5-（（4-（（2-

(Isopropylsulfonyl) phenyl) amino) -5-morpholinopyrimidin-2-yl) amino) -4-methoxyphenyl) ⁰ ].

 <11 3 ñ (2-（(2- (dimethylamino) ethyl) (methyl) amino)-5-（（4-（（2-

(Dimethylphosphpoly) phenyl) amino) -5-morpholinopyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide 2,2,2-trifluoroacetic acid salt:

（디메틸 ⁰！^·미노）에틸）（메틸） ⁶1미노）一4 -더 1톡 시 -5-（（5 -몰포리노- 4-（（（테트라하이드로퓨란 -2 -일）메틸）아미노）피리미 딘- 2 -일）아미노）페닐）아크릴아미드 2, 2, 2 - 트리플로오르아세트산염 ; <11> ^_ 4>

(! ^{0-dimethyl-diamino)} ethyl) (methyl) ⁶¹ Mino)一4- further 1 hour Messenger 5 - ((5-Dimorpholino Reno-4 - (((tetrahydrofuran-2- yl) methyl) amino) Pyrimidin-2-yl) amino) phenyl) acrylamide 2,2,2-trifluoroacetate;

 <11 5 ñ-(5-（（4-（（(2- 川 -dimethylsulfamoyl) phenyl) amino) -5-morpholinopyrimidin-2-yl) amino） -4-methoxy-2- （4 -Methyl piperazine-1-yl) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt;

 <11） -6 ñ 1 company （2-（（2— (dimethylamino) aeryl） (methyl) amino） 一 5 — （（4-((2- -dimethylsulfamoyl) phenyl) amino）- 5-morpholinopyrimidine-2-yl) amino)-

4-methoxyphenyl) acrylamide 2,2,2-trifluoroacetate:

<11） -7 ñ （5-（（4-（(2,4-dimethoxyphenyl) amino） -5-morpholinopyrimidin dii 2-yl o) -2-（(2- （dimethyl ⁰ ] Mino) ethyl) (methyl) ⁰ ] mino) -4-methoxyphenyl) acrylamide 2,2, 2- triflour acetate;

<11） -8 2- 2-（（2-（（5- ⁰ ] ^· Krill ⁰ ！ Mido- 4 （（2_ (dimethyl ⁰ ! Mino) ethyl） (methyl) amino） -2-methoxyphenyl ） Amino） -5-morpholinopyrimidin-4-yl) amino) _ methylbenzeneamide 2,2,2-trifluoroacetic acid

 <113-9 2- 2-（（2-（（5-acrylamido-2-methoxy

1) phenyl) amino) -5 -morpholinopyrimidine- 4 -yl) ami

 2.2.2 -trifluoroacetic acid salt;

 <11 10> （5-（（4-（(2- (isopropylsulfonyl) phenyl) amino) -5-morpholinopyrimidin-2-yl) amino) -4-methoxy-2-2- -(4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt;

 <113-11 ñ (4-methoxy-5-(（4- （1-methyl-111-indole-3-yl) -5-morpholinopyrimidin-2-yl) amino) -2-2- -Methylpiperazine-1 -yl) phenyl) acrylamide

2.2.2 -trifluoroacetic acid salt;

_{<11 3 -12 ñ (2 -} ((2- ( dimethylamino) ethyl) (methyl) amino) - ₄ - methoxy -

5-((4- (1-methyl-in-indole-3-yl) -5-morpholinopyrimidin-2-yl) amino) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt;

 <] -13 (4-methoxy-5-(（4- （1-methyl-in-indole-3-yl) -5-morpholinopyrimidin-2-yl) amino） -2-2- -Morpholinopiperidin-1-yl) phenyl) acrylamide

2.2.2-trifluoroacetic acid salt: 2019/177375 1 »（1 ^ 112019/002915

 19

<113 ^_ 14>-(2- (2- (dimethylamino) ethoxy) -4-methoxy ~ 5-((4- (1-methyl-in-indole-3 -yl) -5-morpholino Pyrimidin-2-yl) amino) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt;

 <11 15 ñ-(4-methoxy- 5-(（4- (methylamino) -5-morpholinopyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) Phenyl) acrylamide 2,2,2-trifluoroacetic acid salt;

 <11 16-(2-((2- (dimethylamino) ethyl) (methyl) amino) -4 -deoxy-

5-((4- (methylamino) -5-morpholinopyrimidin-2-yl) amino) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt. Compound represented by the formula is, as shown in Scheme 113,

Reacting the compound represented by Chemical Formula 7 ₃ with the compound represented by Chemical Formula 813 to prepare a compound represented by Chemical Formula (Step 1); Preparing a compound represented by Chemical Formula 413 by reacting the compound represented by Chemical Formula 51) with the compound represented by Chemical Formula Example (step 2); Reacting the compound represented by Chemical Formula 413 to prepare a compound represented by Chemical Formula (Step 3); And

 It may be prepared by a method for preparing a compound represented by the formula including the step (step 4) of reacting the compound represented by the formula and the compound represented by the formula (Step 4).

 [Scheme 1

 2 \> ratio

(In the above reaction ratio, 1 \ I ² and are as defined in the above formula; And

X ¹³ , X ²³ and the table are independently halogen. 2019/177375 1 »（： 1 ^ 1 {2019/002915

 Hereinafter, a method for preparing a compound represented by the above formula according to the present invention will be described in detail. Step 1 in the reaction scheme is a step of preparing a compound represented by Chemical Formula 513 by reacting the compound represented by Chemical Formula 713 with the compound represented by Chemical Formula 813, specifically, the halogen of the compound represented by Chemical Formula 713 and Chemical Formula 813. The primary amine of the compound to be reacted is a step in which the compound represented by the formula

 The reaction of Step 1 in Scheme 113 is not particularly limited as long as it is a condition capable of combining amine and commonly known halogen and amine.

통하여 반응을 진행하였으며 ， 염기 및 금속 리간드 존재하에 반응을 수행하였으며 ， 상기 염기는 1¾11（：11\ 1（1 63 1011에서 통상적으로 사용하는 염기라면 한정되지 않고， 川 -다이메틸아미노피리딘 쇼?）， 피리딘， 트라이에틸아민 , ， -다이 이소프로필에틸아민， 1,8 -디아자비사이클로 [5.4.0]-7 -운데센내에） 등 의 유기염기 또는 소듐카보네이트， 소둠바이카보네이트， 수산화나트륨， 수산화칼륨 , 애 등의 무기염기가 있으며 , 이를 단독 또는 혼합하여 ， 당량 또는 과량으로 사용할 수 있다 . 또한, 상기 금속 리간드는 팔라 둠， 니켈， 구리 리간드 등을 사용할 수 있다 . 본 발명의 일 실시예에 서는 팔라듐 리간드로서 므〔1₂（北크）₃를 사용하였으나， 이는 일례일 뿐， 이에 한정되는 것은 아니다. In the present invention

The reaction was carried out in the presence of a base and a metal ligand, and the reaction was carried out in the presence of a base and a metal ligand. The base is not limited to 1¾11 (： 11 \ 1 (a base commonly used in 1 63 1011, 川 -dimethylaminopyridine?) , Organic bases such as pyridine, triethylamine,, -diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7 -undecene) or sodium carbonate, sodium bicarbonate, sodium hydroxide, hydroxide There are inorganic bases, such as potassium and arsenic, which can be used alone or in combination and used in equivalent or excessive amounts. In addition, the metal ligand may be used palladium, nickel, copper ligand and the like. In one embodiment of the present invention, Me (1 ₂ (Buk)) ₃ was used as the palladium ligand, but this is only one example, but is not limited thereto.

 The reaction solvent is a lower alcohol containing isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran); Dioxane; Ether solvents containing ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (0¾), Dimethylsulphoxide (0¾0), Methylene chloride, Dichloroethane, Water, Acetonazenesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Ethyl acetate, Phenyl acetate, Phenylpropy Oneates, Phenylbutyrate, Citrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate,. Propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, acetonitrile, and the like, which may be used alone or in combination. Step 2 of Scheme 11) is a step of preparing a compound represented by Chemical Formula by reacting a compound represented by Chemical Formula 5 with a compound represented by Chemical Formula. Specifically, halogen of the compound represented by Chemical Formula 5) 3 and Hydrogen of the compound represented by Chemical Formula 613 is reacted to prepare a compound represented by Chemical Formula.

 The step 2 reaction in the above scheme is not particularly limited as long as it is a condition under which halogen and hydrogen are substituted.

Reaction solvents are isopropanol, methanol, ethanol, propanol and butane 2019/177375 1 »（： 1 ^ 1 {2019/002915

Lower alcohols including 21 ol; Tetrahydrofuran pear); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (ya), dimethyl sulfoxide (), methylene chloride, dichloroethane, water, acetonizensulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, ethyl acetate, phenylacetate, phenylpropionate Phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, maleat, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 -sulfonate, naphthalene-2 -sulfonate, mandelate, aceto Nitrile, and the like, which may be used alone or in combination. Step 3 in the reaction scheme is a step of preparing a compound represented by the formula (D) by reacting the compound represented by the formula (VII). Is a step of preparing a compound. Step 3 of the reaction scheme is not limited as long as the hydrogenation can occur conditions, the catalyst can also be used without limitation if the catalyst is also commonly used, in the present invention (1: 1 ₂ · 2¾0 rule was used, but not limited to It is not.

 The reaction solvent is a lower alcohol containing isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran); Dioxane; Ether solvents containing ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (Ya00, Dimethylsulfoxide) ), Methylene chloride, dichloroethane, water, acetonizensulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, ethyl acetate, phenylacetate, phenylpropionate, phenylbutyrate, cyclate, lactate, hydroxy Butyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 -sulfonate, naphthalene-2 -sulfonate, mandelate, acetonitrile, etc., which may be used alone or in combination Can be. Step 4 in the reaction scheme is a step of preparing a compound represented by Chemical Formula 11) by reacting the compound represented by Chemical Formula 213 with the compound represented by Chemical Formula 313, specifically, the primary amine of the compound represented by Chemical Formula 213. And a halogen of the compound represented by Formula 313 react to form an amine bond, thereby preparing a compound represented by Formula 113.

 Step 4 reaction of the above reaction scheme is not particularly limited as long as it is a condition that can combine the halogen and the amine to form an amine bond.

In the present invention, the basic conditions were used, and the base was gawa-dimethylaminopyridine, pyridine, triethylamine, gawa-diisopropylethylamine, 1,8-diazabicyclo [5. 4 . 0] -7 -undesendae 311) or other organic base or sodium carbonate, sodum bicarbonate, sodium hydroxide, hydroxyl 2019/177375 1 »（： 1 ^ 1 {2019/002915

 22 There are inorganic bases such as potassium sulphate and kerosene, which can be used alone or in mixture and used in equivalent or excessive amounts.

 Reaction solvents include lower alcohols including isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran (large; Dioxane; Ether solvents containing ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (night 00, dimethyl sulfoxide (night 60), methylene chloride, dichloroethane, water, acetonasulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, ethyl acetate, phenylacetate, phenylpropy One Nate, Phenylbutyrate, Citrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate, Naphthalene-2-sulfonate, Mandelate , Acetonitrile, and the like, which may be used alone or in combination. The compound represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid (near 01) is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Obtained from the same organic acid. Examples of such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and eye. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate , Suverate, sebacate, fumarate, maleate, butyne_ 1, 4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dantro benzoate, hydroxybenzo Ates, methoxy benzoates, phthalates, terephthalates, Zensulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Phenyl acetate, Phenylpropionate, Phenylbutyrate, Citrate, Lactate, | 3-Hydroxybutyrate, Glycolate, Maleate, Tart Latex, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, the derivative of formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like The precipitate produced by adding acid may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure and dried to crystallize in an organic solvent.

 Bases can also be used to make pharmaceutically acceptable metal salts. Alkali or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).

 Furthermore, the present invention includes not only the compound represented by Formula 1 and a pharmaceutically acceptable salt thereof, but also solvates, optical isomers, hydrates, and the like that can be prepared therefrom. Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

 In this case, the compound may inhibit EGFR (epidermal growth factor receptor) wild type or EGFR mutation.

 The EGFR mutation is EGFR Del 19, EGFR L858R, EGFR

Dell9 / T790M, EGFR L858R / T790M, EGFR L858R / T790M / C797S, EGFR Dell9 / T790M / C797S, EGFR NPH, EGFR SVD, EGFR NPG, EGFR H, EGFR ASV, EGFR FQEA and HER2 YVMA This may be the phase.

 The compound is ABLKF317I) -phosphoryl at ed, ABLKF317L) -phosphorylated, BLK, BTK, EGFR, EGFR (E746-A750de 1), EGFR (G719C), EGFR (G719S), EGFR (L747-E749de 1, A750P), EGFR (L747-S752de 1, P753S), EGFR (L747-T751del, Sins), EGFRCL858R), EGFR (L858R, T790M),

EGFR L861Q), EGFR (T790M), ERBB2, ERBB4, and TNK2 may exhibit inhibitory activity against one or more protein kinases selected from the group consisting of.

 The cancer may be a mutation expressed for EGFR.

The cancer includes pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, myxocarcinoma, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma , Ovarian epithelial cancer, Ovarian germ cell cancer, Breast cancer, Brain cancer, Pituitary adenoma, Multiple myeloma, Gallbladder cancer, Biliary cancer, Colorectal cancer, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Retinoblastoma, Choroidal melanoma, Bartoenvelope cancer, Bladder cancer ， Peritoneal cancer, Parathyroid cancer, Adrenal cancer, Paranasal sinus cancer, Non-small cell lung cancer, Snow cancer, Astrocytoma, Small cell lung cancer, Pediatric brain cancer, Pediatric lymphoma, Pediatric leukemia, Small intestine cancer, Meningioma, Esophageal cancer, Glioma, Kidney cancer, Kidney Cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, Ureteral cancer, Urethral cancer, Primary unknown cancer, Gastric lymphoma, Gastric cancer, Gastric carcinoma, Gastrointestinal stromal cancer, Wilm's cancer, Breast cancer, Sarcoma, Penis cancer, Pharyngeal cancer, Pregnancy villous disease, Cervical cancer, Endometrial cancer, Uterine sarcoma , Prostate cancer, Metastatic bone cancer, Metastatic brain cancer, Mediastinal cancer, Rectal cancer, Rectal carcinoma, Vaginal cancer, Spinal cord cancer, Auditor neuroma, Pancreatic cancer, Salivary gland cancer, Kaposi's sarcoma, Paget's disease, Tonsil cancer, Squamous cell carcinoma Lung adenocarcinoma, Lung cancer It may be one or more selected from the group consisting of lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematologic cancer, and thymic cancer. The compound represented by the formula (1) of the present invention not only shows an excellent inhibitory effect even in EGFR wild type in Ba / F3 cell line, but also shows a high inhibitory effect against EGFR single, double or triple mutations (see Experimental Examples la and lb).

 In addition, the compound represented by the formula (1) of the present invention shows excellent proliferation inhibitory ability against lung cancer cell lines A549, PC9, PC9GR, H1975 cells (see Experimental Examples la and lb). Therefore, the compound represented by Formula 1 according to the present invention

EGFR (ep i derma 1 growth factor receptor) shows high inhibitory ability against wild type or mutant, and thus can be useful for the treatment of cancer expressing EGFR wild type or EGFR mutant. It can be usefully used for the treatment of lung cancer. The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various formulations, oral and parenteral, during clinical administration. When formulated, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants commonly used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one compound and at least one excipient such as starch, calcium carbonate, sucrose

It is prepared by mixing (sucrose) or lactose (gelatin), gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be included. Can be. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. As the non-aqueous solvent and suspending solvent, propylene glycol, polyethylene glycol, vegetable fractions such as olive oil, injectable esters such as ethyl oleate and the like can be used. Compound represented by Formula 1 or its pharmaceutically acceptable Pharmaceutical compositions comprising an effective salt may be administered parenterally, and parenteral administration may be by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

 In this case, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation in the form of a solution or a suspension, which is prepared in the form of an ampule or a vial unit It may be prepared in a dosage form. The composition may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically valuable substances, and conventional methods of mixing, It may be formulated according to the granulation or coating method. Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), glidants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylylcellulose and / or polyvinylpyrrolidine, and optionally starch, agar, alginic acid or Disintegrants or boiling mixtures such as sodium salts and the like and / or absorbents, colorants, flavors, and sweeteners. A pharmaceutical composition for the prevention or treatment of cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as a separate treatment or in combination with other anticancer agents in use. Can be used. Another aspect of the present invention provides a health functional food for preventing or improving cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

 In this case, the compound may inhibit EGFR (epidermal growth factor receptor) wild type or EGFR mutation.

 The EGFR mutations include EGFR Del 19, EGFR L858R, EGFR Dell9 / T790M, EGFR L858R / T790M, EGFR L858R / T790M / C797S, EGFR DeU9 / T790M / C797S, EGFR NPH, EGFR SVD, EGFR NPG, EGFR H, EGV H, At least one selected from the group consisting of EGFR FQEA and HER2 YVMA.

The compound is ABLKF317I) -phosphorylated, ABLKF317L)-phosphorylatecl, BLK, BTK, EGFR, EGFR (E746-A750del), EGFR (G719C), EGFR (G719S), EGFR (L747_E749de 1, A750P), EGFR (L747-S752de 1 , P753S), 2019/177375 1 »（： 1 ^ 1 {2019/002915

 26

£ 0? Yo (1 747-175 1 ，) £ 0? 1 85810 ， £ 0 yo (581? ， 179)

It may exhibit inhibitory activity against one or more protein kinases selected from the group consisting of EGFR (L861Q), seedlings, seedlings, 790¾0, $ 832, and 1 狀 2.

 The cancer may be a mutation expressed in the yakyo.

바람직하게는 약 5 내지 12 _§이다. ^' 나아가, 상기 외에 본 발명에 따른 화학식 1로 .표사되는 화합은 여러 가지 영양제， 비타민， 광물（전해질）， 합성 풍미제 및 천연 풍미 제 등의 풍미제， 착색제 및 중진제（치즈， 초콜릿 등^· X 펙트산 및 그의 염 , 알긴산 및 그의 염， 유기산， 보호성 콜로이드:^..중점제 , 조절제， 안정화제 , 방부제， 글리세린 , 알코올， 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 화학식 1로 표시되는 화합물 은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과 육을 함유할 수 있다. 본 발명의 다른 측면은， 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성 물 또는 건강기능식품 조성물을 필요한 대상에게 투여하는 단계를 포 함하는 암의 예방 또는 치료 방법을 제공한다. 본 발명의 다른 측면은, 암의 예방 또는 치료에 있어서의， 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 약학적 조성물 또는 건강기능식품 조성물의 용도를 제공한다 . The cancer includes pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, myxocarcinoma, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma , Ovarian epithelial cancer, Ovarian germ cell cancer, Breast cancer, Brain cancer, Pituitary adenoma, Multiple myeloma, Gallbladder cancer, Biliary cancer, Colon cancer, Chronic myeloid leukemia, Chronic lymphocytic leukemia, Retinoblastoma, Choroidal melanoma, Battery swelling cancer, Bladder cancer ， Peritoneal Cancer, Parathyroid Cancer, Adrenal Cancer, Paranasal Sinus Cancer, Non-Small Cell Lung Cancer, Snow Cancer, Astrocytoma, Small Cell Lung Cancer, Pediatric Brain Cancer, Pediatric Lymphoma, Pediatric Leukemia, Small Intestine Cancer, Meningioma, Esophageal Cancer, Glioma, Kidney Cancer, Kidney Cancer, Heart cancer, Duodenal cancer, Malignant soft tissue cancer, Malignant bone cancer, Malignant lymphoma, Malignant mesothelioma, Malignant melanoma, Eye cancer, Vulvar cancer, Ureteral cancer, Urethral cancer Primary cancer, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational chorionic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer ， Metastatic brain cancer, Mediastinal cancer, Rectal cancer, Rectal carcinoma, Vaginal cancer, Spinal cord cancer, Acoustic neuroma, Pancreatic cancer, Salivary gland cancer, Kaposi's sarcoma, Paget's disease, Tonsil cancer, Squamous cell carcinoma, Lung adenocarcinoma, Lung cancer, Lung squamous cell Cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematologic cancer, and thymic cancer. Compound represented by the formula (1) according to the present invention, by showing a high inhibitory ability against wild wild type, mutant, can be added to health supplements, such as food, beverages as a dietary supplement for the prevention or improvement of cancer . The compound represented by Chemical Formula 1 according to the present invention may be added to foods or used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement). In general, the amount of the compound in the health food is 0. It can be added from 1 to 90 parts by weight. However, in the case of long-term intake for health and hygiene or health control, the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety. . In addition, the health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratio, and various flavoring agents or natural carbohydrates as in the general beverage. Water and the like may be included as additional components. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, toll and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tautin, stevia extract (e.g., Rebaudioside Shaw, glycyrrhin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used. . The ratio of the natural carbohydrate is generally about 1 to 100 urine of the composition of the present invention.

Preferably about _{5-12 §} . ^"Further, in formula (I) according to the invention in addition to the. Compound is pyosa are various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring agents and mogul agents (cheese, chocolate, ^etc., X pectic acid and its salts, alginic acid and its salts, organic acid, protective ^colloidal. It may contain a thickener, a regulator, a stabilizer, a preservative, a glycerin, an alcohol, a carbonation agent used in a carbonated beverage, and the like. In addition, the compound represented by the formula (1) of the present invention may contain the flesh for the production of natural fruit juice and fruit juice beverage and vegetable beverage. Another aspect of the present invention, cancer comprising a step of administering a pharmaceutical composition or a nutraceutical composition containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof. Provide a method of prevention or treatment. Another aspect of the present invention provides a use of a pharmaceutical composition or a nutraceutical composition containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer.

[Form for implementation of invention]

 Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.

 However, the following Examples and Experimental Examples are merely illustrative of the present invention, the contents of the present invention is not limited to the following Examples and Experimental Examples.

<Medium Pressure Liquid Chromatography (MPLC) for Purification>

 Medium pressure liquid chromatography was used as CombiFlash Rf + UV by TELEEDYNE I SCO.

<HPLC conditions for analysis (ACQUITY UPLC H-Class Core System) ñ

Waters UPLC system (ACQUITY UPLC PDA Detector) was used the equipment equipped with mass QDA Detector manufactured by Waters. use The column was ACQUITY UPLC®BEH C18 (1.7 _, 2.1X50 _) from Water, and the column temperature was run at 30 ^° C.

 Mobile phase A used water containing 0.1% formic acid and mobile phase B used acetonitrile containing 0.1% formic acid.

 Gradient cond i t i on (3 min at 10-100% B, movement speed = 0.6 ml / min)

<Prep-LCMS (Preparative-Liquid chromatography mass spectrometry)

 Waters 乂！ · Manufacture The equipment equipped with mass QDA detector manufactured by Waters was used in the Autopur i f i cat HPLC system (2767 sample manger, 2545 binary gradient module, 2998 Photodiode Array Detector). The column used was SunFire® Prep C18 0BD ™ (5 × 1, 19 × 50 _) from Water and the column temperature was run at room temperature.

 Mobile phase A used water containing 0.035% trifluoroacetic acid and mobile phase B used methanol containing 0.035% trifluoroacetic acid.

 Gradient cond i t i on (10 min at 10-100% B, travel speed = 25 ml / min) áPrep-150 LC System (Preparative-Liquid chromatography UV spectrometry)

 Manufactured by Waters The equipment manufactured by Waters was used for the Prep 150 LC system (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector 江 []). The column used was XTERRA® Prep RP18 0BD ™ (10 kPa, 30X300 _) from Water and the column temperature was run at room temperature.

 Gradient conditon (120 minutes at 3-100% B, movement speed = 40m 1 / mi n)

<Microwave reaction>

By the Initiator of Biotage, a snap cap react vial was used. Commercial reagents used were used without further purification. In the present invention, the room temperature refers to a temperature of about 20 to 25 ^° C. Concentration under reduced pressure or solvent distillation was carried out using a rotary evaporator.

<Example la-l> 於 (5-((5- (3,6-dihydro-2min-pyran-4-yl) -4-((2- (isopropylsulfonyl) phenyl) amino) pyri) Preparation of midin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide 2019/177375 1 »（： 1/10 公 019/002915

 29

단계 1： 5 로- （2-（이소프로필설포닐）페닐）피리미 딘- 4 아민의 제

Step 1: Preparation of 5-ro- (2- (isopropylsulfonyl) phenyl) pyrimidin-4 amine

Sodium hydride in a mixture of 0 ^° （： 1 / 1.01）

현탁액에 （2.71111八）.3 ） 중의（60%, 234. （½yo,

In suspension (2.71111 八). 3)

2-a (isopropylsulfonyl) aniline (583. ah, 2.93 [1 to ₁₀₎ it was slowly added dropwise thereto. The reaction solution was stirred for 30 minutes at 0, and 5-bromo- 2,4-dichloropyrimidine (1.0-yo, 4.39_01) diluted in 1 "O 0 (2.71111 八) .31]! The reaction solution was slowly warmed up to room temperature and stirred overnight The reaction mixture was quenched by dropwise addition of ice water from 0, and the resulting solid was filtered to give the desired compound as a brown solid 5 -Bromo-2 ᅳ. Chloro- (2- (isopropylsulfonyl) phenyl) pyrimidine-4-amine (789.011, 69%) was obtained.

{^ / å）: 392.1 [1 + 1] ⁺ , 1 正 1 乂 ： I ·. I !!: 1.77 Step 2: 2 -Chloro-5- (3,6-dihydro-2min-pyran-4-yl)-， (2- (isopropylsulfonyl) phenyl) pyrimidine-4 Preparation of Amine

5 obtained in the step of Example 1, -1-bromo-2-chloro- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (200.01, 0.51_ ₀ 1) and 3,6- Dihydro-2 minutes-pyran-4-boronic acid pinacol esters (108.0 _| After adding ₂₂ (： 0 ₃ （1.5 1.53_ ₀ 1）) into a mixed solution of 1,4-dioxane (4.6) in which 0.51 excluding 01) was dissolved, ultrasonic treatment was performed while flowing nitrogen for 10 minutes. [1 1¾ ₃ ) ₄ (59.011, 0.05 _1111110 1) was added to the reaction mixture, followed by stirring for 80 hours. After completion of the reaction, the mixture was extracted using ethyl acetate and water. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by ¾1 此 (: (dichloromethane / methanol) to obtain the target compound (207.011, 100%).

15 (US /: 394.3 [¾! +1] ⁺ , 1. (1 11): 1.77 Step 3: 5- （3,6-dihydro-2min-pyran-4-yl)--(4-fluoro Rho-2- methoxy-5-nitrophenyl)-(2- (isopropylsulfonyl) phenyl) pyrimidine-2,4-dia 2019/177375 1 »（： 1 ^ 1 {2019/002915

 Manufacture of 30 min

 2-Chloro-5- (3,6-dihydro-2 minutes-pyran-4-yl) obtained in step 2 of Example 13-1 above-(2- (isopropylsulfonyl) phenyl) pyrimidine- 4-amine (207.01 ^, 0.53_01), 4-fluoro-2-methoxy-5-nitroaniline 147.01

0.791 01) and potassium carbonate (364. moss 2.63_101) were added to dissolve and sonicated under nitrogen for 10 minutes to remove the gases. [1 ₂ (3) ₃ (for 48.0111, 0.0511111101) and a table] in the reaction mixture! （25.011 ，

0.05_101] was added at 100 I: and stirred for 2 hours. After completion of the reaction was filtered through Celite, washed with dichloromethane. The obtained filtrate was concentrated and purified by (dichloromethane / methanol) to obtain the target compound (104.0111 _§ , 36%).

US:: 544.3 [¾1 + 1] ⁺ , \ JPLC! ·. (： 1.54 step 4: 5- （3,6-dihydro-2min-pyran-4-yl)-#-(2- (isopropylsulfonyl) phenyl)--(2-methoxy-4- Preparation of 4-methylpiperazin-1-yl) -5-nitrophenyl) pyrimidine-2,4-diamine

 5- (3,6-dihydro-2min-pyran-4-yl)-(4-fluoro-2-methoxy-5-nitrophenyl)--obtained in step 3 of Example _1 above 2- (isopropyl sulfonyl) phenyl) pyrimidine-2,4-diamine (55.811, 0.10_01) to 1, 4-dioxane

After dissolving in (2.01111), 1-methylpiperazine (0.1, 1.031111! 101) was added thereto and stirred at 1001: for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by ¾ 1 乂: (dichloromethane / methanol) to obtain the desired compound (32.011, 51%).

/: 624.5 [¾1 + 1] ⁺ , 1 乂: I, I (): 1.23 Step 5:-(5-Amino-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl)- Preparation of 5- (3,6-dihydro-2min-pyran-4-yl)-(2- (isopropylsulfonyl) phenyl) pyrimidine-2,4-diamine

5- (3,6-dihydro-2 "-pyran-4 -yl)--(2- (isopropylsulfonyl) phenyl)--(2-methoxy obtained in step 4 of Example -1 above 4- (4-methylpiperazin-1-yl) -5-nitrophenyl) pyrimidine-2,4-diamine (32.½ yo, 0.05_1 ₀ 1) and SnCl ₂ H ₂ O ll8.Omg, 0.52_ ₀ 1) was dissolved in ethyl acetate (6.0 US1) and stirred for 2 hours at 50 ° C. After the reaction solution was cooled to room temperature, ammonia water solution was added dropwise until 5. Anhydrous sodium carbonate was added to the mixture, which was adjusted to 7. The reaction mixture was filtered through celite and washed with ethyl acetate several times.The filtrate was concentrated under reduced pressure to obtain the target compound (28.0! ^, 92%). It was used for the next reaction without purification.

: 594.5 [1 + 1] ⁺ , 1 止 I, I （）: 1.11 Step 6: 於 （5-（（5- （3,6-dihydro _2min ^~ pyran-4-yl)） 4- 4-（（ 2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpi 2019/177375 1 »（1 ^ 1 {2019/002915

 31 Preparation of Ferrazin-1-yl) phenyl) acrylamide

-(5-amino-2-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5- (3,6-dihydro-2min) obtained in step 5 of Example 13-1 above -Pyran- 4 -yl,--(2- (isopropylsulfonyl) phenyl) pyrimidine-2,4-diamine (28.3!) ^, 0.0511111101) dissolved in 1 ^ (8.01111), then saturated ₃ (8. (½1) was added, and then acryloyl chloride (1 ₀ (± 1, 6) (45.0, 0.4811111101) was slowly added dropwise with vigorous stirring at 01 :. After stirring for 10 minutes, the mixture was diluted with ethyl acetate and distilled water, and the combined organic symptoms were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and then purified by ¾da (silica gel, dichloromethane: methanol = 15: 1) to obtain the target compound (8.011, 26%).

15 (111/2): 648.5 [¾! +1] ⁺ , 1, [(): 1.18 Examples 13-2 to 13-11 were prepared in the same manner as in Example 13-1, and Example 1 ₃ The chemical structures of -1 to 13-11 are shown in Table 1 below, compound names, yields, and 1 平 1 止 analysis results in Table 2 below.

2019/177375 1»（：1/10公019/002915

2019/177375 1 »（： 1/10 公 019/002915

 33

2019/177375 1»（：1^1{2019/002915 table

2019/177375 1 »（： 1 ^ 1 {2019/002915

 34

2019/177375 1»（：1^1{2019/002915

2019/177375 1 »（： 1 ^ 1 {2019/002915

2019/177375 1»（：1^묘2019/002915 35-

2019/177375 1 »（： 1 ^ gravy 2019/002915

 36

 <Example 13-12> 於 （5-（(5- （3,6-dihydro-2 min-pyran-4-yl)） 4- (1-methyl-1 min-indole-3-yl) pyridine Preparation of midin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide

Step 1: Preparation of 3- (5-bromo-2-chloropyrimidin-4-yl)-1 min-indole After dissolving indole (10.3 _§ , 87.77_ ₀ 1) in ash 100.0 1) under nitrogen, a methyl magnesium bromide solution (29.31111, 87.77_ ₀ 1, 3M nyoah) below was slowly added dropwise over 20 minutes. After stirring the mixed solution at room temperature for 100 minutes,! ^'Five times that becomes soluble in (40.01) - bromo - 2,4 - a furnace dikeul pyrimidine (10.0 _§, 43.88_1 ₀ 1) at room temperature. The reaction solution was heated to 60 ^° ： and stirred for 1 hour. The reaction mixture was cooled to room temperature and the reaction was terminated by adding methanol, followed by extraction with ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from nucleic acid / ethyl acetate to give the title compound as a solid (7.4 _§ 54%).

15 （111/2）: 308.0 [¾1 + 1] ⁺ , 卵 沈 1 ^* . I）: 1.79 2019/177375 1 »（： 1 ^ 1 {2019/002915

 37 Step 2: Preparation of 3- （5-bromo-2--2-chloropyrimidin-4-yl) -1-methyl-1min-indole

12.64_₀1）을 넣었다. 혼합용액을 01：에서 30분동안 반응시킨 후, 요오드화메틸 （0.8| ， 12.6411111101）을 적가하였다. 그 반응용액을 상온에서 1.5시간 동안 반응시켰다. 과량의 물을 넣어 형성된 고체를 여과하여 건조 시 켜 고체의 목적 화합물（3.0_§， 96%）을 수득하였다.After dissolving 3- (5-bromo-2-chloropyrimidin-4-yl) -1 indole (3.0 yo, 9.72_ ₀ 1) obtained in step 1 of Example 13-12, the temperature was changed to 01. ： With sodium hydride

12.64_ ₀ 1） was added. The mixed solution was reacted for 30 minutes at 01: methyl iodide (0.8 | , 12.6411111101）. The reaction solution was reacted at room temperature for 1.5 hours. Excess water was added and the solid formed was filtered and dried to obtain the target compound (3.0 _§ 96%) as a solid.

/: 322.5 [¾1 + 1] ⁺ , Ke 1 、: 1.97 3 ： 3- （2-Chloro-5- (3,6-dihydro-2min-pyran-4-yl) pyrimidine-methyl Preparation of 1 minute indole

 A target compound was prepared in a similar manner to Step 2 of Example 13-1.

（ ） : 326.2 [¾1+1] ⁺ , 1正1乂： :、 I （ 비 : 1.81 단계 4： 5-（3, 6 -디하이드로 -2分-피란 -4 -일）- -（4 -플루오로- 2 -메톡 시- 5 -니트로페닐）-4-（1 -메틸- 1分-인돌 -3 -일）피리미딘- 2 -아민의 제조 상기 실시예 -1의 단계 3과 유사하게 수행하여 목적화합물

（） ： 326.2 [¾1 + 1] ⁺ , 1 乂 1 乂 ：: 、 I （Ratio: 1.81 step 4: 5- （3, 6-dihydro-2min-pyran-4-day）--（4 − Preparation of Fluo-2--2-Methoxy-5-nitrophenyl) -4- (1-methyl-1 min-indol-3-yl) pyrimidin-2-amine Performed analogously to step 3 of Example-1 above Target compound

(62%) was prepared.

 15: 476.3 [1 {+1] \ 1 正 1 乂 ： 1.. (US): 1.63 Step 5: 5- （3,6-dihydro-2min-pyran-4-yl)-#-(2-methoxy-4- (4-methylpiperazin-1-day) Preparation of 5-5-nitrophenyl) -4- (1-methyl-1 min-indole-3-yl) pyrimidine-2-amine

 A target compound was carried out similarly to step 4 of Example 13-1.

(62%) was prepared.

七. （111111） : 1.28 단계 6： -（5-（3,6 -디하이드로 -2分-피란 -4 -일）- 4-（1 -메틸- 1分-인 돌- 3 -일）피리미딘- 2 -일）-6 -메톡시 -4-（4 -메틸피페라진- 1-일）벤젠- 1,3- 디아민의 제조

Iii. (111111): 1.28 step 6: ：-（ 5- （3,6-dihydro-2min-pyran-4-yl)-4- (1-methyl-1min-phosphoryl-3-yl) pyrimidine- Preparation of 2-yl) -6-methoxy-4- (4-methylpiperazin-1-yl) benzene-1,3-diamine

 The desired compound was carried out similarly to the step 5 of Example 13-1.

(88%) was obtained and used for the next reaction without purification.

_{13 ((11/2):} 526.4 [¾1 + 1] +, [平. （이） ： 1.12 Step 7 ： （5-（（5_ （3,6-dihydro-2min-pyran-4-yl)） 4- (1-methyl-1min_ indole-3-yl) pyridine Preparation of midin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide

 The desired compound was carried out similarly to the step 6 of Example 13-1.

(30%) was prepared. 2019/177375 1 »（： 1 ^ 1 {2019/002915

분석 결과를 하기 표 4에 정리하여 나타내었 다. 38 出 (111 / X): 580.5 [] \ 1 + 1] ⁺ , 1. 七. (1111 II): 1.16 Examples 13-13 to 1-ch-16 were prepared in the same manner as in Example -12, and the chemical structures of Examples -12 to 13-16 are shown in Table 3, below. ， And

The analysis results are summarized in Table 4 below.

 [Table 3]

2019/177375 1»（：1^1{2019/002915 [Table 4]

2019/177375 1 »（： 1 ^ 1 {2019/002915

 40

2019/177375 1»（：1^1{2019/002915

2019/177375 1 »（： 1 ^ 1 {2019/002915

 41

 <Example 13-17>-(5-((5- （3,6-dihydro-2min-pyran-4-yl)-4-((2-methoxyethyl) .1.mino) pyrimidine -2 -yl) ^ 1, mino) -1- 2-((2- (dimethyl (ga, mino) ethyl)) (methyl) amino) -4-methoxyphenyl) acrylamide 2,2,2-trifluoro Preparation of Loacetate

단계 1： 5 -브로모- 2 -클로로- -（2 -메톡시에틸）피리미딘- 4 -아민의 제조

Step 1: Preparation of 5-Bromo-2-chloro- (2-methoxyethyl) pyrimidine-4-amine

Triethylamine (1.1 1, 7.46 | _01) and 2-methoxy in a solution of 5-bromo-2,4-dichloropyrimidine (1.0 _§ , 4.39_ ₀ 1) diluted in ¾ 0 20. (½1) ethane-1-amine (0.41111, 4.281 to 1 ₀ 1), insert the sequentially at ambient temperature for 5 hours and was half bridge. After completion of the reaction, the reaction solvent was concentrated, and then diluted with ethyl acetate and distilled water, and dried over sodium sulfate. The filtrate was concentrated under reduced pressure to obtain the target compound (for 1.2, 103%), which was used in the next reaction without purification.

1. （1^11） : 1.48 단계 2： 2 -클로로- 5-（3,6 -디하이드로 -2分-피란 -4 -일）- -（2 -메톡시 에틸）피리미딘- 4 -아민의 제조 (111/2): 266.0

1. (1 ^ 11): 1.48 Step 2: 2-chloro-5- (3,6-dihydro-2min-pyran-4-yl)--(2-methoxyethyl) pyrimidin-4-amine Manufacture

 A target compound was carried out similarly to step 2 of Example 13-1.

(63%) was prepared.

15 （111/2）: 270.1 [¾1 + 1] ⁺ , \ JFLC (111111): 1.46 Step 3: 5- （3,6-dihydro-2 minutes-pyran-4-yl）--(4-fluorine Preparation of r-2--2-methoxy-5-nitrophenyl)-(2-methoxyethyl) pyrimidine-2,4-diamine 2019/177375 1 »（： 1 ^ 1 {2019/002915

 42. The target compound (96%) was prepared in the same manner as in Step 3 of Example 13-1.

13 （111 八）: 420.3 +1] ⁺ , Eni ： (11): 1.22 Step 4: 5 kPa (3,6-dihydro-2 minutes-pyran-4-yl)--4-((2- (dimethylamino) ethyl) (methyl) amino) -2 Preparation of -methoxy-5-nitrophenyl)-(2-methoxyethyl) pyrimidine-2,4-diamine

 Performed similarly to Step 4 of Example 13-1, except that, instead of 1 -methylpiperazine, -trimethylethane-1,2-diamine used in Step 4 of Example 13-1 was used The target compound (57%) was prepared.

15 （111/2）: 502.4 [1 + 1] \ 1 ^* . I (01 ^): 1.04 step 5:-(5- （3,6-dihydro-2min-pyran-4-yl)-4-((2-methoxyethyl) amino) pyrimidine ^_ 2- I)--(2_ (dimethylamino) ethyl) _5-methoxy- _methylbenzene-1,2,4-triamine

 A target compound (43%) was prepared in a similar manner to Step 5 of Example 13-1.

15 （1 ^ / ₂ ）: 472.4 +1] ⁺ , 七. (11): 0.80 step 6: 於 （5-（（5- （3,6-dihydro-2 min-pyran-4-yl)） 4-((2-methoxyethyl) amino) pyrimidine 一 2 -Yl) amino) 一 2-((2- (dimethylamino) ethyl) (methyl) amino) -4 -methoxyphenyl) acrylamide, Preparation of 2,2,2-trifluoroacetic acid salt

The target compound (2%) was prepared in a similar manner to Step 6 of Example 1 ₃ _1, except that the show 01 ′:-apparatus was used instead of the chromatography used in Step 6 of Example 13-1. Prepared.

 1 乂 for analysis （1.02 minutes）

Ya /: 526.4 + 1] ⁺ , I (: 1.02 Examples 1-18 and 13-19 were prepared in the same manner as in Example 13-17, Example 1 ₃ -17 to -19 the chemical structure of In Table 5 below, the compound names, yields, and 1 jeong 1 正 analysis results are summarized in Table 6 below.

Table 5

2019/177375 1»（：1^1{2019/002915

2019/177375 1 »（： 1 ^ 1 {2019/002915

43

 [Table 6]

2019/177375 1»（：1^1{2019/002915

2019/177375 1 »（： 1 ^ 1 {2019/002915

44

Example 11-1-1 (5-((4-((2- (isopropylsulfonyl) phenyl) amino) -5-morpholinopyrimidin-2-yl) amino) -4-methoxy- 2- （4-methylpiperazin-! _- - Manufacturing trifluoroacetic acid salt-yl) carbonyl Fe) acrylamide-2, 2, 2

Step 1: Preparation of 5-morpholinpyrimidine-2, 4 (1 min, 3 min) -dione 2019/177375 1 »（： 1 ^ 1 {2019/002915

 45

5-bromouracil (12. , 62.8 _01) were placed in morpholine (1081111, 1.2411101), heated with microwave for 10 minutes at 1001 :, and the reaction was terminated by lowering the temperature to room temperature. The resulting suspension was diluted with methanol and then filtered to obtain the target compound (11.0, 89%).

(US /: 198.2 [¾1 + 1] ⁺ , I (): 0.38 Step 2: Preparation of 4- (2,4-dichloropyrimidin-5-yl) morpholine

The compound obtained in Step 1 of Example 1-1 (12.0 _§ 60.901_01) and triethylamine hydrochloride (25.1 _§ 182.40_101) were added to stir at reflux for 4 hours at 801: for the last 3 hours. It was. After the reaction was cooled to room temperature, the remaining was concentrated under reduced pressure and poured into ice water. The resulting solid was dissolved in excess ethyl acetate, washed with saturated å ^ (： 0 ₃ solution), the organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the desired compound 4- (2,4-dichloropyrimidin-5-day). A morpholine (for 7.0, 50%) was obtained.

¾ （111/2）: 234.1 +1] ⁺ , mi.1 （11 ^ 11）: 1.57 Step 3 ： 2-（（2-chloro (5-5-morpholinopyrimidin-4-yl) amino）-久 -Dimethylbenzenesulfonamide Preparation

Sodium hydride at 0 ^° （： 60%, 319.0! , 7.96_01) to the suspension in ■ ■ 30 (ratio 9/1) mixed solution, 2- (isopropylsulfonyl) aniline (794.51 ^, 3.98 | Or01) to / (ratio 9/1) mixed solution The diluted one was slowly added dropwise. The reaction mixture was stirred at 01: for 30 minutes, and 4- (2,4-dichloropyrimidin-5-yl) morpholine (1.4 _§ , 5.981_ ₀ 1) diluted in ■ / ■ (ratio 9/1). Was slowly added dropwise. The reaction mixture was allowed to stand up to room temperature and stirred overnight. The reaction mixture was added dropwise with ice water at 01: to terminate the reaction, and the resulting solid was filtered to give the target compound of brown solid 2-((2-chloro-5-morpholinopyrimidin-4-yl) amino)- ᄊ -dimethylbenzene sulfonamide (1.2 _§ , 84%) was obtained.

（） ： 397.3 [¾1 + 1] ⁺ ,! 乂 ： I 、 （） ： 1.70 Step 4:-(4-fluoro-2-2-methoxy-5-nitrophenyl)-(2- (isopropylsulfone) Phenyl） -5-morpholinopyrimidine-2,4-diamine

Compound 2-((2-Chloro-5-morpholinopyrimidin-4-yl) amino)-dimethylbenzenesulfonamide (220. Yi, 0.55_01), 4- Fluorine-2-methoxy-5-nitroaniline （154.7 _{| 1} ,

0.83_01) and potassium carbonate (383.01, 2.77_ ₀ 1) were added to-에 (6) to dissolve and sonicated for 10 minutes to remove gas while flowing nitrogen. To the reaction mixture? (! ₂ ((3) ₃ (50.81, 0.05_01) and!) 1103 (26.4111 yo, 0.051 ^ 01) were added at 100, and stirred for 2 hours. After the reaction, the reaction mixture was filtered through celite and washed with dichloromethane. After concentration of the obtained filtrate, medium pressure liquid chromatography (dichloromethane / methane 2019/177375 1 »（： 1 ^ 1 {2019/002915

46 ol) of solid to obtain the desired compound # ² ᅳ (4-fluorine-2-methoxy-5-nitrophenyl)--(2- (isopropylsulfon) phenyl) -5 -morpholinopyrimidine -2,4-diamine (16011, 53%) was obtained.

¾ (US /: 547.3 [¾1 + 1] ⁺ , 1, I (): 1.53 Step 5:-(2- (isopropylsulfonyl) phenyl)--(2 -methoxy-4 (4-) 4-methyl pipepe Preparation of Razine-1-yl) -5-nitrophenyl) -5-morpholinopyrimidine-2,4-diamine

 Example 113-1 compound 4 obtained in step 4-(4-fluoro-2-methoxy-5-nitrophenyl)-#-(2- (isopropylsulfon) phenyl) -5-morpholinopyrimidine- After dissolving 2,4-diamine (80.01, 0.151_01) in 1,4-dioxane (2), 1-methylpiperazine (163.4, 1.46_01) was added and stirred at 1001: for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography (silica gel dichloromethane: methanol = 15: 1) to obtain the desired compound (-(2- (isopropylsulfonyl) phenyl)--(2-meth). Toxy-4- (4-methylpiperazin- 1-yl) -5-nitrophenyl) -5-morpholinopyrimidine-2,4-diamine (67.8 «, 74%) was obtained.

（111 八）: 627.5 [¾! +1] ⁺ , 1 乂 1 ： （1 11）: 1.24 Step 6:-(5 -amino-2-methoxy-4- (4-methylpiperazin-1-) Production of 1) phenyl)--(2- (isopropylsulfonyl) phenyl) -5-morpholinopyrimidine-2,4-diamine

The compound-(2- (isopropyl sulfonyl) phenyl)--(2-methoxy-4- (4-methylpiperazin- 1-yl) -5-nitrope obtained in the above Example 1-1 step 5 Nil) -5-morpholinopyrimidine-2,4-diamine (67.81 ^, 0.11_ ₀ 1) and （: 1 ₂ · 2¾0 (244.11, 1.1_01) are dissolved in ethyl acetate (2 (½1), A drop of concentrated hydrochloric acid was added dropwise. The reaction mixture was stirred at 501: for 5 hours. After the reaction mixture was cooled to room temperature, ammonia water solution was added until it reached 5. The reaction mixture was adjusted to 7 by addition of solid sodium bicarbonate. The reaction mixture was filtered through celite and washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to provide the target compound-(5 -amino-2-mesocies-4_ (4-methylpiperazin-1 -yl) phenyl) -7-(2- (isopropylsulfonyl) phenyl)- 5-Mofolinopyrimidine-2,4-diamine (62.411, 97%) was obtained and used in the next reaction without purification.

(US /: 597.5 +1) ⁺ , 11 ~ 1 石 0 11: 1.08 Step 7: 於 （5-（(4-（(2- (isopropylsulfonyl) phenyl) amino) -5-morphopoly Preparation of Nopyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt

Example 113-1 Compound-(5-Amino-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl)-(2- (isopropylsulfonyl) phenyl) obtained in Step 6 above Dissolve 5, morpholinopyrimidine-2,4-diamine (62.41, 0.11_01) in 1'fold (15). 2019/177375 1 »（： 1 ^ 1 {2019/002915

After the addition of 47, a saturated solvent (： 0 ₃ (151111) was added, and then the group ₀ (± 1 child 1 (16 (84.6 / · ^, 1.10_01)) was slowly added dropwise at 01 :. After stirring vigorously at the same temperature for 10 minutes, the reaction was terminated and extracted with ethyl acetate and distilled water, and then dried over sodium sulfate. The filtrate was purified using a concentrated liquid under reduced pressure ^ 61) -150, and then purified by the target compound (5-（(4-((2- (isopropylsulfonyl) phenyl) amino) -5-morpholinopyrimidine-2 -Yl) amino) -4 -methoxy- 2- (4-methylpiperazin-1 -yl) phenyl) acrylamide trifluoroacetic acid salt (20.3 | 1, 25%) was obtained.

(US): 651.5 [¾ [+1] ⁺ , 1.1; (US): 1.19 Examples 113-2 to 113-10 were prepared by the method similar to the above Example 1-1, and the chemical structures of Examples _1 to 比 -10 in Example 7 are given in Table 7, VIII: The analysis result was put together in following Table 8, and was shown.

2019/177375 1»（：1/10公019/002915

2019/177375 1 »（： 1/10 公 019/002915

 48

2019/177375 1»（：1^1{2019/002915

2019/177375 1 »（： 1 ^ 1 {2019/002915

 49

2019/177375 1»（：1^1{2019/002915

2019/177375 1 »（： 1 ^ 1 {2019/002915

 50

2019/177375 1»（：1^¾2019/002915

2019/177375 1 »（： 1 ^ ¾2019 / 002915

 51

2019/177375 1»（：1^1{2019/002915

2019/177375 1 »（： 1 ^ 1 {2019/002915

 52

<Example 11] -11> 7 ^ (4-4-methoxy-5- (4- (1-methyl-1min.indole-3-yl) -5-morpholinopyrimidin-2-yl) Preparation of amino) -2- (4-methylpiperazin-1-yl) phenyl) acrylamide trifluoroacetic acid salt 2019/177375 1 »（1 ^ 1 {2019/002915

 53

Saboran- 2-days)-1, 4-dioxane, in which 1 minute-indole (79 1, 3.07_ ₀ 1) is dissolved

Into the mixed solution of (11.52) was added 3 ₂ (： 0 ₃ (3.84)) and sonicated with nitrogen flowing for 10 minutes. (1 1¾ ₃ ) ₄ was added to the reaction mixture, followed by stirring ^at 80 ^° 0 for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and brine and the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, concentrated, and then purified by medium-pressure liquid chromatography (silica gel dichloromethane: methanol = 15: 1) to obtain the title compound 4- (2-chloro-4- (1-methyl-) pyrimidine-5. -Day) morpholine (700, 83%) was obtained.

） : 329.2 +1] ⁺， 1 1乂： I （미 ） : 1.84 단계 2： （4 -플루오로- 2ᅳ메톡시 - 5 -나이트로페닐）- 4-（1 -메틸- 1分- 인돌- 3 -일）- 5 -모폴리노피리미딘- 2 -아민의 제조

): 329.2 +1] ⁺ , 1 1 乂 ： I (US): 1.84 Step 2: （4-Fluoro-2′methoxy-5-nitrophenyl) -4- (1-methyl-1min-indole- Preparation of 3-yl) -5-morpholinopyrimidine-2-amine

 In the same manner as in Step 4 of Example 1-1, the target compound (42%) was obtained.

(US /: 479.3 [¾1 + 1] ⁺ , \ JPIC 1 ·. I (111 ^ 1): 1.88 Step 3:-(2-methoxy-4- (4-methylpiperazin-1-yl) -5-nitrophenyl) _ 4- (1-methyl-!-Indole- Preparation of 3-yl) -5-mo # linopyrimidine-2-amine

 In the same manner as in Step 5 of Example 1-1, the target compound (74%) was obtained.

I·. I （ ） : 1.26 단계 4： 6 -메톡시 - -（4-（1 -메틸- 1分-인돌 -3 -일）- 5 -모폴리노피리 미딘- 2 -일）-4-（4 -메틸피페라진- 1 -일）벤젠- 1,3 -디아민의 제조

I ·. I (): 1.26 Step 4: 6-Methoxy--(4- (1 -methyl- 1 min-indol -3 -yl) -5 -morpholinopyrimidin-2 -yl) -4- (4- Preparation of Methylpiperazine-1 -yl) benzene-1,3-diamine

In the same manner as in Step 4 of Example 113-1, 2019/177375 1 »(1 ^ 1 {2019/002915

 54 compound (67%) was obtained. The reaction proceeded without purification.

13 （111 八）: 529.4 large +1] ⁺ , \ JPLC （11）: 1.06 Step 5: （4 -methoxy-5 (（4- (1 -methyl-1 min-indole-3 -yl)-) Preparation of 5-morpholinopyrimidin-2-yl) amino) -2-2- (4-methylpiperazin-1-yl) phenyl) acrylamide trifluoroacetic acid

 In the same manner as in Step 7 of Example 1-1, the target compound (26%) was obtained.

（111111） : 1.03 상기 실시예 11）-11과 유사한 방법으로 실시예 내-12 내지 113-14 를 제조하였으며， 실시예 113-11 내지 11）-14의 화학구조를 하기 표 9에， 화합물명과 1^333 및 1正1止 분석 결과를 하기 표 10에 정리하여 나타내 었다.

(111111): 1.03 Examples 12-12 to 113-14 were prepared in a similar manner to Example 11) -11, and the chemical structures of Examples 113-11 to 11) -14 are shown in Table 9 below. 1 ^ 333 and 1 jeong 1 止 analysis results are summarized in Table 10 below.

 [Table 9]

【표 10】

Table 10

2019/177375 1»（：1^1{2019/002915

2019/177375 1 »（： 1 ^ 1 {2019/002915

56

 Example 11-15- (4-Methoxy-5- (4- (methylamino) -5-morpholinopyrimidin-2-yl) amino) -2- (4-methylpiperazin- Preparation of 1-yl) phenyl) acrylamide trifluoroacetic acid salt

1）을 메탄올（10此）에 녹인 후 33% 메틸아민/에탄올（0.2此， 2.14빼01） 및 디 이소프로필에틸아민 （0.3711止， 2.141_₀1）를 넣고 상온에서 16시동안 교 반하였다. 상기 반응 용액을 감압 농축하고 에틸아세테이트/물로 추출 하였다. 모아진 유기층을 소금물로 세척하고， 황산나트륨으로 건조한 후， 감압하에 농축하였다. 잔사를 에틸아세테이트/핵산으로 재결정하 여 흰색 고체의 목적화합물 2 -클로로- 메틸- 5 -모폴리노피리미딘- 4 -아 수율）을 수득하였다.

1) was dissolved in methanol (10 此), and 33% methylamine / ethanol (0.2 此, 2.14 o01) and diisopropylethylamine (0.3711 止 2.141_ ₀ 1) were added and stirred at room temperature for 16 hours _. . The reaction solution was concentrated under reduced pressure and extracted with ethyl acetate / water. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / nucleic acid to give the title compound 2 -chloro-methyl-5-morpholinopyrimidine-4 -a yield as a white solid.

485.4 [¾1+1] ⁺， 七. （111111） : 1.08 단계 2： #-（4 -플루오로- 2 -메톡시 - 5 -나이트로페닐）- -메틸- 5 -모 2019/177375 1»（：1^1{2019/002915

485.4 [¾1 + 1] ⁺ , 七. (111111): 1.08 Step 2 :： #-(4-Fluoro-2-methoxy-5-nitrophenyl) -methyl-5-mo 2019/177375 1 »（： 1 ^ 1 {2019/002915

 57 Preparation of Polynopyrimidine-2,4-diamine

 In step 4 of Example 1, 2-((2-chloro-5-morpholinopyrimidin-4-yl) amino) -VII-dimethylbenzenesulfonamide was substituted for 2-chloro-methyl-5-morpho. A target compound (64%) was obtained by the same method except that nopyrimidine-4-amine was used.

13 （US /: 379.3 [¾1 + 1] ⁺ , 卵 1 、 （）: 1.19

단계 4: #-（ 5 -아미노- 2 -메톡시 - 4-（ 4 -메틸피페라진- 1 -일）페닐）- # -메틸- 5 -모폴리노피리미딘- 2, 4 -다아민의 제조

Step 4: #-(5-Amino-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl)-#-methyl-5-morpholinopyrimidine-2,4-diamine Produce

 In the same manner as in Step 6 of Example 1, the target compound (100%) was obtained.

 미 （US /: 429.4 [1 {+1] \ 1 正 ： I. One;. (111 1): 0.75 step 5: (4-4-methoxy-5- (4- (methylamino) -5-morpholinopyrimidin-2-yl) amino) -2- (4-methylpiperazin- Preparation of trifluoroacetic acid salt of 1-yl) phenyl) acrylamide

In step 7 of the first embodiment? 1） ₃₃ ）-1 _{1 33} was used in the same manner to obtain the target compound (3%).

¾ {^ / å): 483.3 +1] ⁺ , \ JPLC I 、 I (Preparation: Example 11)-16 was prepared by the method similar to that of Example 1.15 Chemical structure of -15 and 11 ₃ -16 In Table 11, the compound names and the analysis results are summarized in Table 12 below.

 Table 12

Experimental Example la> Evaluation of Ba / F3 and Lung Cancer Cell Proliferation Inhibitory Activity

 In order to evaluate the inhibitory activity against Ba / F3 and lung cancer cell proliferation expressing the EGFR mutation of the compound represented by the formula la according to the present invention was performed as follows.

Among lung cancer cell lines expressing the EGFR gene, A549 is cultured after 10% FBS (HyClone) is added to DMEM (Invitrogen), and other cancer cells use RPMI-1640 (Invi trogen) added with 10% FBS. Ba / F3 cells use RPMI-1640 with 10% FBS and 5 ng / ml IL-3 (R & D Systems). Transduced Ba / F3 cells are cultured by adding 1 ug / mlpuromycin (Invi trogen) to the same medium. Cells are dispensed in 3000-5000 cells per well of a white clear bottom 96 well plate (Corning) 24 hours before compound treatment. Compound is dimethyl sulfoxide 2019/177375 1 »(： 1/10 公 019/002915

59 dilutions (3 dilutions, 12 concentrations in total) were injected in 0.5 increments, with a final concentration of 0.3 nM-50 uM. The viable cell was measured for 10 minutes at room temperature using Cel ITi ter-Glo luminescent cell -viability reagent (Pr omega) 72 hours after compound treatment, and then the luminescence intensity was measured using a reader (SynergyNeo, Biotek). Each test was repeated three times. The results were calculated as the percentage of cellular equipment compared to the control (GraphPad Prism version 5.0 program was used to graph and calculate the IC ₅₀ value.

 The results of evaluation of the proliferation inhibitory activity of Ba / F3 cells expressing the EGFR mutation are shown in Table 13 and Table 14, and the inhibitory activity against lung cancer cell proliferation is shown in Table 15.

Table 13

 SM: Single mutant

 DM: double mutant

 TM: Triple mutant

 WT: wild type (Wi Id Type) As shown in Table 13 above, the example compounds of all compounds represented by the general formula la of the present invention in Ba / F3 cell line not only show excellent inhibitory ability in the EGFR wild type, but also EGFR single , It can be seen that it shows a high inhibitory ability against double or triple mutations.

Table 14

As shown in Table 14, it can be seen that the Example compound of the compound represented by the chemical formula of the present invention in 8 cells / 3 cell line also shows a high inhibitory ability against exon 20 insertion mutation. Table 15

 As shown in Table 15, the example compound of the ¾ compound represented by the general formula la of the present invention can be seen to exhibit excellent proliferation inhibitory ability against lung cancer cell lines PC9GR, H1975, PC9, A549, U87 cells. Therefore, the compound represented by the formula la according to the present invention exhibits high inhibitory ability against ep i derma 1 growth factor receptor (EGFR) wild type or mutation, and therefore, EGFR Del 19, EGFR L858R, EGFR Dell9 / T790M, EGFR L858R / T790M, EGFR L858R / T790M / C797S, EGFR De 1 19 / T790M / C797S, EGFR NPH, EGFR SVD,

EGFR mutations such as EGFR NPG, EGFR H, EGFR ASV, EGFR FQEA, HER2 YVMA, etc. can be useful for the treatment of cancers, and can be useful for the treatment of lung cancer. have. Experimental Example lb Ba / F3 and Lung Cancer Cell Proliferation Inhibitory Activity Assessment

 The inhibitory activity against Ba / F3 and lung cancer cell proliferation expressing the EGFR mutation of the compound represented by the formula lb according to the present invention was evaluated by the same method as Experimental example la.

 The results of evaluating the proliferation inhibitory activity of Ba / F3 cells expressing EGFR mutations are shown in Table 16 and Table 17, and the inhibitory activity against lung cancer cell proliferation is shown in Table 18.

Table 16

 SM: Single mutant 、,

 DM: double mutant

 TM: Triple mutant

 WT: Wild Type As shown in Table 16 above, all of the compounds represented by the formula lb of the present invention in the Ba / F3 cell line, the compounds represented by the formula lb, also show excellent inhibitory ability in the EGFR wild type, as well as the EGFR single. , It can be seen that it shows a high inhibitory ability against double or triple mutations.

Table 17

상기 표 17에 나타난 바와 같이 ， 8크/ 3세포주에서 본 발명의 화 학식 로 표시되는 화합물의 실시예 화합물이 엑손 20 삽입 돌 연변이에 대하여도 높은 억제능을 나타냄을 알 수 있다.

As shown in Table 17, it can be seen that the Example compound of the compound represented by the chemical formula of the present invention in 8 cells / 3 cell line also shows a high inhibitory ability against exon 20 insertion mutation.

Table 18

상기 표 18에 나타난 바와 같이 , 본 발명의 화학식 lb로 표시되 는 화합물의 실시예 화합물은 폐암 세포주인 PC9GR, H1975 , PC9 , A549 세포에 대하여 우수한 증식 억제능을 나타냄을 알 수 있다 . 따라서 ， 본 발명에 따른 화학식 lb로 표시되는 화합물은 EGFR（epidermal growth factor receptor） 야생형 또는 돌연변이에 대 하여 높은 억제능을 나타내므로， EGFR 야생형 뿐만 아니라 , EGFR Dell9 , EGFR L858R, EGFR Dell9 /T790M, EGFR L858R/T790M, EGFR L858R/T790M/C797S, EGFR De 1 19 /T790M/C797S , EGFR NPH, EGFR SVD, EGFR NPG, EGFR H, EGFR ASV, EGFR FQEA, HER2 YVMA 등의 EGFR 돌연변 이가 발현된 암의 치료에 유용하게 사용될 수 있고， 폐암 세포주 증식 억제능이 우수한 바， 특히 ， 폐암의 치료에 유용하게 사용될 수 있다.

As shown in Table 18, the example compound of the compound represented by the formula lb of the present invention can be seen to exhibit excellent proliferation inhibitory ability against lung cancer cell lines PC9GR, H1975, PC9, A549 cells. Therefore, the compound represented by the formula lb according to the present invention shows a high inhibitory ability against EGFR (epidermal growth factor receptor) wild type or mutation, as well as EGFR wild type, EGFR Dell9, EGFR L858R, EGFR Dell9 / T790M, EGFR L858R Treatment of cancers with EGFR mutations such as / T790M, EGFR L858R / T790M / C797S, EGFR De 1 19 / T790M / C797S, EGFR NPH, EGFR SVD, EGFR NPG, EGFR H, EGFR ASV, EGFR FQEA, HER2 YVMA It can be usefully used for, and excellent in inhibiting lung cancer cell line proliferation, in particular, can be useful for the treatment of lung cancer.

Experimental Example 2 Evaluation of Various Kinase Inhibitory Activities of the Compounds According to the Present Invention

 In order to evaluate the inhibitory activity against more enzymes of the compounds according to the present invention, experiments such as Haga were performed.

사에 의뢰하여 효소（ 패36） 선택성을 측정하기 로 하고 ,

분석용 패널을 사용하여 실험을 진행하였 다. 이때， 효소에 처리되는 약물의 농도는 야犯0에 1 로 하였고 , 하기 수학식 1과 같은 방법으로 조절 백분율（% （：01 01^' 1）을 정하였고， 그 결 과를 하기 표 19에 나타내었다 Specifically, for Example 1 ₃ -2 selected from Example compounds of the present invention,

Ask your company to measure the enzyme (L) 36 selectivity.

The experiment was conducted using an analytical panel. At this time, the concentration of the drug to be treated in the enzyme was set at 1 to 0, and the control percentage (% (： 01 01 ^' 1) was determined by the same method as in Equation 1 below, and the results are shown in Table 19 below. Was

Equation 1

 (Example compound-positive control) / (negative control-positive control) X

100 where the positive control refers to a compound that exhibits a control percentage of 0%, and the negative control indicates a control percentage of 100%. In addition, the enzyme selectivity of the present invention was determined to have activity against the enzyme if the control percentage for each enzyme is <35% (ie less than 35%). Table 19

상기 표 19에서 확인할 수 있듯이， 본 발명에 따른 화합물은 쇼81그 3171）_1）}1031）110 1 6（1， 쇼81그 3171）-1）11031）110 1 근선， 묘내, , 도 , 묘6 746-쇼75（½6" , 표0 1 719（：）， 표 묘 ） , 표6?묘（1 47- £749선이， 쇼 애） , 묘 요ᄄ 거 선이 , ?7535） , 표0 1?（1747- 이 ,^때） , £0?요江85810， £0 요（1858묘,179에）， £0 요＜ 86 ）， 묘 요 개에）， £1¾82, 묘1州84， 또는 1狀2 키나아제에 대하여 조절 백분 율 35%보다 작은 값을 가지는 것을 알 수 있다. 이는 본 발명에 따른 화합물이 상기 나열된 효소에 대하여 억제 활성을 갖고 있음을 나타내 는 것이며 , 이로부터 상기 나열된 효소와 관련된 질환에 사용시 유용 한 효과가 있음을 암시하는 것이다. 따라서， 본 발명에 따른 유도체 화합물은 따른 쇼811 3171） - 애 아 1 선， 쇼81」_ 3171_/）-1）110313110 316（1， 1（, ! ， 표 묘, £&?요 746-요750〔 1）, £0 요 719（:）， £0^^7193）, £0 요（1/747새749（!61 , 쇼7501））， EGFR（L747-S752del , ?7533） , 묘 요ᄄ 거 내이， ^때），

As can be seen from Table 19, the compound according to the present invention is Show 81 he 3171) _1)} 1031) 110 1 6 （1 ， Show 81 he 3171） -1） 11031） 110 1 Root, seedling, seedling, seedling 6 746-Show 75 （½6 ”, Table 0 1 719 （：), Table Drawing）, Table 6- Mausoleum (1 47- £ 749 Line, Sho-A), Grave Line, 757535） Table 0 1? (1747- when), £ 0? Yogang85810, £ 0 yo (1858 grave, 179), £ 0 yo <86）, gravestones), £ 1¾82, grave 1 state 84 It can be seen that, for the 1 × 2 kinase, the control percentage is smaller than 35%, indicating that the compound according to the present invention has inhibitory activity against the enzymes listed above, from which the enzymes listed above Therefore, the derivative compound according to the present invention has a show 811 3171)-a first line, a show 81 '' _ 3171 _/ ) -1) 110313110 316 (1, One(, ! ， Ticket mausoleum, £ &? Yo 746-yo750 （1）, £ 0 yo 719 （:） ， £ 0 ^^ 7193）, £ 0 yo （1/747 new 749 （! 61, show 7501） ， EGFR （L747-S752del,? 7533）, Tomb of the Tomb, ^^

Compositions for the treatment or prophylaxis of £ 0 seedlings (58 {0, seedlings 0 1 丄 8581 ?, 179), £ 1 (1861, £ 0? 79), £ 1 花 82, or 狀 2 kinase-related diseases in 2019/177375 1 »（： 1 ^ 1 {2019/002915

 76 can be useful.

Industrial Applicability

 The 2, 4, 5-substituted pyrimidine derivatives according to the present invention can be usefully used for the treatment of cancer.

Claims

2019/177375 1 »<171712019/002915 77 [Claim of claims] [Claim 11] A compound represented by the following Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:  [Formula 1]

^ Is unsubstituted or substituted ⁽ ： _6-14 aryl ，

Or, an unsubstituted or substituted 5 to 15 membered heteroaryl containing one or more heteroatoms selected from the group consisting of 0 and Where is unsubstituted or substituted ( _6-14 aryl, linear or branched alkyl, linear or branched alkoxy (^ _-3 alkyl, unsubstituted or substituted _, cycloalkyl or 0 and The high chain selected from the group is an unsubstituted or substituted 3 to 10 membered heterocycloalkyl or 3 to 10 membered heterocycloalkyl- ₃ alkyl comprising at least one hetero atom, The substituted aryl, heteroaryl, cycloalkyl and heterocyclo alkyl may be selected from _ ⁽ : (= 0) ·, -30 ₂ ^,-· 30 ₂ yo ⁵ , (= 0) yo¾ ⁷ , halogen, straight or branched chain. _May be substituted with one or more selected from the group consisting of (^ _-5 alkyl and straight or branched _-5 alkoxy, and groups ⁵ , ⁶ and ^ are independently straight or branched _-5 alkyl or- ⁸ , yo ⁸ and ⁹ are independently hydrogen or straight or branched ^ _-5 alkyl; is hydrogen or straight or branched chain

ego; Is- ^{1 11} or-ah ² , Wherein... ¹ and yo ¹² are independently hydrogen or straight or branched (ᅦ alkyl, wherein said alkyl may be substituted one or more by amine unsubstituted or substituted by one or more straight or branched (： _{! -5} alkyl) 02019/177375 1 »(1 ^ 1 {2019/002915 78 Alternatively, yo ¹⁰ and FIG. ¹¹ may form an unsubstituted or substituted heterocycloalkyl of 3 to 10 atoms comprising one or more hetero atoms selected from the group consisting of 0 and with the ^ atom to which they are attached. Wherein the substituted heterocycloalkyl contains at least one hetero atom selected from the group consisting of _ ₅ alkyl of straight or branched chain and 0 and unsubstituted or substituted with (^ _-5 alkyl) of straight or branched chain. May be substituted with one or more selected from the group consisting of 5 to 10 atoms of heterocycloalkyl). [Claim 2]  The method of claim 1,  The compound represented by Formula 1 is a compound represented by the following Formula 13, an optical isomer thereof or a pharmaceutically acceptable salt thereof:  [Formula 1

 (In the above formula 13,  Is an unsubstituted or substituted 5 to 15 membered heteroaryl containing one or more heteroatoms selected from the group consisting of unsubstituted or substituted aryl,-,-or 0 and Where, is an unsubstituted or substituted- ₁₄ aryl, linear or branched Ci- ₃ alkyl, unsubstituted or substituted (: _3-1 ()) cycloalkyl or one or more hetero atoms selected from the group consisting of 0 Unsubstituted or substituted 3 to 10 membered heterocyclic or 3 to 10 membered heterocycloalkyl ( _-3 alkyl, and substituted aryl, heteroaryl, cycloalkyl and heterocyclo _ [: (= 0 川⁵ , 0 八⁵ ,-■ 八⁵ , ((= 0 竹⁷ , halogen, linear or _-5 alkyl and linear or branched _-5 alkoxy) can be substituted with one or more selected from the group consisting of, and ^ and poison

Straight or branched ^ _-5 alkyl or ⁹ , V ⁸ and are independently hydrogen or straight or branched _-5 alkyl; Is hydrogen or straight or branched _-1 () alkoxy; 2019/177375 1 »（： 1 ^ 1 {2019/002915  79

May form a substituted 5 to 8 membered heterocycloalkyl, wherein the heterocycloalkyl may further include at least one, wherein the substituted heterocycloalkyl is linear or branched _-5 alkyl. And at least one member selected from the group consisting of 5 to 10 membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of 0 and unsubstituted or substituted at least one straight or branched chain with ₅ alkyl. May be substituted). [Claim 3]  The method of claim 2, Is an unsubstituted or substituted _5-10 membered heteroaryl containing at least one hetero atom selected from the group consisting of: unsubstituted or substituted ( _6-10 aryl, _-fold- , or 0 and Wherein is selected from the group consisting of unsubstituted or substituted （: _6-10 aryl, straight or branched — ₅ alkoxy (^ _-3 alkyl, unsubstituted or substituted ：: _3-7 cycloalkyl or 0 and £ Unsubstituted or substituted 3 to 7 membered heterocycloalkyl or 3 to 7 membered heterocycloalkyl- ₃ alkyl containing at least one hetero atom, The substituted aryl, heteroaryl, cycloalkyl and heterocyclo alkyl may be selected from _ [: (= 0 state 볘 ⁵ , 0 八⁵ ,-■ ⁵ , (= 0 作⁷ , straight or branched ^ _-3 alkyl and ^May be substituted with one or more substituents selected from the group consisting of straight or branched _-3 alkoxy, and V ⁵ , X ⁶ and are independently straight or branched chains of-or- ₃ alkyl or V ⁸ and ⁹ Is independently hydrogen or straight or branched-chain ₃ alkyl; V ² is hydrogen or straight or branched- ₅ alkoxy;

May form a substituted 5 to 8 membered heterocycloalkyl, wherein the heterocycloalkyl may further include at least one, wherein the substituted heterocycloalkyl is linear or branched _-3 alkyl. And one or more heteroatoms selected from the group consisting of 0 and £, unsubstituted or straight or branched, with one or more substituted with ^ _-3 alkyl. 2019/177375 1 »（： 1 '/ 10 {2019/002915  Compounds, optical isomers or pharmaceutically acceptable salts thereof, characterized in that they may be substituted with one or more selected from the group consisting of 5- or 6-membered heterocycloalkyl containing 80 phases. [Claim 4]  The method of claim 2, Is unsubstituted or substituted phenyl,-■ ⁴ or unsubstituted or substituted indolinyl, Wherein at least one or more heteroatoms selected from the group consisting of unsubstituted or substituted phenyl, straight or branched chain 0 _1-3 alkoxy- ₂ alkyl, unsubstituted or substituted _-5 cycloalkyl, or 0 and Unsubstituted or substituted 5 or 6 membered heterocycloalkyl or 5 or 6 membered heterocycloalkylmethyl, Substituted phenyl, indolinyl, cycloalkyl and heterocycloal;

And 0 to _1-3 independently hydrogen or straight chain or branched or straight chained with one or more substituents selected from the group consisting of ethoxy.

2 is hydrogen or straight or branched chain ( _-3 alkoxy; is ¹¹ or-( ¹² ) Wherein V ¹⁰ and ¹ are independently hydrogen, straight or branched chain, 0 _1-3 alkyl or ¹⁴ ethyl, ² is hydrogen or ¹⁶ ethyl, and ³ , 4, _{¥ 15} and ⁶ are independently hydrogen or linear or branched _-3 alkyl, or _{¥ 10} and 1 together with the atoms to which they are attached may form an unsubstituted or substituted piperazine or piperidine, Substituted piperazine and piperidine can be substituted with one or more selected from the group consisting of methyl, ethyl and unsubstituted or straight or branched _-3 alkoxy one or more substituted piperazinyls. , Optical isomers thereof or pharmaceutically acceptable salts thereof. [Claim 5]  The method of claim 2, Said silver

2019/177375 1 »（： 1/10 公 019/002915  81

Compounds, optical isomers thereof or pharmaceutically acceptable salts thereof. [Claim 6]  The method of claim 2,  The compound represented by the formula (13) is any one selected from the group of compounds, optical isomers thereof or pharmaceutically acceptable salts thereof <1 ₃ -1>-（5-（（5- （3,6 -Dehi

(Isoprophylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;  <13-2 （（5-（（5- （3,6-dihydro_21 卜 pyran-4-yl) -4-（(2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl ） Amino） 2- 2-((2- (dimethylamino) ethyl) (methyl) amino) 一 4-methoxyphenyl) acrylamide; <13-3 ᅡ 5- （5-（（5- （3,6-dihydro-e-pyran-4-yl) -4-（(2- (dimethyl phosphpoly) phenyl) amino） pyrimidine-2 Sun) amino)-2-((2- (dimethylamino) ethyl) (methyl) amino) -4 -methoxyphenyl) acrylamide, 2, 2, 2-trifluoroa 2019/177375 1 »（1 ^ 1 {2019/002915  82 trate;  <13-4 ñ-(5-（（5- （3,6-dihydro _e_pyran-411） -4-（(2-2-dimethylsulfamoyl) phenyl) amino) pyrimidin- 2-yl ） Amino） -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide, 2,2,2-trifluoroacetic acid salt;  <13-5> （5-（（5- （3,6-Dihydro-e-pyran-4 4-yl)-4-（(2- thio-dimethylsulfamoyl) phenyl) amino) pyrimidine-2 -Yl) amino)-2-((2- (dimethylamino) ethyl) (methyl) amino) -4 -methoxyphenyl) acrylamide, 2,2,2-trifluoroacetic acid <-6

Dihydro-e_pyran-4-yl) -4-（(2,4-dimethyoxyphenyl) amino) pyrimidin-2-yl) amino) -2 _ ((2_ (dimethylamino) ethyl) (methyl ） Amino） -4-methoxyphenyl) acrylamide, 2, 2, 2-trifluoroacetic acid salt;  <13-7> （5-（（5- （3,6-dihydro-e-pyran- 4-1） -4-（(2- (methylsulfon 0] · mido) phenyl) 6] mino ） Pyrimidin-2-yl) 0] -mino) -2- (2- (dimethyl ^ mino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, 2,2,2-tri Fluoro Acetate:  <13-8> （10- (5-（（5- （3,6-dihydro-e-pyran-4-yl) -4-) （（(tetrahydrofuran-2-yl) methyl） amino ） Pyrimidin-2-yl) amino) 2- 2-((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, 2,2,2-trifluoroacetic acid salt ;  <13-9 （3-（（5- （3,6-dihydro_2pypyran-4-yl) -4-（(2-di-dimethylsulfamoyl) phenyl) amino) pyrimidine-2 -Yl) amino) -5- (4-methylpiperazin-l-yl) phenyl) acrylamide, 2,2,2-trifluoroacetate; <1 ₃ -10 ñ （5-（（5- （3,6-dihydro

Pyran-4-yl) -4-（(2- (isopropylsulfony) phenyl) amino) pyrimidin-2-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin) -1 -yl) piperidine- 1-yl) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt;  <18-11 2- 2-（（2-（（5-acrylamido-4-(（2- (dimethylamino) ethyl） (methyl) amino） -2-methoxyphenyl) amino） -2-5- （ 3,6-dihydropyran-4-yl) pyrimidin-4-yl) amino) -IImethylbenzoamide 2,2,2-trifluoroacetic acid salt; <13-12 ñ- (5-（(5- （3,6-dihi-methyl-; in-indole-3-yl) pyrimidin-2-yl) amino) -4

Jin-1-yl) phenyl) acrylamide;  <-13 ñ-（5-（（5- （3,6-dihydro-e-pyran-4-yl) -4- （1-methyl-111-indole-3-yl) pyrimidin-2-yl ） Amino） 2- 2-（(2- (dimethylamino) ethyl) （methyl）  -Methoxyphenyl) acrylamide; 14 1 1 （5-（（5- （3,6-dihydro_2_2pyran-4-yl) -4_ （1-methyl-in-

） Pyrimidin-2-yl) amino) -4-methoxy-2- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide 2,2,2- Trifluoroacetic acid salt; <13-15--（5-（（5- （3,6-dihydro-2 ^ ｛-pyran-4-yl) -4- （1-methyl-in-indole-3-yl) pyrimidine- 2-yl) amino)-2- (2- (dimethylamino) ethoxy) -4 -methok 2019/177375 1 »（： 1 '/ 10 {2019/002915  83 ciphenyl) acrylamide 2,2,2- trifluoroacetic acid salt;  <13-16 ñ (5-（（5- （3,6-dihydro-la-pyran-4-yl) -4- (my-indole-3_yl) pyrimidin-2-yl) amino) -2 -((2- (dimethylamino) ethyl) (methyl) amino) -4 -methoxyphenyl) acrylamide 2,2,2-trifluoroacetic acid salt;  <13-17 一 （5-（（5- （3,6-dihydro 一 21] -pyran 一 4-yl) 一 4-（(2-methoxyethyl) amino） pyrimidin-2-yl) Amino)-2-((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide 2,2,2-trifluoroacetic acid salt;  <13-18> (5-（（4- (cyclopropylamino) -5- (3,6-dihydro-lan-4-yl) pyrimidin-2-yl) amino) -2-(（2 -(Dimethylamino) ethyl) (methyl) amino)-4-methoxyphenyl) acrylamide; And  <13-19--(5-（（5- （3,6-dihydro-2pyran-4-yl) -4 _ （(1-methylpyridin-4-yl) amino) pyrimidine-2 Sun) amino) -2- (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide 2,2,2-trifluoroacetate. [Claim 7]  The method of claim 2,  Compound represented by the formula (18), as shown in the following scheme 1,  Preparing a compound represented by Formula 5 by reacting the compound represented by Formula 73 with the compound represented by Formula 83 (step 1); Preparing a compound represented by Chemical Formula 4 by reacting a compound represented by Chemical Formula 53 with a compound represented by Chemical Formula 63 (step 2); preparing a compound represented by Chemical Formula 23 by reacting the compound represented by Chemical Formula 43. (Step 3); and  Preparing a compound represented by Chemical Formula 13 by reacting the compound represented by Chemical Formula 23 with the compound represented by Chemical Formula 33 (step 4); A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which may be prepared by a method for preparing a compound represented by Chemical Formula 13 of claim 2; Scheme 13 2019/177375 1 »（： 1/10 公 019/002915 84

[Claim 8]  According to claim 1,  The compound represented by Formula 1 is a compound represented by the following formula: an optical isomer thereof or a pharmaceutically acceptable salt thereof:  [Formula]

 In (Formula 11),  Is unsubstituted or substituted 5 to 15 membered heteroaryl containing one or more hetero atoms selected from the group consisting of ^ or 0 and Is an unsubstituted or substituted 3 to 10 membered group containing at least one hetero atom selected from the group consisting of linear or branched _-1 () alkyl, unsubstituted or substituted 0 _6-14 aryl or 0 and Heterocycloalkyl (： 卜₃ alkyl, 02019/177375 1 »(1 ^ 1 {2019/002915 85 The substituted aryl, heteroaryl, and heterocycloalkyl is -30 ₂ ⁵ ,-? (= 0) å ⁶ å ⁷ ,-ᄄ = 0), straight or branched chain ( _-5 alkyl and straight or branched chain). _May be substituted with one or more substituents selected from the group consisting of _-5 alkoxy, and 1 \ 1 \ I ¹ and are independently straight or branched chains of (^ _-5 alkyl or unsubstituted or straight chained or branched chains- ₅ Amine substituted with one or more alkyl; is hydrogen or straight or branched chain (: ^ ₀ alkoxy; female

Is hydrogen or straight or branched chain alkyl, wherein said alkyl may be substituted one or more with unsubstituted or straight or branched chain amines substituted with one or more ( _-5 alkyl), or ⁹ and. Together with an atom can form a 3 to 10 membered unsubstituted or substituted heterocycloalkyl comprising at least one hetero atom selected from the group consisting of 0 and. The substituted heterocycloalkyl can be linear or branched. Group consisting of heterocycloalkyl unsubstituted or linear or branched 0 _1-5 alkyl of 3 to 10 atoms containing one or more hetero atoms selected from the group consisting of ( _-5 alkyl and 0 and of It may be substituted with one or more selected from). [Claim 9]  The method of claim 8, remind

Or 5 to 5 unsubstituted or substituted containing at least one hetero atom selected from the group consisting of 0 and 3 10 atom heteroaryl, Is unsubstituted or substituted 3 to 8 membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of linear or branched _-5 alkyl, unsubstituted or substituted- ₁₀ aryl or 0 and Alkyl, The substituted aryl, heteroaryl, and heterocycloalkyl are-,-? (= 0) å ⁶ å ⁷ ,-ᄄ = 0) ·, may be substituted with one or more substituents selected from the group consisting of straight or branched chain (: alkyl and straight or branched chain _-3 alkoxy, I ⁵ , I ^6, I ¹ and ⁸ is independently a straight or branched chain (- ₃ alkyl, or unsubstituted or straight or branched chain alkyl of ₃ to 0 ^ one or more substituted amine, and; ^ Is hydrogen or straight or branched chain ( _-5 alkoxy; 3 is-3 4 ¹⁰ or- ¹¹ , 2019/177375 1 »（： 1/10 公 019/002915 86 where

And ¹¹ are independently hydrogen or straight or branched _-3 alkyl, wherein said alkyl may be substituted one or more by amine substituted one or more by unsubstituted or straight or branched _-3 alkyl, or å ^{1 () May} form an unsubstituted or substituted heterocycloalkyl of 3 to 8 atoms containing one or more hetero atoms selected from the group consisting of 0 and with the atoms to which they are attached, the substituted hetero Cycloalkyl is unsubstituted or straight-chain or branched alkyl substituted at least one heterocycloalkyl containing 3 to 8 atoms containing one or more heteroatoms selected from the group consisting of _-5 alkyl and, 0 and. Compound which can be substituted with one or more selected from the group consisting of, optical isomers thereof or A pharmaceutically acceptable salt thereof. [Claim 10]  The method of claim 8,  The silver or an unsubstituted or substituted 5 to 9 membered heteroaryl containing one or more atoms, A straight-chain or _branched-3 alkyl, unsubstituted or substituted phenyl, or, 0, and made The at least one year for interrogating atoms selected from the group heterocycle of the unsubstituted or substituted 5 or 6 atoms comprising Al Kill _-3 alkyl, Heteroaryl, and heterocycloalkyl is _30 ₂ ,

May be substituted with one or more substituents selected from the group consisting of methyl, ethyl, methoxy and ethoxy, and ⁶ , I ¹ and are independently substituted with one or more linear or branched _-3 alkyl or unsubstituted or methyl Amines; 2 is hydrogen or straight or branched chain ( _-3 alkoxy);

( _-3 alkyl of the chain, wherein said alkyl may be unsubstituted or substituted one or more by amine substituted one or more by methyl, Or, 1, and ^{1 ()} together with the atoms to which they are attached may form an unsubstituted or substituted piperidine or piperazine, wherein the substituted piperidine and piperazine are methyl, ethyl and unsubstituted or straight chain Or one or more selected from the group consisting of piperazinyl or morpholinyl substituted with one or more alkyls of branched chain 0 _1-3 alkyl, optical isomers thereof or pharmaceutically acceptable thereof. Salt. [Claim 11] In the low ^1-8, 2019/177375 1 »（： 1 ^ 1 {2019/002915  87

I ² is methoxy; or

The body or a pharmaceutically acceptable salt thereof. [Claim 12]  The method of claim 8,  The compound represented by the formula is any one selected from the group of compounds, optical isomers thereof or pharmaceutically acceptable salts thereof:  ᅡ （5-（(4-（(2- (isopropylsulfonyl) phenyl) amino) -5-morpholinopyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpipepe Razin-1-yl) phenyl) acrylamide 2,2,2-trifluoroacetate;  <1 2 ñ 1 ᅡ (2-（(2- (dimethylamino) ethyl) (methyl) amino)-5-（(4-（(2- (isopropylsulfonyl) phenyl) amino) -5-morphopoly Nopyrimidin-2-yl) amino)-4-methoxyphenyl) acrylamide;  <1 ᅡ 3--(2-（(2- (dimethylamino) ethyl) (methyl) amino)-5-（（4-（（2- (Dimethylphosphpoly) phenyl) amino) -5-morpholinopyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide 2,2,2-trifluoroacetic acid salt; \ ¥ 02019/177375 1 »（： 1 '/ For 0 {2019/002915  88 <1¾ ^_ 4> 00 ^_ 1 ^ ᅳ (2-（(2_ (dimethyl mino) ethyl) (methyl) ⁰ ! · Mino) -4) -methoxy- 5-（（5-morpholino-4- (） Tetrahydrofuran -2-yl) methyl) amino) pyrimidin-2-yl) amino) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt;  <113-5 ñ-(5-（（4-（(2-2--dimethylsulfamoyl) phenyl) amino) -5-morpholinopyrimidin-2-yl) amino) -4-methoxy-2- （ 4-methylpiperazin-1-yl) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt;  <113-6 ñ 1 ^-(2-（(2- (dimethylamino) ethyl) (methyl) amino)-5-（（4-（(2- Daekawa-dimethylsulfamoyl) phenyl) amino） -5 -Morpholinopyrimidine-2 -yl) amino)- 4-methoxyphenyl) acrylamide 2,2, 2- trifluoroacetic acid salt; <11广7 ñ _ ^((_ 2,4-dimethoxyphenyl) amino) - 5 - modeul Reno pyrimidine Dean _2-yl) amino - (dimethylamino) ethyl) (methyl) amino) -4-methoxy-carbonyl Fe Acrylamitritriacetic acid salt; （5_ ⁰ 1 ^· Krill ⁰ ！ Mido ^_ 4-((2- (dimethyl ⁰ ) mino) ethyl) (methyl) amino) -2-yl) amino) -5-morpholinopyrimidin-4-yl) Amino) _ -methylbenzene- 2 -trifluoroacetic acid salt; <11） -9 ñ

5 ^_ Acrylamido-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-morpholinopyrimidin-4-yl) amino) -methylbenzeneamide 2.2.2 -trifluoroacetic acid salt;  <113-10 ñ (5-（（4-（(2- (isopropylsulfonyl) phenyl) amino) -5-morpholinopyrimidin-2-yl) amino) -4-methoxy-2-2- 4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) acrylamide 2,2,2-trifluoroacetoate;  <113-11>-(4-methoxy-5-((4- (1-methyl-in_indol- 3-yl) -5-morpholinopyrimidin-2-yl) amino) -2- 4-Methylpiperazine-1-yl) phenyl) acrylamide 2.2.2 -trifluoroacetic acid salt;  <11） -12 ñ (2-((2- (dimethylamino) ethyl) (methyl) amino) -4 -methoxy- 5-((4- (1-methyl-in-indole-3-yl) -5-morpholinopyrimidin-2-yl) amino) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt; <1, a 13 "(4-methoxy-5 - ((4- (1-methyl-I _ indol-3-yl) -5-morpholinyl nopi limiter Dean-2-yl) amino) - ₂ - (4 -Morpholinopiperidine- 1-yl) phenyl) acrylamide reacetate: 2- ( ^2_ (dimethylamino) ethoxy) -4-methoxy-5 (4 (1- (methyl-morpholinopyrimidin-2-yl) amino) phenyl) acrylamide reacetic acid salt;

4-Methoxy-5- (4- (methylamino) -5-morpholinopyrimidin-2-yl) amino-2- (4-methylpiperazin-1-yl) phenyl) acrylamide 2,2,2-trifluoroacetate; And  <11 16 ñ 1 yarn- (2-((2- (dimethylamino) ethyl) (methyl) amino) -4 -methoxy- 5-((4- (methylamino) -5-morpholinopyrimidin-2-yl) amino) phenyl) acrylamide 2,2,2-trifluoroacetic acid salt. [Claim 13] The method of claim 8, Compound represented by the formula, as shown in the following scheme,  Reacting the compound represented by Formula Dog with the compound represented by Formula Solution to prepare a compound represented by Formula 513 (Step 1); Preparing a compound represented by the formula (VII) by reacting the compound represented by the formula (513) with the compound represented by the formula (61); (step 2); preparing a compound represented by the formula by reacting the compound represented by the formula ( Step 3）; and  Step (step 4) of preparing a compound represented by the formula by reacting the compound represented by the formula and the compound represented by the formula (Step 4), which may be prepared by the method of preparing a compound represented by the formula of claim 8, Compounds, optical isomers thereof or pharmaceutically acceptable salts thereof:  [Scheme]

(In Scheme lb, Z ¹ , Z ² and Z ³ are as defined in formula lb of claim 8; And X ^la , X ^2a and) ( ³³ are independently halogen). [Claim 14]  A pharmaceutical composition for preventing or treating cancer, comprising the compound represented by the formula (1) of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. [Claim 15]  The method of claim 14, The compound is a pharmaceutical composition, characterized in that to inhibit the EGFR (ep i derma 1 grow hf ac t or r ecept or) wild type or EGFR mutation. 2019/177375 1 »（： 1 ^ 1 {2019/002915 90 [Claim 16] The method of claim 15,

Pharmaceutical composition, characterized in that the phase. [Claim 17]  The method of claim 14,  The compound is composed of Sho 1 1 3 1 1-1) 1 103 1 0 1 6 Sho 1 1 3171) -03; 10 13 6 (1,,, Yam, £ 6 yo (£ 746- 八 750 （161) 6 £ 6 grave (07190, grave 犯 £, £ 1? （1747-Table 749 line), grave 0 1 ^ 747-3752 mountain 61? 7535) grave? 1 747-1751 （161 ，）, £ 0 185810, £ 0? 1 858, 17901 A pharmaceutical composition, characterized in that it exhibits inhibitory activity against one or more protein kinases selected from the group consisting of £ 0 yo (丄 861, on the table), Tables 1¾62, £ 1 犯 84, and Jusen. [Claim 18]  The method of claim 14, Pharmaceutical, characterized in that the mutation is expressed relative to

[Claim 19]  The method of claim 14, The cancer includes pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, myxocarcinoma, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma , Ovarian epithelial cancer, Ovarian germ cell cancer, Breast cancer, Brain cancer, Pituitary adenoma, Multiple myeloma, Gallbladder cancer, Biliary cancer, Colon cancer, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Retinoblastoma, Choroidal melanoma, Battery swelling cancer, Bladder cancer , Peritoneal cancer, Parathyroid cancer, Adrenal cancer, Non-sinus cancer, Non-small cell lung cancer, Sulfur cancer, Astrocytoma, Small cell lung cancer, Pediatric brain cancer, Pediatric lymphoma, Pediatric leukemia, Small intestine cancer, Meningioma, Esophageal cancer, Glioma, Kidney cancer, Kidney Cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, Urethral Cancer, Primary Cancer, Gastric Lymphoma, Gastric Cancer, Gastric Carcinoma, Gastrointestinal Interstitial Cancer, Wilms Cancer, Breast Cancer, Sarcoma, Penile Cancer, Pharyngeal Cancer, Pregnancy Induced Disease, Cervical Cancer, Endometrial Cancer, Uterine Sarcoma, Prostate Cancer , Metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, colorectal carcinoma, vaginal cancer, spinal cord cancer, auditory neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung Squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, 2019/177375 1 »（： 1/10 公 019/002915 91 is a pharmaceutical composition, characterized in that at least one member selected from the group consisting of hematological cancer, thymic cancer.