Pyrimidine derivatives having inhibitory activity against protein kinases and pharmaceutical compositions for therapeutic use containing the same

Abstract

The present invention relates to a pharmaceutical composition for preventing and treating cancer diseases (such as lung cancer) caused by abnormal cell proliferation, comprising a novel trisubstituted pyrimidine derivative having inhibitory activity against protein kinases (such as EGFR) and a pharma- ceutical acceptable salt thereof as an active ingredient. The novel compound of the present invention has a strong inhibitory activity against protein kinases. In particular, the novel compound of the present invention has a strong inhibitory effect against various drug-resistant EGFR mutants (such as exon 19 deletion-T790M-C797S-EGFR, L858R-T790M-C797S-EGFR, exon 19 deletion-T790M-EGFR, and L858R-T790M-EGFR), and is useful as a preventive and therapeutic agent for cancer diseases caused by these EGFR mutants.

Description

[Technical Field]

[0001] The present invention relates to a compound selected from novel trisubstituted pyrimidine derivatives having inhibitory activity against protein kinases, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof, a method for preparing the compound, and a pharmaceutical composition containing the compound as an active ingredient for preventing, ameliorating, or treating cancer diseases caused by abnormal cell proliferation. [Background technology]

[0002] Protein kinases are enzymes that catalyze phosphorylation reactions, in which the gamma-phosphate group of ATP is transferred to the hydroxyl groups of tyrosine, serine, and threonine residues within proteins. Protein kinases are involved in cellular metabolism, gene expression, cell growth, differentiation, and cell division, and play an important role in signal transduction. Protein kinases account for approximately 2% of eukaryotic genomes. The human genome contains approximately 518 protein kinases. Protein kinases are classified into tyrosine protein kinases, which phosphorylate tyrosine, and serine / threonine kinases, which phosphorylate serine and threonine. At least approximately 90 protein kinases are tyrosine kinases, which are divided into receptor tyrosine kinases (RTKs) and nonreceptor tyrosine kinases (NRTKs). Receptor tyrosine kinases are membrane proteins that contain a domain capable of accommodating growth factors on the cell surface and an active site where tyrosine residues are phosphorylated in the cytoplasm. Protein kinases are molecular switches, and their transition between their active and inactive states in cells must be smoothly regulated. Abnormal regulation of this transition leads to excessive activation of intracellular signaling, inducing uncontrolled cell division and proliferation. Furthermore, abnormal activation of protein kinases due to genetic mutations, gene amplification, and gene overexpression plays an important role in the proliferation and metastasis of cancer cells, due to its association with the development and progression of various tumors.

[0003] Lung cancer is a malignant tumor of the lungs, a respiratory organ. Lung cancer is divided into non-small cell lung cancer and small cell lung cancer depending on the size and shape of the cancer cells. Non-small cell lung cancer accounts for 80% of all lung cancers. If detected early, non-small cell lung cancer can be completely cured by surgical treatment, but recurrence has been shown in 20-50% of non-small cell lung cancer patients who have undergone surgery. Non-small cell lung cancer is more likely to metastasize to the brain, bone, liver, and contralateral lung than other cancers.

[0004] The most common cause of non-small cell lung cancer is a mutation in the epidermal growth factor receptor (EGFR) tyrosine kinase gene. EGFR mutations are present in 30-40% of Asian non-small cell lung cancer patients, 10-15% of American and European non-small cell lung cancer patients, and 40-50% of Asian female non-smoker non-small cell lung cancer patients. EGFR gene mutations cause lung cancer regardless of smoking status. 90% of all EGFR mutations are activating mutations (exon 19 deletion mutations (43%) and L858R point mutations (41%)) that can activate EGFR without epidermal growth factor receptor (EGF).

[0005] EGFR is a transmembrane tyrosine kinase receptor that dimerizes with ligands such as epidermal growth factor and is activated by phosphorylation of tyrosine residues. Activated EGFR creates conditions for easy binding to downstream molecules, phosphorylating them and activating downstream pathways (e.g., RAS mitogen-activated protein kinase (MAPK), phosphotidylinositol 3-kinase (PI3-K)-Akt, phospholipase Cγ (PLCγ) / protein kinase C (PKC), and signal transduction and activator of transcription (STAT) pathways) to inhibit apoptosis, promote cell growth and proliferation, and regulate gene expression. Because the activated conformation of EGFR is maintained even in the absence of ligand, the occurrence of activating mutations, such as exon 19 deletion mutations or the L858R point mutation, leads to unlimited cell proliferation and cancer formation.

[0006] Gefitinib (Iressa®, AstraZeneca) and erlotinib (Tarceva®, Roche) are first-generation orally administered EGFR tyrosine kinase inhibitors. These first-generation inhibitors have demonstrated their superiority by extending patient survival by 10 months compared with existing cytotoxic anticancer drugs as standard therapy. However, resistance to first-generation inhibitors leads to the development of T790M mutations in 60% of patients. Afatinib (Gilotrif®, Boehringer Ingelheim) has emerged as a second-generation EGFR tyrosine kinase inhibitor capable of inhibiting T790M mutations. Although afatinib has proven clinically effective, it has not been able to secure a therapeutic window. Second-generation inhibitors, with relatively narrow indications, are approved only as first-line treatments for locally advanced or metastatic non-small cell lung cancer with EGFR mutations. Osimertinib (Tagrisso®, AstraZeneca) is a third-generation EGFR tyrosine kinase inhibitor containing a Michael acceptor capable of covalently binding to cysteine. Osimertinib was launched as the first FDA-approved third-generation EGFR-targeted anticancer drug. However, osimertinib induced acquired resistance in patients with the C797S mutation who received osimertinib for approximately 10 months. The C797S mutation refers to a substitution of a cysteine ​​residue in the Tagrisso binding site with a serine. The C797S mutation neutralizes Tagrisso covalent binding. Because Tagrisso can be used to treat the T790M mutation that occurs after treatment with first- and second-generation EGFR inhibitors, patients who develop resistance to Tagrisso have three mutations: an EGFR-activating mutation (exon 19 deletion or L858R), a T790M mutation, and a C797S mutation. Therefore, fourth-generation EGFR inhibitors should have moderate efficacy against double mutations (exon 19 deletion / T790M, or L858R / T790M) and activating mutations (exon 19 deletion or L858R), as well as triple mutations (exon 19 deletion / T790M / C797S, or L858R / T790M / C797S).

[0007] Third-generation inhibitors with Michael acceptors, such as Tagrisso, were discontinued in clinical trials due to their severe side effects, including Stevens-Johnson syndrome, skin rash, and cardiac disease. Therefore, there is a need to develop fourth-generation EGFR inhibitors that overcome resistance to third-generation inhibitors while reducing side effects. Such fourth-generation inhibitors must be able to distinguish between wild-type and mutant EGFR to reduce side effects. Despite their high efficacy, drugs developed to date have shown limited sensitivity to the difference between wild-type and mutant EGFR, resulting in high toxicity.

[0008] Lung cancer is an extremely deadly cancer, with over 20,000 new cases diagnosed annually in South Korea. It is the leading cause of death in the country. In particular, the 5-year survival rate for lung cancer that has metastasized to other organs is low at 8.9%. In 2021, there were approximately 30,000 lung cancer patients in South Korea, of which 30-40% were EGFR mutation-positive. EGFR mutations are also found in several tumor types, such as glioblastoma (50%), triple-negative breast cancer (13-30%), and colorectal cancer (25-77%), as well as lung cancer. EGFR inhibitors are undergoing clinical trials for a wide range of cell types, including lung cancer and head and neck cancer.

[0009] Under these circumstances, the present inventors have conducted extensive research to develop a new substance that can overcome the limitations of third-generation EGFR inhibitors, and have arrived at the present invention. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2018 / 230934 [Patent Document 2] US Patent Application Publication No. 20200207768 [Patent Document 3] Korean Patent Publication No. 10-2019-0114910 [Patent Document 4] International Publication No. 2019 / 112344 [Patent Document 5] International Publication No. 2020 / 147702 [Non-patent literature]

[0011] [Non-Patent Document 1] J. Med. Chem. 2018, 61, 4290-4300 [Non-patent document 2] J. Med. Chem. 2019, 62, 10272-10293 Summary of the Invention [Problem to be solved by the invention]

[0012] Therefore, one object of the present invention is to provide novel pyrimidine derivatives that have inhibitory activity against protein kinases.

[0013] A further object of the present invention is to provide a pharmaceutical composition useful for the treatment, prevention, and amelioration of cancer diseases, which comprises a novel pyrimidine derivative, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a stereoisomer thereof as an active ingredient.

[0014] Another object of the present invention is to provide a therapeutic agent for cancer diseases caused by EGFR mutations, which comprises a novel pyrimidine derivative, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a stereoisomer thereof as an active ingredient.

[0015] One aspect of the present invention is intended to provide a method for preparing said novel compounds.

[0016] One aspect of the present invention is intended to provide novel intermediates synthesized during the preparation of said novel compounds. [Means for solving the problem]

[0017] One aspect of the present invention provides a compound selected from pyrimidine derivatives represented by Formula 10, Formula 11, or Formula 12, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof.

[0018] [Formula 10] [ka]

[0019] wherein R1 is hydrogen, hydroxyl, halo, C1-C 13 alkyl, or C1-C6 alkoxy; R2 is hydrogen, halo, C1-C 13 Alkyl, C3-C 10 cyclyl, amino (-NR8R9), or nitro (-N(O)2); R3 and R4 are each independently hydrogen, C1 to C 13 Alkyl, C3-C 10 cyclyl, sulfide (-SR), sulfonyl (-S(O)R), or phosphoryl (-P(O)RR); R5, R6, and R7 are each independently hydrogen, hydroxyl, halo, C1-C 13 Alkyl, C1-C6 alkoxy, C3-C 10 Cyclyl, C3-C 10 Heterocyclyl, -C(O)-(C1-C 13 alkyl), amino (-NR8R9), nitro (-N(O)2), amide (-(C=O)NR8R9), carboxyl (-C(O)OH), nitrile (-CN), ureido (-NR8(C=O)NR9-), sulfonamide (-NHS(O)2R8), sulfide (-SR8), sulfonyl (-S(O)2R8), or phosphoryl (-P(O)R8R9); X1, X2, and X3 are each independently carbon or nitrogen;

[0020] A is C1~C 13 Alkyl, amino (-NR8R9), C6-C 10 Aryl, C3-C 10 Cyclyl, C3-C10 Heteroaryl or C3-C 10 It is a heterocyclyl or forms a 3- to 7-membered saturated ring together with the carbon atom to which R6 is attached, and the 3- to 7-membered saturated ring may contain at least one of N, O, S, NH, C═N, C═O, —NHC(O)—, —NHC(O)NH—, —NHS(O)2—, and SO2, and may also contain hydrogen, C1-C 13 Alkyl, C6-C 10 Aryl, C3-C 10 optionally substituted with at least one of heteroaryl, hydroxyl, halo, and cyano; B is C6~C 10 Aryl, C3-C 10 Cyclyl, C3-C 10 Heteroaryl or C3-C 10 is heterocyclyl,

[0021] however, When X1 and X3 are each independently nitrogen, R2 or R7 is absent; The above C1~C6 alkoxy, the above C1~C 13 Alkyl, or the C3 to C 10 Cyclyl is hydrogen, hydroxyl, halo, C1-C 13 one or more substituents selected from the group consisting of alkyl, C1-C6 alkoxy, amino (-NR8R9), nitro (-N(O)2), amide (-(C=O)NR8R9), carboxyl (-C(O)OH), nitrile (-CN), ureido (-NR8(C=O)NR9-), sulfonamide (-NHS(O)2-), sulfide (-S-), sulfonyl (-S(O)2-), and phosphoryl (-P(O)R8R9); C6~C 10 Aryl, C3-C 10 Heteroaryl and C3-C 10 Heterocyclyl, the C6-C 10 Aryl, the C3-C 10 Heteroaryl or the C3 to C 10 Heterocyclyl is hydrogen, hydroxyl, halo, carbonyl (—(C═O)R₈R₈), unsubstituted or halo, or C₃-C₁₁₀.10 C1-C3 alkyl, unsubstituted or halo or C3-C substituted by heterocyclyl 10 C1-C3 alkoxy, C6-C substituted by heterocyclyl 10 Phenoxy, amino (-NR8R9), nitro (-N(O)2), amide (-(C=O)NR8R9), carboxyl (-C(O)OH), nitrile (-CN), ureido (-NR8(C=O)NR9-), sulfonamide (-NHS(O)2-), sulfide (-S-), sulfonyl (-S(O)2-), phosphoryl (-P(O)R8R9), C6 to C 10 Aryl, C3-C 10 Heteroaryl and C3-C 10 heterocyclyl; R8 and R9 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Heteroaryl or C3-C 10 heterocyclyl, provided that R8 may form a 3- to 7-membered saturated ring together with the nitrogen atom or carbon atom to which R9 is bonded, and the 3- to 7-membered saturated ring may contain at least one of N, O, S, NH, C═N, C═O, —NHC(O)—, —NHC(O)NH—, —NHS(O)2—, and SO2, and may also contain hydrogen, C1-C 13 Alkyl, C6-C 10 Aryl, C3-C 10 optionally substituted with at least one of heteroaryl, hydroxyl, halo, and cyano; Said C3~C 10 Heteroaryl and the C3-C 10 Heterocyclyl contains at least one heteroatom selected from the group consisting of N, O, and S;

[0022] [Formula 11] [ka]

[0023] In the formula, R1 to R6, X1 to X3, A, and B are as defined in formula 10,

[0024] [Formula 12] [ka]

[0025] In the formula, R1 to R7, X1 to X3, A, and B are as defined in formula 10.

[0026] A further aspect of the present invention provides a pharmaceutical composition for preventing, ameliorating or treating a disease caused by EGFR protein kinase, comprising the compound as an active ingredient.

[0027] In another embodiment of the present invention, the disease caused by EGFR protein kinase can be a metabolic disease caused by EGFR protein kinase, or a neoplastic disease resulting from abnormal cell proliferation caused by EGFR protein kinase.

[0028] In another aspect of the invention, the disease may be selected from the group consisting of lung cancer, liver cancer, esophageal cancer, gastric cancer, colorectal cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, testicular cancer, blood cancer, lymphoma, skin cancer, psoriasis, and fibroadenoma.

[0029] In another aspect of the invention, the active ingredient may inhibit the activity of EGFR kinase or EGFR mutations to prevent, ameliorate or treat disease.

[0030] In another aspect of the invention, the EGFR mutation can be active del19, L858R, T790M, or C797S, or a combination thereof.

[0031] In another aspect of the invention, the active ingredient may be co-administered with a cytotoxic therapeutic agent.

[0032] In another embodiment of the invention, 100 parts by weight of active ingredient may be co-administered with 10 to 1000 parts by weight of a cytotoxic therapeutic agent. [Effects of the Invention]

[0033] Due to their excellent ability to inhibit the activity of EGFR protein kinase, the compounds of the present invention can be used as active ingredients in pharmaceutical compositions for the prevention and treatment of diseases caused by abnormal cell proliferation and metabolism.

[0034] Therefore, the compounds of the present invention can be used as preventive and therapeutic agents for diseases caused by abnormal cell proliferation and metabolism, for example, metabolic diseases such as diabetes and obesity, and various tumor diseases selected from endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing gland disease, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, blood cancer (such as leukemia, multiple myeloma, and myelodysplastic syndrome), lymphoma (such as Hodgkin's disease and non-Hodgkin's lymphoma), and fibroadenoma. DETAILED DESCRIPTION OF THE INVENTION

[0035] definition Unless otherwise specified, all numbers, values, and / or expressions expressing ingredients, reaction conditions, and ingredient contents used herein are intended to mean that these numbers are approximations that reflect, among other things, various uncertainties in measurement inherent in obtaining these values, and therefore should be understood in each instance to be modified by the term "about." When numerical ranges are disclosed herein, such ranges are continuous and, unless otherwise indicated, include both the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Furthermore, when a range refers to integers, all integers between the minimum and maximum values ​​of such range are included unless otherwise indicated.

[0036] When a range is described herein for a variable, it is understood that the variable includes all values ​​within the described range, including the recited endpoints. For example, the range "5 to 10" is understood to include any subranges such as 6 to 10, 7 to 10, 6 to 9, and 7 to 9, as well as the individual values ​​5, 6, 7, 8, 9, and 10, and any value between the valid integers in the described range, such as 5.5, 6.5, 7.5, 5.5 to 8.5, and 6.5 to 9. Also, for example, the range "10% to 30%" is understood to include any subranges such as 10% to 15%, 12% to 18%, and 20% to 30%, as well as all integers, including values ​​from 10%, 11%, 12%, and 13% to 30%, and any value between the valid integers in the described range, for example, 10.5%, 15.5%, and 25.5%.

[0037] As used herein, the terms "individual," "subject," and "patient" refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human mammal. None of these terms require or are limited to situations characterized by the supervision (e.g., constant or intermittent) of a healthcare professional (e.g., a physician, registered nurse, advanced practice nurse, physician's assistant, nursing assistant, or hospice worker).

[0038] "Treatment" is an intervention intended to prevent the onset of disease or alter the pathology or symptoms of disease. Thus, "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disease and those in whom the disease is to be prevented. In tumor (e.g., cancer) treatment, a therapeutic agent may directly reduce the pathology of tumor cells or may make tumor cells more susceptible to treatment with other therapeutic agents, such as radiation therapy and / or chemotherapy and / or immunotherapy. As used herein, the term "amelioration" or "treatment" refers to a condition that reaches a normalized value (e.g., a value obtained in a healthy patient or individual), e.g., a condition that differs from the normalized value by less than 50%, preferably by less than 25%, more preferably by less than 10%, and even more preferably does not differ significantly from the normalized value, as determined using routine statistical tests.

[0039] "Treatment of cancer" refers to one or more of the following effects: (1) inhibition of tumor growth, e.g., (i) slowing and (ii) complete cessation of growth; (2) reduction in tumor cell count; (3) maintenance of tumor size; (4) reduction in tumor size; (5) inhibition of tumor cell infiltration into peripheral organs, e.g., (i) reduction, (ii) slowing, or (iii) complete prevention; (6) inhibition of metastasis, e.g., (i) reduction, (ii) slowing, or (iii) complete prevention; and (7) enhancement of anti-tumor immune response, which may result in (i) maintenance of tumor size, (ii) reduction in tumor size, (iii) delay in tumor growth, (iv) reduction, delay, or prevention of infiltration.

[0040] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to a quantity of a compound disclosed herein sufficient to relieve to some extent one or more symptoms of the disease or condition being treated. In some embodiments, that result is 1) reduction and / or alleviation of the signs, symptoms, or causes of the disease, or 2) any other desired alteration of a biological system in a clinical setting. In some embodiments, an appropriate "effective" amount in any individual case will be determined using any suitable technique, such as a dose escalation study.

[0041] In some embodiments, an "effective amount" is the amount of a disclosed compound that, when administered to an individual in one or more doses in monotherapy or combination therapy, is effective to inhibit EGFR by about 20% (20% inhibition), at least about 30% (30% inhibition), at least about 40% (40% inhibition), at least about 50% (50% inhibition), about 60% or more (60% inhibition), about 70% or more (70% inhibition), about 80% or more (80% inhibition), or about 90% or more (90% inhibition), compared to the EGFR activity in the individual in the absence of treatment with the compound, or compared to the EGFR activity in the individual before or after treatment with the compound.

[0042] In some embodiments, a "therapeutically effective amount" is an amount of a disclosed compound that, when administered to a subject in one or more doses in monotherapy or combination therapy, is effective to reduce a subject's tumor burden by about 20%, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more compared to the subject's tumor burden in the absence of treatment with the compound, or compared to the subject's tumor burden before or after treatment with the compound. As used herein, the term "tumor burden" refers to the total mass of tumor tissue borne by a subject with cancer.

[0043] In some embodiments, a "therapeutically effective amount" is an amount of a disclosed compound that, when administered to a subject in one or more doses in monotherapy or combination therapy, is effective to reduce the dose of radiation therapy required to observe tumor shrinkage in a subject by about 20%, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more compared to the dose of radiation therapy required to observe tumor shrinkage in the subject in the absence of treatment with the compound.

[0044] Pharmaceutical Composition Pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers, and diluents, are readily available to those skilled in the art. Pharmaceutically acceptable auxiliary substances, such as pH adjusting agents, buffering agents, tonicity adjusting agents, stabilizers, and wetting agents, are readily available to those skilled in the art.

[0045] In some embodiments, the compounds of the present invention may be formulated in an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers ranging in strength from 5 mM to 1000 mM. In some embodiments, the aqueous buffer contains a reagent that provides an isotonic solution. Such reagents include, but are not limited to, sodium chloride and a sugar (e.g., mannitol, dextrose, sucrose, etc.). In some embodiments, the aqueous buffer further contains a non-ionic surfactant such as polysorbate 20 or polysorbate 80. The formulation may optionally further contain a preservative. Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, etc. In other embodiments, the formulation may be stored at about 4°C. The formulations may also be lyophilized, in which case they typically contain a cryoprotectant such as sucrose, trehalose, lactose, maltose, and mannitol. When lyophilized, the formulations may be stored for extended periods, even at ambient temperatures.

[0046] The present invention provides pharmaceutical compositions comprising or consisting essentially of the compounds disclosed herein, pharmaceutically acceptable salts, isomers thereof, and tautomers thereof, and further comprising or consisting essentially of one or more additional active agents of interest. Any convenient active agent may be utilized in the methods of the present invention in conjunction with the compounds of the present invention. In one embodiment, the compounds of the present invention and immune checkpoint inhibitors, as well as the additional therapeutic agents described herein for combination therapy, may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by another route. In other embodiments, the compounds of the present invention and chemotherapeutic agents (particularly those capable of inducing the production of cGAMP in the body), as well as the additional therapeutic agents described herein for combination therapy, may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by another route. The compounds of the present invention and the second active agent (if present) may be administered by the same or different routes of administration. Therapeutic agents may be administered by any suitable means, including, but not limited to, oral, rectal, nasal, topical, vaginal, parenteral, intravenous, intranasal, or intratumoral injection into the affected organ.

[0047] The compounds of the present invention may be administered in unit dosage form and may be prepared by any method known in the art. Such methods include combining the compounds of the present invention with pharmaceutically acceptable carriers or diluents, which constitute one or more accessory ingredients. Pharmaceutically acceptable carriers are selected based on the chosen route of administration and standard pharmaceutical practice. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the subject or patient. The carrier may be solid or liquid, and the type is typically selected based on the type of administration being used.

[0048] Examples of suitable solid carriers include lactose, sucrose, gelatin, agar, and bulk powder. Examples of suitable liquid carriers include water, pharmaceutically acceptable oils and fats, alcohol, or other organic solvents (e.g., esters, emulsions, syrups or elixirs, suspensions, and solutions and / or suspensions reconstituted from non-effervescent granules). Such liquid carriers may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents.

[0049] The present invention will be described in detail below. One aspect of the present invention provides a compound selected from a pyrimidine derivative represented by Formula 10, Formula 11, or Formula 12), a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

[0050] [Formula 10] [ka]

[0051] wherein R1 is hydrogen, hydroxyl, halo, C1-C 13 alkyl, or C1-C6 alkoxy; R2 is hydrogen, halo, C1-C 13 Alkyl, C3-C 10 cyclyl, amino (-NR8R9), or nitro (-N(O)2); R3 and R4 are each independently hydrogen, C1 to C 13 Alkyl, C3-C 10 cyclyl, sulfide (-SR), sulfonyl (-S(O)R), or phosphoryl (-P(O)RR); R5, R6, and R7 are each independently hydrogen, hydroxyl, halo, C1-C 13 Alkyl, C1-C6 alkoxy, C3-C 10 Cyclyl, C3-C 10 Heterocyclyl, -C(O)-(C1-C 13alkyl), amino (-NR8R9), nitro (-N(O)2), amide (-(C=O)NR8R9), carboxyl (-C(O)OH), nitrile (-CN), ureido (-NR8(C=O)NR9-), sulfonamide (-NHS(O)2R8), sulfide (-SR8), sulfonyl (-S(O)2R8), or phosphoryl (-P(O)R8R9); X1, X2, and X3 are each independently carbon or nitrogen;

[0052] A is C1~C 13 Alkyl, amino (-NR8R9), C6-C 10 Aryl, C3-C 10 Cyclyl, C3-C 10 Heteroaryl or C3-C 10 It is a heterocyclyl or forms a 3- to 7-membered saturated ring together with the carbon atom to which R6 is attached, and the 3- to 7-membered saturated ring may contain at least one of N, O, S, NH, C═N, C═O, —NHC(O)—, —NHC(O)NH—, —NHS(O)2—, and SO2, and may also contain hydrogen, C1-C 13 Alkyl, C6-C 10 Aryl, C3-C 10 optionally substituted with at least one of heteroaryl, hydroxyl, halo, and cyano; B is C6~C 10 Aryl, C3-C 10 Cyclyl, C3-C 10 Heteroaryl or C3-C 10 is heterocyclyl,

[0053] however, When X1 and X3 are each independently nitrogen, R2 or R7 is absent; The above C1~C6 alkoxy, the above C1~C 13 Alkyl, or the C3 to C 10 Cyclyl is hydrogen, hydroxyl, halo, C1-C 13one or more substituents selected from the group consisting of alkyl, C1-C6 alkoxy, amino (-NR8R9), nitro (-N(O)2), amide (-(C=O)NR8R9), carboxyl (-C(O)OH), nitrile (-CN), ureido (-NR8(C=O)NR9-), sulfonamide (-NHS(O)2-), sulfide (-S-), sulfonyl (-S(O)2-), and phosphoryl (-P(O)R8R9); C6~C 10 Aryl, C3-C 10 Heteroaryl and C3-C 10 Heterocyclyl, the C6-C 10 Aryl, the C3-C 10 Heteroaryl or the C3 to C 10 Heterocyclyl is hydrogen, hydroxyl, halo, carbonyl (—(C═O)R₈R₈), unsubstituted or halo, or C₃-C₁₁₀. 10 C1-C3 alkyl, unsubstituted or halo or C3-C substituted by heterocyclyl 10 C1-C3 alkoxy, C6-C substituted by heterocyclyl 10 Phenoxy, amino (-NR8R9), nitro (-N(O)2), amide (-(C=O)NR8R9), carboxyl (-C(O)OH), nitrile (-CN), ureido (-NR8(C=O)NR9-), sulfonamide (-NHS(O)2-), sulfide (-S-), sulfonyl (-S(O)2-), phosphoryl (-P(O)R8R9), C6 to C 10 Aryl, C3-C 10 Heteroaryl and C3-C 10 heterocyclyl; R8 and R9 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Heteroaryl or C3-C 10heterocyclyl, provided that R8 may form a 3- to 7-membered saturated ring together with the nitrogen atom or carbon atom to which R9 is bonded, and the 3- to 7-membered saturated ring may contain at least one of N, O, S, NH, C═N, C═O, —NHC(O)—, —NHC(O)NH—, —NHS(O)2—, and SO2, and may also contain hydrogen, C1-C 13 Alkyl, C6-C 10 Aryl, C3-C 10 optionally substituted with at least one of heteroaryl, hydroxyl, halo, and cyano; Said C3~C 10 Heteroaryl and the C3-C 10 Heterocyclyl contains at least one heteroatom selected from the group consisting of N, O, and S;

[0054] [Formula 11] [ka]

[0055] In the formula, R1 to R6, X1 to X3, A, and B are as defined in formula 10,

[0056] [Formula 12] [ka]

[0057] In the formula, R1 to R7, X1 to X3, A, and B are as defined in formula 10.

[0058] Pharmaceutically acceptable salts of the pyrimidine compounds represented by Formula 10, Formula 11, or Formula 12 of the present invention can be prepared by common methods known in the art. Pharmaceutically acceptable salts should have low toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound. Free acids that can be used to prepare pharmaceutically acceptable salts can be divided into inorganic acids and organic acids. Inorganic acids may be, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, and hydrobromic acid. Organic acids may be, for example, acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, etc. Examples of organic bases that can be used to prepare organic base addition salts include tris(hydroxymethyl)methylamine dicyclohexylamine, etc. Examples of amino acids that can be used to prepare amino acid addition bases include natural amino acids such as alanine and glycine.

[0059] The pyrimidine compounds of Formula 10, Formula 11, or Formula 12 of the present invention are intended to include all hydrates and solvates thereof, in addition to pharmaceutically acceptable salts. Hydrates and solvates of compounds of Formula 10, Formula 11, or Formula 12 can be prepared by dissolving the compound of Formula 10, Formula 11, or Formula 12 in a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane, adding the free acid or free base to the solution, and crystallizing or recrystallizing the mixture. Thus, the compounds of the present invention are intended to include stoichiometric solvates, including hydrates, in addition to compounds containing varying amounts of water, which can be prepared by suitable methods such as lyophilization or freeze-drying.

[0060] Further details are provided regarding the substituents used to define the compounds of this invention.

[0061] In the definition of substituents in this invention, the term "alkyl" refers to an aliphatic hydrocarbon radical. Alkyl may be a "saturated alkyl" that does not contain an alkenyl or alkynyl moiety, or an "unsaturated alkyl" that contains at least one alkenyl or alkynyl moiety. The term "alkenyl" refers to a group that contains at least one carbon-carbon double bond, and the term "alkynyl" refers to a group that contains at least one carbon-carbon triple bond. Alkyl, when used alone or in combination with another radical, may be cyclic, branched, or straight-chain.

[0062] The term "aryl," as used herein, alone or in combination with another radical, refers to a carbocyclic aromatic monocyclic group containing six carbon atoms, which may be further fused to a second five- or six-membered carbocyclic group, which may be aromatic, saturated, or unsaturated. Such aryl groups include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The aryl may be bonded to one or more other groups at any suitable position on the aromatic ring.

[0063] The term "alkoxy," as used herein, refers to an alkyl group attached to another group via an oxygen atom (i.e., -O-alkyl). An alkoxy group can be unsubstituted or substituted with one or more suitable substituents. Examples of alkoxy groups include, but are not limited to, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-2-methyl-1-propyl, -O-2-methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl-1-propyl, -O-2-methyl-1-pentyl, 3-O-methyl-1-pentyl, -O-4- Examples of the alkoxy groups include (C1-C6) alkoxy groups such as methyl-1-pentyl, -O-2-methyl-2-pentyl, -O-3-methyl-2-pentyl, O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3-dimethyl-butyl, -O-2-ethyl-1-butyl, -O-butyl, -isobutyl, -Ot-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, and -O-hexyl.

[0064] The term "phenoxy" refers to a phenyl group attached to another group through an oxygen atom (i.e., -O-aryl). The phenoxy group can be unsubstituted or substituted with one or more substituents selected from, but not limited to, halo, alkyl, aryl, and heteroaryl groups.

[0065] The term "amino" refers to an alkyl group attached through a nitrogen atom to another group (i.e., -NH- or -N-alkyl). An amino group can be unsubstituted or substituted with one or more suitable substituents.Examples of amino groups include, but are not limited to, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NH-2-methyl-1-propyl, -NH-2-methyl-2-propyl, -NH-2-methyl-1-butyl, -NH-3-methyl-1-butyl, -NH-2-methyl-3-butyl, -NH-2,2-dimethyl-1-propyl, -NH-2-methyl-1-pentyl, 3-NH-methyl-1-pentyl, -NH-4-methyl-1-pentyl, -NH-2-methyl-2-pentyl, -NH- 3-Methyl-2-pentyl, -NH-4-methyl-2-pentyl, -NH-2,2-dimethyl-1-butyl, -NH-3,3-dimethyl-butyl, -NH-2-ethyl-1-butyl, -NH-butyl, -NH-isobutyl, -NH-t-butyl, -NH-pentyl, -NH-isopentyl, -NH-neopentyl, -NH-hexyl, -N,N-dimethyl, -N-methyl-N-ethyl, -N-methyl-N-propyl, -N-methyl-isopropyl, -N-methyl-N-butyl, -N-methyl-N-isobutyl, -N-methyl N-ethyl-N-pentyl, -N-methyl-N-isopentyl, N-methyl-N-hexyl, N-methyl-N-isohexyl, -N,N-diethyl, -N-ethyl-N-propyl, -N-ethyl-N-isopropyl, -N-ethyl-N-butyl, -N-ethyl-N-isobutyl, -N-ethyl-N-pentyl, -N-ethyl-N-isopentyl, -N-ethyl-N-hexyl, -N-ethyl-N-isohexyl, -N,N-dipropyl, -N-propyl-N-isopropyl, -N-propyl-N-butyl, -N-propyl- Examples of (C1 to C6) amino groups include N-isobutyl, -N-propyl-N-pentyl, -N-propyl-N-isopentyl, -N-propyl-N-hexyl, -N-propyl-N-isohexyl, -N,N-dibutyl, -N-butyl-N-isobutyl, -N-butyl-N-pentyl, -N-butyl-N-isopentyl, -N-butyl-N-hexyl, -N-butyl-N-isohexyl, -N,N-dipentyl, -N-pentyl-N-hexyl, -N-pentyl-N-isohexyl, and -N,N-dihexyl.

[0066] The term "halo" refers to fluoro, chloro, bromo, or iodo.

[0067] The term "heterocyclyl," unless otherwise specified, refers to a heteroaromatic group containing at least one heteroatom selected from the group consisting of N, O, and S. Examples of preferred heterocyclyl groups include, but are not limited to, pyrrolidine, furan, morpholine, piperazine, and piperidine groups. Further preferred examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, piperazine, and morpholine groups.

[0068] The term "heteroaryl," unless otherwise specified, refers to a heteroaromatic group containing at least one heteroatom selected from the group consisting of N, O, and S. Examples of preferred heteroaryl groups include, but are not limited to, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, imidazole, triazole, indole, oxadiazole, thiadiazole, quinoline, isoquinoline, isoxazole, oxazole, thiazole, and pyrrole groups.

[0069] In one aspect of the invention, R1 is hydrogen, halo, or C1-C3 alkyl; R2 is hydrogen, C1-C3 alkyl, or amino (-NR8R9); R3 is hydrogen, C1-C3 alkyl, sulfide (-SR8), or sulfonyl (-S(O)2R8); R4 is hydrogen or C1-C3 alkyl; R5 is hydrogen, hydroxyl, halo, C1-C3 alkyl, or C1-C6 alkoxy; R6 is hydrogen, halo, or C1-C3 alkyl; and R7 is hydrogen or C1-C3 alkyl.

[0070] In one aspect of the invention, A is amino (—NR8R9), C3-C 10 Heteroaryl or C3-C 10It is a heterocyclyl or forms a 3- to 7-membered saturated ring together with the carbon atom to which R6 is attached, and the 3- to 7-membered saturated ring may contain at least one of N, O, S, NH, C═N, C═O, —NHC(O)—, —NHC(O)NH—, —NHS(O)2—, and SO2, and may also contain hydrogen, C1-C 13 Alkyl, C6-C 10 Aryl, C3-C 10 B is optionally substituted by at least one of heteroaryl, hydroxyl, halo, and cyano; 10 Aryl or C3-C 10 It is heteroaryl.

[0071] In one aspect of the invention, R1 is halo, R2 is hydrogen or amino (-NR8R9), R3 is hydrogen, C1-C3 alkyl, or sulfonyl (-S(O)2R8), R4 is hydrogen, R5 is hydrogen, halo, or C1-C6 alkoxy, R6 is hydrogen, halo, or C1-C3 alkyl, R7 is hydrogen, A is selected from the group consisting of piperazine, piperidine, morpholine, pyrrolidine, and imidazole, and B is selected from the group consisting of benzene, thiazole, thiophene, pyrazole, benzothiophene, pyridazine, pyrazine, imidazole, oxadiazole, triazole, furan, pyrimidine, oxazole, pyrrole, pyridine, oxadiazole, triazine, thiadiazole, isoxazole, and tetrazole.

[0072] In one aspect of the invention, R1 is Cl or Br, R2 is hydrogen or -NH2, R3 is hydrogen, -CH3, or -S(O)2CH3, R4 is hydrogen, R5 is hydrogen, Cl, Br, -OCH3, -OCH2CH3, or -OCH2CF3, R6 is hydrogen, Cl, Br, F, -CH3, or -CF3, R7 is hydrogen, A is selected from the group consisting of piperazine, piperidine, morpholine, and pyrrolidine, and B is selected from the group consisting of benzene, benzothiazole, quinoline, and quinoxaline.

[0073] In one aspect of the invention, A is selected from the group consisting of: [ka]

[0074] In one aspect of the invention, B is selected from the group consisting of: [ka]

[0075] In one aspect of the invention, R1 is Cl or Br, R2 is hydrogen or -NH2, R3 is hydrogen, -CH3, or -S(O)2CH3, R4 is hydrogen, R5 is hydrogen, Cl, Br, -OCH3, -OCH2CH3, or -OCH2CF3, R6 is hydrogen, Cl, Br, F, -CH3, or -CF3, R7 is hydrogen, and A is [ka] and B is selected from the group consisting of: [ka] is selected from the group consisting of:

[0076] In one embodiment of the present invention, the compound is selected from the group consisting of compound numbers 1 to 283 below.

[0077] Compound No. 1: N-(2-((5-chloro-2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)-4-yl)amino)phenyl)methanesulfonamide;

[0078] Compound No. 2: N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0079] Compound No. 3: N-(2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0080] Compound No. 4: N-(2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0081] Compound No. 5: N-(2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0082] Compound No. 6: N-(2-((5-chloro-2-((6-(1,1-dioxythiomorpholino)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0083] Compound No. 7: N-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0084] Compound No. 8: N-(5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)-N-(2-(methylsulfonamido)phenyl)methanesulfonamide;

[0085] Compound No. 9: N-(5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-N-(2-(methylsulfonamido)phenyl)methanesulfonamide;

[0086] Compound No. 10: N-(5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)-N-(2-(methylsulfonamido)phenyl)methanesulfonamide;

[0087] Compound No. 11: N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)-N-methylsulfonamide;

[0088] Compound No. 12: N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide;

[0089] Compound No. 13: N-(2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide;

[0090] Compound No. 14: N-(2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amido)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0091] Compound No. 15: N-(2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0092] Compound No. 16: N-(2-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0093] Compound No. 17: N-(2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0094] Compound No. 18: N-(2-((5-chloro-2-((6-(4-(2-hydroxymethyl)piperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0095] Compound No. 19: N-(2-((2-((6-(4-acetylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)-5-chloropyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0096] Compound No. 20: N-(2-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0097] Compound No. 21: N-(2-((5-chloro-((6-(4-hydroxypiperidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0098] Compound No. 22: N-(2-((5-chloro-2-((2-methoxy-6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0099] Compound No. 23: N-(2-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0100] Compound No. 24: N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide;

[0101] Compound No. 25: N-(2-((5-bromo-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0102] Compound No. 26: N-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0103] Compound No. 27: N-(2-((5-bromo-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0104] Compound No. 28: N-(2-((5-bromo-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0105] Compound No. 29: N-(2-((5-bromo-2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0106] Compound No. 30: N-(2-((5-bromo-2-((6-(4-cyclopropylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0107] Compound No. 31: N-(2-((5-bromo-2-((2-methoxy-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0108] Compound No. 32: N-(2-((5-bromo-2-((6-(4,4-dimethylpiperidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0109] Compound No. 33: N-(2-((5-bromo-2-((6-(4,4-difluoropiperidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0110] Compound No. 34: N-(2-((5-bromo-2-((2-chloro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0111] Compound No. 35: N-(2-((5-bromo-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0112] Compound No. 36: N-(2-((5-bromo-2-((2-methoxy-6-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0113] Compound No. 37: N-(2-((5-bromo-2-((2-methoxy-6-(4-(1-methyl-4-yl)piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0114] Compound No. 38: N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0115] Compound No. 39: N-(2-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0116] Compound No. 40: N-(2-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0117] Compound No. 41: N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((1-methyl-1H-pyrazol-5-yl)amino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0118] Compound No. 42: N-(2-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0119] Compound No. 43: N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperidin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0120] Compound No. 44: N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0121] Compound No. 45: N-(2-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)fluorophenyl)methanesulfonamide;

[0122] Compound No. 46: 5-chloro-N 2-(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine;

[0123] Compound No. 47: 5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine;

[0124] Compound No. 48: 5-chloro-N 2 -(4-(4-ethylpiperazin-1-yl)phenyl)-N 4 -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine;

[0125] Compound No. 49: 5-chloro-N 2 -(6-morpholinopyridin-3-yl)-N 4 -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine;

[0126] Compound No. 50: 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide;

[0127] Compound No. 51: 2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide;

[0128] Compound No. 52: 2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide;

[0129] Compound No. 53: 2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide;

[0130] Compound No. 54: 2-((5-chloro-2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide;

[0131] Compound No. 55: 2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide;

[0132] Compound No. 56: 2-((5-chloro-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide;

[0133] Compound No. 57: 2-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide;

[0134] Compound No. 58: 2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide;

[0135] Compound No. 59: 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-cyclopropylbenzenesulfonamide;

[0136] Compound No. 60: 2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-cyclopropylbenzenesulfonamide;

[0137] Compound No. 61: 2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylbenzenesulfonamide;

[0138] Compound No. 62: 5-chloro-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine;

[0139] Compound No. 63: 5-chloro-N 2 -(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine;

[0140] Compound No. 64: 5-chloro-N 2 -(2-Methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)-N 4 -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine;

[0141] Compound No. 65: N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0142] Compound No. 66: N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0143] Compound No. 67: N-(4-chloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0144] Compound No. 68: N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0145] Compound No. 69: N-(2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0146] Compound No. 70: N-(2-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0147] Compound No. 71: N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0148] Compound No. 72: N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0149] Compound No. 73: N-(4,5-dichloro-2-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0150] Compound No. 74: N-(4,5-dichloro-2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0151] Compound No. 75: N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0152] Compound No. 76: N-(4,5-dichloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0153] Compound No. 77: N-(4,5-dichloro-2-((5-chloro-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

[0154] Compound No. 78: N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)-N-methylacetamide;

[0155] Compound No. 79: N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)-N-methylacetamide;

[0156] Compound No. 80: N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0157] Compound No. 81: N-(4-chloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)aminophenyl)methanesulfonamide;

[0158] Compound No. 82: N-(4-chloro-2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0159] Compound No. 83: N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0160] Compound No. 84: N-(4-chloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0161] Compound No. 85: N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino-4-chlorophenyl)methanesulfonamide;

[0162] Compound No. 86: N-(2-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0163] Compound No. 87: N-(2-((5-bromo-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0164] Compound No. 88: N-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0165] Compound No. 89: N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonylamide;

[0166] Compound No. 90: N-(2-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0167] Compound No. 91: N-(2-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0168] Compound No. 92: N-(2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0169] Compound No. 93: N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0170] Compound No. 94: N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0171] Compound No. 95: N-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0172] Compound No. 96: N-(2-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0173] Compound No. 97: N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0174] Compound No. 98: N-(2-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0175] Compound No. 99: N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0176] Compound No. 100: N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenylmethanesulfonamide;

[0177] Compound No. 101: N-(4,5-dichloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0178] Compound No. 102: N-(4,5-dichloro-2-((5-chloro-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0179] Compound No. 103: N-(4,5-dichloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)aminophenyl)methanesulfonamide;

[0180] Compound No. 104: N-(4,5-dichloro-2-((5-chloro-2-((4-(4-((2-(dimethylamino)ethyl)(methyl)amino)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0181] Compound No. 105: N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(methyl(3-(4-methylpiperazin-1-yl)propyl)amino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0182] Compound No. 106: N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide;

[0183] Compound No. 107: N-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide;

[0184] Compound No. 108: N-(2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methoxy-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide;

[0185] Compound No. 109: N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide;

[0186] Compound No. 110: N-(5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;

[0187] Compound No. 111: N-(5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;

[0188] Compound No. 112: N-(5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;

[0189] Compound No. 113: N-(5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;

[0190] Compound No. 114: N-(5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;

[0191] Compound No. 115: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide;

[0192] Compound No. 116: N-(6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide;

[0193] Compound No. 117: N-(6-((5-chloro-2-((2-methoxy-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide;

[0194] Compound No. 118: N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methoxypiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide;

[0195] Compound No. 119: N-(6-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide;

[0196] Compound No. 120: N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide;

[0197] Compound No. 121: N-(2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide;

[0198] Compound No. 122: (6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

[0199] Compound No. 123: (6-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

[0200] Compound No. 124: (6-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

[0201] Compound No. 125: (6-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

[0202] Compound No. 126: (6-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

[0203] Compound No. 127: (6-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

[0204] Compound No. 128: (6-((5-chloro-2-((2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

[0205] Compound No. 129: 4-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)thiomorpholine 1,1-dioxide;

[0206] Compound No. 130: (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

[0207] Compound No. 131: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;

[0208] Compound No. 132: N-(6-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;

[0209] Compound No. 133: N-(6-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;

[0210] Compound No. 134: N-(6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;

[0211] Compound No. 135: N-(6-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;

[0212] Compound No. 136: N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;

[0213] Compound No. 137: N-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide;

[0214] Compound No. 138: N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide;

[0215] Compound No. 139: N-(2-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide;

[0216] Compound No. 140: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0217] Compound No. 141: N-(2-((6-amino-5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0218] Compound No. 142: ((2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl-λ 6 -Sulfanone;

[0219] Compound No. 143: ((2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl-λ 6 -Sulfanone;

[0220] Compound No. 144: ((2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl-λ 6 -sulfanone;

[0221] Compound No. 145: N-(2-((5-bromo-2-((2-methoxy-6-(1-methylazepan-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0222] Compound No. 146: N-(2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0223] Compound No. 147: N-(2-((5-bromo-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0224] Compound No. 148: N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0225] Compound No. 149: N-(2-((5-bromo-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0226] Compound No. 150: N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0227] Compound No. 151: N-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0228] Compound No. 152: N-(4-chloro-2-((6-chloro-3-((-2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1,2,4-triazin-5-yl)amino)phenyl)methanesulfonamide;

[0229] Compound No. 153: (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0230] Compound No. 154: (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0231] Compound No. 155: N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)-N-methylmethanesulfonamide;

[0232] Compound No. 156: N-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)-N-methylmethanesulfonamide;

[0233] Compound No. 157: N-(4-chloro-2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0234] Compound No. 158: N-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0235] Compound No. 159: N-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0236] Compound No. 160: N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide;

[0237] Compound No. 161: N-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide;

[0238] Compound No. 162: N-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0239] Compound No. 163: N-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0240] Compound No. 164: N-(2-((6-chloro-3-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1,2,4-triazin-5-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0241] Compound No. 165: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0242] Compound No. 166: 5-chloro-N 4 -(5-chloro-2-(1H-1,2,3-triazol-4-yl)phenyl)-N 2 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;

[0243] Compound No. 167: N-(4-chloro-2-((5-chloro-2-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0244] Compound No. 168: N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0245] Compound No. 169: N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0246] Compound No. 170: N-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide;

[0247] Compound No. 171: N-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide;

[0248] Compound No. 172: N-(6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0249] Compound No. 173: N-(6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0250] Compound No. 174: N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0251] Compound No. 175: N-(6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0252] Compound No. 176: N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0253] Compound No. 177: N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide;

[0254] Compound No. 178: N-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide;

[0255] Compound No. 179: N-(4-chloro-2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide;

[0256] Compound No. 180: N-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide;

[0257] Compound No. 181: N-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0258] Compound No. 182: N-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

[0259] Compound No. 183: N-(6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0260] Compound No. 184: N-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0261] Compound No. 185: 5-chloro-N 4 -(5-chloro-2-(1H-1,2,3-triazol-5-yl)phenyl)-N 2 -(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;

[0262] Compound No. 186: 5-chloro-N 4 -(5-chloro-2-(1H-1,2,3-triazol-5-yl)phenyl)-N 2 -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;

[0263] Compound No. 187: 5-Bromo-N 4 -(5-chloro-2-(1H-1,2,3-triazol-5-yl)phenyl)-N 2 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;

[0264] Compound No. 188: N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0265] Compound No. 189: N-(6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0266] Compound No. 190: (6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

[0267] Compound No. 191: N-(2-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

[0268] Compound No. 192: (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

[0269] Compound No. 193: (6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

[0270] Compound No. 194: (6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

[0271] Compound No. 195: 5-Bromo-N 4 -(5-chloro-2-(1H-1,2,3-triazol-5-yl)phenyl)-N 2 -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;

[0272] Compound No. 196: N-(6-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0273] Compound No. 197: N-(6-((5-chloro-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0274] Compound No. 198: N-(4-chloro-2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

[0275] Compound No. 199: N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0276] Compound No. 200: N-(2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0277] Compound No. 201: N-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0278] Compound No. 202: N-(2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0279] Compound No. 203: N-(2-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0280] Compound No. 204: N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0281] Compound No. 205: N-(6-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0282] Compound No. 206: N-(6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0283] Compound No. 207: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0284] Compound No. 208: N-(6-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0285] Compound No. 209: N-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0286] Compound No. 210: N-(6-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0287] Compound No. 211: N-(6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0288] Compound No. 212: N-(6-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0289] Compound No. 213: N-(6-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0290] Compound No. 214: N-(6-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0291] Compound No. 215: N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0292] Compound No. 216: N-(6-((5-bromo-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0293] Compound No. 217: N-(6-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0294] Compound No. 218: N-(6-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0295] Compound No. 219: N-(6-((5-chloro-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0296] Compound No. 220: N-(6-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0297] Compound No. 221: N-(6-((5-chloro-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0298] Compound No. 222: N-(6-((5-chloro-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0299] Compound No. 223: N-(6-((5-chloro-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0300] Compound No. 224: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-((1-methyl-1H-pyrazol-5-yl)amino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0301] Compound No. 225: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-(trifluoromethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0302] Compound No. 226: N-(4-chloro-2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide;

[0303] Compound No. 227: N-(2-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)-N-methylmethanesulfonamide;

[0304] Compound No. 228: N-(2-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)-N-methylmethanesulfonamide;

[0305] Compound No. 229: N-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0306] Compound No. 230: N-(2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0307] Compound No. 231: N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0308] Compound No. 232: N-(2-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0309] Compound No. 233: N-(2-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0310] Compound No. 234: N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0311] Compound No. 235: N-(2-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0312] Compound No. 236: N-(2-((5-chloro-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0313] Compound No. 237: N-(2-((5-chloro-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

[0314] Compound No. 238: N-(6-((5-bromo-2-((2-methoxy-6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0315] Compound No. 239: N-(6-((5-bromo-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0316] Compound No. 240: N-(6-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0317] Compound No. 241: N-(6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0318] Compound No. 242: N-(6-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0319] Compound No. 243: N-(6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0320] Compound No. 244: N-(6-((5-bromo-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0321] Compound No. 245: N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidin]-1'-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0322] Compound No. 246: N-(6-((5-bromo-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonylamide;

[0323] Compound No. 247: N-(6-((5-bromo-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0324] Compound No. 248: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0325] Compound No. 249: N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0326] Compound No. 250: N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0327] Compound No. 251: N-(6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0328] Compound No. 252: N-(6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0329] Compound No. 253: N-(6-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0330] Compound No. 254: N-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0331] Compound No. 255: N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-(trifluoromethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0332] Compound No. 256: N-(6-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0333] Compound No. 257: N-(6-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0334] Compound No. 258: N-(6-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0335] Compound No. 259: N-(6-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0336] Compound No. 260: N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)-N-methylmethanesulfonamide;

[0337] Compound No. 261: N-(6-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0338] Compound No. 262: N-(6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0339] Compound No. 263: N-(6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0340] Compound No. 264: N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0341] Compound No. 265: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0342] Compound No. 266: N-(6-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0343] Compound No. 267: N-(6-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide;

[0344] Compound No. 268: N-(6-((5-chloro-2-((2,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0345] Compound No. 269: N-(5-((5-bromo-2-((2,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanesulfonamide;

[0346] Compound No. 270: N-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0347] Compound No. 271: N-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0348] Compound No. 272: 5-chloro-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-methylindolin-6-yl)pyrimidine-2,4-diamine;

[0349] Compound No. 273: 5-chloro-N 2 -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-methylindolin-6-yl)pyrimidine-2,4-diamine;

[0350] Compound No. 274: 5-chloro-N 2 -(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-methylindolin-6-yl)pyrimidine-2,4-diamine;

[0351] Compound No. 275: 5-chloro-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-methylindolin-6-yl)pyrimidine-2,4-diamine;

[0352] Compound No. 276: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-methylindolin-5-yl)methanesulfonamide;

[0353] Compound No. 277: 5-chloro-N 2 -(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(indolin-6-yl)pyrimidine-2,4-diamine;

[0354] Compound No. 278: 5-chloro-N 2 -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(indolin-6-yl)pyrimidine-2,4-diamine;

[0355] Compound No. 279: 5-chloro-N 4 -(indolin-6-yl)-N 2 -(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;

[0356] Compound No. 280: N-(6-((2-((5-bromo-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0357] Compound No. 281: N-(6-((5-bromo-2-((5-bromo-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

[0358] Compound No. 282: N-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; and

[0359] Compound No. 283: N-(6-((2-((5-bromo-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide.

[0360] In one aspect of the invention, the pharmaceutically acceptable salt is an inorganic acid or salt of an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid.

[0361] A further aspect of the present invention provides a pharmaceutical composition for preventing, ameliorating or treating cancer, comprising a compound according to any one of the aspects of the present invention as an active ingredient.

[0362] In another aspect of the invention, the cancer is caused by an EGFR mutation.

[0363] In another embodiment of the present invention, the pharmaceutical composition is applied to patients with EGFR mutations.

[0364] In another aspect of the invention, the cancer is selected from the group consisting of glioblastoma, triple-negative breast cancer, colorectal cancer, lung cancer, head and neck cancer, and combinations thereof.

[0365] In another aspect of the invention, the cancer is lung cancer.

[0366] In another embodiment of the present invention, the pharmaceutical composition is administered to a patient with an exon 19 deletion / T790M / C797S triple mutation or an L858R / T790M / C797S triple mutation as an EGFR-associated mutation.

[0367] In another embodiment of the present invention, the pharmaceutical composition is administered to a patient with an exon 19 deletion / T790M double mutation or an L858R / T790M double mutation as an EGFR-associated mutation.

[0368] In another embodiment of the present invention, the pharmaceutical composition is administered to a patient with an exon 19 deletion mutation or an L858R mutation as an EGFR-associated mutation.

[0369] The pharmaceutical composition may be applied to, but is not limited to, laboratory animals such as mice, rabbits, rats, guinea pigs, and hamsters, as well as primates including humans, preferably primates including humans, and more preferably humans.

[0370] As used herein, the terms "treat," "treating," and "treatment" are meant to include alleviation or amelioration of symptoms, diminishment of the extent of disease, delay or slowing of disease progression, improvement, palliation, or stabilization of the disease state, partial or complete remission, prolonged survival, or other beneficial therapeutic outcome.

[0371] As used herein, treating cancer refers to the treatment of all cancer cells, including endothelial cells, angiogenesis, and their mitosis (solid tumors, tumor metastases, and benign tumors). Examples of cancer include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, biliary tract cancer, kidney cancer, myeloid diseases, lymphatic diseases, Hodgkin's disease, hairy cell carcinoma, oral cavity cancer, pharyngeal cancer, lip cancer, tongue cancer, small intestine cancer, colorectal cancer, rectal cancer, brain cancer, central nervous system cancer, leukemia, hemangioma, trachoma, and pyogenic granuloma.

[0372] The content of the compound represented by Formula 10, Formula 11, or Formula 12, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient can be appropriately adjusted according to the selection of a person skilled in the art depending on the purpose and method of use of the pharmaceutical composition of the present invention.

[0373] For example, the pharmaceutical composition may contain 0.1 to 10% by weight, preferably 0.5 to 5% by weight, of the compound represented by Formula 10, Formula 11, or Formula 12, its pharmaceutically acceptable salt, or its hydrate, based on the total weight of the pharmaceutical composition.

[0374] The compound represented by Formula 10, Formula 11, or Formula 12, a pharmaceutically acceptable salt thereof, or a hydrate thereof may be present in the pharmaceutical composition alone or together with one or more other pharmacologically acceptable carriers, non-medicinal ingredients, diluents, or adjuvants.

[0375] Examples of pharmaceutically acceptable carriers, non-medicinal ingredients, or diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, dextrin, calcium carbonate, propylene glycol, liquid paraffin, and physiological saline. Pharmaceutically acceptable carriers, non-medicinal ingredients, or diluents may be those known in the art. The pharmaceutical composition may further comprise one or more additives selected from fillers, extenders, binders, disintegrants, anticoagulants, lubricants, humectants, pH adjusters, nutrients, vitamins, electrolytes, alginic acid and its salts, pectinic acid and its salts, protective colloids, glycerin, flavoring agents, emulsifiers, and preservatives known in the art.

[0376] The compound represented by Formula 10, Formula 11, or Formula 12 of the present invention or a pharmaceutically acceptable salt thereof can be co-administered with one or more other anti-cancer agents for treating cancer or tumors to enhance the therapeutic effect of the anti-cancer agent.

[0377] Pharmaceutical compositions can be oral or parenteral. For example, pharmaceutical compositions can be administered via various routes, including oral, transdermal, subcutaneous, intravenous, or intramuscular. The compositions can be prepared into various formulations depending on the intended use. The compositions can be formulated by methods known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to a mammal. Solid preparations for oral administration typically include tablets, lozenges, soft or hard capsules, pills, powders, and granules. Solid preparations for oral administration may be formulated with one or more non-medicinal ingredients, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple non-medicinal ingredients, lubricants such as magnesium stearate and talc may be used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. Such liquid preparations may contain various non-medicinal ingredients, such as wetting agents, sweeteners, flavoring agents, and preservatives, in addition to the commonly used simple diluents water and liquid paraffin. Formulations for parenteral administration include creams, lotions, ointments, adhesive plasters, liquids, solutions, aerosols, liquid extracts, elixirs, infusions, sachets, patches, and injections. Injectable preparations are preferably in the form of isotonic aqueous solutions or suspensions.

[0378] The pharmaceutical composition may further contain one or more adjuvants, such as sterilizing agents, preservatives, stabilizers, hydrating agents, emulsion promoters, salts for adjusting osmotic pressure, and / or buffers, as well as one or more other therapeutically valuable substances. The pharmaceutical composition may be formulated by conventional mixing or granulation techniques. The pharmaceutical composition may be formulated using any suitable technique known in the art.

[0379] The dosage of the pharmaceutical composition can be determined taking into consideration the mode of administration, the age and sex of the user, the severity of the disease, the patient's condition, the absorption rate of the active ingredient in the body, the inactivation rate, and the type of concomitant medication. The pharmaceutical composition can be administered in a single dose or in divided doses. The active ingredient of the pharmaceutical composition can be administered to mammals, including humans, in an amount of 0.001 to 100 mg per kg of body weight, preferably 0.01 to 35 mg per kg of body weight, via oral or parenteral routes once a day or in divided doses.

[0380] Another embodiment of the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound represented by Formula 10, Formula 11, or Formula 12, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0381] Preferably, the method may further comprise identifying a patient in need of cancer prevention or treatment prior to administration.

[0382] As used herein, the term "therapeutically effective amount" refers to an amount of an active ingredient effective in preventing or treating cancer in a mammal. The therapeutically effective amount may be determined based on various factors, including the type and severity of the disease, the type and amount of the active ingredient and other ingredients in the composition, the type of formulation, the patient's age, weight, general health, sex, and diet, the time and route of administration, the blood clearance of the composition, the duration of treatment, and the type of concomitant medication. As described above, the active ingredient is preferably administered orally or parenterally in an amount of 0.001 to 100 mg per kg of body weight, preferably 0.01 to 35 mg per kg of body weight, once daily or in divided doses.

[0383] The present invention also provides a method for preparing a compound represented by Formula 1.

[0384] [Formula 1] [ka]

[0385] wherein R1 is hydrogen, -Cl, or -Br; R2 is hydrogen, C1-C5 alkyl, —SO2CH3, or —SO2CF3; R3, R4, R8, and R9 are each independently selected from hydrogen, halo, amino, C1-C5 haloalkyl, alkoxy, and C1-C5 alkyl; R5 and R6 are each independently selected from hydrogen, halo, —CF3, C1-C5 haloalkyl, and C1-C5 alkyl; R7 is selected from -CF3, C1-C5 haloalkyl, and C1-C5 alkyl; A is C3~C 10 Heterocycloalkyl, C6-C 13 Heterobicycloalkyl, or C3-C 15 linear or branched heteroalkyl, wherein said heterocycloalkyl, said heterobicycloalkyl, and said linear or branched heteroalkyl are optionally substituted by one or more substituents selected from halo, hydroxyl, alkanol, and C1-C5 alkyl; X is carbon or nitrogen; Y is selected from -N-, -NH-, -CH2-, and -CO-; Z is selected from -NH-, -SO2-, and -SO-(CH3)2; B is a C6 aryl, heteroaryl, or C3-C 10 It is a heterobicycloaryl.

[0386] In one aspect of the invention, B is a monocyclic aryl group or a substituted or unsubstituted bicyclic aromatic group containing one or more heteroatoms selected from N, S, and O. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl, oxochromene, dioxoisoindolinyl, pyrazolopyridinyl, pyrazolo[1,5-a]pyridinyl, isoquinoxalinyl, and the like.

[0387] Pyrimidine compounds represented by formula 1 can be prepared by coupling commercially available pyrimidine compounds represented by formula 2 with amines represented by formula 3, as shown in Reaction Scheme 1.

[0388] [Reaction Scheme 1] [ka]

[0389] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X, Y, Z, A, and B are as defined in Formula 1.

[0390] First, as shown in Reaction Scheme 1, a commercially available pyrimidine compound represented by Formula 2 is coupled with a commercially available amine represented by Formula 3 to obtain a compound represented by Formula 4. This reaction involves stirring at a temperature of 60° C. The reaction solvent may be an organic solvent such as tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylsulfoxide, 2-butanol, or 2-pentanol.

[0391] The compound of formula 4 is then reacted with commercially available sulfonyl chloride or methyl iodide under basic conditions such as sodium hydride in a solvent such as N,N-dimethylformamide at room temperature. As a result of the reaction, the compound of formula 4 is substituted with a sulfonyl or methyl group to give the compound of formula 6.

[0392] The compound of formula 4 or formula 6 is stirred with an amine represented by formula 5 in the presence of 1.25M methanolic hydrochloric acid solution and acetic acid at 120° C. to give the compound of formula 1.

[0393] [Reaction Scheme 2] [ka]

[0394] Reaction Scheme 2 illustrates reactions for preparing amine intermediates of Formula 5. In Reaction Scheme 2, R3, R4, R8, X, and A are as defined in Formula 1, and R8 is fluoro or chloro.

[0395] As shown in Reaction Scheme 2, a commercially available nitro compound represented by formula 7 is coupled with A to give a compound of formula 8.

[0396] Subsequently, the compound of formula 8, iron, and ammonium chloride are stirred in a mixed solvent of tetrahydrofuran, methanol, and water at 85° C. As a result of the reaction, the nitro group of the compound of formula 8 is reduced to an amino group to obtain the compound of formula 5.

[0397] The present invention also provides a pharmaceutical composition comprising a pyrimidine compound represented by Formula 1, Formula 10, Formula 11, or Formula 12, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, or an enantiomer thereof as an active ingredient.

[0398] Due to its excellent ability to inhibit the activity of EGFR protein kinase, the compound of the present invention can be used as the active ingredient of pharmaceutical compositions for preventing and treating the diseases caused by abnormal cell metabolism and glucose metabolism.Therefore, the compound of the present invention can be used as a preventive and therapeutic agent for diseases caused by abnormal cell metabolism and glucose metabolism, such as metabolic diseases such as diabetes and obesity, and various tumor diseases selected from endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing gland disease, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, blood cancer (such as leukemia, multiple myeloma and myelodysplastic syndrome), lymphoma (such as Hodgkin's disease and non-Hodgkin's lymphoma) and fibroadenoma.

[0399] Therefore, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a pyrimidine compound represented by Formula 1, Formula 10, Formula 11, or Formula 12, a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof, and a preventive and therapeutic agent for diseases caused by abnormal cellular metabolism and glucose metabolism.

[0400] The pharmaceutical composition of the present invention contains, as an active ingredient, at least one selected from the group consisting of a pyrimidine compound represented by Formula 1, Formula 10, Formula 11, or Formula 12, a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof. The pharmaceutical composition of the present invention may be formulated, together with a pharmaceutically acceptable carrier, a strengthening agent, and a non-medicinal ingredient, into preparations known in the pharmaceutical field, such as preparations for oral or parenteral administration, for example, tablets, capsules, troches, liquids, and suspensions.

[0401] Examples of non-medicinal ingredients that can be used in the pharmaceutical composition of the present invention include sweeteners, binders, solubilizers, dissolution aids, wetting agents, emulsifiers, isotonicity agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, and flavoring agents. For example, the non-medicinal ingredients may be lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange extract, strawberry extract, and vanilla flavor.

[0402] The dosage of the compound of the present invention for humans may vary depending on the age, weight, and sex of the patient, dosage form, the patient's health condition, and the severity of the disease, and is usually 0.01 to 1,000 mg / day for an adult patient weighing 70 kg. The compound of the present invention may be administered in an amount of 0.01 to 1,000 mg / day for an adult weighing 70 kg once a day or in divided doses at regular intervals, according to the judgment of a physician or pharmacist. [Example]

[0403] The present invention will be described in more detail with reference to the following examples, including formulation examples and experimental examples, although these examples are merely illustrative and do not limit the scope of the present invention.

[0404] [Example] Example 1: Preparation of N-(2-((5-chloro-2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)-4-yl)amino)phenyl)methanesulfonamide [ka]

[0405] Step 1) Preparation of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide 5.0 g (26.9 mmol) of N-(2-aminophenyl)methanesulfonamide and 3.37 ml (35.0 mmol) of 2,4,5-trichloropyrimidine were diluted with 54 ml of isopropyl alcohol, and 9.3 ml (53.8 mmol) of N,N-diisopropylethylamine was added thereto. The mixture was stirred at 60° C. for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The resulting residue was purified by column chromatography (50% ethyl acetate / hexane) to give 4.66 g (yield: 52%) of the title compound.

[0406] Step 2) Preparation of 6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-amine 1.0 g (5.38 mmol) of 6-chloro-2-methoxy-3-nitropyridine and 0.82 ml (5.38 mmol) of 1-ethylpiperazine were diluted with 10 ml of DMSO, and 1.48 g (10.8 mmol) of potassium carbonate was added thereto. The mixture was stirred at 85° C. for 5 hours. The reaction mixture was extracted with dichloromethane and distilled water. The organic layer was dried over magnesium sulfate. The resulting residue was dissolved in 10 ml of a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1 without further purification. 0.3 g (2.7 mmol) of iron powder and 0.16 g (2.7 mmol) of ammonium chloride were added to the solution, followed by stirring at 85° C. for 3 hours. After the reaction was completed, the reaction mixture was washed with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to give 1.2 g (yield: 94%) of the title compound.

[0407] Step 3) Preparation of N-(2-((5-chloro-2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)-4-yl)amino)phenyl)methanesulfonamide 100 mg (0.3 mmol) of the compound prepared in step 1) and 57 mg (0.24 mmol) of the compound prepared in step 2) were dissolved in 1.5 ml of a 1:1 volumetric mixture of acetic acid and 1.25 M HCl / methanol solution, sealed, and stirred at 120 °C for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give 30 mg (yield: 20%) of the title compound. [M+H] + =534.

[0408] Example 2 Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0409] The title compound was prepared from the compound prepared in step 1) of Example 1 and the corresponding aniline in the same manner as in Example 1. [M+H] + =614.

[0410] Example 3 Preparation of N-(2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0411] The title compound was prepared from the compound prepared in step 1) of Example 1 and the corresponding aniline in the same manner as in Example 1. [M+H] + =571.

[0412] Example 4 Preparation of N-(2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0413] The title compound was prepared from the compound prepared in step 1) of Example 1 and the corresponding aniline in the same manner as in Example 1. [M+H] + =669.

[0414] Example 5 Preparation of N-(2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0415] The title compound was prepared from the compound prepared in step 1) of Example 1 and the corresponding aniline in the same manner as in Example 1. [M+H] + =558.

[0416] Example 6 Preparation of N-(2-((5-chloro-2-((6-(1,1-dioxythiomorpholino)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0417] The title compound was prepared from the compound prepared in step 1) of Example 1 and the corresponding aniline in the same manner as in Example 1. [M+H] + =553.

[0418] Example 7 Preparation of N-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0419] The title compound was prepared from the compound prepared in step 1) of Example 1 and the corresponding aniline in the same manner as in Example 1. [M+H] + =634.

[0420] Example 8 Preparation of N-(5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)-N-(2-(methylsulfonamido)phenyl)methanesulfonamide [ka]

[0421] Step 1) Preparation of N-(2,5-dichloropyrimidin-4-yl)-N-(2-(methylsulfonamido)phenyl)methanesulfonamide 1.0 g (3.0 mmol) of the compound prepared in Step 1 of Example 1 was diluted with 6 ml of N,N-dimethylformamide, and 138 mg (6.0 mmol) of 60% sodium hydride was slowly added thereto at 0°C. The mixture was stirred at room temperature for 30 minutes. 0.27 ml (3.6 mmol) of methanesulfonyl chloride was slowly added to the reaction mixture at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate / hexane) to give 1.95 g (yield: 65%) of the title compound.

[0422] Step 2) Preparation of N-(5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)-N-(2-(methylsulfonamido)phenyl)methanesulfonamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and N,N-dimethylpyrrolidin-3-amine was used in step 2) of Example 1. [M+H] + =610.

[0423] Example 9 Preparation of N-(5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-N-(2-(methylsulfonamido)phenyl)methanesulfonamide [ka]

[0424] The title compound was prepared from the compound prepared in Step 1) of Example 8 and the corresponding aniline in the same manner as in Example 1. [M+H] + =692.

[0425] Example 10 Preparation of N-(5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)-N-(2-(methylsulfonamido)phenyl)methanesulfonamide [ka]

[0426] The title compound was prepared from the compound prepared in Step 1) of Example 8 and the corresponding aniline in the same manner as in Example 1. [M+H] + =679.

[0427] Example 11: Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)-N-methylsulfonamide [ka]

[0428] Step 1) Preparation of N-(2-((2,5-dichloropyrimidin-4-yl)(methyl)amino)phenyl)-N-methylmethanesulfonamide 1.0 g (3.0 mmol) of the compound prepared in Step 1 of Example 1 was diluted with 6 ml of N,N-dimethylformamide, and 138 mg (6.0 mmol) of 60% sodium hydride was slowly added thereto at 0°C. The mixture was stirred at room temperature for 30 minutes. 0.22 ml (3.6 mmol) of methyl iodide was slowly added to the reaction mixture at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate / hexane) to give 600 mg (yield: 53%) of the title compound.

[0429] Step 2) Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)-N-methylsulfonamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1. [M+H] + =679.

[0430] Example 12: Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide [ka]

[0431] Step 1) Preparation of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonylamide The title compound was prepared from N-(2-amino-5-fluorophenyl)methanesulfonamide in a similar manner to Example 1, step 1).

[0432] Step 2) Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0433] Example 13 Preparation of N-(2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide [ka]

[0434] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 12 and the corresponding aniline. [M+H] + =493.

[0435] Example 14 Preparation of N-(2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amido)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0436] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 12 and the corresponding aniline. [M+H] + =589.

[0437] Example 15: Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0438] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 12 and the corresponding aniline. [M+H] + =633.

[0439] Example 16: Preparation of N-(2-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0440] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 12 and the corresponding aniline. [M+H] + =607.

[0441] Example 17: Preparation of N-(2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0442] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 12 and the corresponding aniline. [M+H] +=619.

[0443] Example 18: Preparation of N-(2-((5-chloro-2-((6-(4-(2-hydroxymethyl)piperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0444] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 12 and the corresponding aniline. [M+H] + =566.

[0445] Example 19: Preparation of N-(2-((2-((6-(4-acetylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)-5-chloropyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0446] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 12 and the corresponding aniline. [M+H] + =565.

[0447] Example 20 Preparation of N-(2-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0448] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 12 and the corresponding aniline. [M+H] + =565.

[0449] Example 21: Preparation of N-(2-((5-chloro-((6-(4-hydroxypiperidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0450] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 12 and the corresponding aniline. [M+H] + =538.

[0451] Example 22: Preparation of N-(2-((5-chloro-2-((2-methoxy-6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0452] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 12 and the corresponding aniline. [M+H] + =578.

[0453] Example 23: Preparation of N-(2-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0454] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 12 and the corresponding aniline. [M+H] + =550.

[0455] Example 24: Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide [ka]

[0456] Step 1) Preparation of N-(2-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide The title compound was prepared from 5-bromo-2,4-dichloropyrimidine and N-(2-amino-5-fluorophenyl)methanesulfonamide in a manner analogous to Step 1 of Example 1.

[0457] Step 2) Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0458] 1 H NMR(400MHz,DMSO-d6)δ 8.64(s,1H),8.12(s,1H),7.93-7.73(m,2H),7.43(s,1H),7.14(dd,J=10.9,2.8Hz,1H),6.79-6.58(m,2H),3.76(s ,3H),3.06(d,J=11.1Hz,2H),2.84(s,3H),2.78-2.26(m,14H),2.04(s,3H),1.93-1.80(m,2H),1.68-1.50(m,2H). [M+H] + =677.

[0459] Example 25: Preparation of N-(2-((5-bromo-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0460] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =652.

[0461] Example 26: Preparation of N-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0462] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =697.

[0463] Example 27: Preparation of N-(2-((5-bromo-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0464] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =667.

[0465] Example 28: Preparation of N-(2-((5-bromo-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0466] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =664.

[0467] Example 29: Preparation of N-(2-((5-bromo-2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0468] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =568.

[0469] Example 30 Preparation of N-(2-((5-bromo-2-((6-(4-cyclopropylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0470] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =607.

[0471] Example 31: Preparation of N-(2-((5-bromo-2-((2-methoxy-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0472] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =651.

[0473] Example 32: Preparation of N-(2-((5-bromo-2-((6-(4,4-dimethylpiperidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0474] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =594.

[0475] Example 33 Preparation of N-(2-((5-bromo-2-((6-(4,4-difluoropiperidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0476] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =602.

[0477] Example 34: Preparation of N-(2-((5-bromo-2-((2-chloro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0478] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =736.

[0479] Example 35: Preparation of N-(2-((5-bromo-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0480] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =684.

[0481] Example 36: Preparation of N-(2-((5-bromo-2-((2-methoxy-6-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0482] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =664.

[0483] Example 37: Preparation of N-(2-((5-bromo-2-((2-methoxy-6-(4-(1-methyl-4-yl)piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0484] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =732.

[0485] Example 38: Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0486] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =690.

[0487] Example 39 Preparation of N-(2-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0488] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H]+ =705.

[0489] Example 40: Preparation of N-(2-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0490] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =691.

[0491] Example 41: Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((1-methyl-1H-pyrazol-5-yl)amino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0492] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =691.

[0493] Example 42: Preparation of N-(2-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0494] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =703.

[0495] Example 43: Preparation of N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperidin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0496] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =681.

[0497] Example 44: Preparation of N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0498] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =696.

[0499] Example 45: Preparation of N-(2-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)fluorophenyl)methanesulfonamide [ka]

[0500] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =710.

[0501] Example 46: 5-chloro-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine [ka]

[0502] Step 1) Preparation of 2,5-dichloro-N-(2-(trifluoromethyl)phenyl)pyrimidin-4-amine The title compound was prepared from 2-(trifluoromethyl)aniline in a similar manner to Example 1, step 1).

[0503] Step 2) 5-chloro-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0504] Example 47: 5-chloro-N 2 -(2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine [ka]

[0505] The title compound was prepared from the compound prepared in Step 1) of Example 46 and the corresponding aniline in the same manner as in Example 1. [M+H] + =576.

[0506] Example 48: 5-chloro-N 2 -(4-(4-ethylpiperazin-1-yl)phenyl)-N 4 Preparation of -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine [ka]

[0507] The title compound was prepared from the compound prepared in Step 1) of Example 46 and the corresponding aniline in the same manner as in Example 1. [M+H] + =477.

[0508] Example 49: 5-chloro-N 2 -(6-morpholinopyridin-3-yl)-N 4 Preparation of -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine [ka]

[0509] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 46 and the corresponding aniline.

[0510] 1 H NMR(400MHz,CDCl3)δ 8.20(d,J=2.6Hz,1H),8.16(d,J=8.4Hz,1H),8.07(s,1H),7.78(dd,J=9.0,2.5Hz,1H),7.67(d,J=7.7Hz,1H),7 .57-7.47(m,2H),7.30-7.24(m,6H),6.86(s,1H),6.59(d,J=9.0Hz),1H),3.89-3.77(m,4H),3.52-3.28(m,4H). [M+H]+ =451.

[0511] Example 50: Preparation of 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide [ka]

[0512] Step 1) Preparation of 2-((2,5-dichloropyrimidin-4-yl)amino)-N-methylbenzenesulfonamide The title compound was prepared from 2-amino-N-methylbenzenesulfonamide in a similar manner to step 1) of Example 1.

[0513] Step 2) Preparation of 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0514] Example 51: Preparation of 2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide [ka]

[0515] The title compound was prepared from the compound prepared in Step 1) of Example 50 and the corresponding aniline in the same manner as in Example 1. [M+H] + =601.

[0516] Example 52: Preparation of 2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide [ka]

[0517] The title compound was prepared from the compound prepared in Step 1) of Example 50 and the corresponding aniline in the same manner as in Example 1. [M+H] + =572.

[0518] Example 53: Preparation of 2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide [ka]

[0519] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 50 and the corresponding aniline. 1 H NMR(400MHz,DMSO)δ 9.28(s,2H),8.52(s,1H),8.30(s,1H),8.22(s,1H),7.81(dd,J=12.1,5.4Hz,3H),7.60(t,J=7.4Hz, 1H),7.28(t,J=7.6Hz,1H),6.81(d,J=9.1Hz,1H),3.83-3.47(m,4H),3.43-3.18(m,4H),2.44(s,3H). [M+H] + =476.

[0520] Example 54: Preparation of 2-((5-chloro-2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide [ka]

[0521] The title compound was prepared from the compound prepared in Step 1) of Example 50 and the corresponding aniline in the same manner as in Example 1. [M+H] + =533.

[0522] Example 55: Preparation of 2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide [ka]

[0523] The title compound was prepared from the compound prepared in Step 1) of Example 50 and the corresponding aniline in the same manner as in Example 1. [M+H] + =602.

[0524] Example 56: Preparation of 2-((5-chloro-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide [ka]

[0525] The title compound was prepared from the compound prepared in Step 1) of Example 50 and the corresponding aniline in the same manner as in Example 1. [M+H] + =549.

[0526] Example 57: Preparation of 2-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide [ka]

[0527] The title compound was prepared from the compound prepared in Step 1) of Example 50 and the corresponding aniline in the same manner as in Example 1. [M+H] + =533.

[0528] Example 58: Preparation of 2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-methylbenzenesulfonamide [ka]

[0529] The title compound was prepared from the compound prepared in Step 1) of Example 50 and the corresponding aniline in the same manner as in Example 1. [M+H] + =616.

[0530] Example 59: Preparation of 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-cyclopropylbenzenesulfonamide [ka]

[0531] Step 1) Preparation of N-cyclopropyl-2-((2,5-dichloropyrimidin-4-yl)amino)benzenesulfonamide The title compound was prepared from 2-amino-N-cyclopropylbenzenesulfonamide in a similar manner to Example 1, step 1).

[0532] Step 2) Preparation of 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-cyclopropylbenzenesulfonamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in Step 1 was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in Step 2) of Example 1.

[0533] Example 60: Preparation of 2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-cyclopropylbenzenesulfonamide [ka]

[0534] The title compound was prepared from the compound prepared in Step 1) of Example 59 and the corresponding aniline in the same manner as in Example 1. [M+H] + =615.

[0535] Example 61: Preparation of 2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-N-cyclopropylbenzenesulfonamide [ka]

[0536] The title compound was prepared from the compound prepared in Step 1) of Example 59 and the corresponding aniline in the same manner as in Example 1. [M+H] + =628.

[0537] Example 62: 5-chloro-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine [ka]

[0538] Step 1) 2,5-Dichloro-N-(2-((methylsulfonyl)methyl)phenyl)pyrimidin-4-amine The title compound was prepared from 2-((methylsulfonyl)methyl)aniline in a similar manner to Example 1, step 1).

[0539] Step 2) 5-chloro-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 2) of Example 1 was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0540] Example 63: 5-chloro-N 2 -(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine [ka]

[0541] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 62 and the corresponding aniline. [M+H] + =588.

[0542] Example 64: 5-chloro-N 2 -(2-Methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)-N 4Preparation of -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine [ka]

[0543] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 62 and the corresponding aniline. [M+H] + =601.

[0544] Example 65: Preparation of N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0545] Step 1) Preparation of N-(4-chloro-2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)acetamide The title compound was prepared from N-(2-amino-4-chlorophenyl)acetamide in a similar manner to Example 1, step 1).

[0546] Step 2) Preparation of N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0547] Example 66: Preparation of N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0548] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 65 and the corresponding aniline. [M+H] + =614.

[0549] Example 67: Preparation of N-(4-chloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0550] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 65 and the corresponding aniline. [M+H] + =587.

[0551] Example 68: Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0552] Step 1) Preparation of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)acetamide The title compound was prepared from N-(2-aminophenyl)acetamide in a similar manner to step 1) of Example 1.

[0553] Step 2) Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0554] Example 69: Preparation of N-(2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0555] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 68 and the corresponding aniline. [M+H] + =553.

[0556] Example 70: Preparation of N-(2-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0557] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 68 and the corresponding aniline. [M+H] + =554.

[0558] Example 71: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0559] Step 1) Preparation of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)acetamide 5.0 g (22.8 mmol) of N-(2-amino-4,5-dichlorophenyl)acetamide and 3.37 ml (35.0 mmol) of 2,4,5-trichloropyrimidine were diluted with 54 ml of dimethyl sulfoxide, and 7.54 ml (53.8 mmol) of triethylamine and 841 mg (2.28 mmol) of tetrabutylammonium iodide were added thereto. The mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The resulting residue was purified by column chromatography (50% ethyl acetate / hexane) to give 5.01 g (yield: 60%) of the title compound.

[0560] Step 2) Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0561] Example 72: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0562] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 71 and the corresponding aniline.

[0563] 1 H NMR(400MHz,DMSO-d6)δ 9.97(brs,1H),8.37(s,1H),8.10-7.88(m,3H),7.69(s,1H),7.51(d,J=8.5Hz,1H),6.21(d,J=8.5Hz,1H),4.19(d,J=12 .7Hz,2H),3.76(s,3H),2.75(t,J=11.6Hz,3H),2.64-2.30(m,11H),2.09(s,3H),1.87-1.75(m,2H),1.46-1.32(m,2H). [M+H] + =639.

[0564] Example 73: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0565] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 71 and the corresponding aniline. [M+H] + =622.

[0566] Example 74: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0567] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 71 and the corresponding aniline. [M+H] + =508.

[0568] Example 75: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0569] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 71 and the corresponding aniline. [M+H] + =634.

[0570] Example 76: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0571] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 71 and the corresponding aniline. [M+H] + =621.

[0572] Example 77: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide [ka]

[0573] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 71 and the corresponding aniline. [M+H] + =621.

[0574] Example 78: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)-N-methylacetamide [ka]

[0575] Step 1) Preparation of N-(4,5-dichloro-2-((2,5-dichloropyrimidin-4-yl)(methyl)amino)phenyl)-N-methylacetamide 1.0 g (2.73 mmol) of the compound prepared in Step 1 of Example 22 was diluted with 6 ml of N,N-dimethylformamide, and 138 mg (6.0 mmol) of 60% sodium hydride was slowly added thereto at 0°C. The mixture was stirred at room temperature for 30 minutes. 0.22 ml (3.6 mmol) of methyl iodide was slowly added to the reaction mixture at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate / hexane) to give 720 mg (yield: 66%) of the title compound.

[0576] Step 2) Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)-N-methylacetamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0577] Example 79: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)-N-methylacetamide [ka]

[0578] The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) of Example 78 was used and 6-chloro-2-methoxy-3-nitropyridine and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0579] Example 80: Preparation of N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0580] Step 1) Preparation of N-(4-chloro-2-nitrophenyl)methanesulfonamide 5.0 g (29.0 mmol) of 4-chloro-2-nitroaniline was diluted with 60 ml of N,N-dimethylformamide, and 1.33 g (58.0 mmol) of 60% sodium hydride was slowly added thereto at 0°C. The mixture was stirred at room temperature for 30 minutes. 2.68 ml (34.8 mmol) of methanesulfonyl chloride was slowly added to the reaction mixture at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (20% ethyl acetate / hexane) to give 5.1 g (yield: 70%) of the title compound.

[0581] Step 2) Preparation of N-(2-amino-4-chlorophenyl)methanesulfonamide 5.1 g (20.0 mmol) of the compound prepared in step 1) was dissolved in 100 ml of a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1. 11.2 g (200 mmol) of iron powder and 10.8 g (200 mmol) of ammonium chloride were added to the solution, followed by stirring at 85° C. for 3 hours. After completion of the reaction, the reaction mixture was washed with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to give 3.96 g (yield: 90%) of the title compound.

[0582] Step 3) Preparation of N-(4-chloro-2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide The title compound was prepared in the same manner as in Example 21, except that the compound prepared in step 2) of Example 21 was used in step 2).

[0583] Step 4) Preparation of N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 3) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0584] 1 H NMR(400MHz,DMSO-d6)δ 8.74(brs,1H),8.13-8.07(m,2H),8.04(brs,1H),7.36-7.26(m,2H),7.09(dd,J=8.6,2.4Hz,1H),6.68(s,1H),3. 76(s,3H),3.14-3.02(m,2H),2.88(s,3H),2.77-2.24(m,14H),2.06(s,3H),1.94-1.80(m,2H),1.64-1.48(m,2H).

[0585] Example 81: Preparation of N-(4-chloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)aminophenyl)methanesulfonamide [ka]

[0586] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline.

[0587] 1H NMR(400MHz,DMSO-d6)δ 8.66(s,1H),8.23(brs,1H),8.17-8.04(m,2H),7.52(d,J=8.4Hz,1H),7. 28(d,J=8.5Hz,1H),7.05(d,J=6.9Hz,1H),6.31(d,J=8.5Hz,1H),4.25(d, J=13.0Hz,2H),3.78(s,3H)),2.94(d,J=19.2Hz,3H),2.76(t,J=11.8Hz,3 H),2.68-2.42(m,8H),2.32(s,3H),1.90-1.79(m,2H),1.48-1.33(m,2H). [M+H] + =636.

[0588] Example 82: Preparation of N-(4-chloro-2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0589] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline. 1 H NMR(400MHz,DMSO-d6)δ 8.73(brs,1H),8.14(brs,1H),8.12-8.02(m,2H),7.38(d,J=8.6Hz,1H),7.29(d,J=8.5Hz,1H),7.06(dd,J=8.5,2.3Hz,1H),6.6 1(d,J=1.9Hz,1H),6.50-6.41(m,1H),3.83-3.63(m,5H),2.89(s,3H),2.76-2.20(m,14H),1.92-1.80(m,2H),1.60-1.44(m,2H). [M+H] + =635.

[0590] Example 83: Preparation of N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0591] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline. [M+H] + =650.

[0592] Example 84: Preparation of N-(4-chloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0593] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline. [M+H] + =623.

[0594] Example 85: Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino-4-chlorophenyl)methanesulfonamide [ka]

[0595] Step 1) Preparation of N-(2-((5-bromo-2-chloro-4-yl)amino)-4-chlorophenyl)methanesulfonamide The title compound was prepared similarly to step 3) of Example 80, except that 5-bromo-2,4-dichloropyrimidine was used.

[0596] Process 2) The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0597] 1 H NMR(400MHz,DMSO-d6)δ 8.67(brs,1H),8.19-8.11(m,2H),8.07(brs,1H),7.33-7.26(m,2H),7.07(dd,J=8.5,2.4Hz,1H),6.69(s,1H),3. 76(s,3H),3.14-3.03(m,2H),2.90(s,3H),2.78-2.24(m,14H),2.09(s,3H),1.92-1.81(m,2H),1.64-1.49(m,2H).

[0598] Example 86: Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0599] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline. [M+H] + =694.

[0600] Example 87: Preparation of N-(2-((5-bromo-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0601] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline. [M+H] + =667.

[0602] Example 88: Preparation of N-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0603] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline.

[0604] 1 H NMR(400MHz,DMSO-d6)δ 8.68(brs,1H),8.25-8.20(m,2H),8.04(brs,1H),7.58(s,1H),7.30(t,J=8.7Hz,1H),7.10(dd,J=8.5,2.4Hz,1H),6 .78(s,1H),3.80(s,3H),3.36-3.25(m,2H),2.92(s,3H),2.80-2.27(m,14H),1.94-1.80(m,2H),1.66-1.52(m,2H). [M+H] + =713.

[0605] Example 89: Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonylamide [ka]

[0606] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline. [M+H] + =707.

[0607] Example 90: Preparation of N-(2-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0608] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline. [M+H] + =721.

[0609] Example 91: Preparation of N-(2-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0610] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline. [M+H] + =707.

[0611] Example 92: Preparation of N-(2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0612] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline. [M+H] + =696.

[0613] Example 93: Preparation of N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0614] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline. [M+H] + =698.

[0615] Example 94: Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0616] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline. [M+H] + =680.

[0617] Example 95: Preparation of N-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0618] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline. [M+H] + =728.

[0619] Example 96: Preparation of N-(2-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0620] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline. [M+H] + =712.

[0621] Example 97: Preparation of N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0622] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline. [M+H] + =712.

[0623] Example 98: Preparation of N-(2-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0624] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 85 and the corresponding aniline. [M+H] + =726.

[0625] Example 99: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0626] Step 1) Preparation of N-(4,5-dichloro-2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide The title compound was prepared in a manner similar to that of Step 3) of Example 80, except that 4,5-dichloro-2-nitroaniline was used in Step 1) of Example 80.

[0627] Step 2) Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1. [M+H]+ =684.

[0628] Example 100: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenylmethanesulfonamide [ka]

[0629] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 99 and the corresponding aniline. [M+H] + =685.

[0630] Example 101: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0631] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 99 and the corresponding aniline. [M+H] + =658.

[0632] Example 102: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0633] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 99 and the corresponding aniline. [M+H] + =691.

[0634] Example 103: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)aminophenyl)methanesulfonamide [ka]

[0635] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 99 and the corresponding aniline. [M+H] + =704.

[0636] Example 104: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((4-(4-((2-(dimethylamino)ethyl)(methyl)amino)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0637] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 99 and the corresponding aniline. [M+H] + =686.

[0638] Example 105: Preparation of N-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(methyl(3-(4-methylpiperazin-1-yl)propyl)amino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0639] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 99 and the corresponding aniline. [M+H] + =672.

[0640] Example 106: Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide [ka]

[0641] Step 1) Preparation of N-(2-((5-bromo-2-chloropyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide The title compound was prepared in the same manner as in step 3) of Example 24, except that 4-methyl-2-nitroaniline was used in step 1) of Example 24, and 5-bromo-2,4-dichloropyrimidine was used in step 3) of Example 24.

[0642] Step 2) Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0643] Example 107: Preparation of N-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide [ka]

[0644] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 106 and the corresponding aniline. [M+H] + =694.

[0645] Example 108: Preparation of N-(2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methoxy-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide [ka]

[0646] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 106 and the corresponding aniline. [M+H] + =677.

[0647] Example 109: Preparation of N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide [ka]

[0648] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 106 and the corresponding aniline. [M+H] + =678.

[0649] Example 110: Preparation of N-(5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide [ka]

[0650] Step 1) Preparation of N-(2,5-dichloropyrimidin-4-yl)-4-nitrobenzo[d]thiazol-5-amine 5.0 g (25.6 mmol) of 4-nitrobenzo[d]thiazol-5-amine was diluted with 50 ml of N,N-dimethylformamide, and 883 mg (38.4 mmol) of 60% sodium hydride was slowly added thereto at 0°C. The mixture was stirred at room temperature for 30 minutes. 3.5 ml (30.7 mmol) of 2,4,5-trichloropyrimidine was slowly added to the reaction mixture at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (40% ethyl acetate / hexane) to give 6.84 g (yield: 52%).

[0651] Process 2)N 5 Preparation of -(2,5-dichloropyrimidin-4-yl)benzo[d]thiazole-4,5-diamine 6.84 g (20.0 mmol) of the compound prepared in step 1) was diluted with 40 ml of a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1. 11.2 g (200 mmol) of iron powder and 10.8 g (200 mmol) of ammonium chloride were added to the diluted solution, followed by stirring at 85° C. for 3 hours. After completion of the reaction, the reaction mixture was washed with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to give 5.6 g (yield: 90%) of the title compound.

[0652] Step 3) Preparation of N-(2,5-dichloropyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide 5.6 g (18.0 mmol) of the compound prepared in step 2) was diluted with 40 ml of N,N-dimethylformamide, and 5.0 ml (36.0 mmol) of triethylamine and 3.2 ml (45.0 mmol) of methanesulfonyl chloride were slowly added thereto at 0°C. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate / hexane) to give 7.02 g (yield: 83%) of the title compound.

[0653] Step 4) Preparation of N-(5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1. [M+H] + =750.

[0654] Example 111: Preparation of N-(5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide [ka]

[0655] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 110 and the corresponding aniline. [M+H] + =737.

[0656] Example 112: Preparation of N-(5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide [ka]

[0657] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 110 and the corresponding aniline. [M+H] + =724.

[0658] Example 113: Preparation of N-(5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide [ka]

[0659] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 110 and the corresponding aniline. [M+H] + =725.

[0660] Example 114: Preparation of N-(5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide [ka]

[0661] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 110 and the corresponding aniline. [M+H] + =770.

[0662] Example 115: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide [ka]

[0663] Step 1) Preparation of N-(6-((2,5-dichloropyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide The title compound was prepared in a similar manner to Example 80, except that 6-nitroquinolin-5-amine and 2,4-dichloropyrimidine were used in step 1) of Example 80.

[0664] Process 2) The title compound was prepared in the same manner as in Example 1, except that the compound prepared in Example 1 was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0665] Example 116: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide [ka]

[0666] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 115 and the corresponding aniline. [M+H] + =667.

[0667] Example 117: Preparation of N-(6-((5-chloro-2-((2-methoxy-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide [ka]

[0668] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 115 and the corresponding aniline. [M+H] + =640.

[0669] Example 118: Preparation of N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methoxypiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide [ka]

[0670] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 115 and the corresponding aniline. [M+H] + =686.

[0671] Example 119: Preparation of N-(6-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide [ka]

[0672] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 115 and the corresponding aniline. [M+H] + =569.

[0673] Example 120: Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide [ka]

[0674] Step 1) Preparation of 2,5-dichloro-N-methyl-N-(2-nitrophenyl)pyrimidin-4-amine 5.0 g (32.9 mmol) of N-methyl-2-nitroaniline was diluted with 50 ml of N,N-dimethylformamide, and 883 mg (38.4 mmol) of 60% sodium hydride was slowly added thereto at 0°C. The mixture was stirred at room temperature for 30 minutes. 4.6 ml (40.0 mmol) of 2,4,5-trichloropyrimidine was slowly added to the reaction mixture at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (20% ethyl acetate / hexane) to give 5.98 g (yield: 61%) of the title compound.

[0675] Process 2)N 1 -(2,5-dichloropyrimidin-4-yl)-N 1 Preparation of -methylbenzene-1,2-diamine 5.98 g (20.0 mmol) of the compound prepared in step 1) was dissolved in 40 ml of a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1. 11.8 g (200 mmol) of iron powder and 10.8 g (200 mmol) of ammonium chloride were added to the solution, followed by stirring at 85° C. for 3 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to give 4.8 g (yield: 90%) of the title compound.

[0676] Step 3) Preparation of N-(2-((2,5-dichloropyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide The title compound was prepared from 4.8 g (18.0 mmol) of the compound prepared in step 2) in the same manner as in step 1) of Example 26.

[0677] Step 4) Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 3) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0678] Example 121: Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide [ka]

[0679] The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 3) of Example 120 was used and 2-chloro-6-methoxy-3-methyl-5-nitropyridine and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0680] Example 122: Preparation of (6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka]

[0681] Step 1) Preparation of 6-nitroquinoxaline 5.0 g of 4-nitrobenzene-1,2-diamine (32.7 mmol) was diluted with 70 ml of ethanol, and 40% glyoxal solution (35 mmol) was added thereto. The mixture was stirred at 80° C. for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, extracted with ethyl acetate and distilled water, filtered, and concentrated under reduced pressure to obtain 4.9 g (yield: 86%) of the title compound.

[0682] Step 2) Preparation of quinoxalin-6-amine 4.9 g (28.0 mmol) of the compound prepared in step 1) was dissolved in 60 ml of a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1. 11.8 g (200 mmol) of iron powder and 10.8 g (200 mmol) of ammonium chloride were added to the solution, followed by stirring at 85° C. for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, extracted with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to give 3.6 g (yield: 89%) of the title compound.

[0683] Step 3) Preparation of 5-iodoquinoxalin-6-amine 3.6 g (25.0 mmol) of the compound prepared in step 2) was diluted with 60 ml of acetic acid, and 4.9 g (30.0 mmol) of iodine monochloride was added thereto. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated with saturated sodium bicarbonate solution and dichloromethane to give 4.9 g (yield: 72%) of the title compound.

[0684] Step 4) Preparation of (6-aminoquinoxalin-5-yl)dimethylphosphine oxide 4.9 g (18.0 mmol) of the compound prepared in step 3), 1.68 g (21.6 mmol) of dimethylphosphine oxide, and 7.6 g (36.0 mmol) of tripotassium phosphate were diluted with 60 ml of a 5:1 volumetric mixture of N,N-dimethylformamide and distilled water. A catalytic amount of Xantphos and palladium diacetate were added to the diluted mixture, followed by stirring at 120°C for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, extracted with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to give 2.2 g (yield: 56%) of the title compound.

[0685] Step 5) Preparation of 6-((2,5-dichloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 2.2 g (10.0 mmol) of the compound prepared in step 4) was diluted with 20 ml of N,N-dimethylformamide, and 440 mg (19.2 mmol) of 60% sodium hydride was slowly added thereto at 0°C. The mixture was stirred at room temperature for 30 minutes. 2.3 ml (20.0 mmol) of 2,4,5-trichloropyrimidine was slowly added to the reaction mixture at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate / hexane) to give 2.2 g (yield: 60%) of the title compound.

[0686] Step 6) Preparation of (6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 5) was used and 2-chloro-6-methoxy-3-methyl-5-nitropyridine and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1.

[0687] Example 123: Preparation of (6-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka]

[0688] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 5) of Example 122 and the corresponding aniline. [M+H] + =637.

[0689] Example 124: Preparation of (6-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka]

[0690] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 5) of Example 122 and the corresponding aniline. [M+H] + =623.

[0691] Example 125: Preparation of (6-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka]

[0692] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 5) of Example 122 and the corresponding aniline. [M+H] + =624.

[0693] Example 126: Preparation of (6-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka]

[0694] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 5) of Example 122 and the corresponding aniline. [M+H] + =582.

[0695] Example 127: Preparation of (6-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka]

[0696] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 5) of Example 122 and the corresponding aniline. [M+H] + =568.

[0697] Example 128: Preparation of (6-((5-chloro-2-((2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka]

[0698] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 5) of Example 122 and the corresponding aniline. [M+H] + =540.

[0699] Example 129: Preparation of 4-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)thiomorpholine 1,1-dioxide [ka]

[0700] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 5) of Example 122 and the corresponding aniline. [M+H] + =589.

[0701] Example 130: Preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka]

[0702] Step 1) Preparation of 6-nitroquinoxalin-5-amine 5.0 g (28.5 mmol) of the compound prepared in Step 1) of Example 122 was diluted with 60 ml of methanol, and 5.8 g (60 mmol) of sodium t-butoxide and 4.1 g (60 mmol) of hydroxylamine hydrochloride were added thereto at 0° C. The mixture was stirred at 65° C. for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, extracted with dichloromethane, filtered and concentrated under reduced pressure to obtain 3.2 g (yield: 60%) of the title compound.

[0703] Step 2) Preparation of N-(methylsulfonyl)-N-(6-nitroquinoxalin-5-yl)methanesulfonamide 3.2 g (17 mmol) of the compound prepared in step 1) was diluted with 30 ml of N,N-dimethylformamide, and 575 mg (25 mmol) of 60% sodium hydride was slowly added thereto at 0°C. The mixture was stirred at room temperature for 30 minutes. 2.7 ml (36.0 mmol) of methanesulfonyl chloride was slowly added to the reaction mixture at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate / hexane) to give 4.8 g (yield: 82%) of the title compound.

[0704] Step 3) Preparation of N-(6-aminoquinoxalin-5-yl)-N-(methylsulfonyl)methanesulfonamide 4.8 g (14.0 mmol) of the compound prepared in step 2) was dissolved in 30 ml of a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1. 7.8 g (140 mmol) of iron powder and 7.6 g (140 mmol) of ammonium chloride were added to the solution, followed by stirring at 85° C. for 3 hours. After completion of the reaction, the reaction mixture was washed with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to give 3.16 g (yield: 71%) of the title compound.

[0705] Step 4) Preparation of (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide The title compound was prepared from the compound prepared in step 3) in the same manner as in steps 1) and 3) of Example 1. [M+H] + =745.

[0706] Example 131: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide [ka]

[0707] Step 1) Preparation of N-(6-nitroquinoxalin-5-yl)methanesulfonamide 5.0 g (28.5 mmol) of the compound prepared in the same manner as in Step 2) of Example 130 was diluted with 40 ml of 2N sodium hydroxide / tetrahydrofuran. The diluted mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, extracted with dichloromethane, filtered, and concentrated under reduced pressure to give 6.7 g (yield: 87%) of the title compound.

[0708] Step 2) Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide The title compound was prepared in a similar manner to steps 3) and 4) of Example 130.

[0709] 1H NMR(400MHz,DMSO-d6)δ 9.92(brs,1H),9.00(d,J=1.8Hz,1H),8.96(brs,1H),8.93(d,J=1.8Hz,1H),8.71(d,J=8.5Hz,1H),8.25-8.22(m,2H),7.90(d,J=9.3Hz,1H),7 .38(s,1H),6.72(s,1H),3.76(s,3H),3.16-2.96(m,5H),2.74-2.27(m ,11H),2.21(s,3H),2.02(s,3H),1.93-1.80(m,2H),1.65-1.48(m,2H). [M+H] + =667.

[0710] Example 132: Preparation of N-(6-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide [ka]

[0711] The title compound was prepared from the corresponding aniline in a similar manner to Example 131. [M+H] + =654.

[0712] Example 133: Preparation of N-(6-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide [ka]

[0713] The title compound was prepared from the corresponding aniline in a similar manner to Example 131. [M+H] + =653.

[0714] Example 134: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide [ka]

[0715] The title compound was prepared from the corresponding aniline in a similar manner to Example 131. [M+H] + =667.

[0716] Example 135: Preparation of N-(6-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide [ka]

[0717] The title compound was prepared from the corresponding aniline in a similar manner to Example 131. [M+H] + =598.

[0718] Example 136: Preparation of N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide [ka]

[0719] The title compound was prepared from the corresponding aniline in a similar manner to Example 131. [M+H] + =686.

[0720] Example 137: Preparation of N-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide [ka]

[0721] The title compound was prepared in a similar manner to Example 1, except that N-(2-amino-4-(trifluoromethyl)phenyl)methanesulfonamide and the corresponding aniline were used in steps 1) and 2), respectively. [M+H] + =703.

[0722] Example 138: Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide [ka]

[0723] The title compound was prepared similarly to Example 137, except that the corresponding aniline was used. [M+H] + =683.

[0724] Example 139: Preparation of N-(2-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide [ka]

[0725] The title compound was prepared similarly to Example 137, except that the corresponding aniline was used. [M+H] + =709.

[0726] Example 140: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0727] The title compound was prepared in a similar manner to Example 83, except that 6-nitro-2,3-dihydrobenzofuran-5-amine was used in step 1) of Example 80. [M+H] + =657.

[0728] Example 141: Preparation of N-(2-((6-amino-5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0729] The title compound was prepared in a similar manner to Example 1, except that 2,5,6-trichloropyrimidin-4-amine was used in step 1) of Example 1. [M+H] + =648.

[0730] Example 142: ((2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl-λ 6 -Preparation of sulfanone [ka]

[0731] Step 1) N-(dimethyloxide-λ 4 Preparation of (-sulfanylidene)-2-nitro-benzenamine 5.0 g (40.3 mmol) of 1-oxo-1,7a-dihydrobenzo[c][1,2,5]oxadiazol-1-ium was diluted with 80 ml of dimethyl sulfoxide. The mixture was stirred at 120° C. for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The resulting residue was purified by column chromatography (20% ethyl acetate / hexane) to give 4.28 g (yield: 50%) of the title compound.

[0732] Step 2) Preparation of dimethyl((2-nitrophenyl)imino)-16-sulfanone 4.28 g (20 mmol) of the compound prepared in step 1) was dissolved in 40 ml of a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1. 0.3 g (2.7 mmol) of iron powder and 0.16 g (2.7 mmol) of ammonium chloride were added to the solution, followed by stirring at 85° C. for 3 hours. After completion of the reaction, the reaction mixture was washed with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to give 3.3 g (yield: 90%) of the title compound.

[0733] Step 3) Preparation of ((2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)imino)dimethyl-16-sulfanone 3.3 g (18 mmol) of the compound prepared in step 2) and 3.37 ml (35.0 mmol) of 5-bromo-2,4-dichloropyrimidine were diluted with 54 ml of isopropyl alcohol, and 9.3 ml (53.8 mmol) of N,N-diisopropylethylamine was added thereto. The mixture was stirred at 60° C. for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The resulting residue was purified by column chromatography (50% ethyl acetate / hexane) to give 3.31 g (yield: 55%) of the title compound.

[0734] Step 4) ((2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl-λ 6 -Preparation of sulfanone The title compound was prepared from the compound prepared in step 3) and the corresponding aniline in the same manner as in Example 1. [M+H] + =657

[0735] Example 143: ((2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl-λ 6 -Preparation of sulfanone [ka]

[0736] The title compound was prepared in a similar manner to steps 3) and 4) of Example 142. [M+H] + =678.

[0737] Example 144: ((2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl-λ 6 -Preparation of sulfanone [ka]

[0738] The title compound was prepared in a similar manner to steps 3) and 4) of Example 142. [M+H] + =662.

[0739] Example 145: Preparation of N-(2-((5-bromo-2-((2-methoxy-6-(1-methylazepan-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0740] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =594.

[0741] Example 146: Preparation of N-(2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0742] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =681.

[0743] Example 147: Preparation of N-(2-((5-bromo-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0744] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =696.

[0745] Example 148: Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0746] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =730.

[0747] Example 149: Preparation of N-(2-((5-bromo-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0748] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 1) of Example 24 and the corresponding aniline. [M+H] + =726.

[0749] Example 150: Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0750] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 85 and the corresponding aniline. [M+H] + =747.

[0751] Example 151: Preparation of N-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0752] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline. [M+H] + =650.

[0753] Example 152: Preparation of N-(4-chloro-2-((6-chloro-3-((-2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1,2,4-triazin-5-yl)amino)phenyl)methanesulfonamide [ka]

[0754] Step 1) Preparation of N-(4-chloro-2-((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)methanesulfonamide The title compound was prepared from 3,5,6-trichloro-1,2,4-triazine and N-(2-amino-4-chlorophenyl)methanesulfonamide in a similar manner to step 1) of Example 1.

[0755] Step 2) Preparation of N-(4-chloro-2-((6-chloro-3-((-2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1,2,4-triazin-5-yl)amino)phenyl)methanesulfonamide The title compound was prepared in the same manner as in Example 1, except that the compound prepared in step 1) was used and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride were used in step 2) of Example 1. [M+H] + =650.

[0756] Example 153: Preparation of (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide [ka]

[0757] The title compound was prepared from (2-amino-4-chlorophenyl)dimethylphosphine oxide in a similar manner to step 1 of Example 1. [M+H] + =632.

[0758] Example 154: Preparation of (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide [ka]

[0759] The title compound was prepared from the corresponding aniline in analogy to Example 153. [M+H] + =637.

[0760] Example 155: Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)-N-methylmethanesulfonamide [ka]

[0761] Step 1) Preparation of N-(2-((5-bromo-2-chloropyrimidin-4-yl)amino)-4-chlorophenyl)-N-methylmethanesulfonamide The title compound was prepared in the same manner as in step 1) of Example 1, except that N-(2-amino-4-chlorophenyl)-N-methylmethanesulfonamide was used in step 1) of Example 1 and 5-bromo-2,4-dichloropyrimidine was used in step 3) of Example 24.

[0762] Step 2) Preparation of N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)-N-methylmethanesulfonamide The title compound was prepared from the compound prepared in step 1) in the same manner as in step 2) of Example 1. [M+H] + =708.

[0763] Example 156: Preparation of N-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)-N-methylmethanesulfonamide [ka]

[0764] The title compound was prepared from the corresponding aniline in analogy to Example 155. [M+H] + =728.

[0765] Example 157: Preparation of N-(4-chloro-2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0766] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline. [M+H] + =668.

[0767] Example 158: Preparation of N-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0768] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline. [M+H] + =654.

[0769] Example 159: Preparation of N-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0770] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline. [M+H] + =670.

[0771] Example 160: Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide [ka]

[0772] Step 1) Preparation of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide N-(2-amino-4-isopropylphenyl)methanesulfonamide (1 equivalent) was diluted with isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 equivalents) and sodium bicarbonate (4 equivalents) were added thereto. The mixture was stirred at 65°C for 40 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane on a filter packed with Celite, filtered under reduced pressure, diluted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform, and washed with distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (40% tetrahydrofuran / hexane) to give the title compound (yield: 69%).

[0773] Step 2) Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide The compound prepared in step 1) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol solution, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 30%). [M+H] + =657.

[0774] Example 161: Preparation of N-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide [ka]

[0775] The title compound was prepared in a similar manner to step 2) of Example 160. [M+H] + =677.

[0776] Example 162: Preparation of N-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0777] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline. [M+H] + =667.

[0778] Example 163: Preparation of N-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0779] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline. [M+H] + =683.

[0780] Example 164: Preparation of N-(2-((6-chloro-3-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1,2,4-triazin-5-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0781] Step 1) Preparation of N-(2-((3,6-dichloro-1,2,4-triazin-5-yl)amino)-5-fluorophenyl)methanesulfonamide N-(2-amino-5-fluorophenyl)methanesulfonamide (1 equivalent) was diluted with isopropyl alcohol (0.3 M), and 3,5,6-trichloro-1,2,4-triazine (2 equivalents) and diisopropylethylamine (4 equivalents) were added thereto. The mixture was stirred at 65°C under a nitrogen atmosphere for 40 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane on a filter packed with Celite, filtered under reduced pressure, diluted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform, and washed with distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (40% tetrahydrofuran / hexane) to give the title compound (yield: 55%).

[0782] Step 2) Preparation of N-(2-((6-chloro-3-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1,2,4-triazin-5-yl)amino)-5-fluorophenyl)methanesulfonamide The compound prepared in step 1) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol solution, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 34%). [M+H] + =634.

[0783] Example 165: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0784] Step 1) Preparation of N-(methylsulfonyl)-N-(6-nitro-2,3-dihydrobenzofuran-5-yl)methanesulfonamide 6-Nitro-2,3-dihydrobenzofuran-5-amine (1 equivalent) was dissolved in dichloromethane (0.3 M), and triethylamine (4 equivalents) was added thereto at 0° C. Methanesulfonyl chloride (MsCl, 3 equivalents) was slowly added to the mixture, followed by stirring at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was diluted with hexane and stirred for an additional 15 minutes. The resulting yellow solid was collected by filtration under reduced pressure to give the title compound.

[0785] Step 2) Preparation of N-(6-nitro-2,3-dihydrobenzofuran-5-yl)methanesulfonylamide The compound prepared in step 1) was dissolved in a mixture of tetrahydrofuran and 4N NaOH solution (1:1, 0.2M). The solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure and adjusted to pH 5-6 with 1N HCl solution at 0°C. The resulting yellow solid was collected by filtration under reduced pressure to give the title compound.

[0786] Step 3) Preparation of N-(6-amino-2,3-dihydrobenzofuran-5-yl)methanesulfonamide The compound prepared in step 2) was dissolved in a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1. Iron powder and ammonium chloride were added to the solution, followed by stirring at 85°C for 3 hours. After completion of the reaction, the reaction mixture was washed with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to obtain the title compound (yield: 91%).

[0787] Step 4) Preparation of N-(6-((2,5-dichloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide The compound prepared in step 3 (1 equivalent) was diluted with isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 equivalents) and sodium bicarbonate (4 equivalents) were added thereto. The mixture was stirred at 65°C for 40 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with dichloromethane on a filter packed with Celite, filtered under reduced pressure, diluted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform, and washed with distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (40% tetrahydrofuran / hexane) to give the title compound (yield: 62%).

[0788] Step 5) Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide The compound prepared in step 4) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 33%). [M+H] + =671.

[0789] Example 166: 5-Chloro-N 4 -(5-chloro-2-(1H-1,2,3-triazol-4-yl)phenyl)-N 2 Preparation of -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka]

[0790] Step 1) Preparation of 2,5-dichloro-N-(5-chloro-2-iodophenyl)pyrimidin-4-amine 5-Chloro-2-iodoaniline (1 equivalent) was diluted with isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 equivalents) and sodium bicarbonate (4 equivalents) were added to it. The mixture was stirred at 65°C for 40 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with dichloromethane on a filter packed with Celite, filtered under reduced pressure, diluted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform, and washed with distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (40% tetrahydrofuran / hexane) to give the title compound (yield: 62%).

[0791] Step 2) 5-chloro-N 4 -(5-chloro-2-iodophenyl)-N 2 Preparation of -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl))piperidin-1-yl)phenyl)pyrimidine-2,4-diamine The compound prepared in step 1) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 45%).

[0792] Step 3) 5-Chloro-N 4-(5-chloro-2-ethynylphenyl)-N 2 Preparation of -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine The compound prepared in step 2) (1 equivalent), trimethylsilylacetylene (1.5 equivalents), Pd(PPh3)Cl2 (0.3 equivalents), and CuI (0.2 equivalents) were dissolved in a 2:1 mixture of tetrahydrofuran and triethylamine. The solution was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was filtered under reduced pressure through a filter packed with Celite and distilled under reduced pressure. The resulting residue was diluted with methanol (0.3 M), and potassium carbonate (3 equivalents) was added to it. The mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction mixture was diluted with dichloromethane, washed with saturated brine, and purified by column chromatography (yield: 42%).

[0793] Step 4) 5-Chloro-N 4 -(5-chloro-2-(1H-1,2,3-triazol-4-yl)phenyl)-N 2 Preparation of -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine The compound prepared in step 3) (1 equivalent), trimethylsilyl azide (1.5 equivalents), copper sulfate (0.1 equivalents), and sodium ascorbate (0.2 equivalents) were diluted with distilled water (0.3 M). The diluted mixture was stirred at 50°C for 3 hours. After the reaction was completed, the reaction mixture was extracted with a 1:4 volume ratio mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The extract was purified by column chromatography to obtain the title compound (yield: 33%). [M+H] + =623.

[0794] Example 167: Preparation of N-(4-chloro-2-((5-chloro-2-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0795] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline. [M+H] + =499.

[0796] Example 168: Preparation of N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0797] The title compound was prepared in a similar manner to step 5) of Example 165. 1 H NMR(300MHz,DMSO)δ 8.45(s,1H),8.14(s,1H),8.09(s,1H),7.70(s,1H),7.43(s,1H),7.20(s,1H),6.77(s,1H),4.56(t,J=8.6Hz,2H),3.81(s,3H),3.37-3.2 2(m,4H),3.18(t,J=8.6Hz,3H),2.9(s,3H),2.64(t,J=11.0Hz,3H),2.43-2.22(m,5H),2.16(s,3H),1.91-1.79(m,2H),1.67-1.48(m,2H). [M+H] + =677.

[0798] Example 169: Preparation of N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0799] Step 1) Preparation of N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide The compound prepared in Step 3 of Example 165 (1 equivalent) was diluted with isopropyl alcohol (0.3 M), and 5-bromo-2,4-dichloropyrimidine (2 equivalents) and sodium bicarbonate (4 equivalents) were added thereto. The mixture was stirred at 65°C for 40 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane on a filter packed with Celite, filtered under reduced pressure, diluted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform, and washed with distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (40% tetrahydrofuran / hexane) to give the title compound (yield: 60%).

[0800] Step 2) Preparation of N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide The compound prepared in step 1) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol solution, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 34%). 1H NMR(300MHz,DMSO)δ 8.32(s,1H),8.16(s,1H),8.03(s,1H),7.52(s,1H),7.39(s,1H),7.20(s,1H),6.68(s,1H),4.55(t,J=8.7Hz,2H),3.77(s,3H),3.22- 3.09(m,6H),2.96(s,3H),2.89-2.76(m,6H)),2.62(t,J=11.0Hz,3H),2.50(s,3H),2.08(s,3H),1.96-1.85(m,2H),1.69-1.57(m,2H). [M+H] + =701.

[0801] Example 170: Preparation of N-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide [ka]

[0802] Step 1) Preparation of N-(4-chloro-2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide The title compound was prepared in a similar manner to Step 1) of Example 1, except that N-(2-amino-4-chlorophenyl)-N-methylmethanesulfonamide was used.

[0803] Step 2) Preparation of N-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide The compound prepared in step 1) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol solution, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 32%). [M+H] + =683.

[0804] Example 171: Preparation of N-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide [ka]

[0805] The title compound was prepared in a similar manner to step 2) of Example 170. [M+H] + =667.

[0806] Example 172: Preparation of N-(6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0807] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =675.

[0808] Example 173: Preparation of N-(6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0809] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =661.

[0810] Example 174: Preparation of N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0811] The title compound was prepared in a similar manner to step 5) of Example 165. 1 H NMR(300MHz,DMSO)δ 8.48(s,1H),8.14(s,1H),8.09(s,1H),7.69(s,1H),7.44(s,1H),7.20(s,1H),6.77(s,1H),4.55(t,J=8.7Hz,2H),3.81(s,3H) ),3.22-3.12(m,3H),2.93(s,3H),2.82-2.64(m,6H)),2.64-2.52(m,6H),2.28(s,3H),1.84-1.68(m,4H),1.65-1.53(m,2H). [M+H] + =691.

[0812] Example 175: Preparation of N-(6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0813] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =706.

[0814] Example 176: Preparation of N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0815] Step 1) Preparation of N-(4-chloro-2-((2,5-dichloropyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide The title compound was prepared in a similar manner to step 1) of Example 1, except that N-(2-amino-4-chloro-5-fluorophenyl)methanesulfonamide was used.

[0816] Step 2) Preparation of N-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide The compound prepared in step 1) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol solution, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 35%). 1 H NMR(300MHz,DMSO)δ 8.94(s,1H),8.09(s,1H),8.06(s,1H),8.00(s,1H),7.33(s,1H),7.24(s,1H),7.21(s,1H),6.69(s,1H),3.76(s,3H),3.16-3. 03(m,3H),2.89-2.78(m,7H),2.78(s,3H),2.69-2.55(m,3H),2.50(s,3H),2.08(s,3H),1.96-1.82(m,2H),1.70-1.50(m,2H). [M+H] + =667.

[0817] Example 177: Preparation of N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide [ka]

[0818] Step 1) Preparation of N-(2-((5-bromo-2-chloropyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide The title compound was prepared in a similar manner to step 1) of Example 1, except that N-(2-amino-4-chloro-5-fluorophenyl)methanesulfonamide and 5-bromo-2,4-dichloropyrimidine were used.

[0819] Step 2) Preparation of N-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide The compound prepared in step 1) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol solution, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 33%). [M+H] + =716.

[0820] Example 178: Preparation of N-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide [ka]

[0821] The title compound was prepared in a similar manner to step 2) of Example 177. [M+H] + =732.

[0822] Example 179: Preparation of N-(4-chloro-2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide [ka]

[0823] The title compound was prepared in a similar manner to step 2) of Example 170. [M+H] + =682.

[0824] Example 180: Preparation of N-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide [ka]

[0825] The title compound was prepared in a similar manner to step 2) of Example 170. [M+H] + =682.

[0826] Example 181: Preparation of N-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0827] The title compound was prepared in a similar manner to step 2) of Example 176. [M+H] + =688.

[0828] Example 182: Preparation of N-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide [ka]

[0829] The title compound was prepared in a similar manner to step 2) of Example 176. [M+H] + =671.

[0830] Example 183: Preparation of N-(6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0831] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =772.

[0832] Example 184: Preparation of N-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0833] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =715.

[0834] Example 185: 5-chloro-N 4 -(5-chloro-2-(1H-1,2,3-triazol-5-yl)phenyl)-N 2 Preparation of -(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka]

[0835] The title compound was prepared from the corresponding iodo compound in the same manner as in Step 4 of Example 166. [M+H] + =627.

[0836] Example 186: 5-chloro-N 4 -(5-chloro-2-(1H-1,2,3-triazol-5-yl)phenyl)-N 2 Preparation of -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka]

[0837] The title compound was prepared from the corresponding iodo compound in the same manner as in Step 4 of Example 166. [M+H] + =643.

[0838] Example 187: 5-Bromo-N 4 -(5-chloro-2-(1H-1,2,3-triazol-5-yl)phenyl)-N 2 Preparation of -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka]

[0839] The title compound was prepared from the corresponding iodo compound in the same manner as in Step 4 of Example 166. [M+H] + =668.

[0840] Example 188: Preparation of N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0841] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =716.

[0842] Example 189: Preparation of N-(6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0843] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =736.

[0844] Example 190: Preparation of (6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka]

[0845] The title compound was prepared in a similar manner to step 6) of Example 122. [M+H] + =664.

[0846] Example 191: Preparation of N-(2-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide [ka]

[0847] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline. [M+H] + =708.

[0848] Example 192: Preparation of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka]

[0849] Step 1) Preparation of (6-((5-bromo-2-chloro-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide The compound prepared in Step 4 of Example 122 (1 equivalent) was diluted with N,N-dimethylformamide (0.3 M), and 60% sodium hydride (1.5 equivalents) was slowly added thereto at 0°C. The mixture was stirred at room temperature for 30 minutes. 5-Bromo-5-trichloropyrimidine (2 equivalents) was slowly added to the reaction mixture at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate / hexane) to give the title compound (yield: 60%).

[0850] Step 2) Preparation of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide The compound prepared in step 1) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol solution, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 33%). [M+H] + =709.

[0851] Example 193: Preparation of (6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka]

[0852] The title compound was prepared in a similar manner to step 2) of Example 192. [M+H] + =699.

[0853] Example 194: Preparation of (6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka]

[0854] The title compound was prepared in a similar manner to step 2) of Example 192. [M+H] + =715.

[0855] Example 195: 5-Bromo-N 4-(5-chloro-2-(1H-1,2,3-triazol-5-yl)phenyl)-N 2 Preparation of -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka]

[0856] The title compound was prepared from the corresponding iodo compound in the same manner as in Step 4 of Example 166. [M+H] + =688.

[0857] Example 196: Preparation of N-(6-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0858] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =730.

[0859] Example 197: Preparation of N-(6-((5-chloro-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0860] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =689.

[0861] Example 198: Preparation of N-(4-chloro-2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide [ka]

[0862] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 3) of Example 80 and the corresponding aniline. [M+H] + =673.

[0863] Example 199: Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0864] Step 1) Preparation of N-(2-amino-4-methoxyphenyl)methanesulfonamide The title compound was prepared in a manner similar to steps 1) to 3) of Example 165, except that 4-methoxy-2-nitroaniline was used in step 1) of Example 165.

[0865] Step 2) Preparation of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide The compound prepared in step 1 (1 equivalent) was diluted with isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 equivalents) and sodium bicarbonate (4 equivalents) were added thereto. The mixture was stirred at 65°C for 40 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with dichloromethane on a filter packed with Celite, filtered under reduced pressure, diluted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform, and washed with distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (40% tetrahydrofuran / hexane) to give the title compound (yield: 60%).

[0866] Step 3) Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide The compound prepared in step 2) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 30%). [M+H] + =645.

[0867] Example 200: Preparation of N-(2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0868] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =649.

[0869] Example 201: Preparation of N-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0870] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =665.

[0871] Example 202: Preparation of N-(2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0872] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =669.

[0873] Example 203: Preparation of N-(2-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0874] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =659.

[0875] Example 204: Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0876] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =659.

[0877] Example 205: Preparation of N-(6-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0878] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =681.

[0879] Example 206: Preparation of N-(6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0880] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H]+ =671.

[0881] Example 207: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0882] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =643.

[0883] Example 208: Preparation of N-(6-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0884] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =683.

[0885] Example 209: Preparation of N-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0886] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =671.

[0887] Example 210: Preparation of N-(6-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0888] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =675.

[0889] Example 211: Preparation of N-(6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0890] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =716.

[0891] Example 212: Preparation of N-(6-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0892] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =728.

[0893] Example 213: Preparation of N-(6-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0894] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =720.

[0895] Example 214: Preparation of N-(6-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0896] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =734.

[0897] Example 215: Preparation of N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0898] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =688.

[0899] Example 216: Preparation of N-(6-((5-bromo-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0900] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =750.

[0901] Example 217: Preparation of N-(6-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0902] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =726.

[0903] Example 218: Preparation of N-(6-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0904] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =685.

[0905] Example 219: Preparation of N-(6-((5-chloro-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0906] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =705.

[0907] Example 220: Preparation of N-(6-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0908] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =643.

[0909] Example 221: Preparation of N-(6-((5-chloro-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0910] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =647.

[0911] Example 222: Preparation of N-(6-((5-chloro-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0912] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =661.

[0913] Example 223: Preparation of N-(6-((5-chloro-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0914] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =664.

[0915] Example 224: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-((1-methyl-1H-pyrazol-5-yl)amino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0916] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =654.

[0917] Example 225: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-(trifluoromethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0918] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =711.

[0919] Example 226: Preparation of N-(4-chloro-2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide [ka]

[0920] The title compound was prepared in a similar manner to step 2) of Example 170. [M+H] + =688.

[0921] Example 227: Preparation of N-(2-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)-N-methylmethanesulfonamide [ka]

[0922] The title compound was prepared from the corresponding aniline in the same manner as in Example 170, except that 5-bromo-2,4-dichloropyrimidine was used in step 2) of Example 170. [M+H] + =726.

[0923] Example 228: Preparation of N-(2-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)-N-methylmethanesulfonamide [ka]

[0924] The title compound was prepared from the corresponding aniline in the same manner as in Example 170, except that 5-bromo-2,4-dichloropyrimidine was used in step 2) of Example 170. [M+H] + =732.

[0925] Example 229: Preparation of N-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0926] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =679.

[0927] Example 230: Preparation of N-(2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0928] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =663.

[0929] Example 231: Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0930] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =631.

[0931] Example 232: Preparation of N-(2-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0932] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =673.

[0933] Example 233: Preparation of N-(2-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0934] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =671.

[0935] Example 234: Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0936] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =698.

[0937] Example 235: Preparation of N-(2-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0938] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =659.

[0939] Example 236: Preparation of N-(2-((5-chloro-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0940] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =677.

[0941] Example 237: Preparation of N-(2-((5-chloro-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide [ka]

[0942] The title compound was prepared in a similar manner to step 3) of Example 199. [M+H] + =693.

[0943] Example 238: Preparation of N-(6-((5-bromo-2-((2-methoxy-6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0944] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =620.

[0945] Example 239: Preparation of N-(6-((5-bromo-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0946] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =677.

[0947] Example 240: Preparation of N-(6-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0948] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =703.

[0949] Example 241: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0950] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =658.

[0951] Example 242: Preparation of N-(6-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0952] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =632.

[0953] Example 243: Preparation of N-(6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0954] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =688.

[0955] Example 244: Preparation of N-(6-((5-bromo-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0956] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =676.

[0957] Example 245: Preparation of N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine]-1'-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0958] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =755.

[0959] Example 246: Preparation of N-(6-((5-bromo-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonylamide [ka]

[0960] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =692.

[0961] Example 247: Preparation of N-(6-((5-bromo-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[0962] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =709.

[0963] Example 248: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0964] Step 1) Preparation of N-methyl-N-(6-nitro-2,3-dihydrobenzofuran-5-yl)methanesulfonamide The compound prepared in Step 3 of Example 165 was diluted with acetone (0.3 M), and 4N NaOH solution (10 equivalents) was added thereto. Dimethyl sulfate (1.8 equivalents) was slowly added to the mixture at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure and adjusted to pH 5-6 with 1N HCl solution at 0°C. The resulting yellow solid was collected by filtration under reduced pressure and used in the next reaction without further purification.

[0965] Step 2) Preparation of N-(6-amino-2,3-dihydrobenzofuran-5-yl)-N-methylsulfonamide The compound prepared in step 1) was dissolved in a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1. Iron powder and ammonium chloride were added to the solution, followed by stirring at 85°C for 3 hours. After completion of the reaction, the reaction mixture was washed with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to obtain the title compound (yield: 95%, step 2).

[0966] Step 3) Preparation of N-(6-((2,5-dichloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide The compound prepared in step 2 (1 equivalent) was diluted with isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 equivalents) and sodium bicarbonate (4 equivalents) were added thereto. The mixture was stirred at 65°C for 40 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with dichloromethane on a filter packed with Celite, filtered under reduced pressure, diluted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform, and washed with distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (40% tetrahydrofuran / hexane) to give the title compound (yield: 60%).

[0967] Step 4) Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide The compound prepared in step 3) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 35%). [M+H] + =671.

[0968] Example 249: Preparation of N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0969] The title compound was prepared in a similar manner to step 4) of Example 248. [M+H] + =691.

[0970] Example 250: Preparation of N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0971] Step 1) Preparation of N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide The compound prepared in Step 2 of Example 248 (1 equivalent) was diluted with isopropyl alcohol (0.3 M), and 5-bromo-2,4-dichloropyrimidine (2 equivalents) and sodium bicarbonate (4 equivalents) were added thereto. The mixture was stirred at 65°C for 40 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane on a filter packed with Celite, filtered under reduced pressure, diluted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform, and washed with distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (40% tetrahydrofuran / hexane) to give the title compound (yield: 52%).

[0972] Step 2) Preparation of N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide The compound prepared in step 1) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 29%). 1H NMR(300MHz,DMSO)δ 8.22(s,1H),8.19(s,1H),8.17(s,1H),7.71(s,1H),7.44(s,1H),7.32(s,1H),6.70(s,1H),4.55(t,J=8.7Hz,2H),3.76(s,3H),3.23-3.1 3(m,4H),3.14(s,3H),3.10(s,3H),2.68-2.54(m,5H),2.45-2.23(m, 6H), 2.18 (s, 3H), 2.12 (s, 3H), 1.91-1.80 (m, 2H), 1.67-1.50 (m, 2H). [M+H] + =716.

[0973] Example 251: Preparation of N-(6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0974] The title compound was prepared in a similar manner to step 2) of Example 250. [M+H] + =720.

[0975] Example 252: Preparation of N-(6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0976] The title compound was prepared in a similar manner to step 2) of Example 250. [M+H] + =736.

[0977] Example 253: Preparation of N-(6-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0978] The title compound was prepared in a similar manner to step 2) of Example 250. [M+H] + =740.

[0979] Example 254: Preparation of N-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0980] The title compound was prepared in a similar manner to step 2) of Example 250. [M+H] + =730.

[0981] Example 255: Preparation of N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-(trifluoromethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0982] The title compound was prepared in a similar manner to step 2) of Example 250. [M+H] + =770.

[0983] Example 256: Preparation of N-(6-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0984] The title compound was prepared in a similar manner to step 2) of Example 250. [M+H] + =720.

[0985] Example 257: Preparation of N-(6-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0986] The title compound was prepared in a similar manner to step 2) of Example 250. [M+H] + =730.

[0987] Example 258: Preparation of N-(6-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxy-5-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0988] The title compound was prepared in a similar manner to step 2) of Example 250. [M+H] + =744.

[0989] Example 259: Preparation of N-(6-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0990] The title compound was prepared in a similar manner to step 4) of Example 248. [M+H] + =696.

[0991] Example 260: Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)-N-methylmethanesulfonamide [ka]

[0992] Step 1) Preparation of N-(4-methoxy-2-nitrophenyl)-N-methylmethanesulfonamide The compound prepared in Step 1 of Example 229 (1 equivalent) was diluted with acetone, and 4N NaOH solution (10 equivalents) was added thereto. Dimethyl sulfate (1.8 equivalents) was slowly added to the mixture at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure and adjusted to pH 5-6 with 1N HCl solution at 0°C. The resulting yellow solid was collected by filtration under reduced pressure and used in the next reaction without further purification.

[0993] Step 2) Preparation of N-(2-amino-4-methoxyphenyl)-N-methylmethanesulfonamide The compound prepared in step 1) was dissolved in a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1. Iron powder and ammonium chloride were added to the solution, followed by stirring at 85°C for 3 hours. After completion of the reaction, the reaction mixture was washed with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to obtain the title compound (yield: 95%).

[0994] Step 3) Preparation of N-(2-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-4-methoxyphenyl)methanesulfonamide The compound prepared in step 2 (1 equivalent) was diluted with isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 equivalents) and sodium bicarbonate (4 equivalents) were added thereto. The mixture was stirred at 65°C for 40 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with dichloromethane on a filter packed with Celite, filtered under reduced pressure, diluted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform, and washed with distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (40% tetrahydrofuran / hexane) to give the title compound (yield: 60%).

[0995] Step 4) Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)-N-methylmethanesulfonamide The compound prepared in step 3) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 35%). [M+H] + =659.

[0996] Example 261: Preparation of N-(6-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0997] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 2) of Example 250 and the corresponding aniline. [M+H] + =742.

[0998] Example 262: Preparation of N-(6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[0999] The title compound was prepared in the same manner as in Example 1 from the compound prepared in Step 2) of Example 250 and the corresponding aniline. [M+H] + =730.

[1000] Example 263: Preparation of N-(6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[1001] The title compound was prepared in a similar manner to step 4) of Example 248. [M+H] + =675.

[1002] Example 264: Preparation of N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[1003] The title compound was prepared in a similar manner to step 4) of Example 248. [M+H] + =705.

[1004] Example 265: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[1005] The title compound was prepared in a similar manner to step 4) of Example 248. [M+H] + =685.

[1006] Example 266: Preparation of N-(6-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[1007] The title compound was prepared in a similar manner to step 4) of Example 248. [M+H] + =697.

[1008] Example 267: Preparation of N-(6-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide [ka]

[1009] The title compound was prepared in a similar manner to step 4) of Example 248. [M+H] + =699.

[1010] Example 268: Preparation of N-(6-((5-chloro-2-((2,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[1011] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =649.

[1012] Example 269: Preparation of N-(5-((5-bromo-2-((2,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanesulfonamide [ka]

[1013] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =649.

[1014] Example 270: Preparation of N-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[1015] The title compound was prepared in a similar manner to step 5) of Example 165. 1 H NMR(300MHz,DMSO)δ 8.43(s,1H),8.14(d,J=1.8Hz,2H),7.82(s,1H),7.43(s,1H),7.19(s,1H),6.80(s,1H),4.56(t,J=8.7Hz,2H),3.81(s,3H),3.18(t,J=8 .7Hz,3H),2.95(s,3H),2.65(t,J=10.8Hz,3H),2.59-2.50(m,4H),2.43-2.25(m,5H),2.18(s,3H),1.93-1.79(m,2H),1.68-1.50(m,2H). [M+H] + =722.

[1016] Example 271: Preparation of N-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[1017] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =766.

[1018] Example 272: 5-chloro-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(1-methylindolin-6-yl)pyrimidine-2,4-diamine [ka]

[1019] Step 1) Preparation of 1-methyl-6-nitroindoline 6-Nitroindoline (1 equivalent) was diluted with acetone (0.3 M) and potassium carbonate (4 equivalents) was added thereto. Methyl iodide (2 equivalents) was added to the mixture, followed by stirring at 50° C. for 12 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure and purified by column chromatography to give the title compound (yield: 68%).

[1020] Step 2) Preparation of 1-methylindoline-6-amine The compound prepared in step 2) was dissolved in a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1. Iron powder and ammonium chloride were added to the solution, followed by stirring at 85°C for 3 hours. After completion of the reaction, the reaction mixture was washed with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to obtain the title compound (yield: 70%).

[1021] Step 3) Preparation of N-(2,5-dichloropyrimidin-4-yl)-1-methylindoline-6-amine The compound prepared in step 3 (1 equivalent) was diluted with isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 equivalents) and sodium bicarbonate (4 equivalents) were added thereto. The mixture was stirred at 65°C for 40 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with dichloromethane on a filter packed with Celite, filtered under reduced pressure, diluted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform, and washed with distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (40% tetrahydrofuran / hexane) to give the title compound (yield: 61%).

[1022] Step 4) 5-Chloro-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(1-methylindolin-6-yl)pyrimidine-2,4-diamine The compound prepared in step 4) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 35%). [M+H] + =577.

[1023] Example 273: 5-chloro-N 2-(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(1-methylindolin-6-yl)pyrimidine-2,4-diamine [ka]

[1024] The title compound was prepared in a similar manner to step 4) of Example 272. [M+H] + =597.

[1025] Example 274: 5-chloro-N 2 -(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(1-methylindolin-6-yl)pyrimidine-2,4-diamine [ka]

[1026] The title compound was prepared in a similar manner to step 4) of Example 272. [M+H] + =581.

[1027] Example 275: 5-chloro-N 2 -(2-Methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(1-methylindolin-6-yl)pyrimidine-2,4-diamine [ka]

[1028] The title compound was prepared in a similar manner to step 4) of Example 272. [M+H] + =591.

[1029] Example 276: Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-methylindolin-5-yl)methanesulfonamide [ka]

[1030] Step 1) Preparation of 5-bromo-6-nitroindoline 5-Bromoindoline (4.5 g, 22.7 mmol) was dissolved in sulfuric acid (98%, 20 mL), and potassium nitrate (2.35 g, 23 mmol) was slowly added to it at 0 °C. The mixture was stirred at 0-10 °C for 4 h. After the reaction was completed, the reaction mixture was slowly added to ice water and adjusted to pH 8 with a saturated solution of sodium carbonate. The resulting solid was collected by filtration under reduced pressure and used in the next reaction without further purification.

[1031] Step 2) Preparation of 5-bromo-1-methyl-6-nitroindoline The compound prepared in step 1) (2.2 g, 9 mmol) was diluted with acetone (30 mL), and potassium carbonate (5 g, 36 mmol) was added thereto. Methyl iodide (0.9 mL, 14.4 mmol) was added to the mixture, followed by stirring at 50° C. for 12 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure and purified by column chromatography to obtain the title compound (1.57 g, yield: 68%).

[1032] Step 3) Preparation of N-(1-methyl-6-nitroindolin-5-yl)methanesulfonamide The compound prepared in step 2) (200 mg, 0.78 mmol), methanesulfonamide (220 mg, 3 equivalents), cesium carbonate (1 g, 4 equivalents), Xantphos (90 mg, 0.2 equivalents), and Pd(OAc) (20 mg, 0.1 equivalents) were diluted with dioxane, degassed for 10 minutes, and stirred at 100 °C for 24 hours. After completion of the reaction, the reaction mixture was filtered under reduced pressure through a filter packed with Celite and washed with ethyl acetate, distilled water, and saturated brine. The resulting residue was purified by column chromatography to give the title compound (88 mg, yield: 42%).

[1033] Step 4) Preparation of N-(6-amino-1-methylindolin-5-yl)methanesulfonamide The compound prepared in step 3) was dissolved in a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1. Iron powder and ammonium chloride were added to the solution, followed by stirring at 85°C for 3 hours. After completion of the reaction, the reaction mixture was washed with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to give the title compound (yield: 61%).

[1034] Step 5) Preparation of N-(6-((2,5-dichloro-4-yl)amino)-1-methylindolin-5-yl)methanesulfonamide The compound prepared in step 4 (1 equivalent) was diluted with isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 equivalents) and sodium bicarbonate (4 equivalents) were added thereto. The mixture was stirred at 65°C for 40 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane on a filter packed with Celite, filtered under reduced pressure, diluted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform, and washed with distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (40% tetrahydrofuran / hexane) to give the title compound (yield: 61%).

[1035] Step 6) Preparation of N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-methylindolin-5-yl)methanesulfonamide The compound prepared in step 5) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 35%). [M+H] + =670.

[1036] Example 277: 5-chloro-N 2 -(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(indolin-6-yl)pyrimidine-2,4-diamine [ka]

[1037] Step 1) Preparation of tert-butyl 6-nitroindole-1-carboxylate 6-Nitroindoline (1 equivalent) was diluted with dichloromethane (0.3 M), and di-tert-butyl dicarbonate (2 equivalents) and DMAP (0.1 equivalents) were added thereto. The mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane, washed with saturated brine, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was used in the next reaction without further purification.

[1038] Step 2) Preparation of tert-butyl 6-aminoindoline-1-carboxylate The compound prepared in step 1) was dissolved in a mixture of tetrahydrofuran, methanol, and water in a volume ratio of 18:1:1. Iron powder and ammonium chloride were added to the solution, followed by stirring at 85°C for 3 hours. After completion of the reaction, the reaction mixture was washed with dichloromethane on a filter filled with Celite, filtered under reduced pressure, and concentrated to obtain the title compound (yield: 75%).

[1039] Step 3) Preparation of tert-butyl 6-((2,5-dichloropyrimidin-4-yl)amino)indoline-1-carboxylate The compound prepared in step 2 (1 equivalent) was diluted with isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 equivalents) and sodium bicarbonate (4 equivalents) were added thereto. The mixture was stirred at 65°C for 40 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with dichloromethane on a filter packed with Celite, filtered under reduced pressure, diluted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform, and washed with distilled water. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (40% tetrahydrofuran / hexane) to give the title compound (yield: 65%).

[1040] Step 4) 5-Chloro-N 2 -(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(indolin-6-yl)pyrimidine-2,4-diamine The compound prepared in step 5) (1 equivalent) and the corresponding aniline (0.6 equivalents) were dissolved in a 1:1 volumetric mixture of acetic acid (0.3 M) and 1.25 M HCl / methanol, sealed, and stirred at 120 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with a 1:4 volumetric mixture of isopropyl alcohol and chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (10% methanol / dichloromethane) to give the title compound (yield: 35%). [M+H] + =567.

[1041] Example 278: 5-chloro-N 2 -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 Preparation of -(indolin-6-yl)pyrimidine-2,4-diamine [ka]

[1042] The title compound was prepared in a similar manner to step 4) of Example 277. [M+H] + =583.

[1043] Example 279: 5-chloro-N 4 -(indolin-6-yl)-N 2 Preparation of -(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine [ka]

[1044] The title compound was prepared in a similar manner to step 4) of Example 277. [M+H] + =549.

[1045] Example 280: Preparation of N-(6-((2-((5-bromo-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[1046] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =750.

[1047] Example 281: Preparation of N-(6-((5-bromo-2-((5-bromo-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[1048] The title compound was prepared in a similar manner to step 2) of Example 169. [M+H] + =794.

[1049] Example 282: Preparation of N-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[1050] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =735.

[1051] Example 283: Preparation of N-(6-((2-((5-bromo-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide [ka]

[1052] The title compound was prepared in a similar manner to step 5) of Example 165. [M+H] + =735.

[1053] The novel compound represented by formula 1 of the present invention can be formulated in various forms depending on its purpose.The following will illustrate some methods for preparing a formulation containing the compound represented by formula 1 of the present invention as an active ingredient, but the present invention is not limited thereto.

[1054] [Formulation example] Formulation Example 1: Tablets (direct compression) 5.0 mg of active ingredient was sieved, mixed with 14.1 mg lactose, 0.8 mg crospovidone USNF, and 0.1 mg magnesium stearate, and compressed into tablets.

[1055] Formulation Example 2: Tablets (wet granulation) 5.0 mg of the active ingredient was sieved and mixed with 16.0 mg of lactose and 4.0 mg of starch. To the mixture was added an appropriate amount of a pure aqueous solution of 0.3 mg of polysorbate 80. The resulting mixture was atomized, dried, sieved, mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate, and compressed into tablets.

[1056] Formulation Example 3: Powder and capsules 5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filled into hard No. 5 gelatin capsules using suitable equipment.

[1057] Formulation Example 4: Injection An injection containing 100 mg of the active ingredient, 180 mg of mannitol, 26 mg of Na2HPO4·12H2O, and 2974 mg of distilled water was prepared.

[1058] [Experimental Example] Experimental Example 1: Measurement of inhibitory activity against EGFR kinase In this example, it was determined whether the compounds prepared in Examples 1 to 283 have the ability to inhibit the proliferation of Ba / F3 cells expressing EGFR-wt, Ba / F3 cells expressing the del19 / T790M / C797S (EGFR-DTC) mutant, Ba / F3 cells expressing the L858R / T790M / C797S (EGFR-LTC) mutant, Ba / F3 cells expressing the del19 / T790M (EGFR-DT) mutant, and Ba / F3 cells expressing the L858R / T790M (EGFR-LT) mutant.

[1059] The parental Ba / F3 cell line was a cell population without EGFR mutations. Specifically, 100 μl of each mutant-expressing cell line was seeded into a 96-well plate at a density of 100,000 cells / ml. Starting at 2 mM, 10-point, 4-fold serial dilutions of each compound were prepared. After 4 hours, 0.5 μl of compound (0.5% DMSO) was added, followed by incubation at 37°C and 5% CO2 for 72 hours. After incubation, the number of viable cells was measured using a Celltiter glo assay kit (Promega), and the GI50 of the compound was determined. The term "GI50" refers to the molar concentration (μM) of a compound required for 50% cell growth inhibition. The results are summarized in Table 1.

[1060] [Table 1]

[1061] [Table 2]

[1062] [Table 3]

[1063] [Table 4]

[1064] [Table 5]

[1065] [Table 6]

[1066] [Table 7] [Industrial Applicability]

[1067] As is clear from the above, due to its inhibitory activity against EGFR protein kinase, the pyrimidine compound represented by formula 1 of the present invention or a pharmaceutically acceptable salt thereof is useful as a preventive or therapeutic agent for diseases caused by abnormal cellular metabolism and glucose metabolism caused by EGFR protein kinase, for example, metabolic diseases such as diabetes and obesity, as well as tumor diseases selected from the group consisting of endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing gland disease, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, blood cancer (e.g., leukemia, multiple myeloma, and myelodysplastic syndrome), lymphoma (e.g., Hodgkin's disease and non-Hodgkin's lymphoma), and fibroadenoma.

Claims

1. A compound selected from pyrimidine derivatives represented by formula 10, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof. [Formula 10] 【Chemical 1】 During the ceremony, R １ is hydrogen, hydroxyl, halo, C １ ~C １３ Alkyl, or C １ ~C ６ is an alkoxy; R ２ is hydrogen, halo, C １ ~C １３ Alkyl, C ３ ~C １０ Cyclyl, amino (-NR ８ R ９ ), or nitro (—N(O) ２ ) and R ３ and R ４ are each independently hydrogen, C １ ~C １３ Alkyl, C ３ ~C １０ Cyclyl, sulfide (-SR ８ ), sulfonyl (—S(O) ２ R ８ ), or phosphoryl (—P(O)R ８ R ９ ) and R ５ , R ６、 and R ７ are each independently hydrogen, hydroxyl, halo, C １ ~C １３ Alkyl, C １ ~C ６ Alkoxy, C ３ ~C １０ Cyclyl, C ３ ~C １０ Heterocyclyl, —C(O)—(C １ ~C １３ alkyl), amino (-NR ８ R ９ ), nitro (-N(O) ２ ), amide (—(C═O)NR ８ R ９ ), carboxyl (-C(O)OH), nitrile (-CN), sulfonamide (-NHS(O) ２ R ８ ), sulfide (-SR ８ ), sulfonyl (—S(O) ２ R ８ ), or phosphoryl (—P(O)R ８ R ９ ) and X １ and X ３ are each independently carbon or nitrogen, and X ２ is CH or nitrogen, and X １ and X ３ are each independently nitrogen, R ２ and R ７ do not exist, A is amino (-NR ８ R ９ ) or C ３ ~C １０ is heterocyclyl, B is selected from: 【Chemistry 2】 Said C １ ~C ６ Alkoxy, the above C １ ~C １３ alkyl, or the C ３ ~C １０ Cyclyl is hydrogen, hydroxyl, halo, C １ ~C １３ Alkyl, C １ ~C ６ Alkoxy, amino (-NR ８ R ９ ), nitro (-N(O) ２ ), amide (—(C═O)NR ８ R ９ ), carboxyl (-C(O)OH), nitrile (-CN), C ６ ~C １０ Aryl, C ３ ~C １０ Heteroaryl, and C ３ ~C １０ heterocyclyl; Said C ６ ~C １０ aryl, the C ３ ~C １０ Heteroaryl, or the C ３ ~C １０ Heterocyclyl includes hydrogen, hydroxyl, halo, carbonyl (—(C═O)R ８ ), unsubstituted or halo or C ３ ~C １０ C substituted by heterocyclyl １ ~C ３ Alkyl, unsubstituted or halo or C ３ ~C １０ C substituted by heterocyclyl １ ~C ３ Alkoxy, C ６ ~C １０ Phenoxy, amino (-NR ８ R ９ ), nitro (-N(O) ２ ), amide (—(C═O)NR ８ R ９ ), carboxyl (-C(O)OH), nitrile (-CN), C ６ ~C １０ Aryl, C ３ ~C １０ Heteroaryl, and C ３ ~C １０ heterocyclyl; R ８ and R ９ are each independently hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ６ ~C １０ Aryl, C ３ ~C １０ Heteroaryl, or C ３ ~C １０ heterocyclyl, provided that R ８ is R ９ may form a 3- to 7-membered saturated ring together with the nitrogen atom to which it is bonded, and the 3- to 7-membered saturated ring is selected from N, O, S, NH, C═N, C═O, —NHC(O)—, —NHC(O)NH—, —NHS(O) ２ - and SO ２ and may contain at least one of hydrogen, C １ ~C １３ Alkyl, C ６ ~C １０ Aryl, C ３ ~C １０ optionally substituted with at least one of heteroaryl, hydroxyl, halo, and cyano; Said C ３ ~C １０ Heteroaryl and the C ３ ~C １０ The heterocyclyl contains at least one heteroatom selected from the group consisting of N, O, and S.

2. R １ is hydrogen, halo, or C １ ~C ３ alkyl, and R ２ But hydrogen, C １ ~C ３ Alkyl, or amino (—NR ８ R ９ ) and R ３ But hydrogen, C １ ~C ３ Alkyl, sulfide (-SR ８ ), or sulfonyl (—S(O) ２ R ８ ) and R ４ is hydrogen or C １ ~C ３ alkyl, and R ５ is hydrogen, hydroxyl, halo, C １ ~C ３ Alkyl, or C １ ~C ６ is alkoxy, and R ６ is hydrogen, halo, or C １ ~C ３ alkyl, and R ７ is hydrogen or C １ ~C ３ The compound of claim 1 , wherein the aryl group is alkyl.

3. R １ is a halo, and R ２ is hydrogen or amino (—NR ８ R ９ ) and R ３ But hydrogen, C １ ~C ３ Alkyl, or sulfonyl (—S(O) ２ R ８ ) and R ４ is hydrogen, and R ５ is hydrogen, halo, or C １ ~C ６ is alkoxy, and R ６ is hydrogen, halo, or C １ ~C ３ alkyl, and R ７ 2. The compound of claim 1, wherein is hydrogen and A is selected from the group consisting of piperazine, piperidine, morpholine, and pyrrolidine.

4. R １ is Cl or Br, and R ２ is hydrogen or -NH ２ and R ３ is hydrogen, -CH ３ , or -S(O) ２ CH ３ and R ４ is hydrogen, and R ５ is hydrogen, Cl, Br, -OCH ３ , -OCH ２ CH ３ , or -OCH ２ CF ３ and R ６ is hydrogen, Cl, Br, F, -CH ３ , or -CF ３ and R ７ 2. The compound of claim 1, wherein is hydrogen and A is selected from the group consisting of piperazine, piperidine, morpholine, and pyrrolidine.

5. A compound selected from pyrimidine derivatives represented by formula 10, pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof. [Formula 10] 【Chemistry 3】 During the ceremony, R １ is hydrogen, hydroxyl, halo, C １ ~C １３ Alkyl, or C １ ~C ６ is an alkoxy; R ２ is hydrogen, halo, C １ ~C １３ Alkyl, C ３ ~C １０ Cyclyl, amino (-NR ８ R ９ ), or nitro (—N(O) ２ ) and R ３ and R ４ are each independently hydrogen, C １ ~C １３ Alkyl, C ３ ~C １０ Cyclyl, sulfide (-SR ８ ), sulfonyl (—S(O) ２ R ８ ), or phosphoryl (—P(O)R ８ R ９ ) and R ５ , R ６、 and R ７ are each independently hydrogen, hydroxyl, halo, C １ ~C １３ Alkyl, C １ ~C ６ Alkoxy, C ３ ~C １０ Cyclyl, C ３ ~C １０ Heterocyclyl, —C(O)—(C １ ~C １３ alkyl), amino (-NR ８ R ９ ), nitro (-N(O) ２ ), amide (—(C═O)NR ８ R ９ ), carboxyl (-C(O)OH), nitrile (-CN), sulfonamide (-NHS(O) ２ R ８ ), sulfide (-SR ８ ), sulfonyl (—S(O) ２ R ８ ), or phosphoryl (—P(O)R ８ R ９ ) and X １ and X ３ are each independently carbon or nitrogen, and X ２ is CH or nitrogen, and X １ and X ３ are each independently nitrogen, R ２ and R ７ do not exist, A is selected from the following: 【Chemistry 4】 B is selected from: 【Chemistry 5】 Said C １ ~C ６ Alkoxy, the above C １ ~C １３ alkyl, or the C ３ ~C １０ Cyclyl is hydrogen, hydroxyl, halo, C １ ~C １３ Alkyl, C １ ~C ６ Alkoxy, amino (-NR ８ R ９ ), nitro (-N(O) ２ ), amide (—(C═O)NR ８ R ９ ), carboxyl (-C(O)OH), nitrile (-CN), C ６ ~C １０ Aryl, C ３ ~C １０ Heteroaryl, and C ３ ~C １０ heterocyclyl; Said C ６ ~C １０ aryl, the C ３ ~C １０ Heteroaryl, or the C ３ ~C １０ Heterocyclyl includes hydrogen, hydroxyl, halo, carbonyl (—(C═O)R ８ ), unsubstituted or halo or C ３ ~C １０ C substituted by heterocyclyl １ ~C ３ Alkyl, unsubstituted or halo or C ３ ~C １０ C substituted by heterocyclyl １ ~C ３ Alkoxy, C ６ ~C １０ Phenoxy, amino (-NR ８ R ９ ), nitro (-N(O) ２ ), amide (—(C═O)NR ８ R ９ ), carboxyl (-C(O)OH), nitrile (-CN), C ６ ~C １０ Aryl, C ３ ~C １０ Heteroaryl, and C ３ ~C １０ heterocyclyl; R ８ and R ９ are each independently hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ６ ~C １０ Aryl, C ３ ~C １０ Heteroaryl, or C ３ ~C １０ heterocyclyl, provided that R ８ is R ９ may form a 3- to 7-membered saturated ring together with the nitrogen atom to which it is bonded, and the 3- to 7-membered saturated ring is selected from N, O, S, NH, C═N, C═O, —NHC(O)—, —NHC(O)NH—, —NHS(O) ２ - and SO ２ and may contain at least one of hydrogen, C １ ~C １３ Alkyl, C ６ ~C １０ Aryl, C ３ ~C １０ optionally substituted with at least one of heteroaryl, hydroxyl, halo, and cyano; Said C ３ ~C １０ Heteroaryl and the C ３ ~C １０ The heterocyclyl contains at least one heteroatom selected from the group consisting of N, O, and S.

6. R １ is Cl or Br, and R ２ is hydrogen or -NH ２ and R ３ is hydrogen, -CH ３ , or -S(O) ２ CH ３ and R ４ is hydrogen, and R ５ is hydrogen, Cl, Br, -OCH ３ , -OCH ２ CH ３ , or -OCH ２ CF ３ and R ６ is hydrogen, Cl, Br, F, -CH ３ , or -CF ３ and R ７ is hydrogen and A is 【Chemistry 6】 selected from the group consisting of The compound of claim 5.

7. 7. The compound of claim 6, wherein the compound is selected from the group consisting of the following compound numbers: 140, 165, 168, 169, 172-175, 183, 184, 188, 189, 196, 197, 205-222, 224, 225, 238-259, 261-271, 276, and 280-283. Compound No. 140: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 165: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 168: N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)meth sulfonamides; Compound No. 169: N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 172: N-(6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 173: N-(6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 174: N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 175: N-(6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 183: N-(6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 184: N-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 188: N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 189: N-(6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 196: N-(6-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 197: N-(6-((5-chloro-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 205: N-(6-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 206: N-(6-((5-chloro-2-((5-ethyl-2-methoxy- 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 207: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 208: N-(6-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 209: N-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 210: N-(6-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 211: N-(6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 212: N-(6-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 213: N-(6-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 214: N-(6-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 215: N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 216: N-(6-((5-bromo-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 217: N-(6-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 218: N-(6-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) Methanesulfonamide; Compound No. 219: N-(6-((5-chloro-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 220: N-(6-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 221: N-(6-((5-chloro-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 222: N-(6-((5-chloro-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 224: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-((1-methyl-1H-pyrazol-5-yl)amino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 225: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-(trifluoromethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 238: N-(6-((5-bromo-2-((2-methoxy-6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 239: N-(6-((5-bromo-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 240: N-(6-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 241: N-(6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 242: N-(6-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 243: N-(6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 244: N-(6-((5-bromo-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin (benzo-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 245: N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4′-bipiperidine]-1′-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 246: N-(6-((5-bromo-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonylamide; Compound No. 247: N-(6-((5-bromo-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 248: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 249: N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 250: N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 251: N-(6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 252: N-(6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 253: N-(6-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 254: N-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 255: N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-(trifluoromethyl)piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 256: N-(6-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 257: N-(6-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 258: N-(6-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxy-5-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 259: N-(6-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 261: N-(6-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 262: N-(6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 263: N-(6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 264: N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 265: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 266: N-(6-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 267: N-(6-((5-chloro-2-((4-(3-(dimethylamino)-[1,4′-bipiperidine]-1′-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide; Compound No. 268: N-(6-((5-chloro-2-((2,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 269: N-(5-((5-bromo-2-((2,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanesulfonamide; Compound No. 270: N-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloro (Colopyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 271: N-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 276: N-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-methylindolin-5-yl)methanesulfonamide; Compound No. 280: N-(6-((2-((5-bromo-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 281: N-(6-((5-bromo-2-((5-bromo-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; Compound No. 282: N-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; and Compound No. 283: N-(6-((2-((5-bromo-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide.

8. 10. The compound of claim 1, wherein the pharmaceutically acceptable salt is a salt of an organic or inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid.

9. A pharmaceutical composition for preventing, ameliorating, or treating cancer, comprising the compound according to any one of claims 1 to 8 as an active ingredient, The cancer is selected from the group consisting of glioblastoma, triple-negative breast cancer, colorectal cancer, lung cancer, anaplastic large cell lymphoma, gastrointestinal stromal tumor, multiple myeloma, acute myeloid leukemia, liver cancer, gastric cancer, thyroid cancer, head and neck cancer, and combinations thereof; The pharmaceutical composition.

10. The pharmaceutical composition of claim 9 , wherein the cancer is caused by an EGFR mutation.

11. The pharmaceutical composition according to claim 9, which is applied to patients with EGFR mutations.

12. The pharmaceutical composition of claim 9, wherein the cancer is lung cancer.

13. The pharmaceutical composition according to claim 9, which is administered to a patient having an exon 19 deletion / T790M / C797S triple mutation or an L858R / T790M / C797S triple mutation as an EGFR-associated mutation.

14. The pharmaceutical composition according to claim 9, which is administered to a patient having an exon 19 deletion / T790M double mutation or an L858R / T790M double mutation as an EGFR-associated mutation.

15. The pharmaceutical composition according to claim 9, which is administered to a patient having an exon 19 deletion mutation or an L858R mutation as an EGFR-associated mutation.

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