KR20200137087A - Novel 4-substituent-N-(1-substituent-1H-pyrazol-4-yl)-5-morpholinopyrimidin-2-amine derivatives and use thereof - Google Patents

Abstract

The present invention relates to: a novel 4-substituted-N-(1-substituted-1H-pyrazol-4-yl)-5-morpholinopyrimidin-2-amine derivative compound or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for preventing or treating JAK3-related diseases containing the same as an active component; and a method for preventing or treating JAK3-related diseases using the pharmaceutical composition.

Description

Novel 4-substituted-N-(1-substituted-1H-pyrazol-4-yl)-5-morpholinopyrimidin-2-amine derivatives and uses thereof {Novel 4-substituent-N-(1-substituent -1H-pyrazol-4-yl)-5-morpholinopyrimidin-2-amine derivatives and use thereof}

The present invention is a novel 4-substituted-N-(1-substituted-1H-pyrazol-4-yl)-5-morpholinopyrimidin-2-amine derivative compound or a pharmaceutically acceptable salt thereof, effective A pharmaceutical composition for preventing or treating JAK3-related diseases, and the pharmaceutical composition comprising as an ingredient relates to a method for preventing or treating JAK3-related diseases using.

Manning et al. found that 218 of the 518 protein kinase genes in the human kinome are closely related to the development and development of human diseases. There are 20% of drugs targeting enzymes in drugs obtained to date, and drugs targeting protein kinases in particular have special value in clinical use.

Protein kinases catalyze the phosphorylation of specific proteins, and tyrosine protein kinases (JAK, Src, Abl, EGFR, FGFR, PDGFR, etc.), serine/threonine protein kinases (PKC, MAPK, Rho kinases, etc.), bispecific protein kinases (MAPKK, etc.) ) And phosphatidyl inositol kinase (PI3K). It is an intracellular messenger-dependent enzyme that performs signaling processes mainly including. The phosphorylation/dephosphorylation process of protein kinase can regulate several biological processes in various cells such as metabolism, cell differentiation, cell survival, apoptosis, organogenesis, angiogenesis, and immune response.

Among these, JAK kinase (Janus kinase abbreviated as JAK comprising four known members of JAK3, JAK1, TYK2 and JAK2) is a small family of non-receptor tyrosine protein kinase superfamily in the cytoplasm. On the other hand, JAK1, TYK2 and JAK2 are widely distributed in many tissue cells, while JAK3 is distributed in the bone marrow and lymphatic system. For example, when JAK binds to a cytokine receptor on the cell surface, receptor-bound JAK is activated, and accordingly, the receptor is phosphorylated to STAT proteins (STAT1-4, STAT5a, STAT5b and STAT6), which are cytoplasmic signal transducers and transcription activators. It provides a recruiting reaction site for, that is, a JAK phosphorylated STAT protein. After dimerization, the JAK phosphorylated STAT protein is transferred to the nucleus to regulate gene expression. This pathway is called the JAK/STAT signaling pathway.

The JAK/STAT signaling pathway is a signaling pathway stimulated by a plurality of cytokines and growth factor receptors. These factors include interleukin (IL-2-7, IL-9, IL-10, IL-15, and IL-21), interferon (IFN-α, IFN-β, and IFN-γ), erythropoietin (EPO), Granulocyte macrophage colony stimulating factor (GM-CSF), growth hormone (GH), prolactin (PRL), thrombopoietin (TPO), etc., are involved in the proliferation of immune cells and hematopoietic stem cells, and immunomodulatory biological It plays an important role in the process. Various subtypes of JAK kinases can be activated by various receptors to achieve distinct biological functions.

In particular, JAK3 regulates cellular signals by binding to the gamma common chain (γc) in cytokine-receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Mutations in either JAK3 or γc can lead to severe complex immunodeficiency (SCID). Abnormal activity of JAK3 appears as a significant decrease in T-cells and NK cells and loss of B-cell function, which greatly affects the normal biological function of the immune system. JAK3 has been a promising pharmaceutical target for immune system-related diseases according to its functional properties and specific tissue distribution, and therefore its inhibitors are rheumatoid arthritis (RA), Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, and psoriasis. , Allergic disease, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, organ transplant and other diseases have great clinical value in the treatment/prevention.

Non-Patent Document 1: Manning G. et al., 2002, Science, 298: 1912-1934, Non-Patent Document 2: O'Shea J. J. et al., 2013, N. Engl. J. Med., 368: 161-170, Non-Patent Document 3: Villa A. et al., 1996, Blood, 88: 817-823, Non-Patent Document 4: Papageorgiou A. C. et al., 2004, Trends Pharm. Sci., 2004, 25: 558-562.

As a result of intensive research efforts to develop a novel small molecule compound capable of inhibiting or regulating JAK3 activity, the present inventors showed that a series of 2-amino-(heterocyclic fused pyrimidine) derivatives inhibit JAK3 activity, and EGFR mutation dependent cells, For example, it was confirmed that it can suppress the proliferation of various cancer cells, specifically lung cancer cells, and the present invention was completed.

As one aspect for achieving the above object, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

L is a direct bond, -O- or -NH-;

n is an integer of 0 to 2;

R ₁ is C _1-6 alkyl, (C _1-4 alkoxy)-(C _1-6 alkyl), amino-(C _1-6 alkyl), (C _1-4 alkyl)amino-(C _1-6 alkyl ), di(C _1-4 alkyl) amino-(C _1-6 alkyl), (C _1-4 alkyl)-carbamoyl-(C _1-4 alkyl), or unsubstituted or substituted 3-7 membered hetero _Cyclyl (C _0-6 alkyl);

R ₂ is unsubstituted or (C _1-4 alkenyl)carbonylamino or (C _1-4 alkenyl)carbonyl substituted C _6-10 aryl or 5-10 membered heterocyclyl.

For example, the compound may be a compound represented by Formulas 1-1 to 1-3, but is not limited thereto:

[Formula 1-1]

[Formula 1-2]

[Formula 1-3]

In the above formula,

n ₁ to n ₃ are each independently 0 or 1;

m is 0 or 1;

R ₁ is as defined above.

For example, in the above formula, R ₁ is methyl, methoxyethyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, methylcarbamoylmethyl, piperidinyl, tert-butoxycarbonylpiperidinyl or morpholinopropyl Can be

Specifically, the compound is

(1) N-(3-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)phenyl)acrylamide; (2) N-(3-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)phenyl)acrylamide ; (3) N-(4-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)phenyl)acrylamide; (4) N-(4-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)phenyl)acrylamide ; (5) N-(3-((2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)methyl)phenyl)acrylamide; (6) N-(3-((2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)methyl)phenyl ) Acrylamide; (7) N-(3-((2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino) Methyl)phenyl)acrylamide; (8) N-(3-((2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino) Methyl)phenyl)acrylamide; (9) N-(3-((2-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino) Methyl)phenyl)acrylamide; (10) tert-Butyl 4-(4-(4-(3-acrylamidobenzylamino)-5-morpholinopyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidine -1-carboxylate; (11) N-(4-((2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)methyl)phenyl)acrylamide; (12) N-(4-((2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)methyl)phenyl ) Acrylamide; (13) (S)-1-(3-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)piperidin-1- I) prop-2-en-1-one; (14) (R)-1-(3-(2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidine-4- Ylamino)piperidin-1-yl)prop-2-en-1-one; (15) (R)-1-(2-((2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidine-4 -Ylamino)methyl)pyrrolidin-1-yl)prop-2-en-1-one; (16) (S)-1-(3-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino) Piperidin-1-yl)prop-2-en-1-one; (17) (S)-1-(3-(2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidine-4- Ylamino)piperidin-1-yl)prop-2-en-1-one; (18) (S)-1-(3-(2-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidine-4- Ylamino)piperidin-1-yl)prop-2-en-1-one; (19) N-(3-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide; (20) N-(3-(2-(1-(2-(dimethylamino)ethyl)-1H-pyra-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl) Acrylamide; (21) N-(4-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide; (22) N-(3-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide ; (23) N-(3-(2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl ) Acrylamide; (24) N-(3-(2-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl ) Acrylamide; (25) N-(3-(2-(1-(2-(methylamino)-2-oxoethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy Si) phenyl) acrylamide; (26) N-(3-(2-(1-(3-(diethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl ) Acrylamide; (27) N-(3-(5-morpholino-2-(1-(3-morpholinopropyl)-1H-pyrazol-4-ylamino)pyrimidin-4-yloxy)phenyl)acryl Amide; (28) N-(3-((2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)methyl)phenyl)acrylamide; (29) N-(3-((2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)methyl)phenyl ) Acrylamide; (30) N-(3-((2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy) Methyl)phenyl)acrylamide; (31) N-(3-((2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy) Methyl)phenyl)acrylamide; (32) N-(3-((5-morpholino-2-(1-(piperidin-4-yl)-1H-pyrazol-4-ylamino)pyrimidin-4-yloxy)methyl )Phenyl)acrylamide; (33) N-(3-((2-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy) Methyl)phenyl)acrylamide; (34) N-(4-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide ; (35) N-(3-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yl)phenyl)acrylamide; Or (36) N-(3-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yl)phenyl)acrylamide ; May be, but is not limited thereto.

The compound of Formula 1 of the present invention includes not only a pharmaceutically acceptable salt thereof, but also all possible solvates and hydrates that may be prepared therefrom, and includes all possible isomers without limitation.

In addition, the compound of Formula 1 of the present invention may be prepared in a crystalline or amorphous form, and when these compounds are prepared in a crystalline form, it may be optionally hydrated or solvated. The present invention may include stoichiometric hydrates of the compounds of formula 1 as well as compounds containing various amounts of water. That is, the solvate of the compound represented by Formula 1 according to the present invention includes both a stoichiometric solvate and a non-stoichiometric solvate.

In another aspect, the present invention provides a first step of preparing a 4-(2,4-dihalopyrimidin-5-yl)morpholine derivative compound represented by the following Chemical Formula 2;

Intermediate represented by the following formula (3) in which a substituent is introduced into the halogen at carbon position 4 by reacting the compound represented by Formula 2 obtained from the previous step with a precursor containing a boronic acid, amine or hydroxyl group as a reactive functional group A second step of manufacturing; And

A third step of reacting the intermediate represented by Formula 3 obtained from the previous step with a 1-substituted-1H-pyrazol-4-amine derivative compound; including,

It provides a method for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof:

[Formula 2]

[Formula 3]

In the above formula,

X ₁ and X ₂ are each independently halogen;

n, L and R ₂ are as defined above.

For example, in the manufacturing method of the present invention, the first step is to introduce a morpholinyl group at the halogen site by reacting 5-haluracil with morpholine, and triethylamine and an excess of PO (halide) ₃ and 70 to 100 It may be achieved by halogenation by reacting at °C, but is not limited thereto, and may be performed by applying or changing a reaction known in the art.

For example, in the first step, the reaction between 5-haluracil and morpholine may be performed for several to several tens of minutes by heating to 80 to 120°C, but is not limited thereto. In this case, microwaves may be irradiated to increase the temperature of the reaction system, but the present invention is not limited thereto.

Further, the reaction of the triethylamine and the excess PO (halide) ₃ may be performed by maintaining at the increased temperature for several days, but is not limited thereto.

For example, in the manufacturing method of the present invention, the second step

i) C 6 containing a hydroxyl group, an amine group or a boronic acid group linked directly or through a linker with a reactive functional group, (C _1-4 alkenyl) carbonylamino or (C _1-4 alkenyl) carbonyl substituted C _{6 Reacted} directly with _-10 aryl or 5-10 membered heterocycle derivatives, or

ii) a 5-10 membered heterocycle derivative containing a hydroxyl group, an amine group, or a boronic acid group linked directly or through a linker with a reactive functional group as a precursor, an aryl derivative containing a nitro group or a nitrogen atom substituted with a protecting group, and After reacting, reducing or deprotecting, converting to an amine group, and reacting with acryloyl halide at -5 to 10°C in the presence of a base, it is not limited thereto.

For example, the second step may be performed in an organic solvent. In the second step, as the organic solvent, DMF, DMSO, ethyl acetate, THF, dioxane, ethanol, DCM, and methanol may be used alone or in an appropriate ratio, but is not limited thereto.

For example, in the production method of the present invention, when the second step is performed by the method of i), a reactive functional group used as a reactant includes a hydroxyl group, an amine group, or a boronic acid group connected directly or through a linker, ( C _1-4 alkenyl)carbonylamino or (C _1-4 alkenyl)carbonyl substituted C _6-10 aryl or 5-10 membered heterocycle derivatives can be prepared from nitrophenols.

In a specific embodiment of the present invention, after preparing aminophenol by reducing nitrophenol with a Pd/C catalyst while supplying hydrogen, aryloyl chloride is added dropwise at 0° C. in the presence of NaHCO ₃ as a base to vigorously for several to tens of minutes. The reaction was carried out while stirring to prepare the target compound, hydroxyphenylacrylamide.

For example, the third step may be performed by additionally adding a catalyst and/or a cocatalyst in an organic solvent in the presence of a base. For example, the reaction may be carried out by additionally adding a palladium catalyst and a copper cocatalyst, but is not limited thereto. Potassium carbonate, cesium carbonate, etc. as the base, Pd(OAc) ₂ , or Pd ₂ (dba) ₃ as a palladium catalyst, and Xphos and Xantphos as a phosphine derived from biphenyl , BINAP ((1,1'-Binaphthalene-2,2'-diyl)bis(diphenylphosphine)), etc. may be used, but the present invention is not limited thereto. In a specific example of the present invention, it was confirmed that the target compound can be obtained in a high yield by using potassium carbonate as a base, Pd ₂ (dba) ₃ as a palladium catalyst, and expos as a copper cocatalyst. The type and combination of the base, catalyst and/or cocatalyst are not limited thereto.

Furthermore, one method for performing the third step is to remove gas from the reaction mixture by ultrasonicating the reaction solution prior to adding the catalyst and/or cocatalyst in order to achieve a higher yield. It may be selectively included, but is not limited thereto. For example, in a specific embodiment of the present invention, the target compound can be obtained in a higher yield by sonicating for several minutes before adding the catalyst.

In addition, the production method of the present invention may further include the step of using a specific optical isomer as a reactant or selectively separating the optical isomer after the reaction in each step. For example, the preparation method of the present invention may use a compound having a stereocenter as a reactant, that is, a specific optical isomer or a mixture thereof, or may generate a compound having at least one stereocenter in a molecule as a product. As a result, the production method of the present invention may provide a product mainly comprising a compound of a specific isomer such as (R)-type or (S)-type, and in a mixed form, such as 1:1 It can also be provided as a racemic mixture. Therefore, in order to obtain a specific isomer from such a mixture with high purity, the step of separating the optical isomer may be further performed. The separation may be performed using a method known in the art such as supercritical fluid chromatography without limitation.

In addition, the manufacturing method of the present invention may further include any one or more of independently extracting, drying, concentrating, and purifying after at least one of the above steps, but is limited thereto. It doesn't work. For example, the product obtained after the first step or the second step may be separated, recovered and purified to be used in a subsequent step, or a reaction product obtained without a purification process may be used in a subsequent step. The series of steps can be performed using methods known in the art without limitation.

In another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of JAK3-related diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The term "prevention" of the present invention refers to all actions of inhibiting or delaying the occurrence, spread, and recurrence of JAK3-related diseases by administration of the composition of the present invention, and "treatment" refers to the administration of the composition of the present invention. It can refer to any behavior in which the symptoms improve or are beneficially changed.

The composition of the present invention can inhibit the activity of JAK3 and can inhibit the proliferation of cells expressing a mutation thereof, so it can be usefully used in the prevention or treatment of diseases caused by abnormal JAK3 activity or expression of a mutation thereof. I can.

Preferably, the pharmaceutical composition according to the present invention contains a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient, in 0.1 to 75% by weight, more preferably 1 to 50, based on the total weight of the composition. It may contain by weight %.

The composition of the present invention may further include a pharmaceutically acceptable carrier, diluent or excipient, and powders, granules, tablets, capsules, suspensions, emulsions, syrups, according to a conventional method for each purpose of use, It can be formulated and used in various forms such as oral formulations such as aerosols and injections of sterile injection solutions, and can be administered orally or administered through various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like. Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. In addition, the composition of the present invention may further include a filler, an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, a preservative, and the like.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the composition, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. Is formulated by mixing. Further, in addition to simple excipients, lubricants such as magnesium stearate and talc may be used.

Oral liquid preparations may include suspensions, liquid solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to water and liquid paraffin, which are commonly used simple diluents. I can.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. The base for suppositories is Withepsol, Macrogol, and Tween61. Cacao butter, laurin paper, glycerogelatin, and the like may be used. Meanwhile, the injection may include conventional additives such as solubilizing agents, isotonic agents, suspending agents, emulsifying agents, stabilizing agents, and preservatives.

The composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" of the present invention refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is the health condition of the patient, The type of disease, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used in combination or concurrently, and other factors well known in the medical field. I can. The composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and body weight of the patient, and is generally 1 to 100 mg, preferably 5 to 60 mg per kg of body weight daily or every other day or 1 It can be administered in 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, the severity of the disease, sex, weight, age, etc., the dosage amount is not limited by any method.

Specifically, the pharmaceutical composition of the present invention may exhibit its effect by inhibiting the expression or activity of JAK3.

The pharmaceutical composition of the present invention can be usefully used to prevent or treat JAK3-related diseases, such as proliferative diseases, inflammatory diseases, autoimmune diseases, pain (painful conditions), viral infections, or complex diseases thereof.

Specifically, JAK3-related diseases that can be prevented or treated using the pharmaceutical composition of the present invention are rheumatoid arthritis, psoriasis, lupus erythematosus, systemic lupus erythematosus. , Artherosclerosis, idiopathic thrombocytopenia purpura, restenosis, tumors, chronic allograft rejection, acute allograft rejection, chronic graft Chronic graft versus host diseases, asthma, allergic acute rhinitis, psoriatic arthritis, systemic sclerosis, atopical dermatitis, erythema (erythemas), alopecia, multiple sclerosis, immunodeficiency (immunodeficiencies), myeloproliferative disorders (myeloproliferative disorders), or cancer diseases (cancers).

For example, the cancer diseases include lung cancer, small cell lung cancer, non-small cell lung cancer, colon cancer, pancreatic cancer, stomach cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, Hodgkin lymphoma. , Blood cancer, bladder cancer, kidney cancer, ovarian cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, cancer of the anus, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer , Endocrine adenocarcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, gliomas, sub Education tumor, anaplastic astrocytoma, medulloblastoma, cervical carcinoma, chordoma, throat cancer, Kaposi's sarcoma, lymphangiosarcoma, lymphangiocarcinoma, colorectal cancer, renal cell carcinoma, cholangiocarcinoma, choriocarcinoma, testicular tumor, testicular tumor, Wilm's tumor , Awing tumor, angiosarcoma, endothelial sarcoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland sarcoma, papillary sarcoma, papillary adenocarcinoma, cystic adenosarcoma, bronchial carcinoma, medullary carcinoma, mastocytoma, mesothelioma, synovial membrane, leiomyosarcoma, rhabdomyosarcoma , Neuroblastoma, retinoblastoma, oligodendrocyte, inner ear neuroma, hemangioblastoma, meningioma, pineal adenoma, ventricular adenoma, head pharyngoma, epithelial carcinoma, embryonic carcinoma, squamous cell carcinoma, basal cell carcinoma, fibrosarcoma, myxoma, It may be myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, or metastatic cancer thereof.

Meanwhile, the compound of the present invention may exist in the form of a pharmaceutically acceptable salt. As the salt, an acid value formed by a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" of the present invention is a concentration that is relatively non-toxic and harmless to patients, and side effects caused by this salt do not degrade the beneficial efficacy of the compound represented by formula (1). Means any organic or inorganic addition salt.

Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess acid aqueous solution, and precipitating this salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and an acid or alcohol (eg glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.

At this time, organic acids and inorganic acids can be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid can be used as organic acids. (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used. , Not limited to these.

In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, the metal salt is particularly suitable for preparing sodium, potassium, or calcium salt, but is not limited thereto. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate , Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and the like, and preparation of salts known in the art It can be manufactured through a method.

As the salt of the 4-substituted-N-(1-substituted-1H-pyrazol-4-yl)-5-morpholinopyrimidin-2-amine derivative of the present invention, as a pharmaceutically acceptable salt, 4- Substituted-N-(1-substituted-1H-pyrazol-4-yl)-5-morpholinopyrimidin-2-amine derivative 4-substituted-N-(1- Any salt of a substituted-1H-pyrazol-4-yl)-5-morpholinopyrimidin-2-amine derivative may be used without limitation.

As another aspect, the present invention provides a health functional food composition for preventing or improving JAK3-related diseases comprising the compound represented by Formula 1 or a food pharmaceutically acceptable salt thereof as an active ingredient.

At this time, the "JAK3-related disease" and "prevention" are the same as described above.

The term "improvement" of the present invention may mean any action that at least reduces the severity of a parameter related to the condition being treated, for example a symptom.

Food includes all foods in the usual sense.

Since the food composition of the present invention can be consumed on a daily basis, high effects on the prevention or improvement of JAK3-related diseases can be expected, and thus can be very usefully used for health promotion purposes.

Functional food is the same term as food for special health use (FoSHU), and is a food with high medical and medical effects processed so that the bioregulatory function is effectively displayed in addition to nutrition supply. Means. Here, the term'function (sex)' means to control nutrients for the structure and function of the human body or to obtain useful effects for health purposes such as physiological actions.

The health food refers to a food having an active health maintenance or promotion effect compared to general food, and a health supplement food refers to a food for health supplement purposes. In some cases, the terms health functional food, health food, and health supplement food are used interchangeably.

In addition, the health functional food may include additional ingredients that are commonly used in food compositions to improve smell, taste, vision, and the like. In addition, the food composition may include food additives such as preservatives, disinfectants, antioxidants, coloring agents, coloring agents, bleaching agents, seasonings, sweeteners, flavoring agents, expanding agents, reinforcing agents, emulsifying agents, thickening agents, coating agents, gum base agents, foam inhibitors, solvents, and improving agents ( food additives). The additive may be selected according to the type of food and used in an appropriate amount.

As an example of the food composition of the present invention, it may be used as a health drink composition, and in this case, it may contain various flavoring agents or natural carbohydrates, etc. as an additional ingredient, such as a conventional beverage.

In addition to the above, health beverage compositions include various nutrients, vitamins, electrolytes, flavoring agents, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, It may contain alcohol or a carbonation agent. In addition, it may contain flesh for the manufacture of natural fruit juice, fruit juice beverage, or vegetable beverage.

As another aspect, the present invention comprises the step of administering to an individual a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, prevention of JAK3-related diseases or Provide treatment methods.

The term "individual" of the present invention refers to monkeys, cattle, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, mice, rabbits, or guineas, including humans in which the JAK3-related disease is invented or may develop. It means all animals including pigs, and the above diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to an individual. The pharmaceutical composition of the present invention can be administered in combination with an existing therapeutic agent.

The term "administration" of the present invention means providing a predetermined substance to a patient by any suitable method, and the route of administration of the composition of the present invention can be administered through any general route as long as it can reach the target tissue. have. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration, but are not limited thereto. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to target cells. Preferred modes of administration and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drop injections and the like. Injectables include aqueous solvents such as physiological saline solution and ring gel solution, non-aqueous solvents such as vegetable oils, higher fatty acid esters (e.g., oleic acid ethyl, etc.), alcohols (e.g. ethanol, benzyl alcohol, propylene glycol, glycerin, etc.). It can be prepared by using, and stabilizers for preventing deterioration (e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH control, and for inhibiting the growth of microorganisms. Pharmaceutical carriers such as preservatives (eg, mercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.

The term "therapeutically effective amount" used in combination with an active ingredient in the present invention refers to 4-substituted-N-(1-substituted-1H-pyrazol-4-yl)-5- which is effective in preventing or treating a target disease. It means an amount of a morpholinopyrimidin-2-amine derivative compound, or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition of the present invention is 4-substituted-N-(1-substituted-1H-pyrazol-4-yl)-5-morpholinopyrimidine- as an active ingredient, depending on the type of disease to be prevented or treated. It may further include a known drug used for the prophylaxis or treatment of each known disease other than the 2-amine derivative compound, or a pharmaceutically acceptable salt thereof. For example, 4-substituted-N-(1-substituted-1H-pyrazol-4-yl)-5-morpholinopyrimidin-2-amine derivative compound as an active ingredient when used for the prevention or treatment of cancer diseases, Or it may further include a known anticancer agent in addition to its pharmaceutically acceptable salt, and may be used in combination with other known treatments for the treatment of these diseases. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological therapy, immunotherapy, and the like.

As another aspect, the present invention is BLK, BMX, BTK, EGFR, EGFR (E746-A750del), EGFR (L747-E749del) comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. , A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R,T790M), EGFR(L861Q), EGFR(T790M), ERBB2, ERBB4, FLT3( D835V), GSK3B, ITK, JAK3 (JH1domain-catalytic), KIT (L576P), KIT (V559D), TEC, TXK, or TYK2 (JH2domain-pseudokinase) provides a composition for inhibition.

In a specific example of the present invention, as representative compounds according to the present invention, compounds 2, 6, 22 and 28 were selected to confirm inhibitory activity against a total of 460 kinases (including mutations) from AAK1 to ZAP70. As a result, at least one of the four compounds is BLK, BMX, BTK, EGFR, EGFR (E746-A750del), EGFR (L747-E749del, A750P), EGFR (L747-S752del, P753S), EGFR (L747- T751del,Sins), EGFR(L858R), EGFR(L858R,T790M), EGFR(L861Q), EGFR(T790M), ERBB2, ERBB4, FLT3(D835V), GSK3B, ITK, JAK3(JH1domain-catalytic), KIT(L576P ), KIT (V559D), TEC, TXK, or TYK2 (JH2domain-pseudokinase) was shown to have inhibitory activity, indicating that these compounds can be usefully used as inhibitors of the enzymes.

The novel 4-substituted-N-(1-substituted-1H-pyrazol-4-yl)-5-morpholinopyrimidin-2-amine derivative of the present invention inhibits the activity of JAK3 and prevents the mutation of JAK3. As a result, it may inhibit the proliferation of overexpressed cells, and thus may be usefully used in the treatment or prevention of diseases caused by abnormal expression or excessive activity of JAK3.

Hereinafter, the configuration and effects of the present invention will be described in more detail through examples. These examples are for illustrative purposes only, and the scope of the present invention is not limited by these examples.

Commercially available reagents used were those purchased without further purification. In the present invention, room temperature refers to a temperature of 20 to 25°C, and concentration or solvent distillation under reduced pressure was performed using a rotary evaporator.

<Method and conditions for analysis and purification>

In the present invention, a series of compounds synthesized from the examples were synthesized, purified by the following method, and the structure was analyzed.

1. For purification Medium pressure liquid chromatography (Medium Pressure Liquid Chromatography; MPLC)

Medium-pressure liquid chromatography was performed using CombiFlash Rf+UV from TELEEDYNE ISCO.

2. For analysis High performance liquid chromatography (High Performance Liquid Chromatography; HPLC ) Condition

Waters' UPLC system (ACQUITY UPLC PDA Detector) was analyzed using a device equipped with a Mass QDA detector. The column used was ACQUITY UPLC ^® BEH C18 (1.7 μm, 2.1×50 mm) manufactured by Waters, and the column temperature was set to 30°C. Water containing 0.1% formic acid was used as mobile phase A, and acetonitrile containing 0.1% formic acid was used as mobile phase B. The gradient conditions were 10-100% B for 3 minutes, and the moving speed was 0.6 mL/minute.

3. Prep- for purification LCMS (Preparative-Liquid chromatography mass spectrometry)

Waters' Autopurification HPLC system (2767 sample manager, 2545 binary gradient module, 2998 Photodiode Array Detector) was equipped with a Mass QDA detector to purify the compound. The column used was SunFire ^® Prep C18 OBDTM (5 μm, 19×50 mm) manufactured by Waters, and the column temperature was maintained at room temperature. Water containing 0.035% trifluoroacetic acid was used as mobile phase A, and methanol containing 0.035% trifluoroacetic acid was used as mobile phase B. The gradient conditions were 15-100% B for 10 minutes, and the moving speed was 25 mL/minute.

4. Prep-150 LC system for purification (Preparative-Liquid chromatography UV spectrometry)

The compound was purified using Waters' Prep 150 LC system (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector III). The column used was XTERRA ^® Prep RP18 OBDTM (10 μm, 30×300 mm) manufactured by Waters, and the column temperature was maintained at room temperature. Water containing 0.035% trifluoroacetic acid was used as mobile phase A, and methanol containing 0.035% trifluoroacetic acid was used as mobile phase B. The gradient conditions were 3-100% B for 120 minutes, and the moving speed was 40 mL/minute.

5. NMR analysis

The NMR spectrum was recorded and analyzed using Bruker's AVANCEIII400 or AVANCEIII 400 HD, and the acquired data were expressed in ppm (parts per million, δ).

Example 1: N-(3-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)phenyl)acrylamide (compound 1) of Produce

Step 1- 1: 5 - Morpholinopyrimidine -2,4( 1H,3H )- Dion's Produce

After adding 5-bromouracil (12.0 g, 62.8 mmol) to morpholine (108.0 mL, 1.24 mol), it was reacted by heating at 100°C for 10 minutes by irradiating with microwaves, and then lowering the temperature. The reaction was finished. The resulting suspension was diluted with methanol and then filtered to obtain the target compound (11.0 g, 89%).

MS (m/z): 198.2 [M+1] ⁺ ;

UPLC r.t. (min): 0.38.

Step 1- 2: 4 -(2,4- Dichloropyrimidine Preparation of -5-yl)morpholine

5-morpholinopyrimidine-2,4(1H,3H)-dione obtained in step 1-1 of Example 1 -2,4(1H,3H)-dione, 12.0 g, 60.9 mmol) trienylamine hydrochloride (25.1 g, 182.4 mmol) and POCl ₃ (40 mL) were added, and the mixture was stirred at 80° C. for 4 days, and the mixture was stirred and refluxed for the last 3 hours. After the reaction was cooled to room temperature, excess POCl ₃ was concentrated under reduced pressure and added to ice water to precipitate a product. The resulting solid was dissolved in an excess of ethyl acetate and washed with saturated NaHCO ₃ solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (7.0 g, 50%).

MS (m/z): 234.1 [M+1] ⁺ ;

UPLC r.t. (min): 1.57.

Step 1- 3: 2 - Chloro -5- Morpholino -N-(3- Nitrophenyl ) Pyrimidine-4- Amine Produce

3- diluted in DMF/DMSO mixed solution (9/1 mixing ratio) to the suspension of sodium hydride (60%, 228.0 mg, 5.70 mmol) in the DMF/DMSO mixed solution (9/1 mixing ratio) Nitroaniline (794.5 mg, 3.98 mmol) was slowly added dropwise. After stirring the reaction mixture at 0° C. for 30 minutes, 4-(2,4-dichloropyrimidin-5-yl)morpholine (1.4 g, 5.98 mmol) obtained in step 1-2 of Example 1 Was diluted in a DMF/DMSO mixed solution (9/1 mixing ratio) and slowly added dropwise to the reaction mixture. The reaction mixture was added dropwise to ice water at 0° C. to terminate the reaction, and the resulting solid was filtered to obtain the target compound (1.2 g, 84%) as a brown solid.

MS (m/z): 336.2 [M+1] ⁺ ;

UPLC r.t. (min): 1.67.

Step 1-4: N ^One -(2- Chloro -5- Morpholinopyrimidine -4-yl)benzene-1,3- Diamine Produce

2-chloro-5-morpholino-N-(3-nitrophenyl)pyrimidin-4-amine (2-chloro-5-morpholino-N-(3-) obtained in step 1-3 of Example 1 After dissolving nitrophenyl)pyrimidin-4-amine, 0.5 g, 1.49 mmol) and SnCl ₂ ·2H ₂ O (3.36 g, 14.9 mmol) in ethyl acetate (35 mL), the mixture was stirred at 60° C. for 5 hours. After lowering the temperature of the reaction solution to room temperature, an aqueous ammonia solution was added dropwise until the pH reached 5. Furthermore, the pH was adjusted to 7 by adding solid anhydrous sodium hydrogen carbonate to the reaction mixture. The reaction mixture was filtered through celite and washed several times with ethyl acetate. The obtained filtrate was concentrated under reduced pressure to obtain the target compound (225.0 mg, 50%), which was used in the next reaction without further purification.

MS (m/z): 306.2 [M+1] ⁺ ;

UPLC r.t. (min): 1.04.

Step 1-5: N-(3-(2- Chloro -5- Morpholinopyrimidine -4- One amino )Phenyl) Of acrylamide Produce

Obtained in steps 1-4 of Example ¹ N 1 - (2- chloro-5-morpholino-4-yl) benzene-1,3-diamine ^{(N 1 - (2-chloro} -5 -morpholinopyrimidin-4-yl)benzene-1,3-diamine, 225 mg, 0.74 mmol) was dissolved in THF (6 mL), saturated NaHCO ₃ (6 mL) was added, and acryloyl chloride ( acryloyl chloride, 0.6 mL, 7.40 mmol) was slowly added dropwise. After vigorously stirring at the same temperature for 10 minutes, extraction was performed using ethyl acetate and distilled water, and dried over sodium sulfate. After the filtrate was concentrated under reduced pressure, medium pressure liquid chromatography (silica gel, hexane:ethyl acetate = 20:1) was used to obtain the target compound (192.0 mg, 76%).

MS (m/z): 360.3 [M+1] ⁺ ;

UPLC r.t. (min): 1.58.

Step 1-6: N-(3-(2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine Preparation of -4-ylamino)phenyl)acrylamide trifluoroacetate

N-(3-(2-chloro-5-morpholinopyrimidin-4-ylamino)phenyl)acrylamide (N-(3-(2-chloro-) obtained in step 1-5 of Example 1) 5-morpholinopyrimidin-4-ylamino)phenyl)acrylamide, 50.0 mg, 0.14 mmol), 1-methyl-1H-pyrazol-4-amine (20.4 mg, 0.21 mmol) and K ₂ CO ₃ (20.4 mg, 0.70 mmol) Was dissolved in sec-BuOH (3.0 mL), and sonicated under nitrogen for 10 minutes to remove gas. Pd ₂ (dba) ₃ (12.8 mg, 0.01 mmol) and Xphos (Xphos, 6.7 mg, 0.01 mmol) were added to the reaction mixture, followed by reaction at 100° C. for 2 hours. The reaction mixture was filtered through celite and washed with dichloromethane. After the obtained filtrate was concentrated, the target compound (32.7 mg, 44%) was obtained in the form of trifluoroacetate using an autopurification LC-MS purifier.

MS (m/z): 421.4[M+1] ⁺ ;

UPLC r.t. (min): 1.17.

Example 2: N-(3-((2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)methyl)phenyl)acrylamide (Compound 5) Manufacture of

Step 2- 1: 2 - Chloro -5- Morpholino -N-(3- Nitrobenzyl ) Pyrimidine-4- Amine Produce

4-(2,4-dichloropyrimidin-5-yl)morpholine (1 g, 4.27 mmol) and (3-nitrophenyl) methanamine (780 mg, obtained in step 1-2 of Example 1) 5.13 mmol) was dissolved in 1,4-dioxane (25 mL) and stirred. After diisopropylethylamine (2.24 mL, 12.82 mmol) was added dropwise to the reaction mixture, it was gradually warmed to 100° C. and stirred overnight. The reaction mixture was extracted with ethyl acetate and distilled water, and then dried over sodium sulfate. The filtrate was concentrated under reduced pressure, and the target compound (1.28 g, 86%) was obtained using medium pressure liquid chromatography (silica gel, hexane:ethyl acetate = 20:1).

MS (m/z): 350.2 [M+1] ⁺ ;

UPLC r.t. (min): 1.65.

Step 2-2: N-(3- Aminobenzyl )-2- Chloro -5- Morpholinopyrimidine -4- Amine Produce

2-chloro-5-morpholino-N-(3-nitrobenzyl)pyrimidin-4-amine (2-chloro-5-morpholino-N-(3-) obtained in step 2-1 of Example 2 nitrobenzyl)pyrimidin-4-amine, 1.03 g, 2.94 mmol) and SnCl ₂ ·2H ₂ O (6.64 g, 29.4 mmol) were dissolved in ethyl acetate (25 mL), followed by stirring at 50° C. for 5 hours. After lowering the temperature of the reaction solution to room temperature, an aqueous ammonia solution was added dropwise until the pH reached 5. Furthermore, the pH was adjusted to 7 by adding solid anhydrous sodium hydrogen carbonate to the reaction mixture. The reaction mixture was filtered through celite and washed several times with ethyl acetate. The obtained filtrate was concentrated under reduced pressure to obtain the target compound (942.0 mg, 98%), which was used in the next reaction without further purification.

MS (m/z): 320.2[M+1] ⁺ ;

UPLC r.t. (min): 1.09.

Step 2-3: N-(3-((2- Chloro -5- Morpholinopyrimidine -4- One amino ) methyl )Phenyl) Of acrylamide Produce

N-(3-aminobenzyl)-2-chloro-5-morpholinopyrimidin-4-amine (N-(3-aminobenzyl)-2-chloro-5 obtained in step 2-2 of Example 2 above -morpholinopyrimidin-4-amine, 924.0 mg, 2.78 mmol) was dissolved in THF (22.5 mL), saturated NaHCO ₃ (22.5 mL) was added, and acryloyl chloride (0.704 mL, 8.67 mmol) was slowly added at 0°C. Added dropwise. After vigorously stirring at the same temperature for 10 minutes, extraction was performed using ethyl acetate and distilled water, and dried over sodium sulfate. After the filtrate was concentrated under reduced pressure, medium pressure liquid chromatography (silica gel, hexane:ethyl acetate = 20:1) was used to obtain the target compound (77.1 mg, 71.4%).

MS (m/z): 374.2 [M+1] ⁺ ;

UPLC r.t. (min): 1.41.

Step 2-4: N-(3-((2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine Preparation of -4-ylamino)methyl)phenyl)acrylamide trifluoroacetate

N-(3-((2-chloro-5-morpholinopyrimidin-4-ylamino)methyl)phenyl)acrylamide obtained in step 2-3 of Example 2 (N-(3-(( 2-chloro-5-morpholinopyrimidin-4-ylamino)methyl)phenyl)acrylamide, 50.0 mg, 0.134 mmol), 1-methyl-1H-pyrazol-4-amine (21.8 mg, 0.225 mmol) and K ₂ CO ₃ ( 129.0 mg, 0.936 mmol) was dissolved in sec-BuOH (3.0 mL) and then sonicated under nitrogen for 10 minutes to remove gas. Pd ₂ (dba) ₃ (17.1 mg, 0.019 mmol) and expos (8.9 mg, 0.019 mmol) were added to the reaction mixture, followed by reaction at 100° C. for 2 hours. The reaction mixture was filtered through celite and washed with dichloromethane. The obtained filtrate was concentrated and purified by Prep-HPLC to obtain the target compound (48.7 mg, 47.4%) in the form of a solid trifluoroacetate.

MS (m/z): 435.3 [M+1] ⁺ ;

UPLC r.t. (min): 1.05.

Example 3: (S)-1-(3-(2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine Preparation of -4-ylamino)piperidin-1-yl)prop-2-en-1-one (Compound 13)

Step 3-1: (S)- tert -Butyl 3-(2- Chloro -5- Morpholinopyrimidine -4- One amino ) Preparation of piperidine-1-carboxylate

4-(2,4-dichloropyrimidin-5-yl)morpholine (5.0 g, 21.26 mmol) obtained in step 1-2 of Example 1, tert-butyl (S)-3-aminopiperi After dissolving din-1-carboxylate (4.7 g, 23.50 mmol) and triethylamine (4.5 mL, 32.0 mmol) in ethanol (107 mL), the reaction mixture was stirred at 80° C. overnight. After removing the solvent of the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was recovered. The obtained organic layer was washed with brine and dried over sodium sulfate. After the filtrate was concentrated under reduced pressure, medium pressure liquid chromatography (silica gel, hexane:ethyl acetate = 20:1) was used to obtain the target compound (6.0 g, 71%).

MS (m/z): 398.3[M+1] ⁺ ;

UPLC r.t. (min): 1.66.

Step 3-2: (S)-2- Chloro -5- Morpholino -N-(piperidin-3-yl)pyrimidin-4- Amine Produce

(S)-tert-butyl 3-(2-chloro-5-morpholinopyrimidin-4-ylamino)piperidine-1-carboxylate obtained in step 3-1 of Example 3 (( S)-tert-butyl 3-(2-chloro-5-morpholinopyrimidin-4-ylamino)piperidine-1-carboxylate, 3.0 g, 7.54 mmol) was dissolved in DCM (50 mL), and then trifluoroacetic acid (5.8 mL, 75.0 mmol) was slowly added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure to obtain the target compound (2.0 g, 64%), which was used in the next reaction without further purification.

MS (m/z): 298.2 [M+1] ⁺ ;

UPLC r.t. (min): 0.83.

Step 3-3: (S)-1-(3-(2- Chloro -5- Morpholinopyrimidine -4- One amino ) Piperidin-1-yl) prop-2-en-1-one preparation

(S)-2-chloro-5-morpholino-N-(piperidin-3-yl)pyrimidin-4-amine ((S)-2- obtained in step 3-2 of Example 3 above. After dissolving chloro-5-morpholino-N-(piperidin-3-yl)pyrimidin-4-amine, 2.0 g, 4.86 mmol) in THF (20 mL), saturated NaHCO ₃ (20 mL) was added, and 0°C Acryloyl chloride (0.789 mL, 9.71 mmol) was slowly added dropwise. After vigorously stirring at the same temperature for 10 minutes, extraction was performed using ethyl acetate and distilled water, and dried over sodium sulfate. After the filtrate was concentrated under reduced pressure, medium pressure liquid chromatography (silica gel, hexane:ethyl acetate = 20:1) was used to obtain the target compound (1 g, 58.5%).

MS (m/z): 352.2[M+1] ⁺ ;

UPLC r.t. (min): 1.29.

Step 3-4: (S)-1-(3-(2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-ylamino)piperidin-1-yl)prop-2-en-1-one Of trifluoroacetate Produce

(S)-1-(3-(2-chloro-5-morpholinopyrimidin-4-ylamino)piperidin-1-yl)prop- obtained in step 3-3 of Example 3- 2-en-1-one ((S)-1-(3-(2-chloro-5-morpholinopyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one, 50.0 mg, 0.134 mmol), 1-methyl-1H-pyrazol-4-amine (20.7 mg, 0.213 mmol) and K ₂ CO ₃ (98.0 mg, 0.711 mmol) were dissolved in sec-BuOH (3.0 mL), followed by 10 The gas was removed by sonication for minutes. Pd ₂ (dba) ₃ (13.0 mg, 0.014 mmol) and expos (6.8 mg, 0.014 mmol) were added to the reaction mixture, followed by reaction at 100° C. for 2 hours. The reaction mixture was filtered through celite and washed with dichloromethane. The obtained filtrate was concentrated and then purified by Prep-HPLC to obtain the target compound (41.0 mg, 54.8%) in the form of a solid trifluoroacetate.

MS (m/z): 433.3[M+1] ⁺ ;

UPLC r.t. (min): 0.97.

Example 4: Preparation of N-(3-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide (Compound 19)

Step 4- 1: 3 -Preparation of aminophenol

After dissolving 3-nitrophenol (5.0 g, 35.9 mmol) in methanol (30 mL), Pd/C (0.5 g) was added, and a hydrogen balloon was attached, followed by stirring at room temperature for 12 hours. The reaction mixture was filtered through celite to remove solids, and the filtrate was concentrated under reduced pressure to obtain the target compound (4.0 g, 100%), which was used in the next reaction without further purification.

MS (m/z): 110.2[M+1] ⁺ ;

UPLC r.t. (min): 0.22.

Step 4-2: N-(3- Hydroxyphenyl ) Of acrylamide Produce

After dissolving 3-aminophenol (3-aminophenol, 580 mg, 5.30 mmol) obtained in step 4-1 of Example 4 in THF (5 mL), saturated NaHCO ₃ (5 mL) was added, and 0° C. Acryloyl chloride (4.3 mL, 53.0 mmol) was slowly added dropwise. After vigorously stirring at the same temperature for 10 minutes, extraction was performed using ethyl acetate and distilled water, and dried over sodium sulfate. After the filtrate was concentrated under reduced pressure, medium pressure liquid chromatography (silica gel, dichloromethane:methanol = 15:1) was used to obtain the target compound (500.0 mg, 60%).

MS (m/z): 164.2 [M+1] ⁺ ;

UPLC r.t. (min): 1.06.

Step 4-3: N-(3-(2- Chloro -5- Morpholinopyrimidine -4- Oxy )Phenyl) Of acrylamide Produce

To the suspension of sodium hydroxide (60%, 105.0 mg, 4.39 mmol) added to the DMF/DMSO mixed solution (9/1 mixing ratio) at 0° C., N-(3- Hydroxyphenyl) acrylamide (N-(3-hydroxyphenyl)acrylamide, 357.0 mg, 2.19 mmol) was diluted in a DMF/DMSO mixed solution (9/1 mixing ratio) and slowly added dropwise. After stirring the reaction mixture at 0° C. for 30 minutes, 4-(2,4-dichloropyrimidin-5-yl)morpholine (500 mg, 2.19 mmol) obtained in step 1-2 of Example 1 Was diluted in a DMF/DMSO mixed solution (9/1 mixing ratio) and slowly added dropwise to the reaction mixture. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was terminated by adding saturated aqueous NH ₄ Cl solution to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was recovered, washed with brine, and water was removed with magnesium sulfate to obtain the target compound (680 mg, 86%). The residue was used in the next reaction without further purification.

MS (m/z): 361.2 [M+1] ⁺ ;

UPLC r.t. (min): 1.47.

Step 4-4: N-(3-(2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-yloxy)phenyl)acrylamide Of trifluoroacetate Produce

N-(3-(2-chloro-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide (N-(3-(2-chloro-) obtained in step 4-3 of Example 4) 5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide, 20.0 mg, 0.06 mmol), 4-(4-methylpiperazin-1yl) aniline (8.0 mg, 0.08 mmol) and K ₂ CO ₃ (38.0 mg, 0.30 mmol) ) Was dissolved in sec-BuOH (3.0 mL), and then sonicated for 10 minutes under nitrogen to remove gas. Pd ₂ (dba) ₃ (5.0 mg, 0.006 mmol) and expos (3.0 mg, 0.006 mmol) were added to the reaction mixture, and then reacted at 100° C. for 2 hours. The reaction mixture was filtered through celite and washed with dichloromethane. The obtained filtrate was concentrated and purified by Prep-HPLC to obtain the target compound (15.0 mg, 51%) in the form of solid trifluoroacetate.

MS (m/z): 422.4[M+1] ⁺ ;

UPLC r.t. (min): 1.24.

Example 5: N- (3- (2-(1-(2-( Dimethylamino )Ethyl)-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide (Compound 20)

Step 5- 1: 4 -(2- Chloro -4-(3- Nitrophenoxy ) Preparation of pyrimidine-5-yl) morpholine

After dissolving 4-(2,4-dichloropyrimidin-5-yl)morpholine (1.0 g, 4.27 mmol) obtained in step 1-2 of Example 1 in THF (30 mL), 0°C Sodium hydride (60%, 342.0 mg, 8.54 mmol) and 3-nitrophenol (713.0 mg, 5.13 mmol) were added dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. After the reaction was terminated by adding water to the reaction mixture, extraction was performed with ethyl acetate and distilled water. The organic layer was recovered and dried over magnesium sulfate to obtain the target compound (900 mg, 63%).

MS (m/z): 337.1 [M+1] ⁺ ;

UPLC r.t. (min): 1.59.

Step 5- 2: 3 -(2- Chloro -5- Morpholinopyrimidine -4- Oxy ) Preparation of aniline

4-(2-chloro-4-(3-nitrophenoxy)pyrimidin-5-yl)morpholine (4-(2-chloro-4-(3-) obtained in step 5-1 of Example 5) nitrophenoxy)pyrimidin-5-yl)morpholine, 930 mg, 2.76 mmol) and SnCl ₂ ·2H ₂ O (6.2 g, 27.6 mmol) were dissolved in ethyl acetate (30 mL), and then stirred at 60° C. for 5 hours. . After lowering the temperature of the reaction solution to room temperature, an aqueous ammonia solution was added dropwise until the pH reached 5. Furthermore, the pH was adjusted to 7 by adding solid anhydrous sodium hydrogen carbonate to the reaction mixture. The reaction mixture was filtered through celite and washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the target compound (800 mg, 94%), which was used in the next reaction without further purification.

MS (m/z): 307.1 [M+1] ⁺ ;

UPLC r.t. (min): 1.28.

Step 5-3: N-(3-(2- Chloro -5- Morpholinopyrimidine -4- Oxy )Phenyl) Of acrylamide Produce

3-(2-chloro-5-morpholinopyrimidin-4-yloxy)aniline obtained in step 5-2 of Example 5 (3-(2-chloro-5-morpholinopyrimidin-4-yloxy)aniline , 870 mg, 2.84 mmol) was dissolved in THF (7 mL), saturated NaHCO ₃ (7 mL) was added, and acryloyl chloride (1.2 mL, 14.23 mmol) was slowly added dropwise at 0°C. After vigorously stirring at the same temperature for 10 minutes, extraction was performed using ethyl acetate and distilled water, and dried over sodium sulfate. After the filtrate was concentrated under reduced pressure, medium pressure liquid chromatography (silica gel, hexane: ethyl acetate = 20: 1) was used to obtain the target compound (940.0 mg, 92%).

MS (m/z): 361.2 [M+1] ⁺ ;

UPLC r.t. (min): 1.45.

Step 5-4: N-(3-(2-(1-(2-( Dimethylamino )Ethyl)-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide Of trifluoroacetate Produce

N-(3-(2-chloro-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide (N-(3-(2-chloro-) obtained in step 5-3 of Example 5) 5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide, 60.0 mg, 0.15 mmol), 1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-amine (30.8 mg, 0.20 mmol) and K ₂ CO ₃ (115.0 mg, 0.83 mmol) was dissolved in sec-BuOH (3.0 mL), and then sonicated under nitrogen for 10 minutes to remove gas. Pd ₂ (dba) ₃ (15.2 mg, 0.02 mmol) and expos (7.9 mg, 0.02 mmol) were added to the reaction mixture, and then reacted at 100° C. for 2 hours. The reaction mixture was filtered through celite and washed with dichloromethane. The obtained filtrate was concentrated and purified by Prep-HPLC to obtain the target compound (84.9 mg, 86%) in the form of trifluoroacetate.

MS (m/z): 479.3 [M+1] ⁺ ;

UPLC r.t. (min): 1.02.

Example 6: Preparation of N-(4-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide (Compound 21)

Step 6- 1: 4 -(2- Chloro -4-(4- Nitrophenoxy ) Preparation of pyrimidine-5-yl) morpholine

The 4- Nitrophenol (495.0 mg, 3.56 mmol) was slowly added dropwise. After stirring the reaction mixture at 0° C. for 30 minutes, 4-(2,4-dichloropyrimidin-5-yl)morpholine (1.0 g, 4.27 mmol) obtained in step 1-2 of Example 1 Was diluted in a DMF/DMSO mixed solution (9/1 mixing ratio) and slowly added dropwise to the reaction mixture. The reaction mixture was slowly warmed to room temperature and stirred overnight. Ice water was added dropwise to the reaction mixture at 0° C. to terminate the reaction, and the resulting solid was filtered to obtain the target compound (0.9 g, 75%) in the form of a brown solid.

MS (m/z): 337.1 [M+1] ⁺ ;

UPLC r.t. (min): 1.58.

Step 6- 2: 4 -(2- Chloro -5- Morpholinopyrimidine -4- Oxy ) Preparation of aniline

4-(2-chloro-4-(4-nitrophenoxy)pyrimidin-5-yl)morpholine (4-(2-chloro-4-(4-) obtained in step 6-1 of Example 6) nitrophenoxy)pyrimidin-5-yl)morpholine, 900 mg, 2.76 mmol) and SnCl ₂ ·2H ₂ O (6.03 g, 26.7 mmol) were dissolved in ethyl acetate (30 mL), and then stirred at 60° C. for 5 hours. . After lowering the temperature of the reaction solution to room temperature, an aqueous ammonia solution was added dropwise until the pH reached 5. Furthermore, solid anhydrous sodium hydrogen carbonate was added to the reaction mixture to adjust the pH to 7. The reaction mixture was filtered through celite and washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the target compound (850 mg, 85%), which was used in the next reaction without further purification.

MS (m/z): 307.1 [M+1] ⁺ ;

UPLC r.t. (min): 0.91.

Step 6-3: N-(4-(2- Chloro -5- Morpholinopyrimidine -4- Oxy )Phenyl) Of acrylamide Produce

4-(2-chloro-5-morpholinopyrimidin-4-yloxy)aniline (4-(2-chloro-5-morpholinopyrimidin-4-yloxy)aniline obtained in step 6-2 of Example 6 , 611 mg, 1.99 mmol) was dissolved in THF (7 mL), saturated NaHCO ₃ (7 mL) was added, and acryloyl chloride (1.61 mL, 19.92 mmol) was slowly added dropwise at 0°C. After vigorously stirring at the same temperature for 10 minutes, extraction was performed using ethyl acetate and distilled water, and dried over sodium sulfate. After the filtrate was concentrated under reduced pressure, medium pressure liquid chromatography (silica gel, hexane:ethyl acetate = 20:1) was used to obtain the target compound (640.0 mg, 89%).

MS (m/z): 361.1 [M+1] ⁺ ;

UPLC r.t. (min): 1.36.

Step 6-4: N-(4-(2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-yloxy)phenyl)acrylamide Of trifluoroacetate Produce

N-(4-(2-chloro-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide (N-(4-(2-chloro-) obtained in step 6-3 of Example 6 5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide, 60.0 mg, 0.17 mmol), 4-(4-methylpiperazin-1-yl)aniline (19.38 mg, 0.20 mmol) and K ₂ CO ₃ (115.0 mg, 0.83 mmol) was dissolved in sec-BuOH (3.0 mL), and then sonicated under nitrogen for 10 minutes to remove gas. Pd ₂ (dba) ₃ (15.2 mg, 0.02 mmol) and expos (7.9 mg, 0.02 mmol) were added to the reaction mixture, and then reacted at 100° C. for 2 hours. The reaction mixture was filtered through celite and washed with dichloromethane. The obtained filtrate was concentrated and purified by Prep-HPLC to obtain the target compound (67.5 mg, 76%) in the form of trifluoroacetate.

MS (m/z): 422.3[M+1] ⁺ ;

UPLC r.t. (min): 1.13.

Example 7: N-(3-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yl)phenyl)acrylamide (compound 34) of Produce

Step 7- 1: 4 -(2- Chloro -4-(3- Nitrophenyl ) Preparation of pyrimidine-5-yl) morpholine

4-(2,4-dichloropyrimidin-5-yl)morpholine (1.0 g, 4.27 mmol) and (3-nitrophenyl) boronic acid (784 mg, obtained in step 1-2 of Example 1) 4.70mmol) was dissolved in 1,4-dioxane (39 mL), 1M Na ₂ CO ₃ (12.8 mL, 12.82 mmol) was added, followed by sonication under nitrogen for 10 minutes to remove gas. Pd(PPh ₃ ) ₄ (tetrakis(triphenylphosphine) palladium(0), 494 mg, 0.43 mmol) was added to the reaction mixture, followed by stirring at 80°C. After reacting for 3 hours, it was cooled to room temperature and the reaction was diluted with EtOAc. The organic layer was washed sequentially with a saturated aqueous NaHCO ₃ solution and brine, and then residual moisture was removed with sodium sulfate. The reaction mixture was concentrated under reduced pressure and purified by MPLC (dichloromethane/methanol) to obtain the title compound (1.2 g, 88%).

MS (m/z): 321.1 [M+1] ⁺ ;

UPLC r.t. (min): 1.65.

Step 7- 2: 3 -(2- Chloro -5- Morpholinopyrimidine Preparation of -4-yl)aniline

4-(2-chloro-4-(3-nitrophenyl)pyrimidin-5-yl)morpholine (4-(2-chloro-4-(3-nitrophenyl) obtained in step 7-1 of Example 7) )pyrimidin-5-yl)morpholine, 1.2 g, 3.74 mmol) and SnCl ₂ ·2H ₂ O (8.44 g, 37.4 mmol) were dissolved in ethyl acetate (30 mL), then a drop of concentrated hydrochloric acid was added dropwise, and 50°C The mixture was stirred for 5 hours. After lowering the temperature of the reaction solution to room temperature, an aqueous ammonia solution was added dropwise until the pH reached 5. Furthermore, the pH was adjusted to 7 by adding solid anhydrous sodium hydrogen carbonate to the reaction mixture. The reaction mixture was filtered through celite and washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the target compound (626 mg, 57.5%), which was used in the next reaction without further purification.

MS (m/z): 291.1 [M+1] ⁺ ;

UPLC r.t. (min): 1.09.

Step 7-3: N-(3-(2- Chloro -5- Morpholinopyrimidine -4-yl)phenyl) Of acrylamide Produce

3-(2-chloro-5-morpholinopyrimidin-4-yl)aniline (3-(2-chloro-5-morpholinopyrimidin-4-yl)aniline obtained in step 7-2 of Example 7, 600 mg, 2.064 mmol) was dissolved in THF (7 mL), saturated NaHCO ₃ (7 mL) was added, and acryloyl chloride (934 mg, 10.32 mmol) was slowly added dropwise at 0°C. After vigorously stirring at the same temperature for 10 minutes, extraction was performed using ethyl acetate and distilled water, and dried over sodium sulfate. The obtained residue was purified by medium pressure liquid chromatography (silica gel, DCM: methanol = 15:1) to obtain the target compound (500.0 mg, 70.3%).

MS (m/z): 345.1 [M+1] ⁺ ;

UPLC r.t. (min): 1.45.

Step 7-4: N-(3-(2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-yl)phenyl)acrylamide Of trifluoroacetate Produce

N-(3-(2-chloro-5-morpholinopyrimidin-4-yl)phenyl)acrylamide (N-(3-(2-chloro-5) obtained in step 7-3 of Example 7) -morpholinopyrimidin-4-yl)phenyl)acrylamide, 50.0 mg, 0.17 mmol), 4-(4-methylpiperazin-1-yl)aniline (16.9 mg, 0.17 mmol) and K ₂ CO ₃ (100.0 mg, 0.72 mmol) ) Was dissolved in sec-BuOH (3.0 mL), and then sonicated for 10 minutes under nitrogen to remove gas. Pd ₂ (dba) ₃ (13.28 mg, 0.01 mmol) and expos (6.91 mg, 0.01 mmol) were added to the reaction mixture, followed by reaction at 100° C. for 2 hours. The reaction mixture was filtered through celite and washed with dichloromethane. The obtained filtrate was concentrated and purified by Prep-HPLC to obtain the target compound (10.0 mg, 17%) in the form of a solid trifluoroacetate.

MS (m/z): 406.3[M+1] ⁺ ;

UPLC r.t. (min): 1.29.

Hereinafter, a series of 4-substituted-N-(1-substituted-1H-pyrazol-4-yl)-5-morpholino by selecting an appropriate reactant and reacting according to Examples 1 to 7 or in a similar manner It was synthesized in the form of a pyrimidine-2-amine derivative compound or a trifluoroacetate salt thereof, and these compounds were identified through MS (m/z), NMR, yield and/or UPLC analysis, and the results are shown below with the structural formula It is shown in summary.

Compound 1: N-(3-(2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-ylamino)phenyl)acrylamide trifluoroacetate

MS (m/z): 421.4[M+1] ⁺ ;

Yields: 44%;

HPLC r.t.(min): 1.17;

¹ H NMR (400 MHz, CD ₃ OH) δ 8.08 (s, 1H), 7.71 (s, 1H), 7.61-7.38 (m, 4H), 7.32 (s, 2H), 6.54-6.32 (m, 2H) , 5.82 (dd, J = 9.7, 1.9 Hz, 1H), 5.51 (s, 1H), 3.93 (d, J = 4.3 Hz, 5H), 3.74 (s, 4H), 2.98 (s, 4H), 1.33 ( d, J = 14.7 Hz, 2H), 0.92 (t, J = 6.7 Hz, 1H).

Compound 2: N-(3-(2-(1-(2- Methoxyethyl )-1H- Pyrazole -4- One amino )-5- Morpholino Pyrimidin-4-ylamino)phenyl)acrylamide trifluoroacetate

MS (m/z): 465.4[M+1] ⁺ ;

Yields: 28%;

HPLC r.t. (min): 1.19;

¹ H NMR (400 MHz, CD ₃ OH) δ 8.06 (s, 2H), 7.50 (t, J = 74.2 Hz, 18H), 6.52-6.33 (m, 4H), 5.82 (dd, J = 9.7, 1.9 Hz , 2H), 4.11 (s, 6H), 3.97-3.88 (m, 9H), 3.64 (s, 8H), 3.51 (s, 2H), 3.26 (s, 7H), 2.99 (s, 9H), 2.82 ( s, 1H), 1.31 (s, 4H), 0.92 (t, J = 6.7 Hz, 2H).

Compound 3: N-(4-(2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-ylamino)phenyl)acrylamide Trifluoroacetate

MS (m/z): 421.3 [M+1] ⁺ ;

Yields: 62.2%;

HPLC r.t. (min): 1.00;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.82 (d, J = 7.1 Hz, 2H), 7.68 (s, 1H), 7.43 (d, J = 24.5 Hz, 4H), 6.45 (qd, J = 16.9 , 5.8 Hz, 2H), 6.14 (s, 1H), 5.82 (dd, J = 9.6, 2.0 Hz, 1H), 4.32 (d, J = 2.3 Hz, 2H), 3.99 (t, J = 5.3 Hz, 2H ), 3.70 (s, 3H), 2.43 (s, 2H), 1.41-1.23 (m, 2H), 0.92 (t, J = 6.7 Hz, 1H).

Compound 4: N-(4-(2-(1-(2- Methoxyethyl )-1H- Pyrazole -4- One amino )-5- Morpholino Pyrimidin-4-ylamino)phenyl)acrylamide trifluoroacetate

MS (m/z): 465.3 [M+1] ⁺ ;

Yields: 90%;

HPLC r.t. (min): 1.01;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.87-7.39 (m, 7H), 6.45 (qd, J = 16.9, 5.8 Hz, 2H), 5.83 (dd, J = 9.7, 1.9 Hz, 1H), 4.20 (d, J = 38.3 Hz, 2H), 3.93 (dd, J = 10.1, 5.9 Hz, 4H), 3.62 (s, 2H), 3.25 (s, 3H), 2.97 (s, 4H), 1.32 (d, J = 14.5 Hz, 2H), 0.92 (t, J = 6.8 Hz, 1H).

Compound 5: N-(3-((2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-ylamino)methyl)phenyl)acrylamide trifluoroacetate

MS (m/z): 435.3 [M+1] ⁺ ;

Yields: 47.4%;

HPLC r.t. (min): 1.05;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.83 (s, 1H), 7.55 (d, J = 21.7 Hz,2H), 7.47-7.45 (m, 1H), 7.41 (s,1H), 7.35 (t , J = 7.8 Hz, 1H), 7.11 (d, J = 7.5 Hz,1H), 6.40 (qd, J = 16.9, 5.8 Hz, 2H), 5.78 (dd, J = 9.7, 2.0 Hz, 1H), 4.80 (s, 2H), 3.93-3.85 (m, 4H), 3.81 (s, 3H), 2.93 (s,4H), 1.32 (d, J = 14.7 Hz, 2H), 0.92 (t, J = 6.7 Hz, 1H).

Compound 6: N-(3-((2-(1-(2- Methoxyethyl )-1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-ylamino)methyl)phenyl)acrylamide Trifluoroacetate

MS (m/z): 479.4 [M+1] ⁺ ;

Yields: 59.9%;

HPLC r.t. (min): 1.06;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.82 (s, 1H), 7.71 (s, 1H), 7.52 (d, J = 11.5 Hz, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.40 (qd, J = 16.9, 5.8 Hz, 2H), 5.78 (dd, J = 9.7, 1.9 Hz, 1H ), 4.84-4.75 (m, 2H), 4.20 (s, 2H), 3.91-3.82 (m, 4H), 3.67 (s, 2H), 3.27 (s, 3H), 2.93 (s, 4H), 1.38- 1.23 (m, 1H), 0.92 (t, J = 6.7 Hz, 1H).

Compound 7: N-(3-((2-(1-(2-( Dimethylamino )Ethyl)-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-ylamino)methyl)phenyl)acrylamide trifluoroacetate

MS (m/z): 492.4[M+1] ⁺ ;

Yields: 43.2%;

HPLC r.t. (min): 0.87.

Compound 8: N-(3-((2-(1-(3-( Dimethylamino )Propyl)-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-ylamino)methyl)phenyl)acrylamide Trifluoroacetate

MS (m/z): 506.4[M+1] ⁺ ;

Yields: 57.9%;

HPLC r.t. (min): 0.85;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.82 (s, 1H), 7.58 (s, 2H), 7.55 (s, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.45 (dd, J = 17.0, 9.6 Hz, 1H), 6.39 (d, J = 2.3 Hz, 1H), 5.80 (dd, J = 9.6, 2.3 Hz, 1H), 4.83 (d, J = 6.1 Hz, 1H), 4.14 (s, 4H), 3.93-3.85 (m, 4H), 3.09 (s, 4H), 2.97-2.92 (m, 4H), 2.87 (s, 4H), 2.83 (s, 6H).

Compound 9: N-(3-((2-(1-(2-( Diethylamino )Ethyl)-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-ylamino)methyl)phenyl)acrylamide trifluoroacetate

MS (m/z): 520.4[M+1] ⁺ ;

Yields: 54.3%;

HPLC r.t. (min): 0.86;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.83 (s, 1H), 7.77 (s, 1H), 7.61 (s, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.44 (dd, J = 17.0, 9.6 Hz, 1H), 6.38 (d, J = 2.3 Hz, 1H), 5.80 (dd, J = 9.6, 2.3 Hz, 1H), 4.84 (s, 2H), 4.47 (s, 2H), 3.92-3.86 (m, 4H), 3.60 (t, J = 5.6 Hz, 2H), 3.25 (q, J = 7.2 Hz, 4H), 2.96-2.91 (m, 4H), 1.28 (t, J = 7.3 Hz, 6H).

Compound 10: tert -Butyl 4-(4-(4-(3- Acrylamide benzylamino )-5- Morpholino Pyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate Trifluoroacetate

MS (m/z): 604.5[M+1] ⁺ ;

Yields: 6.2%;

HPLC r.t. (min): 1.32;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.55 (s, 3H), 7.43 (s, 1H), 7.28 (s, 1H), 7.23 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 7.3 Hz, 1H), 6.31 (dd, J = 17.0, 9.6 Hz, 1H), 6.25 (d, J = 2.2 Hz, 1H), 5.65 (dd, J = 9.6, 2.2 Hz, 1H), 4.66 (s , 2H), 4.03 (d, J = 13.4 Hz, 2H), 3.92 (s, 1H), 3.78-3.71 (m, 4H), 2.85-2.73 (m, 6H), 1.75 (d, J = 10.2 Hz, 2H), 1.56 (s, 3H).

Compound 11: N-(4-((2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-ylamino)methyl)phenyl)acrylamide trifluoroacetate

MS (m/z): 435.3 [M+1] ⁺ ;

Yields: 91.0%;

HPLC r.t. (min): 1.00.

Compound 12: N-(4-((2-(1-(2- Methoxyethyl )-1H- Pyrazole -4- One amino )-5- Morpoli Nopyrimidin-4-ylamino)methyl)phenyl)acrylamide trifluoroacetate

MS (m/z): 479.4 [M+1] ⁺ ;

Yields: 86.0%;

HPLC r.t. (min): 1.00;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.74 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.54 (s, 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.40 (qd, J = 16.9, 5.9 Hz, 2H), 5.78 (dd, J = 9.6, 2.1 Hz, 1H), 4.81-4.72 (m, 2H), 4.24 (s, 2H), 3.92-3.82 (m, 5H), 3.69 (s,2H), 3.28 (s, 3H), 2.90 (d, J = 4.0 Hz, 5H).

Compound 13: (S)-1-(3-(2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholino flute Midin-4-ylamino) piperidin-1-yl) prop-2-en-1-one trifluoroacetate

MS (m/z): 413.3[M+1] ⁺ ;

Yields: 54.8%;

HPLC r.t. (min): 0.97;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.83 (d, J = 30.0 Hz, 1H), 7.68 (d, J = 13.6 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 6.94- 6.81 (m, 1H), 6.54 (s, 1H), 6.22 (dd, J = 53.2, 15.9 Hz, 1H), 5.83 (d, J = 9.5 Hz, 1H), 5.58 (d, J = 10.2 Hz, 1H ), 4.17 (s, 2H), 3.88-3.76 (m, 9H), 3.62 (d, J = 32.6 Hz, 3H), 2.83 (s, 4H), 1.83 (s, 2H), 1.70 (s, 1H) .

Compound 14: (R)-1-(3-(2-(1-(3-( Dimethylamino )Propyl)-1H- Pyrazole -4- Work Mino)-5-morpholinopyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one Trifluoroacetate

MS (m/z): 484.4 [M+1] ⁺ ;

Yields: 32.0%;

HPLC r.t. (min): 0.82.

Compound 15: (R)-1-(2-((2-(1-(3-( Dimethylamino )Propyl)-1H- Pyrazole -4- Work Mino)-5-morpholinopyrimidin-4-ylamino)methyl)pyrrolidin-1-yl)prop-2-en-1-one Trifluoroacetate

MS (m/z): 484.4 [M+1] ⁺ ;

Yields: 56.7%;

HPLC r.t. (min): 0.81.

Compound 16: (S)-1-(3-(2-(1-(2- Methoxyethyl )-1H- Pyrazole -4- One amino )-5- Do not know Polynopyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one trifluoroacetate

MS (m/z): 457.4[M+1] ⁺ ;

Yields: 56.7%;

HPLC r.t. (min): 1.00;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.91 (d, J = 32.2 Hz, 1H), 7.68 (d, J = 14.8 Hz, 1H), 7.54 (d, J = 10.2 Hz, 1H), 6.86 ( d, J = 12.4 Hz, 1H), 6.54 (s, 1H), 6.29 (d, J = 17.9 Hz, 1H), 6.15 (d, J = 15.9 Hz, 1H), 5.83 (d, J = 10.3 Hz, 1H), 5.59 (d, J = 11.2 Hz, 1H), 4.35-4.08 (m, 6H), 3.93-3.49 (m, 10H), 2.83 (s, 4H), 1.77 (d, J = 46.8 Hz, 3H ).

Compound 17: (S)-1-(3-(2-(1-(3-( Dimethylamino )Propyl)-1H- Pyrazole -4- Work Mino)-5-morpholinopyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one Trifluoroacetate

MS (m/z): 484.4 [M+1] ⁺ ;

Yields: 55.3%;

HPLC r.t. (min): 0.82;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.91 (d, J = 34.6 Hz, 1H), 7.70 (s, 1H), 7.57 (d, J = 10.8 Hz, 1H), 6.95-6.82 (m, 1H ), 6.56 (s, 1H), 6.21 (dd, J = 49.6, 17.2 Hz, 1H), 5.84 (d, J = 8.9 Hz, 1H), 5.59 (d, J = 8.6 Hz, 1H), 4.21 (d , J = 19.4 Hz, 4H), 3.82 (s, 4H), 3.51 (d, J = 50.5 Hz, 3H), 2.94 (s, 2H), 2.78 (d, J = 38.9 Hz, 10H), 2.21 (s , 2H), 2.03 (s, 1H), 1.77 (d, J = 62.7 Hz, 3H).

Compound 18: (S)-1-(3-(2-(1-(2-( Diethylamino )Ethyl)-1H- Pyrazole -4- Japanese Army No)-5-morpholinopyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one Trifluoroacetate

MS (m/z): 498.4[M+1] ⁺ ;

Yields: 57.5%;

HPLC r.t. (min): 0.83;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.97 (d, J = 41.0 Hz, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 6.95-6.82 (m, 1H), 6.56 (s , 1H), 6.21 (dd, J = 42.3, 16.5 Hz, 1H), 5.83 (d, J = 9.0 Hz, 1H), 5.60 (d, J = 11.1 Hz, 1H), 4.41 (d, J = 23.1 Hz , 2H), 4.20 (d, J = 31.6 Hz, 2H), 3.82 (s, 6H), 3.63 (d, J = 43.3 Hz, 2H), 3.43 (s, 2H), 3.04 (s, 4H), 2.83 (s, 4H), 2.04 (s, 1H), 1.76 (d, J = 53.4 Hz, 3H), 1.31 (s, 4H).

Compound 19: N-(3-(2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-yloxy)phenyl)acrylamide Trifluoroacetate

MS (m/z): 422.4[M+1] ⁺ ;

Yields: 51.0%;

HPLC r.t. (min): 1.24;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.35 (s, 1H), 9.29 (s, 1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.58 (d, J = 9.4 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.40 (ddd, J = 9.0, 5.2, 2.2 Hz, 1H), 6.25 (dd, J = 17.0 , 1.8 Hz, 1H), 5.77 (dd, J = 10.1, 1.9 Hz, 1H), 3.78-3.70 (m, 4H), 3.54 (s, 3H), 3.09-2.98 (m, 4H).

Compound 20: N-(3-(2-(1-(2-( Dimethylamino )Ethyl)-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide trifluoroacetate

MS (m/z): 479.3 [M+1] ⁺ ;

Yields: 86.0%;

HPLC r.t. (min): 1.02;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.93 (s, 1H), 7.81-7.70 (m, 1H), 7.64-7.50 (m, 2H), 7.42 (s, 1H), 7.06 (dd, J = 15.9, 8.7 Hz, 1H), 6.51-6.34 (m, 2H), 5.83 (dd, J = 9.4, 2.3 Hz, 1H), 4.30 (d, J = 17.9 Hz,2H), 3.94-3.77 (m, 5H ), 3.61-3.49 (m,2H), 3.28-3.09 (m, 6H), 3.00-2.86 (m, 6H), 1.41-1.28 (m, 2H) 7H).

Compound 21: N-(4-(2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-yloxy)phenyl)acrylamide trifluoroacetate

MS (m/z): 422.3[M+1] ⁺ ;

Yields: 76.0%;

HPLC r.t. (min): 1.12;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.87 (t, J = 13.5 Hz, 3H), 7.29 (d, J = 8.9 Hz, 3H), 6.45 (qd, J = 16.9, 5.8 Hz, 2H), 5.84 (dd, J = 9.5, 2.2 Hz, 1H), 3.92-3.81 (m, 4H), 3.65 (s, 3H), 3.17 (d, J = 4.2 Hz, 3H), 1.33 (d, J = 14.4 Hz , 3H), 0.92 (t, J = 6.7 Hz, 2H).

Compound 22: N-(3-(2-(1-(2- Methoxyethyl )-1H- Pyrazole -4- One amino )-5- Morpoli Nopyrimidin-4-yloxy)phenyl)acrylamide trifluoroacetate

MS (m/z): 466.3[M+1] ⁺ ;

Yields: 69.0%;

HPLC r.t. (min): 1.26;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.34 (s, 1H), 9.30 (s, 1H), 8.04 (s, 1H), 7.65 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.46-6.37 (m, 1H), 6.25 (dd, J = 16.9, 1.9 Hz, 1H), 5.77 (dd, J = 10.0, 1.9 Hz, 1H), 3.92 (s, 2H), 3.80-3.68 (m, 4H), 3.48 (s, 2H), 3.14 (s, 3H), 3.09-3.00 (m, 4H).

Compound 23: N-(3-(2-(1-(3-( Dimethylamino )Propyl)-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide trifluoroacetate

MS (m/z): 493.4[M+1] ⁺ ;

Yields: 76.0%;

HPLC r.t. (min): 1.00;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.94 (d, J = 13.7 Hz, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.73-7.49 (m, 3H), 7.35 (d, J = 9.4 Hz, 1H), 7.14-6.99 (m, 2H), 6.54-6.32 (m,2H), 5.83 (dt, J = 14.5, 7.2 Hz, 1H), 3.99 (d, J = 22.3 Hz, 2H) , 3.88 (d, J = 4.2 Hz, 5H), 3.24-3.01 (m, 8H), 2.89 (d, J = 17.6 Hz, 6H), 2.15 (d, J = 6.5 Hz, 2H), 1.31 (s, 1H), 0.92 (t, J = 6.7 Hz, 1H).

Compound 24: N-(3-(2-(1-(2-( Diethylamino )Ethyl)-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide trifluoroacetate

MS (m/z): 507.4[M+1] ⁺ ;

Yields: 63.2%;

HPLC r.t. (min): 1.07;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.95 (s, 1H), 7.76 (d, J = 5.3 Hz, 1H), 7.64-7.50 (m, 2H), 7.40 (s, 1H), 7.09 (t , J = 9.8 Hz, 1H), 6.44 (qd, J = 17.0, 5.8 Hz, 2H), 5.83 (dd, J = 9.5, 2.2 Hz, 1H), 4.33 (s, 2H), 3.88 (dd, J = 11.8, 7.5 Hz, 5H), 3.56 (t, J = 5.5 Hz, 2H), 3.25 (q, J = 7.2 Hz, 5H), 3.20-3.08 (m, 5H), 1.31 (dt, J = 14.5, 7.3 Hz, 8H).

Compound 25: N-(3-(2-(1-(2-( Methylamino )-2-oxo ethyl )-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide trifluoroacetate

MS (m/z): 479.3 [M+1] ⁺ ;

Yields: 14.2%;

HPLC r.t. (min): 1.12.

Compound 26: N-(3-(2-(1-(3-( Diethylamino )Propyl)-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide trifluoroacetate

MS (m/z): 521.4[M+1] ⁺ ;

Yields: 92.0%;

HPLC r.t. (min): 1.06;

¹ H NMR (400 MHz, CD ₃ OH) δ 8.03 (s, 1H), 7.82 (s, 1H), 7.52 (d, J = 17.8 Hz, 2H), 7.30 (s, 1H), 7.16 (s, 1H) ), 7.03 (s, 1H), 6.44 (q, J = 18.0 Hz, 2H), 5.83 (d, J = 8.7 Hz, 1H), 3.98 (s, 2H), 3.88 (s, 4H), 3.14 (d , J = 12.8 Hz, 8H), 2.97 (s, 2H), 2.07 (s, 2H), 1.28-1.19 (m, 6H).

Compound 27: N-(3-(5- Morpholino -2-(1-(3- Morpholinopropyl )-1H- Pyrazole -4- One amino )Pyrimidin-4-yloxy)phenyl)acrylamide Trifluoroacetate

MS (m/z): 535.4[M+1] ⁺ ;

Yields: 97.0%;

HPLC r.t. (min): 1.03;

¹ H NMR (400 MHz, CD ₃ OH) δ 8.02 (s, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.53 (s, 1H), 7.24 (s, 1H), 7.11 (s , 1H), 7.02 (s, 1H), 6.41 (t, J = 15.8 Hz, 2H), 5.82 (d, J = 9.1 Hz, 1H), 3.88 (s, 6H), 3.70 (s, 4H), 3.15 (s, 4H), 2.50 (s, 4H), 2.32 (s, 2H), 1.88 (s, 2H).

Compound 28: N-(3-((2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-yloxy)methyl)phenyl)acrylamide Trifluoroacetate

MS (m/z): 436.3[M+1] ⁺ ;

Yields: 32.4%;

HPLC r.t. (min): 1.13;

¹ H NMR (400 MHz, CD ₃ OH) δ 8.02 (s, 1H), 7.84 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H ), 7.40 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.51-6.34 (m, 2H), 5.81 (dd, J = 9.5, 2.2 Hz, 1H), 5.65 (s, 2H), 3.93 (s, 3H), 3.85-3.77 (m, 4H), 3.71 (t, J = 6.2 Hz, 1H), 3.10-3.01 (m, 4H), 2.94 (s, 3H), 2.27-2.17 (m, 1H).

Compound 29: N-(3-((2-(1-(2- Methoxyethyl )-1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-yloxy)methyl)phenyl)acrylamide Trifluoroacetate

MS (m/z): 480.3 [M+1] ⁺ ;

Yields: 16.0%;

HPLC r.t. (min): 1.46;

¹ H NMR (400 MHz, CD ₃ OH) δ 8.01 (s, 1H), 7.93 (s, 1H), 7.60 (d, J = 22.9 Hz, 2H), 7.48 (d, J = 8.2 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 6.51-6.34 (m, 2H), 5.81 (dd, J = 9.5, 2.2 Hz, 1H), 5.64 (s , 2H), 4.33 (t, J = 5.0 Hz, 2H), 3.84-3.72 (m, 6H), 3.08-3.01 (m, 4H), 1.31 (s, 1H).

Compound 30: N-(3-((2-(1-(2-( Dimethylamino )Ethyl)-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-yloxy)methyl)phenyl)acrylamide Trifluoroacetate

MS (m/z): 493.3[M+1] ⁺ ;

Yields: 37.2%;

HPLC r.t. (min): 0.94;

¹ H NMR (400 MHz, CD ₃ OH) δ 9.16 (s, 1H), 7.96 (s, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.54 (s, 1H), 7.33 (d , J = 34.5 Hz, 3H), 4.37 (d, J = 3.8 Hz, 3H), 4.03-3.74 (m, 13H), 3.04 (d, J = 30.6 Hz, 6H), 1.31 (s, 1H), 0.91 (s, 1H).

Compound 31: N-(3-((2-(1-(3-( Dimethylamino )Propyl)-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-yloxy)methyl)phenyl)acrylamide Trifluoroacetate

MS (m/z): 507.4[M+1] ⁺ ;

Yields: 6.5%;

HPLC r.t. (min): 0.94.

Compound 32: N-(3-((5- Morpholino -2-(1-(piperidin-4-yl)-1H- Pyrazole -4- One amino )Pyrimidin-4-yloxy)methyl)phenyl)acrylamide Trifluoroacetate

MS (m/z): 505.4[M+1] ⁺ ;

Yields: 13.6%;

HPLC r.t. (min): 0.92;

¹ H NMR (400 MHz, CD ₃ OH) δ 8.00 (d, J = 24.2 Hz, 2H), 7.74-7.52 (m, 3H), 7.48-7.34 (m,2H), 7.23 (d, J = 7.3 Hz , 1H), 6.53-6.33 (m, 2H), 5.80 (dt, J = 13.4, 6.6 Hz, 1H), 5.64 (d, J = 7.6 Hz, 2H), 4.65-4.49 (m, 1H), 3.80 ( d, J = 4.3 Hz, 4H), 3.59 (d, J = 13.1 Hz, 3H), 3.23 (t, J = 10.5 Hz, 3H), 3.06 (s, 4H), 2.39-2.16 (m, 5H), 1.31 (s,1H), 0.91 (d, J = 6.8 Hz, 1H).

Compound 33: N-(3-((2-(1-(2-( Diethylamino )Ethyl)-1H- Pyrazole -4- One amino )-5-morpholinopyrimidin-4-yloxy)methyl)phenyl)acrylamide Trifluoroacetate

MS (m/z): 521.4[M+1] ⁺ ;

Yields: 39.0%;

HPLC r.t. (min): 1.02;

¹ H NMR (400 MHz, CD ₃ OH) δ 8.00 (d, J = 24.2 Hz, 2H), 7.74-7.52 (m, 3H), 7.48-7.34 (m,2H), 7.23 (d, J = 7.3 Hz , 1H), 6.53-6.33 (m, 2H), 5.80 (dt, J = 13.4, 6.6 Hz, 1H), 5.64 (d, J = 7.6 Hz, 2H), 4.65-4.49 (m, 1H), 3.80 ( d, J = 4.3 Hz, 4H), 3.59 (d, J = 13.1 Hz, 3H), 3.23 (t, J = 10.5 Hz, 3H), 3.06 (s, 4H), 2.39-2.16 (m, 5H), 1.31 (s,1H), 0.91 (d, J = 6.8 Hz, 1H).

Compound 34: N-(4-(2-(1-(2- Methoxyethyl )-1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-yloxy)phenyl)acrylamide Trifluoroacetate

MS (m/z): 466.3[M+1] ⁺ ;

Yields: 76.0%;

HPLC r.t. (min): 1.15;

¹ H NMR (400 MHz, CD ₃ OH) δ 7.88 (t, J = 12.6 Hz, 3H), 7.31 (t, J = 11.7 Hz, 3H), 7.07 (brs, 1H), 6.46 (qd, J = 16.9 , 5.8 Hz, 2H), 5.84 (dd, J = 9.7, 2.0 Hz, 1H), 4.02 (s, 2H), 3.93-3.84 (m, 5H), 3.54 (s, 2H), 3.24 (s, 3H) , 3.20-3.09 (m, 5H).

Compound 35: N-(3-(2-(1- methyl -1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-yl)phenyl)acrylamide Trifluoroacetate

MS (m/z): 406.3[M+1] ⁺ ;

Yields: 17%;

HPLC r.t.(min): 1.29.

Compound 36: N-(3-(2-(1-(2- Methoxyethyl )-1H- Pyrazole -4- One amino )-5- Morpholinopyrimidine -4-yl)phenyl)acrylamide Trifluoroacetate

MS (m/z): 450.3 [M+1] ⁺ ;

Yields: 16.8%;

HPLC r.t. (min): 1.31.

Experimental example One: JAK3 Evaluation of enzyme inhibitory activity against kinase

The inhibitory activity against JAK3 kinase of the compound synthesized according to the above example was evaluated. Specifically, each compound was reacted with purified human JAK3 enzyme (SignalChem #J03-11G). As the reaction buffer, a composition of 40 mM Tris-HCl pH 7.4, 20 mM MgCl ₂ , 0.5 mg/mL BSA, and 50 μM DTT was used, and reactions of all test materials were performed on the reaction buffer. The compound was diluted 12 steps by a series dilution method of a stock solution (stock) dissolved in DMSO at a concentration of 10 mM, and the final 50, 10, 2, 0.4 0.08, 0.016, 0.0032, 0.00064, 0.000128, 0.0000256, 0.00000512, and 0.000001024 μM concentrations Enzyme activity was measured. In the test, human JAK3 enzyme (1 ng) was reacted with purified ATP (5 μM) and enzyme substrate (0.2 μg) at 25° C. for 2 hours, and then the enzyme was subjected to in vitro ADP-Glo™ kinase assay (Promega). The activity was confirmed. The enzyme activity reaction solution, the ADP-Glo reaction solution, and the enzyme activity detection solution were reacted in a ratio of 2:2:1 to measure the degree of inhibition of enzyme activity by Luminoscence. Using the solvent-treated group not treated with the compound as a control, the degree of inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on its enzyme activity fluorescence, and the enzyme activity was measured using Prism software (version 7.01, Graphpad) The concentration of each compound that inhibits 50%, IC ₅₀ (nM) was determined.

The enzyme inhibitory ability was measured as described above, and the calculated IC ₅₀ values are shown in Table 1 below.

Compound# JAK3 (nM) Compound# JAK3 (nM) One 8.7 2 28.8 3 949.0 4 891.0 5 629.0 6 723.0 7 490.0 8 406.0 9 2,230 10 1,496 11 83.4 12 1,450 13 8,353 14 1,097 15 2,867 16 4,488 17 4,258 18 1,963 19 4.3 20 21.0 21 1,050 22 12.5 23 17.4 24 22.1 25 114.0 26 0.2 27 5.0 28 195.0 29 85.1 30 84.4 31 58.4 32 56.0 33 18.8 34 1,570 35 36

As shown in Table 1, it was confirmed that the compound of the present invention has an effect of inhibiting the activity of JAK3 kinase. This indicates that the compounds of the present invention can be usefully used in the prevention or treatment of JAK3-related diseases.

Experimental example 2: Ba /F3 cells Inhibitory activity against proliferation evaluation

The inhibitory activity of Ba/F3 expressing the EGFR mutation of Compounds 1 to 35 synthesized according to the above example and the proliferation of lung cancer cells was evaluated. Specifically, lung cancer cell line A549 (EGFR wild type) was cultured in DMEM (Invitrogen) added with 10% FBS (HyClone), and other cancer cells were cultured in RPMI-1640 (Invitrogen) added with 10% FBS. The transduced Ba/F3 cells were cultured by adding 1 μg/L puromycin (Invitrogen) to the same medium. The cells were dispensed into each well of a white transparent bottom 96-well plate (Corning) with 3000 to 5000 cells 24 hours before treatment with the compound. The compound was diluted in dimethylsulfoxide (DMSO) (diluted three times, to a total of 12 concentrations) and injected in 0.5 μL each so that the final concentration was 0.3 nM to 50 μM. After compound treatment has passed 72 hours, and to process the CellTiter-Glo ^® Luminescent Cell Viability Assay (Promega) stored at room temperature for 10 minutes and the reader measures the light emission intensity by (SynergyNeo, Biotek), and counted for viable cells. Each experiment was repeated three times. The resulting value was calculated as the percentage of cell growth compared to the control treated with the solvent. Graphs were derived using the GraphPad Prism program (version 5.0) and IC ₅₀ values were calculated.

The inhibitory activity against Ba/F3 and lung cancer cells expressing the EGFR mutations measured as described above was measured and shown in Tables 2 and 3, respectively.

Compound# Ba/F3 cell (IC ₅₀ in μM) SM DM DM SM SM WT WT JAK3 EGFR
Del19/T790M EGFR
L858R/T790M EGFR
L858 EGFR
Del19 EGFR wt naive One 1.39 0.203 0.198 0.007 11.130 2 2.78 22.820 3 ＞10 2.510 13.100 15.420 4 ＞10 6.186 39.780 34.650 5 8.48 7.386 9.704 17.050 6 ＞10 4.305 15.300 17.580 7 ＞10 ＞10 8 ＞10 ＞10 9 ＞10 ＞10 10 8.9 9.54 11 9.8 5.510 11.280 10.320 12 ＞10 5.722 35.750 6.726 13 0.57 6.58 14 ＞10 ＞10 15 ＞10 ＞10 16 ＞10 ＞10 17 4.22 ＞10 18 3.11 ＞10 19 5.53 0.382 0.282 0.01 0.158 0.028 20 ＞10 ＞10 21 ＞10 6.519 31.340 20.240 22 3.08 1.177 0.637 0.119 35.485 23 ＞10 ＞10 24 ＞10 ＞10 25 ＞10 ＞10 26 9.89 3.147 ＞10 27 ＞10 4.847 ＞10 28 4.63 3.791 16.170 2.710 ＞10 5.526 7.263 29 ＞10 13.090 ＞50 1.735 9.572 7.345 9.210 30 ＞10 18.490 36.230 20.260 31 ＞10 17.740 26.510 24.440 32 ＞10 31.890 34.140 ＞50 33 4.18 ＞10 34 ＞10 12.180 39.140 50.060 35 ＞10 ＞10 36 ＞10 ＞10

Compound# Cancer Cell (IC ₅₀ , μM) PC9GR H1975 PC9 A549 One 0.146 0.646 0.023 9.587 19 0.189 1.427 0.017 28.440 22 0.662 4.576 0.044 78.620

Experimental Example 3: Evaluation of inhibitory activity against various kinases

The activities of the compounds according to the present invention to more various enzymes were evaluated. Specifically, by requesting DiscoverX, the enzyme selectivity was determined for the selected compounds 2, 6, 22, and 28 among the compounds 1 to 35, and an experiment was conducted using a scanMAX™ Kinase analysis panel. At this time, as a drug treated with the enzyme, a solution prepared by dissolving in DMSO at a concentration of 1 μM was used, and the control percentage (% control) was determined by the method of Equation 1 below, and the results are shown in Table 3 below.

[Equation 1]

In the above formula, the positive control and the negative control refer to a compound showing a percentage control of 0% and 100% as DMSO, respectively. At this time, when the calculated control percentage value for each enzyme is less than 35%, it was determined to have inhibitory activity for the enzyme. Accordingly, among the series of enzymes tested, the enzymes that the compound of the present invention exhibits inhibitory activity are summarized and shown in Table 4 below together with the percentage control therefor.

Claims (18)

A compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
L is a direct bond, -O- or -NH-;
n is an integer of 0 to 2;
R ₁ is C _1-6 alkyl, (C _1-4 alkoxy)-(C _1-6 alkyl), amino-(C _1-6 alkyl), (C _1-4 alkyl)amino-(C _1-6 alkyl ), di(C _1-4 alkyl) amino-(C _1-6 alkyl), (C _1-4 alkyl)-carbamoyl-(C _1-4 alkyl), or unsubstituted or substituted 3-7 membered hetero _Cyclyl (C _0-6 alkyl);
R ₂ is unsubstituted or (C _1-4 alkenyl)carbonylamino or (C _1-4 alkenyl)carbonyl substituted C _6-10 aryl or 5-10 membered heterocyclyl.
The method of claim 1,
The compound is a compound represented by the following formulas 1-1 to 1-3, or a pharmaceutically acceptable salt thereof:
[Formula 1-1]

[Formula 1-2]

[Formula 1-3]

In the above formula,
n ₁ to n ₃ are each independently 0 or 1;
m is 0 or 1;
R ₁ is as defined in claim 1 above.
The method of claim 1,
R ₁ is methyl, methoxyethyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, methylcarbamoylmethyl, piperidinyl, tert-butoxycarbonylpiperidinyl or morpholinopropyl. Or a pharmaceutically acceptable salt thereof.
The method of claim 1,
The compound is
(1) N-(3-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)phenyl)acrylamide;
(2) N-(3-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)phenyl)acrylamide ;
(3) N-(4-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)phenyl)acrylamide;
(4) N-(4-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)phenyl)acrylamide ;
(5) N-(3-((2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)methyl)phenyl)acrylamide;
(6) N-(3-((2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)methyl)phenyl ) Acrylamide;
(7) N-(3-((2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino) Methyl)phenyl)acrylamide;
(8) N-(3-((2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino) Methyl)phenyl)acrylamide;
(9) N-(3-((2-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino) Methyl)phenyl)acrylamide;
(10) tert-Butyl 4-(4-(4-(3-acrylamidobenzylamino)-5-morpholinopyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidine -1-carboxylate;
(11) N-(4-((2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)methyl)phenyl)acrylamide;
(12) N-(4-((2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)methyl)phenyl ) Acrylamide;
(13) (S)-1-(3-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino)piperidin-1- I) prop-2-en-1-one;
(14) (R)-1-(3-(2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidine-4- Ylamino)piperidin-1-yl)prop-2-en-1-one;
(15) (R)-1-(2-((2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidine-4 -Ylamino)methyl)pyrrolidin-1-yl)prop-2-en-1-one;
(16) (S)-1-(3-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-ylamino) Piperidin-1-yl)prop-2-en-1-one;
(17) (S)-1-(3-(2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidine-4- Ylamino)piperidin-1-yl)prop-2-en-1-one;
(18) (S)-1-(3-(2-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidine-4- Ylamino)piperidin-1-yl)prop-2-en-1-one;
(19) N-(3-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide;
(20) N-(3-(2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl ) Acrylamide;
(21) N-(4-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide;
(22) N-(3-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide ;
(23) N-(3-(2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl ) Acrylamide;
(24) N-(3-(2-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl ) Acrylamide;
(25) N-(3-(2-(1-(2-(methylamino)-2-oxoethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy Si) phenyl) acrylamide;
(26) N-(3-(2-(1-(3-(diethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl ) Acrylamide;
(27) N-(3-(5-morpholino-2-(1-(3-morpholinopropyl)-1H-pyrazol-4-ylamino)pyrimidin-4-yloxy)phenyl)acryl Amide;
(28) N-(3-((2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)methyl)phenyl)acrylamide;
(29) N-(3-((2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)methyl)phenyl ) Acrylamide;
(30) N-(3-((2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy) Methyl)phenyl)acrylamide;
(31) N-(3-((2-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy) Methyl)phenyl)acrylamide;
(32) N-(3-((5-morpholino-2-(1-(piperidin-4-yl)-1H-pyrazol-4-ylamino)pyrimidin-4-yloxy)methyl )Phenyl)acrylamide;
(33) N-(3-((2-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy) Methyl)phenyl)acrylamide;
(34) N-(4-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yloxy)phenyl)acrylamide ;
(35) N-(3-(2-(1-methyl-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yl)phenyl)acrylamide; or
(36) N-(3-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-ylamino)-5-morpholinopyrimidin-4-yl)phenyl)acrylamide;
Which is, a compound or a pharmaceutically acceptable salt thereof.
A first step of preparing a 4-(2,4-dihalopyrimidin-5-yl)morpholine derivative compound represented by Formula 2 below;
An intermediate represented by the following formula (3) in which a substituent is introduced into the halogen at carbon position 4 by reacting the compound represented by Formula 2 obtained from the previous step with a precursor containing a boronic acid, amine or hydroxyl group as a reactive functional group A second step of manufacturing; And
A third step of reacting the intermediate represented by Formula 3 obtained from the previous step with a 1-substituted-1H-pyrazol-4-amine derivative compound; including,
A method for preparing the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof:
[Formula 2]

[Formula 3]

In the above formula,
X ₁ and X ₂ are each independently halogen;
n, L and R ₂ are as defined in claim 1 above.
The method of claim 5,
The first step is achieved by halogenation by reacting 5-haluracil with morpholine to introduce a morpholinyl group at the halogen site, and reacting with triethylamine and an excess of PO (halide) ₃ at 70 to 100°C. , Manufacturing method.
The method of claim 5,
The second step
i) C 6 containing a hydroxyl group, an amine group or a boronic acid group linked directly or through a linker with a reactive functional group, (C _1-4 alkenyl) carbonylamino or (C _1-4 alkenyl) carbonyl substituted C _{6 Reacted} directly with _-10 aryl or 5-10 membered heterocycle derivatives, or
ii) a 5-10 membered heterocycle derivative containing a hydroxyl group, an amine group, or a boronic acid group linked directly or through a linker with a reactive functional group as a precursor, an aryl derivative containing a nitro group or a nitrogen atom substituted with a protecting group, and After reacting, reducing or deprotecting, converting to an amine group, and reacting with acryloyl halide at -5 to 10°C in the presence of a base
The method of claim 5,
The third step is carried out by adding a catalyst and/or a cocatalyst in an organic solvent in the presence of a base.
The method of claim 8,
Prior to adding the catalyst and/or cocatalyst, further comprising the step of removing gas from the reaction mixture.
The method of claim 5,
Using a specific optical isomer as a reactant, or optionally further comprising the step of separating the optical isomer after each step of the reaction.
The method of claim 5,
After at least one of the first to third steps, each independently extracting, drying, concentrating, and purifying any one or more of the steps of further comprising.
Comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient,
A pharmaceutical composition for the prevention or treatment of JAK3-related diseases.
The method of claim 12,
To inhibit the expression or activity of JAK3, pharmaceutical composition.
The method of claim 12,
The JAK3-related disease is a proliferative disease, an inflammatory disease, an autoimmune disease, a pain (painful condition), a viral infection, or a combination thereof, a pharmaceutical composition.
The method of claim 12,
The pharmaceutical composition further comprising a pharmaceutically acceptable carrier, excipient or diluent.
A health functional food composition for the prevention or improvement of JAK3-related diseases comprising the compound of any one of claims 1 to 4 or a food pharmaceutically acceptable salt thereof as an active ingredient.
The prevention or treatment of JAK3-related diseases, comprising administering a pharmaceutical composition comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient to an individual other than humans Way.
BLK, BMX, BTK, EGFR, EGFR (E746-A750del), EGFR (L747-E749del, A750P) comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient, EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R,T790M), EGFR(L861Q), EGFR(T790M), ERBB2, ERBB4, FLT3(D835V), GSK3B , ITK, JAK3 (JH1domain-catalytic), KIT (L576P), KIT (V559D), TEC, TXK, or TYK2 (JH2domain-pseudokinase) inhibitory composition.