KR20230054567A - Compounds inhibiting ALK and/or EGFR mutation kinases and medical use thereof - Google Patents

Abstract

The present disclosure provides a novel compound exhibiting inhibitory activity against ALK overexpression, ALK mutation, EGFR overexpression, EGFR mutation, etc., and medicinal uses thereof. The present disclosure provides pharmaceutical compositions comprising such compounds or pharmaceutically acceptable salts thereof. The compounds according to the present disclosure not only exhibit excellent inhibitory activity against both ALK mutations and EGFR mutations, but also have desirable physicochemical and pharmacokinetic properties to be used as active ingredients in pharmaceuticals.

Description

Compounds inhibiting ALK and/or EGFR mutation kinases and their medicinal use

The present disclosure relates to compounds exhibiting an ALK and/or EGFR mutant kinase inhibitory effect and their medicinal uses.

Recently, anaplastic lymphoma kinase (ALK) has been discovered in various human tumors and is being studied as a target for targeted therapy. ALK carcinogenesis is known to be related to the ALK-NPM (Nucleophosmin, nucleophosmin) fusion gene, which is mainly observed in anaplastic large cell lymphoma. When ALK is activated by gene fusion, ALK's tyrosine kinase behaves abnormally and causes cancer. In other words, abnormally activated ALK induces cell proliferation and prevents cell death by interfering with apoptosis.

ALK connects to and interacts with other tyrosine kinases, either normal or oncogenic, or activates a variety of different pathways. In particular, inside lung cancer cells, the ALK gene fuses with the Echinoderm Microtubule-Associated Protein-Like 4 (EML4) gene to produce EML4-ALK, an active tyrosine kinase. It has been known that this is dependent on the enzymatic activity. In addition, Mosse et al. reported about 26% of ALK gene amplification in 491 neuroblastoma specimens (Nature. 2008 Oct 16; 455(7215): 930-935). In addition, the ALK gene has been expressed in numerous non-hematopoietic cells, including large B-cell lymphoma, systemic hemangiocytosis, inflammatory myofibroblastic sarcoma, esophageal squamous cell carcinoma, non-small cell lung cancer, rhabdomyosarcoma, myofibroblastoma, breast cancer, gastric cancer, and melanoma cell lines. It has been found to be expressed in tumors, and in the case of a rare disease called inflammatory myelofibroblastoma, several types of ALK fusion proteins are commonly found, and these fusion proteins are thought to be deeply involved in tumor development.

Thus, by blocking the activation pathway of ALK, a therapeutic agent for ALK-NPM for the purpose of cancer treatment is being developed. Crizotinib (PF-02341066) developed by Pfizer is an ATP-competitive c-Met/HGFR and ALK inhibitor, and is known to be effective in the treatment of non-small cell lung cancer. In addition, NVP-TAE684 and LDK-378 from Novartis and CH5424802 from Chugai are also known to have an effect of reducing tumor size in neuroblastoma cell lines as well as anaplastic large cell lymphoma cell lines.

On the other hand, like other kinase inhibitors, ALK inhibitors also suffer from resistance. The most common mutation observed is G1202R, a mutation in the solvent exposed region of ALK, which causes steric hindrance to most ALK inhibitors. In addition, in the case of non-small cell lung cancer, resistance to the first-generation ALK inhibitor crizotinib develops within 1 to 2 years. There are resistant mutations within the TK domain of ALK, most commonly L1196M. This mutation causes steric hindrance at the binding site, reducing the efficacy of the response to crizotinib. In addition, various ALK-resistant mutations exist, which reduce the therapeutic effect of ALK inhibitors. Therefore, there is a need for a therapeutic agent exhibiting an inhibitory effect on various ALK mutations.

In addition, the epidermal growth factor receptor (EGFR) is a protein composed of a receptor part and a tyrosine kinase part, and serves to transmit signals from outside the cell to the inside of the cell through the cell membrane. EGFR plays an essential role in normal cell regulation through intracellular signal transduction. However, overexpression of EGFR or activating EGFR mutations characterized by ligand-independent tyrosine kinase activity are known to induce growth, differentiation, angiogenesis, metastasis, resistance expression, etc. of cancer cells by abnormally activating the cell signaling system. . It has been reported that EGFR is abnormally overexpressed or frequently mutated in most solid cancer cells, which is associated with poor prognosis. For example, lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, It is known that testicular cancer, blood cancer, lymphoma, skin cancer, psoriasis, and fibroadenoma are related to EGFR mutation (Cancer Communications. 2020;40:43-59).

Among them, EGFR activating mutations such as the L858R point mutation in exon 21 of the EGFR tyrosine kinase domain or the in-frame deletion in exon 19 are known to be important causes of non-small cell lung cancer. Therefore, according to the prediction that the anticancer effect will be excellent if cancer cell signaling through the epidermal growth factor receptor is blocked, research for developing anticancer drugs targeting the epidermal growth factor receptor is being actively conducted.

The first drug developed as an EGFR tyrosine kinase inhibitor among small molecules is gefitinib, which is a reversible inhibitor that selectively inhibits EGFR (Erb-B1) among EGFR subtypes. Another drug with such characteristics is erlotinib, and this EGFR targeting therapy is mainly used for patients with EGFR activating mutations for non-small cell lung cancer (NSCLC) as a main indication.

However, it has been reported that NSCLC patients with EGFR activating mutations treated with gefitinib or erlotinib develop resistance to the drug after about 8 to 16 months, and about 60% of them show resistance due to the EGFR T790M mutation. (Helena A. Yu et al., Clin Cancer Res. 19(8), 2240, 2013).

Irreversible inhibitors have been proposed to overcome resistance to existing EGFR inhibitors such as gefitinib or erlotinib. However, since EGFR irreversible inhibitors also have high activity against EGFR WT (wild-type), which also exists in normal cells, serious side effects are caused when doses to overcome resistance due to EGFR T790M mutation are administered. It indicates the limitations of clinical application.

As an alternative to this, a number of drugs including osimertinib, olmutinib, naquotinib, and avitinib, which are EGFR mutation-selective inhibitors, are under development in the clinical stage. However, according to the clinical results of osimertinib for non-small cell lung cancer patients with EGFR-resistant mutations, after about 10 months, other resistance mechanisms become resistant to the drug, and among them, the C797S mutation has a high rate of more than 20%. It is known to appear as The C797S mutation is a point mutation in which cysteine 773 (Cys773), which forms a covalent bond with irreversible inhibitors of EGFR, is changed to serine. .

As such, the development of EGFR-targeted therapeutics has shown limitations in not being able to maintain efficacy over a certain period of time due to the expression of primary and secondary resistance. In particular, research on the EGFR C797S mutation is not even a substance under clinical study other than reports on early-stage preclinical studies, so effective treatment for this is urgently required.

In addition, it has recently been found that the combination of an ALK inhibitor and an EGFR inhibitor is effective as a method for treating patients suffering from cancer induced by ALK mutation, etc. (WO2020-030977 A2), and therefore, both ALK mutation and EGFR mutation Substances having inhibitory activity against cancer will be very useful for the treatment of various cancers, especially those that may develop resistance.

International Patent Application Publication WO2020-030977 A2 International Patent Application Publication WO2016-060443 A2 International Patent Application Publication WO2015-130014 A1 International Patent Application Publication WO2019-190259 A1

Therefore, the problem to be solved by the present invention is to provide a novel compound that exhibits inhibitory activity against ALK overexpression, ALK mutation, EGFR overexpression, EGFR mutation, etc., and its medicinal use.

Another problem to be solved by the present invention is to provide a novel compound exhibiting inhibitory activity against both ALK mutation and EGFR mutation and its medicinal use.

Another problem to be solved by the present invention is to provide a novel compound having inhibitory activity against ALK overexpression, ALK mutation, EGFR mutation, etc., and pharmacokinetic properties desirable for use as an active ingredient in pharmaceuticals, and its medicinal use. .

In order to solve the above problems, the present disclosure provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

In Formula 1,

, 또는

이고, A is direct connection,

, or

ego,

,

,

, 또는

이고, 여기에서 R은 수소, C1~C6 알킬, 또는 C1~C6 플루오로알킬이며, R ₁ is -C(O)NHR, -NH-C(O)-R, -NH-S(O)(O)R,

,

,

, or

, wherein R is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl,

,

, 또는

이고, 여기에서 R' 및 R"는 서로 독립적으로 수소, C1~C6 알킬, 또는 C1~C6 플루오로알킬이며,R ₂ is

,

, or

, wherein R' and R" are independently of each other hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl,

R ₃ is hydrogen, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or Cl;

R ₄ is hydrogen, F, Cl, CN, or CF ₃ .

When described as “C _1-6 ”, “C1~6”, or “C1~C6” in the present specification, it means that the number of carbon atoms is 1 to 6. For example, C1-C6 alkyl means an alkyl having 1 to 6 carbon atoms, and the alkyl is straight-chain or branched.

In the present specification, C1~C6 fluoroalkyl means that at least one hydrogen atom of C1~C6 alkyl is substituted with fluoro.

In a preferred aspect of the present invention, in Formula 1,

이고,A is a direct connection or

ego,

,

,

,

,

, 또는

이고, R ₁ is -C(O)NHCH ₃ ;

,

,

,

,

, or

ego,

,

, 또는

이고,R ₂ is

,

, or

ego,

R ₃ is hydrogen, methoxy, or Cl;

R ₄ is Cl.

The present inventors have found that the novel compounds according to the present invention not only show excellent inhibitory activity against both ALK mutation and EGFR mutation, but also have better stability, especially in vivo metabolic stability, etc. than other compounds having similar structures, The present invention was completed by confirming that the dynamic characteristics were also excellent.

In the present invention, the compound represented by Formula 1 may be used in the form of a salt derived from an inorganic or organic acid, such as 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, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzene It may be used in the form of a salt induced by at least one acid selected from the group consisting of phonic acid and toluenesulfonic acid.

As used herein, the term "compound of the present invention" is meant to include not only each compound of Formula 1, but also clathrates, hydrates, solvates, or polymorphs thereof. In addition, the term "compound of the present invention" is meant to include pharmaceutically acceptable salts of the compounds of the present invention when pharmaceutically acceptable salts thereof are not mentioned. In one embodiment, the compounds of the present invention are stereomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, 97% ee or more, or 99% ee or more))). That is, when the compound of Formula 1 or a salt thereof according to the present invention is a tautomeric isomer and/or a stereoisomer (eg, geometrical isomer and conformational isomers), the separated isomer thereof and mixtures each are also included within the scope of the compounds of the present invention. In case the compounds of the present invention or their salts have an asymmetric carbon in their structure, their optically active compounds and racemic mixtures are also included in the scope of the compounds of the present invention.

As used herein, the term "polymorph" refers to a solid crystal form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in terms of physical properties include, but are not limited to, stability (e.g. heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't. Differences in stability may be due to chemical reactivity changes (e.g. differential oxidation such as faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g. kinetically Tablet fragments stored as the preferred polymorph may be thermodynamically converted to a more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity). Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates, or may be more difficult to filter or wash, than another polymorph, eg, due to its shape or particle size distribution.

As used herein, the term “solvent compound” refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and can be administered in very small amounts to humans.

As used herein, the term "hydrate" refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. .

As used herein, the term "clathrate" refers to a compound of the present invention in the form of a crystal lattice containing spaces (eg, channels) in which guest molecules (eg, solvent or water) are confined. or a salt thereof.

As used herein, the term "purified" means that when isolated, the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and In other embodiments, at least 99.9% pure.

As used herein, “treatment” includes eradication, removal, transformation, or control of primary, localized, or metastatic cancerous tissue; to minimize or delay the spread of cancer.

Non-limiting examples of compounds according to the present invention include the following compounds and pharmaceutically acceptable salts thereof.

N-(2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-(4-methylpipette razin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide;

N-(5-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4- (4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)isobutyramide;

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

N-(2-((5-chloro-2-((methoxy-5-((1-methyl-1H-pyrazol-3-yl)amino)-4-(4-(4-methylpiperazine- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide;

5-((5-chloro-4-((2-(N-methylmethanesulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-N-methyl-2-(4 -methylpiperazin-1-yl)benzamide;

2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-(4-methylpiperazine-1 -yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide,

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

N-(2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-methylpiperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide;

(E)-N-(5-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide, or

N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-(thiazole -2-ylamino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide.

In one preferred aspect of the present invention, the compound according to the present disclosure is N-(2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazole-4- yl)amino)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfone Amide, N-(2-((5-chloro-2-((2-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-( methylmethylsulfonamido)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, or 5-chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ^2- (2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-(4-methylpiperazin-1-yl)piperidin-1- yl)phenyl)pyrimidine-2,4-diamine. These compounds are preferred in various aspects of the present invention, such as inhibitory activity against ALK mutations and EGFR mutations, pharmacokinetic properties, and the like.

In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient. These pharmaceutical compositions may further contain pharmaceutically acceptable excipients.

In another aspect, the present disclosure provides a method for treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof. Methods are provided, wherein the disease or condition is an ALK mutation and/or EGFR mutation associated disease. In another embodiment, the disease associated with ALK mutation and/or EGFR mutation is cancer or psoriasis. In another embodiment, the subject is a human. In another embodiment, the cancer is lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethra Cancer, bladder cancer, testicular cancer, hematological cancer, lymphoma, skin cancer, fibroadenoma, non-small cell lung cancer, neuroblastoma, inflammatory myelofibroblastoma, rhabdomyosarcoma, myofibroblastoma, large B-cell lymphoma, systemic hemangiocytosis, inflammatory myofibroblastic sarcoma , or esophageal squamous cell carcinoma. In another embodiment, the cancer is non-small cell lung cancer.

In one aspect of the present invention, the ALK mutation is any one or more of G1202R, L1196M, C1156Y, F1174L, F1174S, G1269A, G1269S, L1152R, R1275Q, S1206R, T1151-L1152insT, or T1151M. In another aspect of the invention, the ALK mutation is any one or more of G1269S, G1202R, and L1196M. In one aspect of the invention, the EGFR mutation is d746-750/T790M/C797S and/or T790M/C797S/L858R.

In one aspect, "an effective amount" as used herein means to destroy, transform, control or eliminate primary, localized or metastatic cancer cells or tissue; slowing or minimizing the spread of cancer; or an amount of a compound of the present invention sufficient to provide a therapeutic benefit in the treatment or management of cancer, neoplastic disease, or tumor. "Effective amount" also refers to an amount of a compound of the present invention sufficient to cause cancer or neoplastic cell death. "Effective amount" also refers to an amount sufficient to inhibit or reduce the activity of cancer cells either in vitro or in vivo.

In another embodiment, an "effective amount" as used herein also refers to an amount sufficient to inhibit or reduce the activity of an ALK mutation and/or an EGFR mutation, either in vitro or in vivo.

That is, the present disclosure provides a pharmaceutical use characterized by using the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient. In one aspect, the medical use of the present disclosure is the treatment or prevention of diseases associated with ALK mutations and/or EGFR mutations. In another aspect, the medicinal use of the present disclosure is the treatment or prevention of cancer or psoriasis. In another embodiment, the cancer is lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethra Cancer, bladder cancer, testicular cancer, hematological cancer, lymphoma, skin cancer, fibroadenoma, non-small cell lung cancer, neuroblastoma, inflammatory myelofibroblastoma, rhabdomyosarcoma, myofibroblastoma, large B-cell lymphoma, systemic hemangiocytosis, inflammatory myofibroblastic sarcoma , or esophageal squamous cell carcinoma. In another embodiment, the cancer is non-small cell lung cancer.

Therefore, in another aspect, the present invention provides a pharmaceutical composition for treating or preventing cancer or psoriasis, characterized in that it contains the compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. In another aspect, the present invention provides a pharmaceutical composition for the treatment or prevention of ALK mutation and/or EGFR mutation-related diseases, comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. .

A compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is generally administered in a therapeutically effective amount. The compounds of the present invention can be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in a dosage effective for the intended treatment. An effective dosage is generally about 0.0001 to about 200 mg/kg of body weight/day, preferably about 0.001 to about 100 mg/kg/day, in single or divided administration. Dosage levels below the lower end of this range may be suitable depending on the age, species, and disease or condition being treated. In other cases, still larger doses can be used without detrimental side effects. Larger doses may be divided into several smaller doses for administration throughout the day. Methods for determining the appropriate dosage are well known in the art.

For medicinal use according to the present disclosure, the compound described herein or a pharmaceutically acceptable salt thereof can be administered in a variety of ways as follows.

Oral administration

The compound of the present invention can be administered orally, and oral is a concept including swallowing. Oral administration allows the compounds of the present invention to enter the gastrointestinal tract or be directly absorbed from the mouth into the bloodstream, eg, by buccal or sublingual administration.

Compositions suitable for oral administration may be in solid, liquid, gel, or powder form, and may have formulations such as tablets, lozenges, capsules, granules, powders, and the like. .

Compositions for oral administration may optionally be enteric coated and exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.

Liquid formulations may include solutions, syrups and suspensions, and such liquid compositions may be contained in soft or hard capsules. Such formulations may include a pharmaceutically acceptable carrier such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulation may also contain one or more emulsifying and/or suspending agents.

In tablet formulations, the amount of active ingredient drug may be present from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the total weight of the tablet. Tablets may also contain a disintegrant comprising from about 0.5% to about 35% by weight, more usually from about 2% to about 25% by weight of the dosage form. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

Suitable glidants included for making into tablets may be present in amounts from about 0.1% to about 5% by weight, and include talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like. It can be used as a lubricant, but the present invention is not limited to these types of additives.

Gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. may be used as a binder for preparing tablets. Mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. may be used as suitable diluents for preparing tablets, but the present invention is not limited to these types of additives. .

Optionally, the solubilizing agent that may be included in the tablet may be used in an amount of about 0.1% to about 3% by weight based on the total weight of the tablet, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, Diethylene glycol monoethyl ether, dimethylisosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR ^™ (Nikkol), oleyl ester, Gelucire ^™ , caprylic/caprylic mono/ Diglyceride, sorbitan fatty acid ester, Solutol HS ^TM and the like can be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to the specific types of these solubilizing agents.

Parenteral Administration

Compounds of the present invention may be administered directly into the bloodstream, muscle, or intestine. Suitable methods for parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, and the like. include Suitable devices for parenteral administration include injectors (including needle and needleless syringes) and infusion methods.

Compositions for parenteral administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.

Most parenteral formulations are liquid compositions, and these liquid compositions are aqueous solutions containing the active ingredient, salt, buffer, tonicity agent and the like according to the present invention.

Parenteral formulations may also be prepared in dried form (eg lyophilized) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle such as sterile water. Solubility-enhancing agents may also be used in the preparation of parenteral solutions.

Topical Administration

The compounds of the present invention may be administered topically to the skin or transdermally. Formulations for this topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical formulations may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be performed by electroporation, iontophoresis, phonophoresis, and the like.

Compositions for topical administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.

The present disclosure provides novel compounds exhibiting inhibitory activity against ALK overexpression, ALK mutation, EGFR overexpression, EGFR mutation and the like, and pharmaceutical uses thereof. In particular, the compounds according to the present disclosure not only exhibit excellent inhibitory activity against both ALK mutation and EGFR mutation, but also have desirable physicochemical and pharmacokinetic properties for use as active ingredients in pharmaceuticals.

1 to 4 are pharmacokinetic evaluation results of control substances and the compounds of the present invention.

Hereinafter, examples and the like will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Example 1 N-(2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-( Preparation of 4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide

Step 1: Preparation of 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (1-1)

1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (1.0 g, 4.0 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (0.88 g, 4.8 mmol) ) and potassium carbonate (1.1 g, 8.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 80 degrees (°C) overnight. The mixture was extracted by diluting with ethyl acetate and brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, purification with a silica gel column gave the title compound (1.35 g, 82%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.20 (s, 1H), 6.56 (s, 1H), 3.95 (s, 3H), 3.60 (m, 2H), 2.44-2.77 (m, 11H), 2.34 (s, 3H), 1.98 (m, 2H), 1.77 (m, 2H)

Step 2: N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)-1-methyl-1H-pyrazole- Preparation of 4-amine (1-2)

1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (1.0 g, 2.42 mmol), 1-methyl-1H-pyra _Dioxane ( ₂₄ mL) The mixture was purged with argon gas and stirred at 100 degrees overnight. The mixture was extracted by diluting with dichloromethane and water, and dried over anhydrous sodium sulfate. After filtration and concentration, purification with a silica gel column gave the title compound (0.40 g, 39%).

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.64 (s, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 6.81 (s, 1H), 6.43 (s, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.37 (m, 2H), 2.65 (m, 2H), 2.51 (m, 5H), 2.32 (m, 4H), 2.14 (s, 3H), 1.81 ( m, 2H), 1.74 (m, 2H)

Step 3: 4-Methoxy-N ^One Preparation of -(1-methyl-1H-pyrazol-4-yl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene-1,3-diamine ( 1-3)

N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)-1-methyl-1H-pyrazol-4-amine (0.25 g, 0.58 mmol) in methanol (5 mL) was added 10% Pd/C (125 mg, 50 wt%) and replaced with H ₂ . Stirred for 12 hours, diluted with dichloromethane, and filtered through Celite. Concentration and purification by silica gel column gave the title compound (150 mg, 65%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.38 (s, 1H), 7.28 (s, 1H), 6.63 (s, 1H), 6.27 (s, 1H), 5.92 (s, 1H), 3.87 (s , 3H), 3.77 (s, 3H), 3.59 (br s, 2H), 3.06 (m, 2H), 2.65 (m, 2H), 2.36-2.85 (m, 9H), 2.35 (s, 3H), 1.97 (m, 2H), 1.67 (m, 2H)

Step 4: N-(2-((5-chloro-2-((methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-(4-methyl Preparation of piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide (1)

4-methoxy-N ¹ -(1-methyl-1H-pyrazol-4-yl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene-1 Isopropanol of ,3-diamine (100 mg, 0.25 mmol) and N-(2-((2,5-dichloropyrimidin-4yl)amino)phenyl)-N-methylmethanesulfonamide (105 mg, 0.26 mmol) (2.5 mL) into the solution was added methanesulfonic acid (24 μL, 0.38 mmol) and stirred under reflux overnight. The mixture was extracted by diluting with ethyl acetate and aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. After filtration and concentration, purification with a silica gel column gave the title compound (120 mg, 63%).

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.29 (m, 2H), 8.19 (br s, 1H), 8.12 (s, 1H), 7.57 (dd, 1H), 7.51 (s, 1H), 7.26 (s, 1H), 7.11-7.22 (m, 4H), 6.80 (s, 1H), 6.26 (s, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 3.19 (s, 3H) , 3.10 (s, 3H), 3.07 (m, 2H), 2.65 (m, 2H), 2.54 (m, 6H), 2.31 (m, 3H), 2.15 (s, 3H), 1.85 (m, 2H), 1.72 (m, 2H).

LC/MS (ESI) m/z 710 [M+H] ⁺

Example 2: N-(5-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2 Preparation of (4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)isobutyramide

Step 1: Preparation of 2-fluoro-4-methoxyaniline (2-1)

10% Pd/C (300 mg, 10 wt%) was added to a solution of 2-fluoro-4-methoxy-1-nitrobenzene (3.0 g, 17.53 mmol) in methanol (60 mL) and replaced with H ₂ . The mixture was stirred for 4 hours, filtered through celite, and concentrated. The residue was solidified with ether and heptane to give the title compound (1.8 g, 73%).

Step 2: Preparation of N-(2-fluoro-4-methoxyphenyl)isobutyramide (2-2)

Isobutyryl chloride (91 mg, 0.85 mmol) was added to a solution of 2-fluoro-4-methoxyaniline (100 mg, 0.71 mmol) in pyridine (0.5 mL) and stirred for 2 hours. 4N HCl (10 mL) was added and stirred for 1 hour. Filtered and washed with water and heptane to obtain the title compound (63 mg, 42%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13 (t, 1H), 6.65 (m, 2H), 3.76 (s, 3H), 2.53 (m, 1H), 1.23 (d, 6H)

Step 3: Preparation of N-(2-fluoro-4-methoxy-5-nitrophenyl)isobutyramide (2-3)

To a solution of N-(2-fluoro-4-methoxyphenyl)isobutyramide (63 mg, 0.30 mmol) in dichloromethane (2 mL) was added 70% HNO ₃ (40 mg) and stirred for 2 hours. The reaction mixture was concentrated, stirred for 10 minutes after adding water (5 mL), and filtered to obtain the title compound (64 mg, 82%).

Step 4: Preparation of N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)isobutyramide (2-4 )

N-(2-fluoro-4-methoxy-5-nitrophenyl)isobutyramide (63 mg, 0.25 mmol), 1-methyl-4-(piperidin-4yl)piperazine (45 mg, 0.25 mmol) and potassium carbonate (68 mg, 0.49 mmol) in N,N-dimethylformamide (0.5 mL) was stirred overnight at 80 degrees. The reaction mixture was cooled to room temperature, extracted with water and dichloromethane, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was solidified with ether and heptane to give the title compound (82 mg, 80%).

Step 5: Preparation of N-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)isobutyramide (2-5 )

N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)isobutyramide (82 mg, 0.20 mmol) in methanol / 10% Pd/C (20 mg) was added to a solution of dichloromethane (10/2 mL) and replaced with H ₂ . The mixture was stirred for 2 hours, filtered through celite, and concentrated. The residue was solidified with ether to give the title compound (63 mg, 83%).

Step 6: N-(5-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2- Preparation of (4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)isobutyramide (2)

Using N-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)isobutyramide (63 mg, 0.16 mmol) and the title compound (106 mg, 94%) was obtained using a method similar to the step 4 synthesis method of Example 1 above.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.71 (s, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.26 (m, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.57 (dd, 1H), 7.23 (m, 1H), 7.13 (m, 1H), 6.82 (s, 1H), 6.26 (s, 1H), 3.74 (s, 3H), 3.18 ( s, 3H), 3.10 (s, 3H), 3.03 (m, 2H), 2.70 (m, 3H), 2.54 (m, 5H), 2.31 (m, 4H), 2.15 (s, 3H), 1.88 (m , 2H), 1.67 (m, 2H), 1.09 (d, 6H).

LC/MS (ESI) m/z 700 [M+H] ⁺

Example 3: N-(2-((5-chloro-2-((2-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5 Preparation of -(methylmethylsulfonamido)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide

Step 1: Preparation of 2-fluoro-4-methoxy-5-nitroaniline (3-1)

KNO ₃ (360 mg, 3.56 mmol) was added to a solution of 2-fluoro-4-methoxyaniline (500 mg, 3.54 mmol) in sulfuric acid (2.6 mL) at 0 °C and stirred for 2 hours. It was neutralized to pH 7-8 with 6N NaOH aqueous solution and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, filtration and concentration, the title compound (510 mg, 77%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.44 (d, 1H), 6.80 (d, 1H), 3.90 (s, 3H)

Step 2: Preparation of N-(2-fluoro-4-methoxy-5-nitrophenyl)methanesulfonamide (3-2)

Methanesulfonyl chloride (0.11 mL, 1.47 mmol) was added and the temperature was gradually raised and stirred at room temperature overnight. It was diluted with 4N HCl aqueous solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was solidified with methyl tertiary butyl ether to obtain the title compound (286 mg, 80%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13 (d, 1H), 6.90 (d, 1H), 3.96 (s, 3H), 3.06 (s, 3H)

Step 3: Preparation of N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)methanesulfonamide (3-3 )

N- (2-fluoro-4-methoxy-5-nitrophenyl) methanesulfonamide (280 mg, 1.06 mmol), 1-methyl-4- (piperidin-4yl) piperazine (194 mg, 1.06 mmol) and potassium carbonate (293 mg, 2.12 mmol) in N,N-dimethylformamide (2 mL) was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature, extracted with water and dichloromethane, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was solidified with methyl tert-butyl ether to give the title compound (240 mg, 53%).

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.86 (br s, 1H), 7.81 (s, 1H), 6.73 (s, 1H), 3.95 (s, 3H), 3.60 (m, 2H), 3.06 (s, 3H), 2.78 (m, 2H), 2.49 (m, 5H), 2.33 (m, 4H), 2.15 (s, 3H), 1.82 (m, 2H), 1.62 (m, 2H)

Step 4: Preparation of N-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)methanesulfonamide (3-4 )

Using N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)methanesulfonamide (240 mg, 0.56 mmol) and the title compound (200 mg, 90%) was obtained using a method similar to the step 3 synthesis method of Example 1 above.

Step 5: N-(2-((5-chloro-2-((2-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5- Preparation of (methylmethylsulfonamido)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (3)

N-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)methanesulfonamide (200 mg, 0.50 mmol) was used , The title compound (260 mg, 73%) was obtained using a method similar to the step 4 synthesis method of Example 1 above.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.27-8.33 (m, 4H), 8.15 (s, 1H), 7.60 (dd, 1H), 7.58 (br s, 1H), 7.34 (m, 1H) ), 7.17 (m, 1H), 6.89 (s, 1H), 3.77 (s, 3H), 3.19 (s, 3H), 3.11 (s, 3H), 3.08 (m, 2H), 2.99 (s, 3H) , 2.71 (m, 2H), 2.54 (m, 6H), 2.31 (m, 3H), 2.15 (s, 3H), 1.83 (m, 2H), 1.64 (m, 2H).

LC/MS (ESI) m/z 708 [M+H] ⁺

Example 4: N-(2-((5-chloro-2-((methoxy-5-((1-methyl-1H-pyrazol-3-yl)amino)-4-(4-(4- Preparation of methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide

Step 1: Preparation of N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-nitrophenyl)-1-methyl-1H-pyrazol-3-amine (4-1)

1-(2-Bromo-5-methoxy-4-nitrophenyl)-4-methylpiperazine (600 mg, 1.82 mmol), 1-methyl-1H-pyrazol-3-amine (185 mg, 1.92 mmol) ), a 1,4-dioxane (18 mL) mixture of BINAP (113 mg, 0.18 mmol) and cesium carbonate (889 mg, 2.73 mmol) was purged with argon gas and Pd ₂ (dba) ₃ (83 mg, 0.09 mmol) ) was added. Stir overnight at 100 degrees and concentrate. The mixture was extracted with dichloromethane and water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by a silica gel column to give the title compound (400 mg, 64%).

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.39 (s, 1H), 7.53 (d, 1H), 7.04 (s, 1H), 6.89 (s, 1H), 5.94 (d, 1H), 3.89 (s, 3H), 3.74 (s, 3H), 3.00 (m, 4H), 2.55 (m, 4H), 2.26 (s, 3H)

Step 2: 4-Methoxy-N ^One Preparation of -(1-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (4-2)

N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-nitrophenyl)-1-methyl-1H-pyrazol-3-amine (400 mg, 1.21 mmol) , The title compound (7350 mg, 91%) was obtained using a method similar to the step 3 synthesis method of Example 1 above.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.49 (d, 1H), 6.92 (s, 1H), 6.88 (s, 1H), 6.68 (s, 1H), 5.90 (d, 1H), 4.45 (br s, 2H), 3.73 (s, 3H), 3.70 (s, 3H), 2.72 (m, 4H), 2.49 (m, 4H), 2.24 (s, 3H)

Step 3: N-(2-((5-chloro-2-((methoxy-5-((1-methyl-1H-pyrazol-3-yl)amino)-4-(4-(4-methyl Preparation of piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (4)

4-methoxy-N ¹ -(1-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (90 mg, 0.28 mmol) and the title compound (55 mg, 31%) was obtained using a method similar to the step 4 synthesis method of Example 1 above.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.28 (m, 3H), 8.13 (s, 1H), 7.93 (s, 1H), 7.55 (m, 1H), 7.44 (d, 1H), 7.09 (m, 2H), 6.90 (s, 1H), 6.87 (s, 1H), 5.89 (d, 1H), 3.70 (s, 3H), 3.65 (s, 3H), 3.18 (s, 3H), 3.09 ( s, 3H), 2.86 (m, 4H), 2.57 (m, 4H), 2.28 (s, 3H)

LC/MS (ESI) m/z 627 [M+H] ⁺

Example 5: 5-((5-chloro-4-((2-(N-methylmethanesulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-N-methyl- Preparation of 2-(4-methylpiperazin-1-yl)benzamide

Step 1: Preparation of 2-fluoro-4-methoxy-5-nitrobenzoic acid (5-1)

A solution of 2-fluoro-4-methoxy-5-nitrobenzonitrile (50 mg, mmol) in acetic acid (1 mL), sulfuric acid (1 mL) and water (1 mL) was stirred at 120 °C for 3 hours. After cooling to room temperature, water was added to precipitate a solid, followed by filtration and drying to quantitatively obtain the title compound.

Step 2: Preparation of 2-fluoro-4-methoxy-N-methyl-5-nitrobenzamide (5-2)

HATU (265 mg, 0.70 mmol) and diisopropyldiamine in a solution of 2-fluoro-4-methoxy-5-nitrobenzoic acid (100 mg, 0.47 mmol) in N,N-dimethylformamide (1 mL). (0.24 mL, 1.39 mmol) was added and stirred for 15 minutes. To the reaction mixture was added methylamine hydrochloride (47 mg, 0.70 mmol) and stirred overnight. After adding water and stirring for 20 minutes, the mixture was filtered and dried to obtain a labeled compound (80 mg, 75%).

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.31 (m, 1H), 8.25 (d, 1H), 7.42 (d, 1H), 3.99 (s, 3H), 2.78 (d, 3H)

Step 3: Preparation of 4-methoxy-N-methyl-2-(4-methylpiperazin-1-yl)-5-nitrobenzamide (5-3)

The title compound (81 mg, 75%) was obtained.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.32 (m, 1H), 8.01 (s, 1H), 6.65 (s, 1H), 3.97 (s, 3H), 3.14 (m, 4H), 2.76 (d, 3H), 2.50 (m, 4H), 2.22 (s, 3H)

Step 4: Preparation of 5-amino-4-methoxy-N-methyl-2-(4-methylpiperazin-1-yl)-5-nitrobenzamide (5-4)

A procedure similar to the step 3 synthesis of Example 1 above, using 4-methoxy-N-methyl-2-(4-methylpiperazin-1-yl)-5-nitrobenzamide (80 mg, 0.26 mmol) was used to obtain the title compound (73 mg, 99%).

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.12 (m, 1H), 7.30 (s, 1H), 6.79 (s, 1H), 4.71 (br s, 2H), 3.81 (s, 3H), 2.84 (m, 4H), 2.81 (d, 3H) 2.76 (d, 3H), 2.50 (m, 4H), 2.25 (s, 3H)

Step 5: 5-((5-chloro-4-((2-(N-methylmethanesulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-N-methyl-2 Preparation of (4-methylpiperazin-1-yl)benzamide (10)

Step 4 of Example 1 above, using 5-amino-4-methoxy-N-methyl-2-(4-methylpiperazin-1-yl)-5-nitrobenzamide (71 mg, 0.26 mmol) The title compound (66 mg, 44%) was obtained using a method similar to the synthetic method.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.30 (q, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.55 (dd, 1H), 7.21 (t, 1H), 7.12 (td, 1H), 6.89 (s, 1H), 3.82 (s, 3H), 3.18 (s, 3H), 3.09 ( s, 3H), 2.95 (t, 4H), 2.84 (d, 3H), 2.54 (m, 4H), 2.26 (s, 3H).

LC/MS (ESI) m/z 589 [M+H] ⁺

Example 6: 2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-(4-methyl Preparation of piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

4-methoxy-N ¹ -(1-methyl-1H-pyrazol-4-yl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene-1 Using ,3-diamine (70 mg, 0.18 mmol) and (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (58 mg, 0.18 mmol), The title compound (60 mg, 50%) was obtained using a method similar to the synthesis method in Step 4 of Example 1.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.23 (s, 1H), 8.52 (m, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.52 (dd, 1H), 7.50 (s, 1H), 7.30 (m, 1H), 7.25 (s, 1H), 7.13 (m, 1H), 7.06 (m, 1H), 6.80 (s, 1H), 6.26 (s, 1H), 3.73 ( s, 3H), 3.70 (s, 3H), 3.06 (m, 2H), 2.65 (m, 2H), 2.54 (m, 5H), 2.31 (m, 4H), 2.15 (s, 3H), 1.85 (m , 2H), 1.79 (s, 3H), 1.75 (s, 3H), 1.71 (m, 2H).

LC/MS (ESI) m/z 679 [M+H] ⁺

Example 7: 5-Chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl ) phenyl) pyrimidine-2,4-diamine preparation

4-methoxy-N ¹ -(1-methyl-1H-pyrazol-4-yl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene-1 Using ,3-diamine (70 mg, 0.18 mmol) and 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (64 mg, 0.18 mmol), The title compound (50 mg, 40%) was obtained using a method similar to the synthesis method in Step 4 of Example 1.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.57 (s, 1H), 8.62 (m, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 7.77 (dd, 1H), 7.53 (m, 1H), 7.52 (s, 1H), 7.27 (m, 1H), 7.24 (s, 1H), 7.11 (m, 1H), 6.81 (s, 1H), 6.26 (s, 1H), 3.73 ( s, 3H), 3.69 (s, 3H), 4.44 (m, 1H), 3.07 (m, 2H), 2.66 (m, 2H), 2.54 (m, 5H), 2.32 (m, 4H), 2.15 (s , 3H), 1.85 (m, 2H), 1.71 (m, 2H), 1.14 (d, 6H).

LC/MS (ESI) m/z 709 [M+H] ⁺

Example 8: N-(2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-methyl Preparation of piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide

Step 1: Preparation of N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-nitrophenyl)-1-methyl-1H-pyrazol-4-amine (8-1)

1-(2-Bromo-5-methoxy-4-nitrophenyl)-4-methylpiperazine (100 mg, 0.30 mmol) and 1-methyl-1H-pyrazol-4-amine (31 mg, 0.32 mmol) ), and the title compound (45 mg, 42%) was obtained using a method similar to the step 1 synthesis method of Example 4 above.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.62 (s, 1H), 7.35 (s, 1H), 7.24 (s, 1H), 6.83 (s, 1H), 6.37 (s, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.03 (m, 4H), 2.53 (m, 4H), 2.24 (s, 3H)

Step 2: 4-Methoxy-N ^One Preparation of -(1-methyl-1H-pyrazol-4yl)-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (8-2)

N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-nitrophenyl)-1-methyl-1H-pyrazol-4-amine (250 mg, 0.72 mmol) was used , The title compound (155 mg, 68%) was obtained using a method similar to the step 3 synthesis method of Example 1 above.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.56 (s, 1H), 7.30 (s, 1H), 6.63 (s, 1H), 6.23 (s, 1H), 6.08 (s, 1H), 4.38 (br s, 2H), 3.77 (s, 3H), 3.66 (s, 3H), 2.73 (m, 4H), 2.48 (m, 4H), 2.23 (s, 3H)

Step 3: N-(2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-methylpipette Preparation of razin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (8)

4-methoxy-N ¹ -(1-methyl-1H-pyrazol-4yl)-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (50 mg, 0.14 mmol) and the title compound (28 mg, 31%) was obtained by a method similar to the step 4 synthesis method of Example 1 above.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.30 (m, 2H), 8.29 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.57 (dd, 1H), 7.52 (s, 1H), 7.25 (s, 1H), 7.11-7.21 (m, 3H), 6.83 (s, 1H), 6.21 (s, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 3.19 (s, 3H), 3.11 (s, 3H), 2.87 (m, 4H), 2.55 (m, 4H), 2.27 (s, 3H).

LC/MS (ESI) m/z 627 [M+H] ⁺

Example 9: (E)-N-(5-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4- Preparation of methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide

Step 1: N-(2-((5-chloro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methyl Preparation of methanesulfonamide (9-1)

Using 4-fluoro-2-methoxy-5-nitroaniline (1.0 g, 5.37 mmol), the title compound (2.6 g, 97%) was obtained using a method similar to the synthesis method in step 4 of Example 1 above. .

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.53 (d, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 8.13 (d, 1H), 7.56 (dd, 1H), 7.30 (d, 1H), 7.20 (m, 2H), 3.91 (s, 3H), 3.15 (s, 3H), 3.06 (s, 3H)

Step 2: N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5- Preparation of nitrophenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide (9-2)

N-(2-((5-chloro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (1.5 g, 3.02 mmol), and the title compound (1.7 g, 90%) was obtained by a method similar to the synthesis method in step 1 of Example 1 above.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.41 (s, 1H), 8.37 (s, 1H), 8.22 (m, 1H), 8.20 (s, 1H), 7.59 (dd, 1H), 7.20 (m, 2H), 6.77 (s, 1H), 3.90 (s, 3H), 3.28 (m, 2H), 3.18 (s, 3H), 3.10 (s, 3H), 2.85 (m, 2H), 2.51 ( m, 5H), 2.32 (m, 4H), 2.15 (s, 3H), 1.84 (m, 2H), 1.58 (m, 2H)

Step 3: N-(2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (9-3)

N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl) Using amino) pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide (1.8 g, 2.72 mmol), the title compound (1.7 g , 99%) was obtained.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.32 (m, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.58 (dd, 1H), 7.32 (m, 2H), 7.17 (m, 1H), 7.02 (s, 1H), 6.65 (s, 1H), 4.31 (br s, 2H), 3.66 (s, 3H), 3.19 (s, 3H), 3.12 (m, 2H), 3.10 (s, 3H), 2.55 (m, 2H), 2.51 (m, 5H), 2.32 (m, 4H), 2.25 (s, 3H), 1.85 (m, 2H), 1.64 ( m, 2H)

Step 4: (E)-N-(5-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methyl Preparation of Toxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide (9)

N-(2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5 -chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (100 mg, 0.16 mmol) and (E)-2-cyano-4,4-dimethylpent-2-enoic acid ( 27 mg, 0.18 mmol) was used, and the title compound (42 mg, 35%) was obtained using a method similar to the step 2 synthesis method of Example 5 above.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.57 (s, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 8.21 (m, 1H), 8.14 (s, 1H), 7.55 (s, 1H), 7.54 (d, 1H), 7.26 (s, 1H), 7.13 (m, 2H), 7.02 (s, 1H), 3.77 (s, 3H), 3.18 ( s, 3H), 3.09 (s, 3H), 2.95 (m, 2H), 2.80 (m, 2H), 2.51 (m, 5H), 2.33 (m, 4H), 2.14 (s, 3H), 1.75-1.85 (m, 4H).

LC/MS (ESI) m/z 765 [M+H] ⁺

Example 10: N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5 Preparation of -(thiazol-2-ylamino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide

N-(2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5 -chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (50 mg, 0.08 mmol) and 2-bromotiazole (14 mg, 0.08 mmol), using the steps of Example 1 above. The title compound (35 mg, 62%) was obtained using a method similar to the synthesis method of 4.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.80 (s, 1H), 8.31 (s, 1H), 8.29 (s, 1H), 8.23 (m, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.53 (dd, 1H), 7.11 (d, 1H), 7.10 (m, 2H), 6.81 (s, 1H), 6.74 (d, 1H), 3.75 (s, 3H), 3.17 ( s, 3H), 3.09 (s, 3H), 3.07 (m, 2H), 2.66 (m, 2H), 2.54 (m, 5H), 2.33 (m, 4H), 2.16 (s, 3H), 1.80 (m , 2H), 1.71 (m, 2H).

LC/MS (ESI) m/z 713 [M+H] ⁺

Experimental Example 1: Evaluation of ALK/EGFR Enzyme Inhibiting Activity

It was confirmed whether the compounds obtained in the above examples showed ALK normal (WT) or mutant (G1202R, L1196M) and EGFR normal (WT) or mutant (d746-750/T790M/C797S, T790M/C797S/L858R) inhibitory activity. Enzyme inhibition activity was evaluated by Reaction Biology (USA, MA), and the test method was as follows.

Each enzyme (human ALK normal (WT), ALK mutant (G1202R, L1196M), EGFR normal (WT), or EGFR mutant (d746-750/T790M/C797S, T790M/C797S/L858R)), poly[Glu:Tyr] (4:1) substrate phosphorylation was measured by mixing 0.2 mg/ml of substrate and 10 μM of ATP with the compound. Specifically, the compound prepared in the above examples was made into a 10 nM DMSO solution. Substrate was added to the kinase solution (20 mM Hepes (pH7.5), 10 mM MgCl ₂ , 1 mM EGTA, 0.02% Brij35, 0.2 mg/ml BSA, 0.1 mM Na ₃ VO ₄ , 2 mM DTT, 1% DMSO) and the enzymes were added and mixed gently after each addition. A compound prepared using Acoustic Technology (Echo550; nanoliter range) was added to the mixed solution and reacted at room temperature for 20 minutes. After this, ³³ P-ATP was further added and reacted at room temperature for 2 hours. Kinase activity permeated through the filter was measured, and Alectinib and Osimertinib were used as comparative examples. The results are shown in Table 1 below.

Example % Enzyme Activity (relative to DMSO control) ALK
(WT) ALK (G1202R) ALK (L1196M) EGFR
(WT) EGFR
(d746-750/T790M/C797S EGFR (T790M/C797S/L858R) One 10.3 10.2 2.1 35.8 2.1 4.6 2 14.9 23.1 8.0 72.0 5.7 19.8 3 2.8 3.0 1.7 59.5 2.6 6.7 6 37.9 44.4 8.8 49.6 8.6 18.3 7 3.0 1.1 1.1 69.7 10.9 10.1 9 5.3 23.9 2.3 1.0 6.8 31.1 10 2.1 1.6 0.9 6.9 0.5 0.4 Alectinib 3.6 35.4 4.3 96.1 85.5 89.9 Osimertinib 90.9 95.0 89.6 0.6 82.6 81.8

As shown in Table 1, the examples of the present invention not only showed high inhibitory ability against ALK and the two mutant forms of ALK, but also showed higher inhibitory ability against ALK (G1202R) than the control substance, Alectinib. In addition, the examples of the present invention showed a higher inhibitory ability to EGFR mutants (d746-750/T790M/C797S, T790M/C797S/L858R) compared to the control substance, Osimertinib.

Experimental Example 2: Evaluation of ALK/EGFR enzyme inhibition activity (IC ₅₀ )

Activity was evaluated by the same test method as in Experimental Example 1, and each test substance was diluted 3 times from 1 μM and used to make 10 different concentrations. IC ₅₀ values were obtained from the results. The results are as shown in Table 2 below.

Example IC ₅₀ , nM ALK
(WT) ALK (G1202R) ALK (L1196M) EGFR
(WT) EGFR (d746-750/T790M/C797S) EGFR (T790M/C797S/L858R) One 1.76 3.77 0.60 8.68 0.91 3.03 4 0.51 1.05 0.075 0.85 0.45 0.58 5 0.62 6.48 0.12 24.00 0.45 4.15 8 2.41 8.18 1.10 18.80 0.69 3.67

As shown in Table 2, the examples of the present invention showed high inhibitory ability at nM unit concentration for ALK, two mutant forms of ALK, and EGFR mutations (d746-750/T790M/C797S, T790M/C797S/L858R). .

Experimental Example 3: Evaluation of ALK enzyme inhibition activity (% enzyme activity)

Activity was evaluated in the same test method as in Experimental Example 1, and Example 7 and the control substance Lorlatinib were used as the test substance. The results are as shown in Table 3 below.

enzyme type % Enzyme Activity (relative to DMSO controls) Example 7 Lorlatinib ALK 4.64 4.95 ALK (C1156Y) 0.91 1.69 ALK (F1174L) 0.30 1.55 ALK (F1174S) 2.54 1.02 ALK (G1202R) 2.29 14.15 ALK (G1269A) 1.98 8.62 ALK (G1269S) 2.36 19.57 ALK (L1152R) 3.19 3.83 ALK (L1196M) 1.26 6.10 ALK (R1275Q) 0.46 0.84 ALK (S1206R) 1.61 0.25 ALK (T1151-L1152insT) 2.32 3.09 ALK (T1151M) 3.81 2.99

As shown in Table 3, Example 7 of the present invention not only showed high inhibitory ability against various ALK mutant forms, but also showed higher inhibitory ability against ALK (G1202R) and ALK (G1269S) compared to the control substance Lorlatinib. .

Experimental Example 4: Pharmacokinetic evaluation

A pharmacokinetic test for the compound of the present invention was conducted as follows. After a single oral administration of the compound of the present invention to ICR mice, the concentration of the compound over time was followed up and analyzed.

The compound of the present invention was suspended in 10% DMSO/90% (30% HPbCD aqueous solution) and orally administered to mice at a dose of 5 mg/kg. Blood was collected at a fixed time and plasma was separated. The drug was analyzed using HPLC (XBridge column C18, Waters, mobile phase 0.1% formic acid:acetonitrile (30:70, %/%)) and MS/MS (ESI positive, MRM). Mouse donor plasma and each commercially available standard solution were mixed at a ratio of 9:1, and concentrations of 5, 50, 100, 500, 100, and 5,000 ng/mL were prepared and calibrated. In addition, the preparation of the QC sample was prepared by mixing the mouse blood plasma and the standard solution for QC at a ratio of 9: 1, and prepared at concentrations of 100, 750, and 2,500 ng/mL. 100 μL of the plasma sample was transferred to a centrifugation tube, and 10 μL of the internal standard solution and 300 μL of methanol were added, followed by mixing for about 30 seconds for pretreatment. The tube was centrifuged at 3,000 x g (4° C.) for about 5 minutes, and the supernatant was taken and transferred to an LC vial and injected into the instrument. Then, the concentration of the compound in mouse plasma was quantified by applying a previously validated assay. As a control material, a compound having the structure of Chemical Formula 2 was used.

For pharmacokinetic parameters, the program WinNonlin 5.2 (Pharsight, USA) was used. AUC _0-t , AUC _0-∞ , Cmax, Tmax, and t _1/2 were calculated by noncompartment modeling (best fit). The pharmacokinetic parameter results were expressed as the mean (Mean) and statistically processed using the SPSS program (Statistical Package for the Social Sciences, 10.0K, USA). The results are as shown in Table 4 and Figures 1 to 4 below.

Example AUC _0-24
(ng.h/mL) AUCinf
(ng.h/mL) Cmax Tmax T1/2 relative absorbance
(relative to control, %) control substance 3,572 3,609 306 1.0 10.9 100 One 11,046 11,066 1,829 1.33 2.19 307 3 7,434 7,439 1,510 2.67 2.27 206 7 18,877 19,201 3,416 0.42 3.99 532

As shown in Table 4, Examples 1, 3, and 7 of the present invention showed an oral absorption rate about 2 to 5 times higher in AUC compared to the control material without a substituent in R ₁ .

Claims (7)

A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
[Formula 1]

In Formula 1,
A is direct connection,

, or

ego,
R ₁ is -C(O)NHR, -NH-C(O)-R, -NH-S(O)(O)R,

,

,

, or

, wherein R is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl,
R ₂ is

,

, or

, wherein R' and R" are independently of each other hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl,
R ₃ is hydrogen, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or Cl;
R ₄ is hydrogen, F, Cl, CN, or CF ₃ . The method of claim 1, wherein in Formula 1
A is a direct connection or

ego,
R ₁ is -C(O)NHCH ₃ ;

,

,

,

,

, or

ego,
R ₂ is

,

, or

ego,
R ₃ is hydrogen, methoxy, or Cl;
R ₄ is Cl, or a pharmaceutically acceptable salt thereof. The method of claim 2, wherein the compound
N-(2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-(4-methylpipette razin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide;
N-(5-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4- (4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)isobutyramide;
N-(2-((5-chloro-2-((2-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-(methylmethyl sulfonamido)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide;
N-(2-((5-chloro-2-((methoxy-5-((1-methyl-1H-pyrazol-3-yl)amino)-4-(4-(4-methylpiperazine- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide;
5-((5-chloro-4-((2-(N-methylmethanesulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-N-methyl-2-(4 -methylpiperazin-1-yl)benzamide;
2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-(4-methylpiperazine-1 -yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide,
5-chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;
N-(2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-methylpiperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide;
(E)-N-(5-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide, or
N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-(thiazole -2-ylamino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide
A compound or a pharmaceutically acceptable salt thereof. The method of claim 3, wherein the compound
N-(2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-(4-methylpipette razin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide;
N-(2-((5-chloro-2-((2-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-(methylmethyl sulfonamido)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, or
5-chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine
A compound or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for the treatment or prevention of cancer or psoriasis, comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 5, wherein the cancer is lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, Urethral cancer, bladder cancer, testicular cancer, hematological cancer, lymphoma, skin cancer, fibroadenoma, non-small cell lung cancer, neuroblastoma, inflammatory myelofibroblastoma, rhabdomyosarcoma, myofibroblastoma, large B-cell lymphoma, systemic hemangiocytosis, inflammatory myofibroblastic Sarcoma, or esophageal squamous cell carcinoma, the pharmaceutical composition. The pharmaceutical composition according to claim 6, wherein the cancer is non-small cell lung cancer.

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