WO2023063751A1 - Composés inhibant les kinases de mutation alk et/ou egfr et leur utilisation médicale - Google Patents

Composés inhibant les kinases de mutation alk et/ou egfr et leur utilisation médicale Download PDF

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WO2023063751A1
WO2023063751A1 PCT/KR2022/015520 KR2022015520W WO2023063751A1 WO 2023063751 A1 WO2023063751 A1 WO 2023063751A1 KR 2022015520 W KR2022015520 W KR 2022015520W WO 2023063751 A1 WO2023063751 A1 WO 2023063751A1
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cancer
amino
phenyl
methoxy
chloro
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Korean (ko)
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유형철
김재선
임지웅
이주영
최광현
이수미
김광해
강효진
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제이투에이치바이오텍 주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present disclosure relates to compounds exhibiting an ALK and/or EGFR mutant kinase inhibitory effect and their medicinal uses.
  • ALK anaplastic lymphoma kinase
  • ALK carcinogenesis is known to be related to the ALK-NPM (Nucleophosmin, nucleophosmin) fusion gene, which is mainly observed in anaplastic large cell lymphoma.
  • ALK-NPM Nucleophosmin, nucleophosmin
  • ALK's tyrosine kinase behaves abnormally and causes cancer. In other words, abnormally activated ALK induces cell proliferation and prevents cell death by interfering with apoptosis.
  • ALK connects to and interacts with other tyrosine kinases, either normal or oncogenic, or activates a variety of different pathways.
  • the ALK gene fuses with the Echinoderm Microtubule-Associated Protein-Like 4 (EML4) gene to produce EML4-ALK, an active tyrosine kinase. It has been known that this is dependent on the enzymatic activity.
  • EML4-ALK Echinoderm Microtubule-Associated Protein-Like 4
  • Mosse et al. reported about 26% of ALK gene amplification in 491 neuroblastoma specimens (Nature. 2008 Oct 16; 455(7215): 930-935).
  • the ALK gene has been expressed in numerous non-hematopoietic cells, including large B-cell lymphoma, systemic hemangiocytosis, inflammatory myofibroblastic sarcoma, esophageal squamous cell carcinoma, non-small cell lung cancer, rhabdomyosarcoma, myofibroblastoma, breast cancer, gastric cancer, and melanoma cell lines. It has been found to be expressed in tumors, and in the case of a rare disease called inflammatory myelofibroblastoma, several types of ALK fusion proteins are commonly found, and these fusion proteins are thought to be deeply involved in tumor development.
  • PF-02341066 Crizotinib (PF-02341066) developed by Pfizer is an ATP-competitive c-Met/HGFR and ALK inhibitor, and is known to be effective in the treatment of non-small cell lung cancer.
  • NVP-TAE684 and LDK-378 from Novartis and CH5424802 from Chugai are also known to have an effect of reducing tumor size in neuroblastoma cell lines as well as anaplastic large cell lymphoma cell lines.
  • ALK inhibitors also suffer from resistance.
  • the most common mutation observed is G1202R, a mutation in the solvent exposed region of ALK, which causes steric hindrance to most ALK inhibitors.
  • resistance to the first-generation ALK inhibitor crizotinib develops within 1 to 2 years.
  • resistant mutations within the TK domain of ALK most commonly L1196M. This mutation causes steric hindrance at the binding site, reducing the efficacy of the response to crizotinib.
  • various ALK-resistant mutations exist, which reduce the therapeutic effect of ALK inhibitors. Therefore, there is a need for a therapeutic agent exhibiting an inhibitory effect on various ALK mutations.
  • the epidermal growth factor receptor is a protein composed of a receptor part and a tyrosine kinase part, and serves to transmit signals from outside the cell to the inside of the cell through the cell membrane.
  • EGFR plays an essential role in normal cell regulation through intracellular signal transduction.
  • overexpression of EGFR or activating EGFR mutations characterized by ligand-independent tyrosine kinase activity are known to induce growth, differentiation, angiogenesis, metastasis, resistance expression, etc. of cancer cells by abnormally activating the cell signaling system. . It has been reported that EGFR is abnormally overexpressed or frequently mutated in most solid cancer cells, which is associated with poor prognosis.
  • lung cancer liver cancer, esophageal cancer, stomach cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, It is known that testicular cancer, blood cancer, lymphoma, skin cancer, psoriasis, and fibroadenoma are related to EGFR mutation (Cancer Communications. 2020;40:43-59).
  • EGFR activating mutations such as the L858R point mutation in exon 21 of the EGFR tyrosine kinase domain or the in-frame deletion in exon 19 are known to be important causes of non-small cell lung cancer. Therefore, according to the prediction that the anticancer effect will be excellent if cancer cell signaling through the epidermal growth factor receptor is blocked, research for developing anticancer drugs targeting the epidermal growth factor receptor is being actively conducted.
  • the first drug developed as an EGFR tyrosine kinase inhibitor among small molecules is gefitinib, which is a reversible inhibitor that selectively inhibits EGFR (Erb-B1) among EGFR subtypes.
  • gefitinib is a reversible inhibitor that selectively inhibits EGFR (Erb-B1) among EGFR subtypes.
  • Another drug with such characteristics is erlotinib, and this EGFR targeting therapy is mainly used for patients with EGFR activating mutations for non-small cell lung cancer (NSCLC) as a main indication.
  • NSCLC non-small cell lung cancer
  • Irreversible inhibitors have been proposed to overcome resistance to existing EGFR inhibitors such as gefitinib or erlotinib.
  • EGFR irreversible inhibitors also have high activity against EGFR WT (wild-type), which also exists in normal cells, serious side effects are caused when doses to overcome resistance due to EGFR T790M mutation are administered. It indicates the limitations of clinical application.
  • osimertinib As an alternative to this, a number of drugs including osimertinib, olmutinib, naquotinib, and avitinib, which are EGFR mutation-selective inhibitors, are under development in the clinical stage.
  • the C797S mutation has a high rate of more than 20%. It is known to appear as The C797S mutation is a point mutation in which cysteine 773 (Cys773), which forms a covalent bond with irreversible inhibitors of EGFR, is changed to serine. .
  • the problem to be solved by the present invention is to provide a novel compound that exhibits inhibitory activity against ALK overexpression, ALK mutation, EGFR overexpression, EGFR mutation, etc., and its medicinal use.
  • Another problem to be solved by the present invention is to provide a novel compound exhibiting inhibitory activity against both ALK mutation and EGFR mutation and its medicinal use.
  • Another problem to be solved by the present invention is to provide a novel compound having inhibitory activity against ALK overexpression, ALK mutation, EGFR mutation, etc., and pharmacokinetic properties desirable for use as an active ingredient in pharmaceuticals, and its medicinal use. .
  • the present disclosure provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • A is direct connection, , or ego,
  • R 1 is -C(O)NHR, -NH-C(O)-R, -NH-S(O)(O)R, or , wherein R is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl,
  • R 2 is or , wherein R' and R" are independently of each other hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl,
  • R 3 is hydrogen, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or Cl;
  • R 4 is hydrogen, F, Cl, CN, or CF 3 .
  • C1-C6 alkyl means an alkyl having 1 to 6 carbon atoms, and the alkyl is straight-chain or branched.
  • C1 ⁇ C6 fluoroalkyl means that at least one hydrogen atom of C1 ⁇ C6 alkyl is substituted with fluoro.
  • A is a direct connection or ego
  • R 1 is -C(O)NHCH 3 ; or ego,
  • R 2 is or ego
  • R 3 is hydrogen, methoxy, or Cl
  • R 4 is Cl.
  • the present inventors have found that the novel compounds according to the present invention not only show excellent inhibitory activity against both ALK mutation and EGFR mutation, but also have better stability, especially in vivo metabolic stability, etc. than other compounds having similar structures, The present invention was completed by confirming that the dynamic characteristics were also excellent.
  • the compound represented by Formula 1 may be used in the form of a salt derived from an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid , glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzene It may be used in the form of a salt induced by at least one acid selected from the group consisting of phonic acid and toluenesulfonic acid.
  • an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
  • the term "compound of the present invention” is meant to include not only each compound of Formula 1, but also clathrates, hydrates, solvates, or polymorphs thereof.
  • the term “compound of the present invention” is meant to include pharmaceutically acceptable salts of the compounds of the present invention when pharmaceutically acceptable salts thereof are not mentioned.
  • the compounds of the present invention are stereomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, 97% ee or more, or 99% ee or more))).
  • the compound of Formula 1 or a salt thereof according to the present invention is a tautomeric isomer and/or a stereoisomer (eg, geometrical isomer and conformational isomers), the separated isomer thereof and mixtures each are also included within the scope of the compounds of the present invention.
  • the compounds of the present invention or their salts have an asymmetric carbon in their structure, their optically active compounds and racemic mixtures are also included in the scope of the compounds of the present invention.
  • polymorph refers to a solid crystal form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in terms of physical properties include, but are not limited to, stability (e.g. heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't. Differences in stability may be due to chemical reactivity changes (e.g. differential oxidation such as faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g.
  • kinetically Tablet fragments stored as the preferred polymorph may be thermodynamically converted to a more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity).
  • Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates, or may be more difficult to filter or wash, than another polymorph, eg, due to its shape or particle size distribution.
  • solvent compound refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and can be administered in very small amounts to humans.
  • hydrate refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate refers to a compound of the present invention in the form of a crystal lattice containing spaces (eg, channels) in which guest molecules (eg, solvent or water) are confined. or a salt thereof.
  • the term "purified" means that when isolated, the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and In other embodiments, at least 99.9% pure.
  • treatment includes eradication, removal, transformation, or control of primary, localized, or metastatic cancerous tissue; to minimize or delay the spread of cancer.
  • Non-limiting examples of compounds according to the present invention include the following compounds and pharmaceutically acceptable salts thereof.
  • the compound according to the present disclosure is N-(2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazole-4- yl)amino)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfone Amide, N-(2-((5-chloro-2-((2-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-( methylmethylsulfonamido)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide, or 5-chloro-N 4 -(2-(isopropylsulfonyl)phenyl)-N 2- (2-methoxy-5
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient.
  • These pharmaceutical compositions may further contain pharmaceutically acceptable excipients.
  • the present disclosure provides a method for treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • Methods are provided, wherein the disease or condition is an ALK mutation and/or EGFR mutation associated disease.
  • the disease associated with ALK mutation and/or EGFR mutation is cancer or psoriasis.
  • the subject is a human.
  • the cancer is lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethra Cancer, bladder cancer, testicular cancer, hematological cancer, lymphoma, skin cancer, fibroadenoma, non-small cell lung cancer, neuroblastoma, inflammatory myelofibroblastoma, rhabdomyosarcoma, myofibroblastoma, large B-cell lymphoma, systemic hemangiocytosis, inflammatory myofibroblastic sarcoma , or esophageal squamous cell carcinoma.
  • the cancer is non-small cell lung cancer.
  • the ALK mutation is any one or more of G1202R, L1196M, C1156Y, F1174L, F1174S, G1269A, G1269S, L1152R, R1275Q, S1206R, T1151-L1152insT, or T1151M.
  • the ALK mutation is any one or more of G1269S, G1202R, and L1196M.
  • the EGFR mutation is d746-750/T790M/C797S and/or T790M/C797S/L858R.
  • an effective amount means to destroy, transform, control or eliminate primary, localized or metastatic cancer cells or tissue; slowing or minimizing the spread of cancer; or an amount of a compound of the present invention sufficient to provide a therapeutic benefit in the treatment or management of cancer, neoplastic disease, or tumor.
  • Effective amount also refers to an amount of a compound of the present invention sufficient to cause cancer or neoplastic cell death.
  • Effective amount also refers to an amount sufficient to inhibit or reduce the activity of cancer cells either in vitro or in vivo.
  • an "effective amount” as used herein also refers to an amount sufficient to inhibit or reduce the activity of an ALK mutation and/or an EGFR mutation, either in vitro or in vivo.
  • the present disclosure provides a pharmaceutical use characterized by using the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient.
  • the medical use of the present disclosure is the treatment or prevention of diseases associated with ALK mutations and/or EGFR mutations.
  • the medicinal use of the present disclosure is the treatment or prevention of cancer or psoriasis.
  • the cancer is lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethra Cancer, bladder cancer, testicular cancer, hematological cancer, lymphoma, skin cancer, fibroadenoma, non-small cell lung cancer, neuroblastoma, inflammatory myelofibroblastoma, rhabdomyosarcoma, myofibroblastoma, large B-cell lymphoma, systemic hemangiocytosis, inflammatory myofibroblastic sarcoma , or esophageal squamous cell carcinoma.
  • the cancer is non-small cell lung cancer.
  • the present invention provides a pharmaceutical composition for treating or preventing cancer or psoriasis, characterized in that it contains the compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for the treatment or prevention of ALK mutation and/or EGFR mutation-related diseases, comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is generally administered in a therapeutically effective amount.
  • the compounds of the present invention can be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in a dosage effective for the intended treatment.
  • An effective dosage is generally about 0.0001 to about 200 mg/kg of body weight/day, preferably about 0.001 to about 100 mg/kg/day, in single or divided administration. Dosage levels below the lower end of this range may be suitable depending on the age, species, and disease or condition being treated. In other cases, still larger doses can be used without detrimental side effects. Larger doses may be divided into several smaller doses for administration throughout the day. Methods for determining the appropriate dosage are well known in the art.
  • the compound described herein or a pharmaceutically acceptable salt thereof can be administered in a variety of ways as follows.
  • the compound of the present invention can be administered orally, and oral is a concept including swallowing.
  • Oral administration allows the compounds of the present invention to enter the gastrointestinal tract or be directly absorbed from the mouth into the bloodstream, eg, by buccal or sublingual administration.
  • compositions suitable for oral administration may be in solid, liquid, gel, or powder form, and may have formulations such as tablets, lozenges, capsules, granules, powders, and the like. .
  • compositions for oral administration may optionally be enteric coated and exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.
  • Liquid formulations may include solutions, syrups and suspensions, and such liquid compositions may be contained in soft or hard capsules.
  • Such formulations may include a pharmaceutically acceptable carrier such as water, ethanol, polyethylene glycol, cellulose, or oil.
  • the formulation may also contain one or more emulsifying and/or suspending agents.
  • the amount of active ingredient drug may be present from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the total weight of the tablet.
  • Tablets may also contain a disintegrant comprising from about 0.5% to about 35% by weight, more usually from about 2% to about 25% by weight of the dosage form.
  • disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.
  • Suitable glidants included for making into tablets may be present in amounts from about 0.1% to about 5% by weight, and include talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like. It can be used as a lubricant, but the present invention is not limited to these types of additives.
  • Gelatin polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. may be used as a binder for preparing tablets.
  • Mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. may be used as suitable diluents for preparing tablets, but the present invention is not limited to these types of additives. .
  • the solubilizing agent that may be included in the tablet may be used in an amount of about 0.1% to about 3% by weight based on the total weight of the tablet, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, Diethylene glycol monoethyl ether, dimethylisosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR TM (Nikkol), oleyl ester, Gelucire TM , caprylic/caprylic mono/ Diglyceride, sorbitan fatty acid ester, Solutol HS TM and the like can be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to the specific types of these solubilizing agents.
  • Compounds of the present invention may be administered directly into the bloodstream, muscle, or intestine.
  • Suitable methods for parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, and the like.
  • Suitable devices for parenteral administration include injectors (including needle and needleless syringes) and infusion methods.
  • compositions for parenteral administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
  • parenteral formulations are liquid compositions, and these liquid compositions are aqueous solutions containing the active ingredient, salt, buffer, tonicity agent and the like according to the present invention.
  • Parenteral formulations may also be prepared in dried form (eg lyophilized) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle such as sterile water. Solubility-enhancing agents may also be used in the preparation of parenteral solutions.
  • the compounds of the present invention may be administered topically to the skin or transdermally.
  • Formulations for this topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like.
  • Pharmaceutically acceptable carriers for topical formulations may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be performed by electroporation, iontophoresis, phonophoresis, and the like.
  • compositions for topical administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
  • the present disclosure provides novel compounds exhibiting inhibitory activity against ALK overexpression, ALK mutation, EGFR overexpression, EGFR mutation and the like, and pharmaceutical uses thereof.
  • the compounds according to the present disclosure not only exhibit excellent inhibitory activity against both ALK mutation and EGFR mutation, but also have desirable physicochemical and pharmacokinetic properties for use as active ingredients in pharmaceuticals.
  • 1 to 4 are pharmacokinetic evaluation results of control substances and the compounds of the present invention.
  • Step 3 4-Methoxy-N 1 -(1-methyl-1H-pyrazol-4-yl)-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of benzene-1,3-diamine (1-3)
  • Step 4 N-(2-((5-chloro-2-((methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-(4-methyl Preparation of piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide (1)
  • Step 4 Preparation of N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)isobutyramide (2-4 )
  • N-(2-fluoro-4-methoxy-5-nitrophenyl)isobutyramide 63 mg, 0.25 mmol
  • 1-methyl-4-(piperidin-4yl)piperazine 45 mg, 0.25 mmol
  • potassium carbonate 68 mg, 0.49 mmol
  • the reaction mixture was cooled to room temperature, extracted with water and dichloromethane, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was solidified with ether and heptane to give the title compound (82 mg, 80%).
  • Step 5 Preparation of N-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)isobutyramide (2-5 )
  • Step 6 N-(5-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2- Preparation of (4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)isobutyramide (2)
  • Methanesulfonyl chloride (0.11 mL, 1.47 mmol) was added and the temperature was gradually raised and stirred at room temperature overnight. It was diluted with 4N HCl aqueous solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was solidified with methyl tertiary butyl ether to obtain the title compound (286 mg, 80%).
  • Step 3 Preparation of N-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)methanesulfonamide (3-3 )
  • N- (2-fluoro-4-methoxy-5-nitrophenyl) methanesulfonamide (280 mg, 1.06 mmol), 1-methyl-4- (piperidin-4yl) piperazine (194 mg, 1.06 mmol) and potassium carbonate (293 mg, 2.12 mmol) in N,N-dimethylformamide (2 mL) was stirred overnight at 80 °C.
  • the reaction mixture was cooled to room temperature, extracted with water and dichloromethane, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was solidified with methyl tert-butyl ether to give the title compound (240 mg, 53%).
  • Step 4 Preparation of N-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)methanesulfonamide (3-4 )
  • Step 5 N-(2-((5-chloro-2-((2-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5- Preparation of (methylmethylsulfonamido)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (3)
  • Step 1 Preparation of N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-nitrophenyl)-1-methyl-1H-pyrazol-3-amine (4-1)
  • Step 2 Preparation of 4-methoxy-N 1 -(1-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (4 -2)
  • Step 3 N-(2-((5-chloro-2-((methoxy-5-((1-methyl-1H-pyrazol-3-yl)amino)-4-(4-(4-methyl Preparation of piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (4)
  • HATU (265 mg, 0.70 mmol) and diisopropyldiamine in a solution of 2-fluoro-4-methoxy-5-nitrobenzoic acid (100 mg, 0.47 mmol) in N,N-dimethylformamide (1 mL). (0.24 mL, 1.39 mmol) was added and stirred for 15 minutes. To the reaction mixture was added methylamine hydrochloride (47 mg, 0.70 mmol) and stirred overnight. After adding water and stirring for 20 minutes, the mixture was filtered and dried to obtain a labeled compound (80 mg, 75%).
  • Step 5 5-((5-chloro-4-((2-(N-methylmethanesulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-N-methyl-2 Preparation of (4-methylpiperazin-1-yl)benzamide (10)
  • Example 6 2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-(4-methyl Preparation of piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide
  • Example 7 5-chloro-N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino Preparation of )-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine
  • Step 1 Preparation of N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-nitrophenyl)-1-methyl-1H-pyrazol-4-amine (8-1)
  • Step 2 Preparation of 4-methoxy-N 1 -(1-methyl-1H-pyrazol-4yl)-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (8- 2)
  • Step 3 N-(2-((5-chloro-2-((2-methoxy-5-((1-methyl-1H-pyrazol-4-yl)amino)-4-(4-methylpipette Preparation of razin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (8)
  • Step 1 N-(2-((5-chloro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methyl Preparation of methanesulfonamide (9-1)
  • Step 2 N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5- Preparation of nitrophenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide (9-2)
  • Step 3 N-(2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (9-3)
  • Step 4 (E)-N-(5-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methyl Preparation of Toxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-cyano-4,4-dimethylpent-2-enamide (9)
  • Each enzyme human ALK normal (WT), ALK mutant (G1202R, L1196M), EGFR normal (WT), or EGFR mutant (d746-750/T790M/C797S, T790M/C797S/L858R)
  • poly[Glu:Tyr] (4:1) substrate phosphorylation was measured by mixing 0.2 mg/ml of substrate and 10 ⁇ M of ATP with the compound.
  • the compound prepared in the above examples was made into a 10 nM DMSO solution.
  • Substrate was added to the kinase solution (20 mM Hepes (pH7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij35, 0.2 mg/ml BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO) and the enzymes were added and mixed gently after each addition.
  • a compound prepared using Acoustic Technology (Echo550; nanoliter range) was added to the mixed solution and reacted at room temperature for 20 minutes. After this, 33 P-ATP was further added and reacted at room temperature for 2 hours.
  • Kinase activity permeated through the filter was measured, and Alectinib and Osimertinib were used as comparative examples. The results are shown in Table 1 below.
  • Example % Enzyme Activity (relative to DMSO control) ALK (WT) ALK (G1202R) ALK (L1196M) EGFR (WT) EGFR (d746-750/T790M/C797S EGFR (T790M/C797S/L858R)
  • WT ALK
  • G1202R ALK
  • L1196M EGFR
  • WT EGFR
  • T790M/C797S/L858R One 10.3 10.2 2.1 35.8 2.1 4.6 2 14.9 23.1 8.0 72.0 5.7 19.8 3 2.8 3.0 1.7 59.5 2.6 6.7 6 37.9 44.4 8.8 49.6 8.6 18.3 7 3.0 1.1 1.1 69.7 10.9 10.1 9 5.3 23.9 2.3 1.0 6.8 31.1 10 2.1 1.6 0.9 6.9 0.5 0.4 Alectinib 3.6 35.4 4.3 96.1 85.5 89.9 Osimertinib 90.9
  • the examples of the present invention not only showed high inhibitory activity against ALK and the two mutant forms of ALK, but also showed higher inhibitory activity against ALK (G1202R) than the control substance, Alectinib.
  • the examples of the present invention showed a higher inhibitory ability to EGFR mutants (d746-750/T790M/C797S, T790M/C797S/L858R) compared to the control substance, Osimertinib.
  • Example IC 50 nM ALK (WT) ALK (G1202R) ALK (L1196M) EGFR (WT) EGFR (d746-750/T790M/C797S) EGFR (T790M/C797S/L858R)
  • WT ALK
  • G1202R ALK
  • L1196M L1196M
  • EGFR WT
  • EGFR EGFR
  • T790M/C797S/L858R One 1.76 3.77 0.60 8.68 0.91 3.03 4 0.51 1.05 0.075 0.85 0.45 0.58 5 0.62 6.48 0.12 24.00 0.45 4.15 8 2.41 8.18 1.10 18.80 0.69 3.67
  • the examples of the present invention showed high inhibitory ability at nM unit concentration for ALK, two mutant forms of ALK, and EGFR mutations (d746-750/T790M/C797S, T790M/C797S/L858R). .
  • Example 7 Activity was evaluated in the same test method as in Experimental Example 1, and Example 7 and the control substance Lorlatinib were used as the test substance. The results are as shown in Table 3 below.
  • Example 7 of the present invention not only showed high inhibitory ability against various ALK mutant forms, but also showed higher inhibitory ability against ALK (G1202R) and ALK (G1269S) compared to the control substance Lorlatinib. .
  • a pharmacokinetic test for the compound of the present invention was conducted as follows. After a single oral administration of the compound of the present invention to ICR mice, the concentration of the compound over time was followed up and analyzed.
  • the compound of the present invention was suspended in 10% DMSO/90% (30% HPbCD aqueous solution) and orally administered to mice at a dose of 5 mg/kg. Blood was collected at a fixed time and plasma was separated. The drug was analyzed using HPLC (XBridge column C18, Waters, mobile phase 0.1% formic acid:acetonitrile (30:70, %/%)) and MS/MS (ESI positive, MRM). Mouse donor plasma and each commercially available standard solution were mixed at a ratio of 9:1, and concentrations of 5, 50, 100, 500, 100, and 5,000 ng/mL were prepared and calibrated.
  • the preparation of the QC sample was prepared by mixing the mouse blood plasma and the standard solution for QC at a ratio of 9: 1, and prepared at concentrations of 100, 750, and 2,500 ng/mL. 100 ⁇ L of the plasma sample was transferred to a centrifugation tube, and 10 ⁇ L of the internal standard solution and 300 ⁇ L of methanol were added, followed by mixing for about 30 seconds for pretreatment. The tube was centrifuged at 3,000 x g (4° C.) for about 5 minutes, and the supernatant was taken and transferred to an LC vial and injected into the instrument. Then, the concentration of the compound in mouse plasma was quantified by applying a previously validated assay. As a control material, a compound having the structure of Chemical Formula 2 was used.
  • Examples 1, 3, and 7 of the present invention showed an oral absorption rate about 2 to 5 times higher in AUC compared to the control material without a substituent in R 1 .

Abstract

La présente divulgation concerne de nouveaux composés ayant une activité inhibitrice contre la surexpression d'ALK, la mutation d'ALK, la surexpression d'EGFR, la mutation d'EGFR, etc, et leur utilisation médicale. La présente divulgation concerne une composition pharmaceutique comprenant les composés ou des sels pharmaceutiquement acceptables de ceux-ci. Les composés selon la présente invention présentent non seulement une excellente activité inhibitrice contre la mutation d'ALK et la mutation d'EGFR, mais ont également des caractéristiques physico-chimiques et pharmacocinétiques, de préférence disponibles en tant que principe actif dans des produits pharmaceutiques.
PCT/KR2022/015520 2021-10-15 2022-10-13 Composés inhibant les kinases de mutation alk et/ou egfr et leur utilisation médicale WO2023063751A1 (fr)

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