Crystalline forms, salt crystal forms, preparation methods and uses of substituted 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-C]quinolin-2-one derivatives

Abstract

The present invention provides crystalline forms of free base and salt of substituted 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivatives (represented by formula (I)), their preparation method and use, specifically the crystalline forms of free base and fumarate of 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivatives represented by formula (I). The crystalline forms of free base and salt provided by the present invention have good stability, can be used for the treatment of cancer, cancer with CNS metastasis, meningeal metastasis, primary brain cancer or glioma, etc., especially when combined with DNA double strand break inducer, and have good bioavailability and half-life, all of which are very important for further research on the efficacy of such solid drugs. [Formula 1] JPEG2025514643000015.jpg5364

Description

[Technical Field]

[0001] This invention relates to the crystalline form and salt of a substituted 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivative. form Regarding its crystalline form, specifically, the free base crystalline form and fumarate of (R)-1-(3,3-difluoro-1-methylpiperidine-4-yl)-8-(6-methoxypyridine-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinoline-2-one(I). Crystal form This relates to fumarate crystal, as well as methods for preparing them and their uses. [Background technology]

[0002] Glioblastoma, or glioblastoma multiforme (GBM), is an advanced WHO Grade IV malignant brain tumor. Due to the blood-brain barrier (BBB), no targeted therapies that can achieve an effective dose in the brain are approved for the treatment of GBM or diffuse endogenous pontine glioma (DIPG) patients. Radiation therapy and surgery, along with temozolomide, are primary treatment options, but their efficacy is limited. Radiation therapy, in particular, is ineffective in DIPG patients. This is the only treatment option, but it recurs within 5.5 months. (See, for example, Hamer et al., Neuro-Oncology 12(3):304-316, 2010) GBM is a whole-brain disease, and all GBMs have clinically significant tumor areas where the blood-brain barrier (BBB) ​​is not compromised. If effective treatment does not reach all areas of GBM, treatment will fail, and recurrence will be inevitable (SaRkaRIa et al. Neuro-Oncology 2 0(2):184-191, 2018). GBM is inherently resistant to radiotherapy (RT), and the development of brain-penetrating radiosensitizers is one strategy to overcome this limitation. Repair of RT-induced DNA double-strand breaks is linked to protein kinase That is Telangiectasia sex Ataxia mutation protein ( Ataxia Telangiectasia mutated mediated by ATM. The role of ATM in radiosensitivity, and the availability of brain-penetrating ATM inhibitors as radiosensitizers, could be crucial for the treatment of brain cancer or cancers with central nervous system metastases, especially those where radiation is the only treatment option, such as DIPG. Indications This could be very effective in treating [the condition].

[0003] Therefore, as a radiosensitizer in combination with radiotherapy for the treatment or prevention of gliomas, High biological activity against ATM kinase, Developing drugs that possess both the ability to cross the blood-brain barrier and other similar abilities is particularly useful.

[0004] As is well known, even the same drug can exhibit significant differences in stability, solubility, and bioavailability in its crystalline, salt, and salt crystal forms, which can affect its efficacy. Therefore, drug processing and pharmaceutical compositions are crucial. Suitable for preparation Substitution 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5- c Development of new salt forms and new crystal forms of quinoline-2-one derivatives. Doing so is very useful, and also, Regarding the efficacy and safety of solid drugs 、 twist many Providing qualitative and quantitative information is very important. important That is the case. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] This invention aims to solve the problem Let's assume The challenges are that existing ATM inhibitors cannot effectively cross the blood-brain barrier and reach effective drug concentrations within the skull, and that the properties of the free base amorphous 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention are relevant to pharmaceutical processing and pharmaceutical composition. It is not suitable for use in [location]. , Pharmaceutical processing and pharmaceutical compositions Suitable for useThe objective is to provide the free base crystalline form and salt crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative. The free base crystalline form, salt crystalline form, preparation method, and uses provide more qualitative and quantitative information for studies on the efficacy and safety of solid drugs. [Means for solving the problem]

[0006] The 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative provided by the present invention is used in ATM kinase. Opposite It possesses biological activity and effectively crosses the blood-brain barrier. The 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative is represented by formula (I): [ka]

[0007] The object of the present invention is achieved by the following technical solutions.

[0008] The technical solution employed by the present invention is to provide a novel 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) having R chirality. A chiral purity of ee>90% is preferred, and ee>97% is more preferred.

[0009] The technical solution employed in this invention is ATM kinase against A novel 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-] with biological activity and R chirality. c The objective is to provide a quinoline-2-one derivative (I).

[0010] The technical solution employed in this invention is ATM kinase againstTo provide a novel 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivative (I) which has biological activity, high blood-brain barrier penetration ability, and R chirality.

[0011] The present invention also provides a synthesis method for preparing the 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivative (I) of the present invention.

[0012] The technical solution adopted by the present invention is to provide a free base crystalline form of 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivative, whose XRPD pattern has peaks at the following 2θ values.

[0013] Main characteristic peaks: 10.2, 16.9, 20.3, 25.6 Secondary characteristic peaks: 10.8, 12.6, 13.5, 14.8, 16.1, 20.6, 21.2, 23.3 The error range of the 2θ values is ±0.2.

[0014] Preferably, the XRPD pattern of the free base crystalline form of 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivative (I) provided by the present invention has peaks at 2θ=10.19, 10.76, 12.56, 13.37, 14.84, 16.08, 16.87, 20.30, 20.51, 21.22, 23.26, 25.56. Diffraction peak peaks are located at 5.08, 15.33, 16.53, 19.12, 19.51, 22.65, 23.72, 24.77, 26.67, 27.04, 28.38, 28.77, 29.26, 29.60, 30.09, 31.05, 32.61, 32.97, 34.90, 36.96, 38.21, 38.50, and the error range of the above 2θ values is ±0.2.

[0015] Another technical solution employed by the present invention is 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5- c The objective is to provide a crystalline form of quinoline-2-one derivative fumarate.

[0016] Main characteristic peaks: 6.8, 8.6, 12.2, 13.7, 17.3, 19.4, 26.1 Secondary characteristic peaks: 6.1, 11.0, 14.6, 16.1, 16.5, 18.0, 20.2, 22.1, 26.8 The error range for the 2θ value is ±0.2.

[0017] The XRPD patterns of the fumarate crystal form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) provided by the present invention are preferably at 2θ = 6.07, 6.78, 8.60, 10.99, 12.21, 13.66, 14.55, 16.09, 16.49, 17.32, 18.04, 19.41, 20.24, 22.15, 26.06, and 26.81. Diffraction peak The values ​​are 12.57, 18.37, 18.64, 20.96, 23.54, 24.82, 25.40, 28.23, 30.19, 33.40, and 36.25, and the error range for the above 2θ values ​​is ±0.2.

[0018] The free base crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of the present invention preferably has an XRPD pattern substantially as shown in Figure 1.

[0019] The fumarate crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of the present invention preferably has an XRPD pattern substantially as shown in Figure 2.

[0020] The present invention also provides a method for preparing the free base crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention, the method comprising adding 100 to 120 mg of the amorphous form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative sample of formula (I) to 1 to 1.5 mL of an organic solvent mixture and stirring at 50°C or higher. The lower solid is separated by centrifugation to obtain the free base crystal form.

[0021] The present invention also provides a method for preparing the fumarate crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention, the method comprising adding 2 to 2.5 equivalents of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative represented by formula (I) and fumaric acid to an organic solvent, stirring the mixture at 22 to 28°C, and collecting the solid by centrifugation. In this case, 10 to 200 mg of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative represented by formula (I) is added per 1 ml of organic solvent.

[0022] In the above method, organic solvent teeth A mixture of dichloromethane and methanol (1:1 to 1:1.7, v / v) is preferred.

[0023] Furthermore, in the method for preparing the free base crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I), the organic solvent is preferably an alcohol, ether, ester, ketone, aliphatic alkane, or aromatic solvent, and more preferably methyl tert-butyl ether / water (1:10, v / v).

[0024] The present invention also provides a pharmaceutical composition comprising a free base crystalline form or fumarate crystalline form of a 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative represented by formula (I), or a combination thereof, and a pharmaceutically acceptable excipient or auxiliary component.

[0025] The adjuvant or auxiliary component preferably includes a carrier, excipient, diluent, vehicle, and adjuvant.

[0026] The present invention also provides for the use of a free base crystalline form, a fumarate crystalline form, or a pharmaceutical composition of a 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative represented by formula (I) in the manufacture of a drug for the treatment or prevention of diseases mediated by ATM kinase.

[0027] Preferably, this drug is intended to be a drug for the treatment or prevention of diseases mediated by ATM kinase and caused by ATM activation following DNA double-strand breaks.

[0028] This drug is more preferably manufactured for the treatment or prevention of non-small cell lung cancer brain metastases, pancreatic cancer, meningeal metastases, head and neck squamous cell carcinoma, squamous cell carcinoma, brainstem tumors, DIPG, primary brain cancer, or glioma. [Effects of the Invention]

[0029] Those skilled in the art can adjust the dosage and method of the reagents used in the present invention, including increasing or decreasing the amount of raw materials or solvents, based on their knowledge and experience, and these adjustment schemes are also included in the method of the present invention. Compared to the prior art, the present invention has the following beneficial effects: (1) The novel chiral (R)-1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention and its pharmaceutical free base and salt have a blood-brain barrier crossability that exceeds expectations, in particular Pathophysiology mediated by ATM activationIt can be used as a protein kinase inhibitor, and especially when combined with a DNA double-strand break inducer, it can be used to treat or prevent disorders associated with abnormal protein kinase activity, such as cancer, cancer with brain metastases, cancer with meningeal metastases, and central nervous system diseases. (2) The 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention and its pharmaceutically free base and salt have low efflux rates and are not P-glycoprotein efflux enzyme substrates, breast cancer drug resistance efflux enzyme substrates, or aldehyde oxidase substrates. Reduce tolerance caused by drug efflux, Absorption can be improved. (3) The free base crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of the present invention and its pharmaceutical salt have good pharmacokinetics, a long half-life, and high biological activity, reducing the burden of tablet intake for patients. Con Pricing can be improved. (4) The free base crystalline form and fumarate crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention provided by the present invention have good stability and water solubility and are useful for use in pharmaceutical processing and pharmaceutical compositions and can treat ATM kinase-mediated cancers such as non-small cell lung cancer brain metastases, meningeal metastases, head and neck squamous cell carcinoma, pancreatic cancer, squamous cell carcinoma, brainstem tumors, primary brain cancer or glioma, and have good bioavailability and half-life and are of great significance for further research on the efficacy of such solid drugs as they provide qualitative and quantitative information on efficacy and safety. [Brief explanation of the drawing]

[0030] Further features, purposes, and advantages of the present invention will become clearer by referring to the following drawings and reading the detailed description of the non-limiting embodiments. [Figure 1] This is the XRPD pattern of the free base crystal form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of the present invention. [Figure 2]This is the XRPD pattern of the fumarate crystal form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of the present invention. [Figure 3] This is a schematic diagram of the efficacy study of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of the present invention in a humanized glioma mouse intracranial model. [Figure 4A] Figure 4A shows the TGA and DSC spectra of the free base crystal form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of the present invention. Figure 4B shows the DSC spectrum, which is stable even at high temperatures, with no change in crystal form and a melting point of 206°C. [Figure 4B] Figure 4A shows the TGA and DSC spectra of the free base crystal form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of the present invention. Figure 4B shows the DSC spectrum, which is stable even at high temperatures, with no change in crystal form and a melting point of 206°C. [Figure 5A] Figure 5A shows the TGA and DSC spectra of the fumarate of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of the present invention. Figure 5B shows the TGA spectrum, which does not show significant weight loss. Figure 5B shows the DSC spectrum, which is stable even at high temperatures, with no change in crystal form and a melting point of 220°C. [Figure 5B] Figure 5A shows the TGA and DSC spectra of the fumarate of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of the present invention. Figure 5B shows the TGA spectrum, which does not show significant weight loss. Figure 5B shows the DSC spectrum, which is stable even at high temperatures, with no change in crystal form and a melting point of 220°C. [Figure 6] This is the synthesis scheme for the intermediate 3,3-difluoro-1-methylpiperidine-4-amine A6. [Figure 7]This is the synthesis scheme for compound (I). [Modes for carrying out the invention]

[0031] (Explanation of terms used in this invention) The terms “improve” and “treat” are used interchangeably to mean, in addition to therapeutic and / or preventive benefits, reducing, inhibiting, preventing, or stabilizing the onset or progression of a disease (e.g., a disease or disorder described herein).

[0032] "Disease" refers to a specific disorder or condition that damages or interferes with the normal functioning of cells, organs, or tissues.

[0033] A "marker" refers to any change associated with a disease or disorder. For example, a marker associated with a disease or disorder. do Expression level or activity Any It is a protein or polynucleic acid.

[0034] In this context, “contains,” “contains,” and “are,” as well as other similar terms, have the meanings given in patent law; “substantially consists of” or “essentially consists of” have the same meanings given in patent law; the term is open, and the presence of non-referenced subjects is permissible, provided that the presence of non-referenced subjects does not alter the basis or new features of the referenced subject, but does not include practices of prior art.

[0035] As used herein, the terms “antagonist” and “inhibitor” are used interchangeably and refer to the ability of a compound or drug to inhibit the biological function of a target protein or polypeptide, for example, by inhibiting the activity or expression of that protein or polypeptide. Some of the antagonists herein interact with specific target proteins or polypeptides (e.g., bind to ATM kinase), but their inhibitors also, within the definition, Tumor development, growth, or spreadTargeting proteins or polypeptides, including those that inhibit or are related to undesirable immune responses exhibited by autoimmune diseases. Let's assume It inhibits the biological activity of a target protein or polypeptide by interacting with other members of the signaling pathway.

[0036] As used herein, the terms “anticancer agent,” “antitemoid agent,” or “chemotherapeutic agent” refer to any agent useful for treating tumor disorders. The class of anticancer agents includes chemotherapeutic agents. “Chemotherapy” refers to one or more chemotherapeutic agents and / or other agents administered by various means, including intravenous, oral, subcutaneous, intramuscular, intraperitoneal, intravesical, percutaneous, buccal, or inhalation.

[0037] As used herein, “cell proliferation” refers to an increase in the number of cells as a result of cell division, and cell growth (e.g., an increase in size) that is consistent with proliferation signals by cell morphology.

[0038] As used herein, the term “combined administration” means the simultaneous use of two or more drugs, the use of a composition containing two or more drugs, the administration of two or more drugs and / or their metabolites at different time points, or the administration of two or more drugs and / or their metabolites alone.

[0039] As used herein, the terms “effective dose” or “effective therapeutic dose” mean that the amount of the compound or pharmaceutical composition described herein is sufficient to achieve an intended use, including but not limited to the treatment of a disease. In some embodiments, the amount is It is effective in killing cancer cells, inhibiting their proliferation or spread, reducing the size or number of tumors, or suppressing the severity, stage, or progression of cancer.The effective therapeutic dose may vary depending on the intended application, such as whether it is in vitro or in vivo, the state and severity of the disease, the subject's age, weight, or method of administration. This term also refers to doses that induce target cells, such as reducing cell migration in a specific response. Specific doses vary, for example, depending on the selected compound, the subject's species (including age and pre-existing health conditions), route of administration, disease severity, combination with other drugs, time of administration, tissue to which the drug is administered, and administration device.

[0040] As used herein, the term “therapeutic effect” includes therapeutic and / or preventive benefits. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms or impairments of a disease, delaying, stopping, or reversing a disease or condition, or a combination thereof.

[0041] As used herein, the term “signaling” refers to the process by which stimuli or inhibitory signals are sent to a cell to initiate an intracellular response. A “modulator” of a signaling pathway refers to a compound that modulates the activity of one or more cellular proteins mediated by a particular signaling pathway. A “modulator” can either enhance the activity of a signaling molecule (agonist) or inhibit it (antagonist).

[0042] As used herein, the term “selective inhibition” refers to the ability of a compound to selectively reduce target signaling activity compared to target activity against an off-target, either through direct or indirect interactions. For example, the activity of a compound that selectively inhibits ATM may be at least approximately 2, 3, 5, 10, 20, 50, or 100 times that of ATR or DNA-PK kinase. or That's all.

[0043] As used herein, the term “radiotherapy” refers to the exposure of a subject to radioactive emitters such as alpha-emitting radioactive elements (e.g., actinium and thorium radioactive elements) (e.g., beta emitters), conversion electron emitters (e.g., strontium-89 and samarium-153-EDTMP), or high-energy radiation including but not limited to X-rays, gamma rays, and neutrons.

[0044] As used herein, the term “subject” includes, but is not limited to, humans (e.g., of any age or sex) and / or other primates (e.g., crab-eating macaques, rhesus macaques), mammals including commercial mammals such as cattle, sheep, goats, pigs, horses, cats and / or dogs, and / or birds including commercial birds such as chickens, geese, quail, ducks and / or turkeys.

[0045] As used herein, the term "in vivo" refers to activities occurring within the subject's body. rat This also includes cases occurring in rodents such as mice and guinea pigs.

[0046] As used herein, the term "in vitro" refers to events that occur outside the body. For example, an in vitro test includes any detection performed outside the body. An in vitro assay includes cell determination based on whether cells are live or dead, and Includes cell-free assays that do not use complete cells. .

[0047] As used herein, the term “compound” includes salts of the compounds of the general formulas herein. This term also includes any of the solvates, hydrates, and polymorphs described herein. In certain aspects of the invention described in this application, “solvate,” “hydrate,” or “polymorph” Specific references to this should not be interpreted restrictively. In other aspects of the invention where the term “compound” is used without reference to these other forms, such forms are not excluded.

[0048] The salt of the compound of the present invention is formed between an acid and a basic group of the compound, such as an amino functional group. According to another preferred embodiment, it is a pharmaceutically acceptable acid addition salt.

[0049] As used herein, the term “pharmaceutically acceptable” means suitable for use in contact with human and other mammalian tissues without causing reasonable toxicity, irritation, allergic reactions, etc. Having a reasonable profit / risk ratio This refers to the following: "Pharmacologically acceptable salt" means a non-toxic salt that, when administered to a recipient, can directly or indirectly provide a prodrug or compound of the present invention.

[0050] Acids commonly used to form pharmaceutically acceptable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, hydroiodic acid, and inorganic acids such as phosphoric acid, trifluoroacetic acid, and citric acid. ,Ma Leic acid, oxalic acid, picric acid, acetic acid, adipic acid, alginic acid, aspartic acid, sulfuric acid, boric acid, butyric acid, valeric acid, camphoric acid, camphor sylthiocyanate, diglycerides Con Acids, dodecyl sulfate, pivalic acid Formic acid, fumaric acid, hydroiodic acid, benzoic acid, 2-hydroxyethanesulfonic acid, fumaric acid, stearic acid, lactobionic acid, propionic acid, lauric acid, oleic acid, nicotinic acid, lactic acid, cinnamic acid, succinic acid Mandelic acid, malic acid, tartaric acid, tartaric acid, lactic acid, pyruvic acid, pectinic acid, methanesulfonic acid, pamoic acid, benzenesulfonic acid, persulfate, palmitic acid, malonic acid, glycerophosphate, 2-naphthalenesulfonic acid, p- Tor Ethulfonic acid, salicylic acid, ascorbic acid, 3 - Phenylpropionic acid, Glu Con Acids, glucuronic acid, phosphoric acid, glutamic acid, ethanesulfonic acid, p-bromobenzenesulfonic acid and carbon acid, This also includes related inorganic and organic acids.

[0051] As used herein, “hydrate” refers to a compound containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. As used herein, the term “solvate” refers to a compound containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces, such as water, dichloromethane, 2-propanol, acetone, methanol, and ethanol. Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, 1 to about 10, 1 to about 4, about 3, or about 2 solvent or water molecules. As used herein, the term “compound” is understood to include the compounds described and their solvates, hydrates, and mixtures thereof.

[0052] As used herein, “polymorph” refers to the solid crystalline form of a compound or a complex of a compound. Different polymorphs of the same compound have different physical, chemical, and / or properties. spectrum It may exhibit certain properties. These different physical properties include, but are not limited to, stability (e.g., heat, light, or moisture), density, hygroscopicity, solubility, compressibility, and dissolution rate.

[0053] As used herein, the term “isomer” refers to different compounds having the same molecular formula. “Stereoisomer” refers only to isomers in which atoms are arranged in different ways. As used herein, the term “isomer” includes all geometric isomers and stereoisomers. For example, geometric double bond cis- and trans-isomers, also called E- and Z-isomers, R- and S-enantiomers, diastereomers, (D) isomers and (L) isomers, racemic mixtures thereof, and other mixtures thereof are disclosed herein.

[0054] Carbon-carbon Around the substituent Double bonds are designated as either "Z" or "E" configurations, where "Z" and "E" are used according to IUPAC nomenclature. Unless otherwise specified, structures represent both "E" and "Z" isomers.

[0055] carbon-carbon double bond surroundingSubstituents are sometimes called "cis" or "trans," where "cis" refers to a substituent on the same side of the double bond, and "trans" refers to a substituent on both sides. substituents on a carbon ring The configuration can also be specified as "cis" or "trans." "Cis" refers to substituents on the same side of the ring plane, while "trans" refers to substituents on both sides of the ring plane. Here, a mixture of substituents on the same side and opposite sides of the plane of two rings is represented as "cis / trans."

[0056] As used herein, the term "enantiomer" means A pair of stereoisomers that are mirror images of each other and cannot be superimposed. It refers to. any A mixture of enantiomers in a certain proportion is sometimes called a "racemic" mixture. "(±)" is used to specify a racemic mixture as needed. "Diastereomers" are... Stereoisomers having at least two chiral centers that are not mirror images of each other. This refers to the absolute stereochemistry, which is specified according to the Cahn-Ingold-PRelog RS system. If the compound is an enantiomer, the stereochemistry of each chiral carbon may be specified as R or S. Since the absolute configuration of a compound is unknown, it may be specified as (+) or (-) depending on the direction of polarization rotation (right or left) at the wavelength of the sodium D line. Some of the substances described herein contain one or more chiral centers, and therefore each chiral atom (R) or (S) Absolute three-dimensional arrangement Enantiomers, diastereomers, and other stereoisomers can be produced as defined by [the formulas provided], and the pharmaceutical compositions and methods include all possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)- can also be produced by chiral synthesis methods or chiral reagents, or by conventional techniques.

[0057] As used herein, the terms “enantiomer excess” or “enantiomer excess” can be calculated using the following formula. In the example below, the composition is one enantiomer 、 For example, if the S enantiomer makes up 90% and the other enantiomer 、 For example, it contains 10% of the R enantiomer. ee value = (90 - 10) / 100 = 80%

[0058] Therefore, a composition containing 90% of one enantiomer and 10% of the other enantiomer has an enantiomer excess of 80%. Let's assume Some of the compositions described herein contain at least about 50% enantiomer excess, about 75%, about 90%, about 95%, or about 99% of the S enantiomer. In other words, the composition has an enantiomer excess of the S enantiomer in the R enantiomer. In other embodiments, some of the compositions described herein contain at least about 50% enantiomer excess, about 75%, about 90%, about 95%, or about 99% of the R enantiomer. In other words, the composition has an enantiomer excess of the R enantiomer in the S enantiomer. For example, in some embodiments, the isomer / enantiomer may provide an ee value of the corresponding enantiomer and may be referred to as “optically concentrated,” “enantiomerically concentrated,” “enantiomerically pure,” and “non-racemic,” as used herein in the same sense. These terms mean that the weight percentage of one enantiomer is greater than the amount of the racemic composition in the other enantiomer compared to the amount of the control mixture (e.g., greater than 1:1 by weight). For example, S enantiomer no E Nanchiomar, The Enantiomer about 75 weight%It is present in an amount greater than about 50% by weight of the compound, or at least about 80% by weight. In some embodiments, the concentration is greater than about 80% by weight, providing a mixture that is "substantially enantiomerically concentrated," "substantially pure," or "substantially non-racemic," meaning that the weight of the enantiomer is at least 85% by weight of the composition, e.g., at least about 90% by weight of the formulation, and further e.g., at least about 95% by weight of one of the other enantiomers. In certain embodiments, the compound provided herein may be present in an amount of about 90% by weight of at least one enantiomer. In other embodiments, the compound may be present in an amount of at least about 95% by weight, about 98% by weight, or about 100% by weight of the enantiomer. In some embodiments, the compound is a (S)- and (R)-racemic mixture. In other embodiments, a process is provided in which the individual compounds (S) of the mixture are mainly a mixture of compounds, or (R) is mainly a mixture of compounds. For example, the compound mixture contains approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 99.5%, or more. In other embodiments, the compound mixture has an excess of (S)-enantiomer of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, about 99% to about 99.5%, or more. In other embodiments, the purity of the compound mixture (R)-enantiomer is greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.5%, or higher.In other embodiments, the compound mixture has an excess of (R)-enantiomer of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 95% to about 99.5%, about 85% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, and about 99% to about 99.5% or more.

[0059] In other embodiments, the compounds constituting the compound mixture are identical chemical entities except for their stereochemical configuration, i.e., (S)- or (R)-. For example, if a compound has a -CH(R)- unit and R is not hydrogen, Compounds having either an (S) configuration or an (R) configuration with respect to the -CH(R)- unit are identical chemical entities except for their stereochemical configuration. In some embodiments, the (S) isomers in a mixture of the same chemical substance are present in excess amounts of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 90% to about 99.5%, about 90% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, about 99% to about 99.5%, or more (S) enantiomers.

[0060] In another embodiment, the (R) isomer, which is the same chemical entity as the (S) isomer except for its stereochemical configuration, is present in proportions of about 55%, about 60%, about 65%, about 90%, about 95%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more. In some embodiments, the excess of (R)-enantiomers (excluding their stereochemical orientation) in a mixture of the same chemical is greater than 55% to about 99.5%, greater than 60% to about 99.5%, greater than 75% to about 99.5%, greater than 75% to about 99.5%, greater than 75% to about 99.5%, greater than 90% to about 99.5%, greater than 95% to about 99.5%, greater than 96% to about 99.5%, greater than 97% to about 99.5%, greater than 98% to about 99.5%, greater than 99% to about 99.5%, or more.

[0061] Enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), chiral salt formation and crystallization, or asymmetric synthesis.

[0062] Optical isomers can also be obtained by conventional methods of separating racemic mixtures using optically active acids or bases, for example, by forming diastereomer salts. Suitable acids include, but are not limited to, tartaric acid, diacetyl, dibenzoyl, dibenzoyltartaric acid, and camphorsulfonic acid. Separation of isomers from a mixture of optically active bases of these salts. teeth, This can be achieved by diastereomer crystallization. Alternatively, covalent diastereomer molecules can be synthesized by reacting an open compound with an active, optically pure acid or optically pure isocyanate. Synthetic enantiomers can be isolated by conventional methods such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to obtain compounds with concentrated enantiomers. Optically active compounds can also be obtained by using the active substance. In some embodiments, these isomers may be in the form of free acids, free bases, esters, or salts.

[0063] In certain embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, “tautomer” means This refers to isomeric forms of two or more compounds that interconvert through the movement of hydrogen atoms and changes in covalent bonds. (For example, from a single bond to a double bond, from a triple bond to a single bond, or vice versa). "Tautomerism" includes proton or proton transfer tautomerism, which is considered a subset of acid-base chemistry. "Proton transfer tautomerism" involves proton transfer accompanied by bond changes. The exact proportion of tautomers depends on various factors, including temperature, solvent, and pH. Between these, tautomerism is possible (e.g., in solution), and a chemical equilibrium of tautomerism can be reached. Tautomerism (i.e., a reaction that provides a pair of tautomers) is Can it be catalyzed by an acid or a base? or can occur regardless of the presence or absence of external factors. Such tautomerism conversion This involves converting ketones to enols, amides to imides, enamines to imines, and different forms of enamines. Conversion to formincluding, but not limited to. Specific examples of tautomers from ketone to enol include pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is the tautomerism between phenol and ketone. Specific examples of phenol and ketone tautomers include pyridine 4-phenol and pyridine-4-(1H)-one tautomers.

[0064] Unless otherwise specified, the structures described herein include one or more isotope-enriched atoms including it is meant to include compounds. For example, the compound has a structure in which one hydrogen is replaced by deuterium or tritium, or a structure enriched with carbon-13 or carbon-14 within the disclosed range.

[0065] The present disclosure also includes "isotope-labeled derivatives", which are pharmaceutically acceptable forms of the compounds listed herein, except for one or more atoms of different atomic masses commonly found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F and 36 isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine such as Cl. Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 those labeled with C) are useful for determining the tissue distribution of compounds and / or substrates. Tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be readily prepared and tested. Furthermore, deuterium (i.e., 2Substitution with heavier isotopes, such as H or D, can result in certain therapeutic benefits arising from higher metabolic stability (e.g., extended half-life in vivo or reduced dose requirements). The disclosed isotope-labeled compounds can generally be prepared by substituting an isotope-labeling reagent for a non-isotope-labeling reagent. Some embodiments provided herein may also include one or more non-natural atomic isotopes to produce such compounds. All isotope variants of the disclosed compounds, whether radioactive or not, are used herein within the scope of this disclosure. In some embodiments, radioactively labeled compounds may also be used to study the metabolism and tissue distribution of compounds by altering their metabolic pathway or rate, or other biological function.

[0066] The term "CDCl3" refers to deuterated chloroform.

[0067] The term "DMSO-d6" refers to deuterated dimethyl sulfoxide.

[0068] The term "LC-MS:(ESI)" refers to electro-ionized liquid chromatography-mass spectrometry.

[0069] As used herein, the term “change” refers to a relative change in physiological state. do Examples of changes include mutations, deletions, fusion with other proteins, overexpression, or low expression.

[0070] Compounds of the present invention: In one embodiment, the present invention provides a compound of formula (I), or a salt thereof, or a hydrate, solvate, or polymorph thereof. [ka]

[0071] The synthesis of the novel 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) having R chirality according to the present invention can be readily achieved by general synthetic researchers. For example, relevant methods and intermediates are disclosed herein. All patents, patent applications, and publications mentioned herein are either published in conventional journals or are only available on the internet. Regardless, For reference, see the whole thing. This is incorporated herein by reference.

[0072] Other methods for synthesizing compound (I) described herein can be readily modified from the references cited herein. These modifications and optimizations can be performed with the skills of a general engineer.

[0073] The present invention also provides compositions comprising an effective amount of the compounds described herein, or, where applicable, pharmaceutically acceptable salts, solvates, hydrates, or polymorphs of the compounds. The compositions of the present invention are preferably formulated for pharmaceutical use ("pharmaceutical compositions"). Here, the carrier is a pharmaceutically acceptable carrier. In the case of a pharmaceutically acceptable carrier, taking into account compatibility with other components of the formulation, the carrier must be "acceptable" and not harmful to the recipient at amounts commonly used in pharmaceuticals.

[0074] "Pharmacopoeia-acceptable carriers" or "pharmacopoeia-acceptable excipients" include all solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption retarders. Pharmaceutically acceptable carriers or excipients do not interfere with the pharmacological activity of the disclosed compound and are non-toxic when administered in a dose of the compound sufficient to deliver it. The use of such media and reagents for pharmaceutically effective substances is well known in the art. The use of the therapeutic compositions disclosed herein should be considered unless conventional media or reagents are incompatible with the active ingredient. Examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, sucrose, and glucose; starches such as potato starch and corn starch; celluloses and their derivatives such as sodium methylcellulose, cellulose acetate, and ethylcellulose; gelatin, tragacanth powder, talc, malt, cocoa butter, and suppository wax; oils such as peanut oil, safflower oil, cottonseed oil, olive oil, sesame oil, corn oil, and soybean oil; diols such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; buffers such as agar, magnesium hydroxide, and aluminum hydroxide; alginic acid, aldehydes, phosphates, phosphate buffers, sodium lauryl sulfate, and Non-toxic compatible lubricants such as magnesium stearate, colorants, coatings, release agents, sweeteners, flavorings and fragrances, surfactants for pharmaceutical dosage forms such as vitamin E polyethylene glycol 1000 succinate (SEDDS), Tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, electrolytes such as glycine, solubate, potassium solubate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or protamine sulfate, potassium hydrogen phosphate, disodium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic materials, polyacrylate, wax, polyethylene-polyoxypropylene block polymers, and cyclodextrins such as alpha, beta and gamma cyclodextrins, hydroxyalkyl cyclodextrins including 2- and 3-hydroxypropyl cyclodextrins. transformationOther solubilizing derivatives, such as chemically modified derivatives, that improve the delivery of compounds are available, but are not limited to these.

[0075] The pharmaceutical composition of the present invention can be administered in solid or liquid form. Examples include oral administration such as irrigation (aqueous or non-aqueous solution or suspension), tablets (for oral, subcutaneous, and systemic absorption), hard or soft capsules, pills, syrups, powders, granules, tongue pastes, and duodenal routes; parenteral administration including intravenous, intra-arterial, subcutaneous, and intramuscular administration; local administration via sublingual, catheter, or stent; intrathecal or intranasal administration via inhalation (e.g., as a fine powder or liquid aerosol).

[0076] Suitable aqueous and non-aqueous carriers in the pharmaceutical composition to be injected include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), and suitable mixtures thereof, vegetable oils such as olive oil, and organic esters such as ethyl oleate. The desired particle size of the dispersion can be maintained by using coating materials such as lecithin, and appropriate fluidity can be maintained by using surfactants. These compositions may include adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, lubricants, and / or antioxidants. The microbial preventive action of the compounds described herein is, for example, p-Hydroxybenzoic acid esters chlorobutanol, phenol sorbic acid This can be ensured by including various antibacterial and antifungal agents. Furthermore, the composition may include isotonic agents such as sugar and sodium chloride. Additionally, the absorption of the injectable dosage form can be extended by including delayed absorption agents such as aluminum monostearate and gelatin.

[0077] A method for producing such a formulation or composition includes the step of selecting the compounds and / or chemotherapy vehicles and one or more auxiliary components described herein. Generally, formulations are produced by uniformly structuring the compounds disclosed herein with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, shaping the product. Excipients are also within the scope of this disclosure, unless any conventional excipient medium is incompatible with the compounds provided herein, for example, by interacting with any other component of a pharmaceutically acceptable composition to produce undesirable biological or adverse effects.

[0078] In some embodiments, the concentrations of one or more of the disclosed compounds are approximately 100%, 90%, 80%, 70%, 60%, 50%, 40%, 14%, 13%, 12%, 11%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, and 0. The weight / weight ratio, weight / volume ratio, or volume / volume ratio may be less than 0.01%, approximately 0.009%, approximately 0.008%, approximately 0.007%, approximately 0.006%, approximately 0.005%, approximately 0.004%, approximately 0.003%, approximately 0.002%, approximately 0.001%, approximately 0.0009%, approximately 0.0008%, approximately 0.0007%, approximately 0.0006%, approximately 0.0005%, approximately 0.0004%, approximately 0.0003%, approximately 0.0002%, or approximately 0.0001%.

[0079] In some embodiments, the concentrations of one or more compounds disclosed herein are approximately 90%, approximately 80%, approximately 70%, approximately 60%, approximately 50%, approximately 40%, approximately 30%, approximately 20%, approximately 18.5%, approximately 18.25%, approximately 17.5%, approximately 17.25%, approximately 17%, approximately 16.5%, approximately 16.25%, approximately 16%, approximately 15.5%, approximately 15.25%, approximately 15%, approximately 14.5%, approximately 14.25%, approximately 14%, approximately 13.5%, approximately 13.25%, and approximately 13%. Approximately 12.5%, approximately 12.25%, approximately 12%, approximately 11.5%, approximately 11.25%, approximately 11%, approximately 10.75%, approximately 10.5%, approximately 10%, approximately 9.75%, approximately 9.5%, approximately 9.25%, approximately 9%, approximately 8.75%, approximately 8.5%, approximately 8.25%, approximately 8%, approximately 7.75%, approximately 7.5%, approximately 7.25%, approximately 7%, approximately 6.75%, approximately 6.5%, approximately 6.25%, approximately 6%, approximately 5.75%, approximately 5.5%, approximately 5.25%, approximately 5%, approximately 4.75%, approximately 4.5%, Approximately 4.25%, approximately 4%, approximately 3.75%, approximately 3.5%, approximately 3%, approximately 2.75%, approximately 2.50%, approximately 2.25%, approximately 2%, approximately 1.75%, approximately 1.50%, approximately 1.25%, approximately 1%, approximately 0.9%, approximately 0.8%, approximately 0.7%, approximately 0.6%, approximately 0.5%, approximately 0.4%, approximately 0.3%, approximately 0.2%, approximately 0.1%, approximately 0.09%, approximately 0.08%, approximately 0.07%, approximately 0.06%, approximately 0.05%, approximately 0.04%, approximately 0.03%, approximately 0.02%, approximately 0.0 It may exceed a weight / weight ratio, weight / volume ratio, or volume / volume ratio of 1%, approximately 0.009%, approximately 0.008%, approximately 0.007%, approximately 0.006%, approximately 0.005%, approximately 0.004%, approximately 0.003%, approximately 0.002%, approximately 0.001%, approximately 0.0009%, approximately 0.0008%, approximately 0.0007%, approximately 0.0006%, approximately 0.0005%, approximately 0.0004%, approximately 0.0003%, approximately 0.0002%, or approximately 0.0001%.In some embodiments, the concentration ranges of one or more compounds disclosed herein are approximately 0.0001% to 50%, approximately 0.001% to 40%, approximately 0.01% to 30%, approximately 0.02% to 20%, approximately 0.09% to 24%, approximately 0.08% to 23%, approximately 0.07% to 22%, approximately 0.06% to 24%, and approximately 0.2% to 2 The weight / weight ratio, weight / volume ratio, or volume / volume ratio may be 0%, approximately 0.1% to 21%, approximately 0.2% to 20%, approximately 0.3% to 19%, approximately 0.4% to 18%, approximately 0.5% to 17%, approximately 0.6% to 16%, approximately 0.7% to 15%, approximately 0.8% to 14%, approximately 0.9% to 12%, or approximately 1% to 10%. In some embodiments, the concentration range of one or more compounds disclosed herein may be in the weight / weight ratio, weight / volume ratio, or volume / volume ratio of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9%.

[0080] In some embodiments, the amounts of one or more compounds disclosed herein are approximately 10 grams, approximately 9.5 grams, approximately 9.0 grams, approximately 8.5 grams, approximately 8.0 grams, approximately 7.5 grams, approximately 7.0 grams, approximately 6.5 grams, approximately 6 grams, approximately 5.5 grams, approximately 5 grams, approximately 4.5 grams, approximately 4 grams, approximately 3.5 grams, approximately 3 grams, approximately 2.5 grams, approximately 2 grams, approximately 1.5 grams, approximately 1.0 grams, approximately 0.95 grams, approximately 0.9 grams, approximately 0.85 grams, approximately 0.8 grams, approximately 0.75 grams, approximately 0.7 grams, approximately 0.65 grams, approximately 0.6 grams, approximately 0.55 grams, approximately 0.5 grams, approximately 0.45 grams, approximately 0.4 grams, approximately 0.35 grams, approximately 0.3 grams, approximately 0.25 grams, approximately 0.2 grams, approximately 0.15 grams, approximately It may be 0.1 grams, approximately 0.09 grams, approximately 0.08 grams, approximately 0.07 grams, approximately 0.06 grams, approximately 0.05 grams, approximately 0.04 grams, approximately 0.03 grams, approximately 0.02 grams, approximately 0.01 grams, approximately 0.009 grams, approximately 0.008 grams, approximately 0.007 grams, approximately 0.006 grams, approximately 0.005 grams, approximately 0.004 grams, approximately 0.003 grams, approximately 0.002 grams, approximately 0.001 grams, approximately 0.0009 grams, approximately 0.0008 grams, approximately 0.0007 grams, approximately 0.0006 grams, approximately 0.0005 grams, approximately 0.0004 grams, approximately 0.0003 grams, approximately 0.0002 grams, or approximately 0.0001 grams or less.In some embodiments, the amounts of one or more compounds disclosed herein are approximately 0.0001 grams, approximately 0.0002 grams, approximately 0.0003 grams, approximately 0.0004 grams, approximately 0.0005 grams, approximately 0.0006 grams, approximately 0.0007 grams, approximately 0.0008 grams, approximately 0.0009 grams, approximately 0.001 grams, approximately 0.0015 grams, approximately 0.002 grams, approximately 0.0025 grams, approximately 0.003 grams, approximately 0.0035 grams, approximately 0.004 grams, approximately 0.0045 grams, approximately 0.005 grams, approximately 0.0055 grams, approximately 0.006 grams, approximately 0.0065 grams, approximately 0.007 grams, approximately 0.0075 grams, approximately 0.008 grams, approximately 0.0085 grams, approximately 0.009 grams, approximately 0.0095 grams, approximately 0.01 grams, approximately 0.015 grams, approximately 0.02 grams, approximately 0.025 grams, approximately 0.03 grams, approximately 0.035 grams, approximately 0.04 grams, approximately 0.045 grams Lamb, approximately 0.05 grams, approximately 0.055 grams, approximately 0.06 grams, approximately 0.065 grams, approximately 0.07 grams, approximately 0.075 grams, approximately 0.08 grams, approximately 0.085 grams, approximately 0.09 grams, approximately 0.095 grams, approximately 0.1 grams, approximately 0.15 grams, approximately 0.2 grams, approximately 0.25 grams, approximately 0.3 grams, approximately 0.35 grams, approximately 0.4 grams, approximately 0.45 grams, approximately 0.5 grams, approximately 0.55 grams, approximately 0.6 grams, approximately 0.65 grams The amount may be approximately 0.7 grams, 0.75 grams, 0.8 grams, 0.85 grams, 0.9 grams, 0.95 grams, 1 gram, 1.5 grams, 2 grams, 2.5 grams, 3 grams, 3.5 grams, 4 grams, 4.5 grams, 5 grams, 5.5 grams, 6 grams, 6.5 grams, 7 grams, 7.5 grams, 8 grams, 8.5 grams, 9 grams, 9.5 grams, or more than 10 grams.

[0081] In some embodiments, the amount of one or more compounds disclosed herein may range from about 0.0001 grams to about 10 grams, about 0.0005 grams to about 9 grams, about 0.001 grams to about 0.5 grams, about 0.001 grams to about 8 grams, about 0.005 grams to about 7 grams, 0.01 grams to about 6 grams, about 0.05 grams to about 5 grams, about 0.1 grams to about 4 grams, about 0.5 grams to about 4 grams, or about 1 gram to about 3 grams.

[0082] Specific preferred embodiments are disclosed herein. Composition for oral administration of compounds , and This is a pharmaceutical composition containing a pharmaceutical excipient suitable for oral administration. In some embodiments, (1) Optionally, A pharmaceutical composition for oral administration is provided, comprising (2) an effective amount of a disclosed compound, (3) an effective amount of one or more second agents, and (4) one or more pharmaceutically acceptable excipients for oral administration. In some embodiments, the pharmaceutical composition further comprises (4) an effective amount of a third reagent.

[0083] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. The pharmaceutical composition suitable for oral administration may be a capsule, cachet, tablet, or liquid, solution, aerosol spray or suspension, water or non-aqueous liquid, or a predetermined amount of the active ingredient including powder or granules. Oil-in-water emulsion or water-in-oil emulsion It can be used as individual dosage forms such as, any Pharmaceuticals can be manufactured by the following pharmaceutically acceptable methods, all of which involve the step of producing a composition by uniformly and tightly binding the active ingredient with a liquid carrier, liposome, or finely divided solid carrier, or both. Generally, pharmaceutical compositions are formed by uniformly and tightly mixing the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and shaping the product into a desired form as needed. For example, Tablets can be manufactured by compression or molding and may optionally contain one or more auxiliary ingredients. Tablets contain active ingredients in a free-flowing form, such as powder or granules. Optionally, Excipients include, but are not limited to, binders, lubricants, inert diluents, and / or surfactant or dispersant mixtures. andIt can be manufactured by mixing and compressing with a dedicated device. Molded tablets can be manufactured by molding a mixture of powder compounds moistened with an inert liquid diluent using a dedicated device. The tablets can be coated, uncoated, or nicked, and the active ingredient within them... Sustained release Alternatively, it may be formulated to provide controlled release, thereby containing glyceryl monostearate or teeth Some formulations, such as glyceryl distearate, can provide a sustained effect over a long period. Oral formulations can be manufactured as rigid gelatin capsules in which the active ingredient can be mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient can be mixed with water or an oily medium, such as peanut oil, liquid paraffin, olive oil, or a mixture thereof.

[0084] The active ingredient can be tightly combined with a pharmaceutically acceptable carrier by conventional drug mixing techniques. The carrier can be in various forms depending on the desired dosage form of the formulation. In the manufacture of pharmaceutical compositions for oral dosage forms, any of the usual pharmaceutical media such as water, glycol, oil, ethanol, flavoring agents, preservatives, colorants, and oral liquid formulations (e.g., liquids, solutions, elixirs) or aerosols can be used as carriers, or carriers such as starch, sugar, microcrystalline cellulose, diluents, granules, lubricants, binders, and disintegrants can be used for oral solid formulations. In some embodiments, lactose is not used. In some embodiments, the compound can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, calcium phosphate, sodium phosphate, calcium sulfate, sodium sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol for further formulation. For example, carriers suitable for the manufacture of solid oral dosage forms also include powder, capsule, and tablet forms. In some embodiments, tablets can be coated by standard aqueous or non-aqueous techniques.

[0085] Suitable materials for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural binders, synthetic gums such as gum arabic, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, curly boxymethylcellulose calcium, curly boxymethylcellulose sodium), polyvinylpyrrolidone, cellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0086] Examples of fillers suitable for use in pharmaceutical compositions and dosage forms include talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, glucose binders, kaolin, mannitol, silicic acid, Sol This includes, but is not limited to, vitol, starch, pregelatinized starch, and mixtures thereof.

[0087] Disintegrants are described herein as being usable in pharmaceutical compositions to provide tablets that disintegrate when exposed to an aquatic environment. Too much disintegrant may cause the tablets to disintegrate in the bottle. Too little will not be sufficient for disintegration, but it can alter the release rate and extent of the active ingredient in the dosage form. Therefore, the amount of disintegrant must be sufficient, but amounts that are too small or too large impair the release of the active ingredient should be avoided. The amount of disintegrant depends on the formulation and method of administration, but can be easily adjusted by those skilled in the art. About 0.5 to about 15% by weight or about 1 to about 5% by weight of disintegrant can be used in pharmaceutical compositions. Agar, alginate, calcium carbonate, and microcrystalline cellulose are examples of disintegrants for pharmaceutical compositions and for forming dosage forms. Cross-Culture Mellows ,cross Povidone, sodium acetate, potato or tapioca starch, other starches, pre-formed starches, clay, other algae, other celluloses, gums, or mixtures thereof are included but not limited to these.

[0088] Lubricants can be used to form pharmaceutical compositions. These include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, solubitol, mannitol, polyethylene glycol, other diols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Lubricants may also include silica gel, solidifying aerosols, or mixtures thereof. They may also be added in amounts less than about 1% by weight of the pharmaceutical composition.

[0089] When aqueous suspensions and / or elixirs are used for oral administration, the active ingredient may be a variety of sweeteners or flavorings, colorants or dyes. ,milk Reacting agents and / or suspending agents, and It can be combined with diluents such as water, ethanol, propylene glycol, glycerol, and combinations thereof.

[0090] Surfactants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. A suitable hydrophilic surfactant typically has an HLB value of at least about 10, while a suitable lipophilic surfactant may typically have an HLB value of less than about 10. An empirical parameter that can be used to characterize relative hydrophilicity and hydrophobicity is the hydrophilic-lipophilic equilibrium value HLB ("HLB" value). The lower the HLB value of a surfactant, the more lipophilic or hydrophobic it is and the higher its solubility in oil. On the other hand, Surfactants with higher HLB values ​​tend to be more hydrophilic. They have higher solubility in aqueous solutions. Hydrophilic surfactants are generally considered to have an HLB value greater than about 10, but the HLB value is generally not applicable to anionic, cationic, or amphoteric compounds. Similarly, lipophilic (i.e., hydrophobic) surfactants have an HLB value of about 10 or less. However, the HLB value of surfactants is generally not applicable to the common use of emulsions in industrial, pharmaceutical, and cosmetic applications. Maka It's just a rough guideline.

[0091] Hydrophilic surfactants can be either ionic or nonionic. Suitable ionic surfactants includeExamples of ionic surfactants include, but are not limited to, alkylammonium salts, fusidic acid salts, fatty acid derivatives of amino acids, oligopeptides and polypeptides, glycerol ester derivatives of amino acids, oligopeptides and polypeptides, lecithin and phospholipids and their derivatives, curlnitine fatty acid ester salts, alkyl sulfates, fatty acid salts, docusate sodium, acyl lactate, tartaric acid esters of mono / diacetylated mono / diglycerides, succinylated mono / diglycerides, citrate esters of mono / diglycerides, and mixtures thereof. Examples of ionic surfactants include, but are not limited to, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives, curlnitine fatty acid ester salts, alkyl sulfates, fatty acid salts, acyl lactate, diacetyl tartaric acid esters of mono / mono / diglycerides, succinylated mono / diglycerides, citrate esters of mono / diglycerides, and mixtures thereof. Examples of hydrophilic nonionic surfactants include, but are not limited to, alkyl glycosides, alkyl maltose, alkyl thioglycosides, lauroyl polyethylene glycol glycerides, polyethylene glycols such as polyethylene glycol alkylphenols, polyoxyalkylene alkyl ethers such as polyoxyalkylene alkylphenols, polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters, diol glycerol fatty acid esters, polyglycerin fatty acid esters, polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitol fatty acid esters, glycerol esters, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, polyoxyethylene sterols, and their derivatives, polyoxyethylene-polyoxypropylene block copolymers and mixtures thereof, hydrophilic transesterification products of polyethylene glycol sorbitan fatty acid esters and triglycerides, vegetable oils, and at least one polyol from hydrogenated vegetable oils.Possible polyols include glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or carbohydrates. Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 lauric acid, PEG-12 lauric acid, PEG-20 lauric acid, PEG-32 lauric acid, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-40 oleate, PEG-15 stearate, PEG-32 distearate-tractone, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glycerol trioleate, PEG-32 dioleate, PEG-20 glyceryl laure-tractone, PEG-30 glyceryl laureate, and PEG-20 glycate. PEG-20 glyceryl oleate, PEG-30 glycerol, PEG-30 glycerol, PEG-40 castor oil, PEG-40 castor oil, PEG-40 castor oil, PEG-40 castor oil, PEG-40 castor oil, PEG-40 castor oil, PEG-40 castor oil, PEG-40 castor oil, PEG-40 castor oil, PEG-40 castor oil, PEG-40 castor oil, PEG-40 castor oil, PEG-40 castor oil, PEG-40 castor oil. PEG-hydrogenated castor oil, PEG-60 Corn Oil, PEG-6 Glyceryl / Capric Glyceride, PEG-8 Capric Acid / Capylate Glyceride, Polyglyceride 1-10 Laurate, PEG-30 Cholesterol, PEG-25 Plant Sterols, PEG-30 Soybean Sterols, PEG-20 Trioleate, PEG-40 Solubitol Oleate, PEG-80 Solubitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Dodecyl Ether, POE-23 Lauryl Ether, POE-10 Oleyl Ether, POE-20 Oleyl Ether, POE-20 Stearin, PEG-100 Tocopherol Succinate, PEG-24 Cholesterol, Tween 40, Tween 60, Sucrose Monostearate 、Sucrose monolaurate 、 Sucrose monopartite 、 Suitable lipophilic surfactants include, but are not limited to, the PEG10-100 nonylphenol series, the PEG15-100 octylphenol series, and poloxamers. Suitable lipophilic surfactants include, but are not limited to, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, solubitol fatty acid esters, diol solubitol fatty acid esters, sterols and sterol derivatives, polyoxyethylene sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, and mono / diglyceride lactic acid derivatives.

[0092] Pharmaceutical compositions may include solubilizers to ensure good solubilization and / or dissolution of compounds and to minimize precipitation of compounds. Solubilizers can be particularly useful in pharmaceutical compositions for parenteral use, such as injectable pharmaceutical compositions. Solubilizers can be added to increase the solubility of other components, such as hydrophilic agents and / or surfactants, or to maintain the pharmaceutical composition as a stable or homogeneous solution or dispersion. Examples of suitable solubilizers include ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and its isomers, glycerol, pentaerythritol, solbitol, mannitol, and dimethyliso SolExamples include, but are not limited to, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, and other cellulose derivatives, alcohols and polyols such as cyclodextrin and cyclodextrin derivatives, and polyethylene glycol ethers with molecular weights of approximately 200 to 6000, such as tetrahydrofurfuryl alcohol PEG ether (tetrahydrofuran polyglycol ether) or methoxy PEG. Also include, 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidine, N-alkylcaprolactam, and dimethyl Seto Amides, amides such as polyvinylpyrrolidone and other nitrogen-containing compounds, ethyl propionate, esters, acetyl triethyl citrate, triethyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, ethyl butyrate, glycerol triacetate, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, delta-valine esters and their isomers, butyrolactone and its isomers and other esters, and other known dimethyl compounds. Seto Amides, dimethyliso Sol Examples of solubilizers include, but are not limited to, vid, N-methylpyrrolidone, diethylene glycol monoethyl ether, and water. Mixtures of solubilizers can also be used.

[0093] The amount of the solubilizer is limited to a bioacceptable amount and can be easily determined by those skilled in the art. The amount of the solubilizer is determined based on the total weight of the drug and other excipients, approximately 10 weight %, about 25 weight %, about 50 weight %, about 100 weight %, or up to approximately 200 weight % It can exist in a certain proportion Furthermore, the concentration can be reduced to approximately 5%, 2%, 1%, or less, as needed. Typically, the solubilizer is used in concentrations of approximately 1% to 100%. Typically about 5 weight % ~ approx. 25 weight Exists in % Possible.

[0094] The pharmaceutical compositions described may also include one or more pharmaceutically acceptable additives and excipients, flavoring agents, colorants, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. Preservatives include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Antioxidants include alpha-tocopherol, ascorbic acid, butylhydroxyanisole, butylhydroxy Tor En, monothioglycerol, potassium pyrosulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfate (Sodium bisulfate) and sodium sulfite are included, but are not limited to these. Chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), citrate monohydrate, disodium ethylenediaminetetraacetic acid, dipotassium ethylenediaminetetraacetic acid, edetate, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and triethylenediaminetetraethyl citrate. Antimicrobial preservatives include, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bromonitropylene glycol, cetrimonium bromide, cetylpyridinium chloride, chlorocresol, cresol, ethanol, glycerol, heptacidine, imidazolidine, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercury nitrate, and propylene glycol. Antifungal agents include, for example, Butyl p-hydroxybenzoate, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoateThese include, but are not limited to, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenol compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethanol. Acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include, for example, tocopherol acetate, cetetrimonium bromide, butylhydroxyanisole (BHA), and butylhydroxy Tor This includes, but is not limited to, ene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium pyrosulfite, potassium sulfite, potassium pyrosulfite, and methyl p-hydroxybenzoate. In certain embodiments, the preservative may be an antioxidant. In other embodiments, the preservative may be a chelating agent.

[0095] In some embodiments, as used herein, (1) an effective amount of the disclosed compound, at will (2) an effective amount of one or more second reagents, (3) one or more pharmaceutical excipients suitable for parenteral administration, and (4) a pharmaceutical composition for parenteral administration comprising an effective amount of a third reagent.

[0096] The above pharmaceutical composition is an aqueous or oily suspension or emulsion. It can be administered in this form. Sesame oil, corn oil, cottonseed oil or peanut oil, and elixirs, mannitol, glucose, or sterile aqueous solutions. appropriateDrug carriers can be used. Physiological saline solutions are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, benzyl alcohol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, sodium chloride, tragacanth, buffers, and vegetable oils can also be used. Appropriate fluidity can be maintained by using coating agents such as lecithin, or in the case of dispersions, by using surfactants to maintain the desired particle size. Prevention of microbial action can be achieved, for example, by using p-hydroxybenzoic acid esters, chlorobutanol, phenol, Sol This can be achieved with various antibacterial and antifungal agents such as vitate and thimerosal. The pharmaceutical composition is a suitable carrier containing physiological saline, glucose, or water. Using It may be injected, or a cyclodextrin, co-solvent (e.g., propylene glycol), or micelles (e.g., Tween80) may be used. Using It can be solubilized.

[0097] Sterile injectable solutions can be prepared by filtration and sterilization using a desired amount of the compounds disclosed herein, along with a solvent suitable for the various other components mentioned above. Typically, dispersions are prepared by incorporating various sterile active ingredients into a sterile carrier containing a basic dispersion medium and other suitable components listed above. Sterile injection solutions can be prepared using sterile powders, which can be prepared by vacuum drying or freeze-drying pre-sterilized and filtered active ingredients and the other ingredients mentioned above. Sterile injection formulations can also be prepared by solutions of non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol or sterile injection solutions. Acceptable carriers and solvents that can be used include, but are not limited to, water, Ringer's solution, and isotonic sodium chloride solutions. Sterile non-volatile oils are also commonly used as solvents or suspension media, as are synthetic monoglycerides. teeth This includes, but is not limited to, diglycerides. Furthermore, fatty acids, such as oleic acid, can also be used in the manufacture of injectable formulations. Injectable formulations can be sterilized, for example, by a bacterial-retaining filter, or by adding a sterilizing agent incorporated into a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media. Injectable compositions may contain about 0.1% to about 5% by weight of the compounds disclosed herein. weight % It may contain.

[0098] The pharmaceutical compositions provided herein can be formulated in solid, semi-solid, or liquid forms suitable for topical or external use, such as gelling agents, water-soluble gels, topical medications, creams, lotions, suspensions, foams, powders, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, physiological saline, and dimethyl sulfoxide (DMSO)-based solutions. Generally, carriers with higher density can provide areas that are exposed to the active ingredient for longer periods. On the other hand, solution formulations allow the active ingredient to come into more direct contact with the selected application site. For example, ointment formulations may have a paraffin base or a water-miscible base. . Alternatively, the active ingredient can be formulated as a cream using an oil-in-water cream base. The aqueous phase of the cream matrix may contain at least about 30% by weight of polyols such as propylene glycol, butane-1,3-diol, mannitol, solbitol, glycerol, polyethylene glycol, and mixtures thereof. The above pharmaceutical composition may also include a suitable solid or gel phase carrier or excipient that enhances the penetration of the compound through the skin barrier layer of the stratum corneum, assists in delivery, or enables such action. Examples include urea (e.g., urea), (e.g., menthol), amines, amides, alkanes, alkanols, water, and isopropyl myristate and sodium sulfate, pyrrolidone, glycerol monolaurate. To, Suru Examples include polymers such as phosphates, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polyethylene glycol.

[0099] The pharmaceutical compositions of the present invention can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient that is solid at room temperature but becomes liquid at rectal temperature and melts in the rectum to release the active ingredient. Such materials include, but are not limited to, polyethylene glycol, beeswax, and cocoa butter.

[0100] The pharmaceutical composition of the present invention can be administered by nasal aerosol or inhalation. This composition can be prepared using known pharmaceutical preparation techniques. It can be prepared as a physiological saline solution. , benzyl alcohol or other suitable preservatives, Absorption enhancers to increase bioavailability, fluorocarbon, or known in the relevant technical field Other solubilizers or dispersants It can contain .

[0101] When applying the therapeutic agent to a subject, it can be administered locally to the target site. To deliver the composition to the target site Various techniques can be used, such as injections, catheters, gels, stents, trocars, propellants, drug-releasing polymers, or other devices to provide internal access.

[0102] In another embodiment, the present invention provides an implantable medical device comprising the compound of the present invention or a composition comprising the compound of the present invention, so that the compound of the present invention provides an effective treatment.

[0103] In another embodiment, the present invention provides a method for injecting an implantable drug delivery device, comprising the step of contacting the drug delivery device with a compound or composition of the present invention. The implantable drug delivery device is a biodegradable polymer. Cap Cells or pills, non-degradable dispersible polymers Cap This includes, but is not limited to, cells and biodegradable polymer flakes.

[0104] In another embodiment, the composition of the present invention also includes a second therapeutic agent. The second therapeutic agent includes certain compounds or therapeutic agents that are known to exhibit beneficial properties when administered alone or in combination with any of the compounds of the general formula herein. Drugs that can be obtained in combination with these compounds include other kinase inhibitors and / or other chemotherapeutic agents for treating the diseases and disorders listed above. Such drugs are described in detail in the art. The second therapeutic agent is used for cancer Treatment or prevention Any drug that can be used for this purpose is preferable.

[0105] In another embodiment, the present invention provides independent dosage forms of the compounds of the present invention and a second therapeutic agent that are related to each other. As used herein, the term “related to each other” means that the individual dosage forms are packaged together or joined together, assuming that the individual dosage forms are provided or administered simultaneously (less than 24 hours, consecutively or simultaneously).

[0106] The pharmaceutical compositions of the present invention contain an effective amount of the compound of the present invention. As used herein, the term “effective amount” means an amount sufficient to reduce or improve the severity, duration, or onset of a disorder to be treated, prevent the progression of the disorder, halt the disorder to be treated, or enhance or improve the preventive or therapeutic effect of another treatment, when administered in an appropriate dosage regimen.

[0107] The effective dose of the compound of the present invention may range from about 0.001 to 1 mg / kg to about 500 mg / kg, about 0.01 mg / kg to about 50 mg / kg, and about 0.1 mg / kg to about 2.5 mg / kg. As will be understood by those skilled in the art, the effective dose will vary depending on the disease being treated, the severity of the disease, the route of administration, the patient's age, sex and overall health, the use of excipients, and other commonly used treatments (e.g., use of other drugs), and the judgment of the treating physician.

[0108] In the case of a pharmaceutical composition containing a second therapeutic agent, the effective amount of the second therapeutic agent is between approximately 20% and 100% of the dose typically used in a monotherapy regimen using only the drug. Preferably, it is between approximately 70% and 100% of the usual monotherapy dose.

[0109] Some of the second therapeutic agents referred to herein are expected to act synergistically with the compounds of the present invention. If so, the effective dose of the second therapeutic agent and / or the compounds of the present invention will be less than the dose required for monotherapy. The adverb The advantages include minimizing the effects, improving efficacy, facilitating administration or use, and / or reducing the overall cost of manufacturing or formulating the compound.

[0110] The treatment is as follows:

[0111] In another embodiment, the present invention provides a method for treating a subject who is suffering from or susceptible to a disease or disorder or its symptoms (e.g., those described herein), the method comprising the step of administering an effective amount of the compound or composition of the present invention to the subject. These diseases are well known in the art and are disclosed herein.

[0112] This treatment includes the treatment of diseases mediated by protein kinases, such as ATM kinase.

[0113] In another embodiment, the present invention provides a method for treating a disease in a subject, comprising administering to the subject a composition comprising any of the compounds of the general formulas herein.

[0114] In certain embodiments, the disease is mediated by ATM kinase.

[0115] In another embodiment, the disease is cancer or a proliferative disorder.

[0116] In another embodiment, Compounds of formula (I) and their pharmaceutically acceptable salts are expected to be useful in the treatment of diseases involving or partially mediated by ATM kinase activity (e.g., cancer and other medical conditions). This involves treatment using the compound of formula (I) or a pharmaceutically acceptable salt. As for cancers that can develop This includes, but is not limited to, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, bone cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, bile duct cancer, endometrial cancer, renal cell carcinoma, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, brain cancer, adenocarcinoma, skin cancer, or head and neck squamous cell carcinoma.

[0117] In another embodiment, the disease is a glioma.

[0118] In another embodiment, the disease is non-small cell lung cancer (NSCLC) with central nervous system metastases.

[0119] In another embodiment, the disease is a central nervous system disorder.

[0120] In one embodiment, the method of the present invention is used to treat a subject who is suffering from or susceptible to a disease or condition. These diseases, disorders, or symptoms thereof include, for example, those controlled by protein kinases (e.g., ATM protein kinases). The disease or symptoms of the disease may be, for example, cancer or proliferative disorders or disorders. Examples of diseases or symptoms of the disease may include ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), gastric cancer, lung cancer, liver cancer, multiple myeloma, melanoma, mesothelioma, brain tumor, membranous adenocarcinoma, skin cancer, or head and neck squamous cell carcinoma. The method described herein requires the treatment specifically described. Let's assume This includes subjects identified as such. Subject identification requires that the treatment is within the scope of the subject's or healthcare professional's judgment and may be subjective (e.g., opinion) or objective (e.g., measurable by test or diagnostic method).

[0121] In another embodiment, compounds (and compositions thereof) of the general formulas herein are other therapeutic agents (e.g., anticancer agents, neurotrophic agents, psychotropic agents, cardiovascular disease treatment agents, anti-obesity agents or anti-diabetic agents) Useful for treating diseases or disorders in subjects who have received treatment with and developed resistance to said treatment. In one embodiment, the methods of this specification involve administering a compound (or a composition thereof) of the formula of those methods to a subject who is resistant to treatment (or has been identified as resistant to treatment with gefitinib, erlotinib). In other embodiments, the subject thus responds to the treatment, and as a result, the disorder is regulated or improved prior to treatment with the compound of the formula of the present invention.

[0122] In another embodiment, the present invention provides a method for regulating the activity of intracellular protein kinases (e.g., protein kinases, kinases as described herein) comprising contacting cells with one or more compounds of the general formula herein.

[0123] The above anti-cancer treatments can be carried out as monotherapy, in combination with conventional compounds, or as radiotherapy, chemotherapy, or immunotherapy using the compounds of the present invention.Such chemotherapy may be administered concurrently, sequentially, or separately with the compounds of the present invention, and may include antiproliferative / antitemogenic agents, alkylating agents (e.g., cisplatin, oxaliplatin, carlboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea), antimetabolites (e.g., antifungal acids such as gemcitabine, 5-fluorouracil, and tegafur, larcitrexed, methotrexate, cytarabine, and hydroxyurea), and antitumor antibiotics (e.g., doxorubicin, bleomycin, adriamycin, daunorubicin, epirubicin, idarubicin, mitomycin). Cell proliferation inhibitors such as C, anthracycline drugs such as gentamicin and grilamycin, antimitotic agents (e.g., vincaryl caroids such as vincristine, alkaloids such as paclitaxel and tacrolimus, and polokinase inhibitors), and topoisomerase inhibitors (e.g., etoposide of epipodophyllotoxin, pyridine glycosides, acridine, topotecan and camptothecin), antihormones (e.g., tamoxifen, flubasetrand, toremifene, raloxifene, droloxifen and difoxifen), antiandrogens (e.g., amylamine, flutamide, nilutamide acetate and cyclopropanone), LHRH antagonists or LHRH agonists (e.g., This may include, but is not limited to, one or more categories of antitumor agents, such as goserelin, leuprolide, and bucolin; progesterone (e.g., megestrol acetate); aromatase inhibitors (e.g., anastrozole, letrozole, buxazole, and exemestane); 5α-reductase inhibitors such as finasteride; anti-invasive agents (e.g., c-Src kinase family inhibitors such as cetatinib, dasatinib, and bosutinib, and bosutinib); and metalloproteinase inhibitors such as horse, urokinase plasminogen activator receptor, or antibody heparinase inhibitors.Examples of inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin trademark], anti-EGFR antibody panitumumab, anti-ErbB antibody cetuximab (Elvit, C225), and those by Stem et al.). A critical review of oncology / hematology disclosed growth factor receptors or growth factor receptor antibodies (2005, Vol. 54, pp. 11-29). Aurora kinase inhibitors are also tyrosine kinase inhibitors such as epidermal growth factor family inhibitors (e.g., EGFR family inhibitors such as gefititinib, erlotinib, icotinib, afatinib, dacomitinib, and tagrisso; erbB2 tyrosine kinase inhibitors such as lapatinib and neratinib); hepatocyte growth factor family inhibitors; platelet-derived growth factor family inhibitors such as imatinib and / or nilotinib; and serine / threonine kinase inhibitors (e.g., RAS / RAF signaling inhibitors, e.g., soraphenib). Bevacizumab (Avastin), an antibody that inhibits the effects of vascular endothelial growth factor, such as phenyltransferase inhibitors (including tipifanib and ronafanib), MEK and / or AKT kinase cell signaling inhibitors, c-kit inhibitors, abl fusion kinase inhibitors, PI3 kinase inhibitors, PLT3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors, aurora kinase inhibitors, CDK2 and / or CDK4 inhibitors, and angiogenesis inhibitors. 商標), as well as VEGF receptor tyrosine kinase inhibitors such as vandetanib, batalanib, sunitinib, axitinib, pazopanib and cedilanib, compounds that act through other mechanisms (e.g., tricarboxyaminoquinoline, integrin αV3 function inhibitors and angiogenesis inhibitors), ISIS 2503, anti-ras gene antisense (nucleic acid) (e.g., olaparnib, niraparib, rucaparib, talazoparib), antisense (nucleic acid) therapies including substitution of abnormal genes such as the above-mentioned abnormal p53 or abnormal BRCA1 or BRCA2, transfecting the immunogenicity of T cells using cytokines such as interleukin 2, 4 and granulocyte-macrophage-stimulating factor, and transfecting immune cells such as cytokine-transfected dendritic cells and cytokine-transfected anti-idiotype antibodies to control regulatory T cells, medullary suppressor cells, or IDO, TDO This includes methods to reduce unresponsiveness to immunosuppressive cell function, such as enzymes using cytosine deaminase, thymidine kinase, and bacterial nitroreductase, and gene-directed prodrug therapy (GDEPT) methods that improve patient resistance to chemotherapy or radiotherapy, such as multidrug-resistant gene therapy immunotherapy, and the use of antibodies derived from tumor-associated antigens such as proteins or peptides derived from NY-ES0-1, MAGE-3, WTI, or HER2 / neu, or other drugs commonly used as a base agent or phagevant in cancer treatment plans (e.g., antiemetics, anti-anemia agents).

[0124] As used herein, the term “combined administration” refers to a second therapeutic agent. of , in combination with the compound of the present invention, Single dosage form (For example, as a composition comprising the compound of the present invention and the second therapeutic agent described above), or independently. Multiple dosage formsThis means that it can be administered as follows. Alternatively, additional reagents may be administered before, in connection with, or after the administration of the compound of the present invention. In such combination therapy, the compound of the present invention and the second therapeutic agent are administered by conventional methods. Administering a subject to a composition of the present invention comprising the compound of the present invention and the second therapeutic agent does not preclude the administration of the same therapeutic agent, another second therapeutic agent, or the compound of the present invention independently to the subject at any other point in the course of treatment. The benefits of the effects obtained from the use of the combination should not be lost by administering the second component sequentially, separately, or with delays in administration.

[0125] In one embodiment of the present invention, when the second therapeutic agent is administered to a subject, the effective amount of the compound of the present invention is lower than the effective amount of the second therapeutic agent when the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than the effective amount of the second therapeutic agent when the compound of the present invention is not administered. In this way, As a result of using any of these drugs in high doses Undesirable side effects can be minimized. The potential benefits for those skilled in the art are obvious (including, but not limited to, improved dosing regimens and / or reduced drug costs).

[0126] In another aspect, the present invention provides for the use of any of the compounds of the general formula herein, alone or in combination with one or more of the second therapeutic agents described herein, as a single composition or in another dosage form, in the manufacture of a pharmaceutical product for the treatment or prevention of a disease, disorder or symptom described herein in a subject. Another aspect of the present invention is the use of the compounds of the general formula herein for the treatment or prevention of a disease, disorder or symptom described herein in a subject.

[0127] In other embodiments, the methods herein further include methods for monitoring a subject's response to therapeutic administration. Such monitoring includes periodic sampling of the subject's tissues, body fluids, cerebrospinal fluid, samples, cells, proteins, chemical markers, genetic material, etc., as markers or indicators of the treatment plan. In other methods, by evaluating the applicability of relevant markers or indicators to such treatment, the subject may determine whether such treatment is necessary. Let's assume It is pre-screened or identified as such.

[0128] In one embodiment, the present invention provides a method for monitoring the progress of treatment. This method involves determining a diagnostic marker (marker) in a subject who is suffering from, susceptible to, or diagnosed (e.g., screening, assay) a disorder or condition described herein (e.g., any target or cell type described herein modified by the compounds herein), and the subject , disease The illness or its symptoms To treat Sufficient treatment valid A certain amount of the compound of the present invention is administered. The level of the marker determined by this method may be compared to a well-known level in a healthy normal control or other affected patient to establish the patient's condition. In a preferred embodiment, a second level of the marker in the patient is measured at a later time than the measurement of the first level, and the two levels are compared to monitor disease progression or the effectiveness of the treatment. In a particular preferred embodiment, the pre-treatment level of the marker in the patient is measured before initiating treatment according to the present invention, and the pre-treatment level of the marker may be the same as the level of the marker in the patient after initiation of treatment to determine the effectiveness of the treatment.

[0129] In a particular embodiment of the method, the level of a marker or marker activity in a subject is determined at least once. The marker level can be compared, for example, with another measurement from the same patient, another patient, or another subject previously or subsequently obtained from the subject, to determine whether the treatment according to the present invention has the desired effect, and the dose level can be adjusted as needed. The determination of the marker level can be performed using any suitable sampling / expression assay method known in the art or described herein. Preferably, a tissue or liquid sample is taken from the subject first. Examples of suitable samples include blood, urine, cerebrospinal fluid, tissue, mouth or cheek cells, and hair samples including roots. Other suitable samples are known to those skilled in the art. Measurement of protein levels, ctDNA, cfDNA and / or mRNA levels (e.g., marker levels) in the sample can be performed using any suitable technique known in the art, including but not limited to enzyme immunoassay, ELISA, radiolabeling techniques, Western blotting / chemiluminescence, real-time PCR, electrochemical signals, etc.

[0130] The present invention also provides kits for treating diseases, disorders, or symptoms described herein. Such kits include (1) a pharmaceutical composition containing one of the compounds of the general formulas herein or a salt thereof, or a prodrug thereof, or a salt thereof, or a hydrate, solvate, or polymorph thereof, in a container, and (2) a description of a method for treating a disease, disorder, or symptom described herein using the pharmaceutical composition. The container may be any container or other sealed or sealable device that can contain the pharmaceutical composition. Examples include a bottle, a reservoir bottle having separate or multiple chambers, each compartment or section containing a single dose of the composition, and each compartment containing a single dose doseThe composition comprises a separate foil package for dispensing the single-dose composition. The container may be any conventional shape or form known in the art and may be made of pharmaceutically acceptable material such as a paper or corrugated box, a glass or plastic bottle or can, a resealable bag (e.g., used for "refilling" tablets into another container), or a single-dose blister pack may be A single dose can be dispensed and used according to the treatment schedule. The container used may depend on the exact dosage form in question; for example, conventional cardboard boxes are not typically used because they contain liquid suspensions. Multiple containers can be used together in a single package to sell a single dosage form. For example, tablets may be placed in bottles and then housed in boxes. Preferably, the container is a blister pack.

[0131] The kit may further include information and / or instructions from a physician, pharmacist, or subject. These memory aids may include numbers printed on each compartment or divider containing medication (corresponding to the number of days the procedure or capsule should be taken), or weeks printed on each compartment or divider, or cards containing the same type of information.

[0132] When the present invention is used in combination with ATM kinase, the enantiomer purity of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention is approximately 55% to approximately 99.5%, approximately 60% to approximately 99.5%, approximately 65% ​​to approximately 99.5%, approximately 70% to approximately 99.5%, approximately 75% to approximately 99.5%, approximately 80% to approximately 99.5%, approximately 85% to approximately 99.5%, approximately 90% to approximately 99.5%, approximately 95% to approximately 99.5%, approximately 96% to approximately 99.5%, and approximately 97% to approximately 99.5%. %,about It is over 98% to approximately 99.5%, over approximately 99% to approximately 99.5%, or higher.

[0133] The compounds described herein can be evaluated for their biological activity using protocols known in the art, including, for example, those described herein. Some of the compounds described herein exhibit unexpectedly excellent properties (e.g., metabolic stability, high selectivity, low efflux rate, high permeability, It is not a substrate for the efflux of P-glycoprotein (P-gp). These factors indicate that it is a promising candidate for a potential therapeutic agent.

[0134] All references cited herein, whether electronic, printed, computer-readable, or otherwise, are referred to in their entirety. detail This includes, but is not limited to, abstracts, articles, journals, publications, textbooks, papers, technical data sheets, internet sites, databases, patents, patent applications, and patent gazettes, which are explicitly incorporated into the book.

[0135] The present invention will be described in detail below with reference to examples. The following examples will not limit the present invention in any way, but will be helpful to those skilled in the art in further understanding it. It should be noted that many modifications and improvements are possible by those skilled in the art without departing from the spirit of the invention. All of these are within the scope of the present invention. [Examples]

[0136] Example 1. Preparation of 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I)

[0137] 1.1 The intermediate 3,3-difluoro-1-methylpiperidine-4-amine A6 was synthesized as follows. [ka] Step 1: At 25°C, a solution of 2-methylpropane-2-sulfinamide (404 g, 3.33 mol) and TI(OEt)4 (1003 g, 4.44 mol) was added to THF (2.5 L) and then added dropwise to a solution of A1 (500 g, 2.22 mol). The reaction mixture was stirred at 70°C for 1 hour, then cooled to 0°C. Next, the reaction mixture was added at 0°C to NaBH4 (166 g, 2.0 equivalents) in THF (2.5 L) in a separate reactor. The reaction mixture was stirred at 0°C for 0.5 hours, then slowly warmed to 25°C and stirred for 0.5 hours. Methanol (2.5 L) was added and stirred for 0.5 hours. The mixture was added to a container with saturated NaCl solution (2.5 L) and stirred at 25°C for 1 hour. The reaction mixture was extracted twice with DCM (2.5 L). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to obtain product A2.

[0138] Step 2: Add the crude A2 solution in ethyl acetate (1 L) at 25°C to HCl (5.0 equivalents, 4 M in ethyl acetate), stir at 25°C for 1 hour, and filter to obtain A3.

[0139] Step 3: After adding water (1.5L) to filter cake A3, At 25℃ 20% NaOH aqueous solution Using The pH was adjusted to 8-9. The solution was added. The mixture was extracted with DCM (1.5 L), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Triethylamine (267 g, 1.2 equivalents) was added to the crude product, followed by (Boc)2O (577 g, 1.2 equivalents), and the mixture was stirred at 25°C for 1 hour. Next, 10% citric acid solution (2 L) was added to the mixture, and the organic layer was separated. The aqueous layer was extracted with DCM (1 L). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain A4 (430 g, 59.4%).

[0140] Step 4: Pd(OH)2 / C (20%, w / w) was added to a solution of A2 (380g, 1.0 equivalent) in MeOH (3.8L), and the mixture was stirred at 20 atmospheres at 25°C for at least 1 hour. The mixture was filtered, and the filtrate was concentrated to obtain A5 (250g, 91%).

[0141] Step 5: Add HCHO (37% in water, w / w) to a solution of A5 (236 g, 1.0 equivalent) in MeOH (2.4 L) at 5°C. After stirring the reaction mixture at 5°C for 1 hour, NaBH(OAc)3 was added little by little until LC-MS indicated that A5 had disappeared. Add 10% to the reaction mixture. NaOH Add the aqueous solution 、 25℃ pH The solution was adjusted to 8-9 and stirred at 25°C for 0.5 hours. After evaporating methanol under vacuum, the residue was extracted with ethyl acetate (1.2 L). The organic layer was separated and concentrated. After adding HCl (5.0 equivalents, 4 M in ethyl acetate), it was filtered. The filtered cake was collected and dried under vacuum at 45°C to obtain the HCl salt of A6 (125.1 g, 53.7%).

[0142] 1.2 Synthesis of 1-(3,3-difluoro-1-methylpiperidine-4-yl)-8-(6-methoxypyridine-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinoline-2-one derivative (I):

[0143] The synthesis route is as follows: [ka]

[0144] Step 1: To a mixture of B1 (25 g, 79.48 mmol) in DMA (500 mL), 2 (14.92 g, 99.34 mmol) and DIEA (30 g, 238.744 mmol) were added. The mixture was heated at 60°C for 5 hours. The mixture was cooled to room temperature and injected into a mixture of DCM (500 mL) and H2O (250 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and... Decompression Concentration was performed below to obtain B2 (15g, 44.09%) as an off-white solid. LC-MS: (ESI) m / z = 404[M+H]+.

[0145] Step 2: At room temperature, NaOH (8 g, 100 mmol) was added to a mixture of B2 (15 g, 33.35 mmol) in MeOH / H2O / THF (300 mL / 150 mL / 150 mL) and heated at 50 °C for 2 hours. The mixture was cooled to room temperature and concentrated under vacuum to remove the organic layer. The residue was added to H2O (150 mL), 10% HCl was added to adjust the pH to 4, and the mixture was filtered to obtain B3 (11 g, 78.57%) as an off-white solid: ¹H NMR (400 MHz, DMSO-d6) δ 12 -11.85 (m, ¹H), 8.80-8.65 (m, ¹H), 8.01-7.67 (m, ²H), 5.35-5.01 (m, ¹H), 3.68-3.51 (m, ¹H), 3.30-3.22 (m, ¹H), 3.17 (d, J = 8.0 Hz, ¹H), 2.92 (d, J = 12.0 Hz, ¹H), 2.63-2.53 (m, ¹H), 2.47-2.29 (m, ⁴H), 2.07-1.92 (m, ¹H).

[0146] Step 3: TEA (28.2 mL, 82.5 mmol) was added to a solution of B3 (11 g, 27.5 mmol) and DPPA (7.12 mL, 33 mmol) in DMF (350 mL). The mixture was stirred at 60°C for 2 hours. After the reaction mixture cooled to room temperature, it was poured into H2O (500 mL). The precipitate was filtered, washed with H2O (50 mL), and the filter cake was dried to obtain B4 (10 g, 91.82%) as a brown solid.

[0147] Step 4: Add DMF-DMA (15.15 g, 126 mmol) to a mixture of B4 (10 g, 25.2 mmol) in DMF (250 mL) at room temperature. Then, heat the mixture at 80°C. inThe mixture was heated for 2 hours, cooled to room temperature, and then filtered. The filtrate was washed with H2O and dried to obtain B5 (9 g, 86.95%) as an off-white solid. 1H NMR(400MHz,DMSO-d6) δ 9.05-8.95(m,1H),8.75-8.36(m,1H),8.04-7.71(m,2H),5.37-5.16(m,1H),3.67-3.55(m,1H),3.50(s,2H),3 .30-3.23(m,1H),2.93(d,J=8.0Hz,1H),2.74-2.53(m,1H),2.48-2.32(m,4H),2.07-1.93(m,1H).LC-MS:(ESI) m / z=411,413[M+H]+.

[0148] Step 5: A mixture of B5 (2 g, 4.87 mmol), (6-methoxypyridine-3-yl)boronic acid (888 mg, 5.844 mmol), PdCl2 (dtdppf) (318 mg, 4.87 mmol), and K2CO3 (2 g, 14.61 mmol) in 1,4-dioxane / H2O (100 mL / 40 mL) was degassed twice with N2 and then heated at 80°C for 3 hours. The mixture was injected into a mixture of DCM (500 mL) and H2O (500 mL), the organic layer was washed with brine, dried over anhydrous Na2SO4, and purified by column chromatography (DCM:MeOH = 30:1) to obtain Product 1 (1.2 g, 56.07%) as a white solid. 1H NMR(400MHz,DMSO) δ 8.94 (d,J =25.6 Hz,1H),8.80 (s,1H),8.68 (dd,J =39.6,2.0Hz,1H),8.38 (s,1H),8.29-8.10(m,2H),8.05-7.95 (m,1H),7.01 (dd,J=18.8,8.8Hz,1H),5.45-5.25(m,1H),3.94(d,J=4.8Hz,3H),3.73-3.61(m,1H),3.56(d,J=33.2Hz,3H),3.44- 3.35(m,1H),3.15-2.87(m,1H),2.72-2.53(m,1H),2.48-2.39(m,2H),2.35(s,2H),2.10-1.91(m,1H).LC-MS:(ESI) m / z=440.1 [M+H]+.

[0149] Dissolve the sample in approximately 150 mL of EtOH and fill a chiral Pre-SFC column (WaterRs SFC150, 250 × 25 mm, 10 μm Enantiomers were separated by injecting 7 mL at a time using a DAISELCHIRALPAK® AS SFC column (flow rate 70 g / min). Mobile phase: supercritical CO 2 / EtOH = 55:45, at a wavelength of 214 nm (Monitoring). The R enantiomer was dissolved in 2,2,2-trifluoroethanol and concentrated to obtain an amorphous free base product.

[0150] The above method The product obtained by It is amorphous, and different solvent systems and In the heating process The crystal form changes. It is difficult to manufacture solid dosage forms under pharmaceutical processing conditions. Therefore, there is a need to further prepare preferred free base crystal forms, salt forms and salt crystal forms of 1-(3,3-difluoro-1-methylpiperidine-4-yl)-8-(6-methoxypyridine-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinoline-2-one derivatives that have excellent physicochemical properties and can be advantageously used in pharmaceutical processing and pharmaceutical compositions.

[0151] Example 2. Preparation of the free base crystalline form of the (R)-1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention. 100-120 mg of an amorphous sample of the (R)-1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of formula (I) was added to 1-1.5 mL of a mixture of methyl tert-butyl ether / water (1:10, v / v), stirred at 50°C for 6 hours, and the lower solid layer was separated by centrifugation to obtain the free base crystalline form. XRPD detection confirmed that the solid was in the free base crystalline form.

[0152] Example 3. Preparation of the fumarate crystalline form of the (R)-1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention. Weigh approximately 500 mg of a sample of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative represented by formula (I) (i.e., (R)-1-(3,3-difluoro-1-methylpiperidine-4-yl)-8-(6-methoxypyridine-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinoline-2-one(I)), place it in a 100 ml vial, and add 8 ml of chloromethane / methanol (1:1 ~ 132.5 mg of fumaric acid (1:1.7, v / v) was added and stirred at room temperature for approximately 4 hours. The moist solid at the bottom was then separated by centrifugation. XRPD detection revealed that the solid was in the fumarate crystalline form.

[0153] Example 4. The free base and salt crystalline forms of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention are characterized by XRPD patterns.

[0154] The information for the XRPD device is as follows:

[0155] XRPD spectrum Using a Bruker X-ray powder diffraction analyzer measurement The XRPD parameters are shown in Table 1.

[0156] [Table 1] Figure 1 shows the XRPD (X-ray powder diffraction) pattern of the free base crystal form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) prepared according to the method described in this example, and its specific properties are shown in Table 2 below.

[0157] [Table 2]

[0158] Figure 2 shows the XRPD (X-ray powder diffraction) pattern of the fumarate crystal form of 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) prepared according to the method described in this example, and its specific properties are shown in Table 3 below. [Table 3]

[0159] The "d value" is the distance between two adjacent crystal planes in a crystal lattice in angstroms, and "I%" is the relative intensity.

[0160] From Figure 1 Karu As shown above, the XRPD patterns of the free base crystal form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) provided by the present invention are 2θ = 5.08, 10.19, 10.76, 12.56, 13.37, 14.84, 15.33, 16.08, 16.53, 16.87, 19.12, 19.5 The values ​​are 1, 20.30, 20.51, 21.22, 22.65, 23.26, 23.72, 24.77, 25.56, 26.67, 27.04, 28.38, 28.77, 29.26, 29.60, 30.09, 31.05, 32.61, 32.97, 34.90, 36.96, 38.21, and 38.50, and the error range for the above 2θ values ​​is ±0.2.

[0161] From Figure 2 Karu As shown above, the XRPD patterns of the fumarate crystal forms of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) provided by the present invention are 2θ = 6.07, 6.78, 8.60, 10.99, 12.21, 12.57, 13.66, 14.55, 16.09, 16.49, 17.32, 18.04, 18.37, 18.64, 19.41, 20.24, 20.96, 22.15, 23.54, 24.82, 25.40, 26.06, 26.81, 28.23, 30.19, 33.40, and 36.25, with an error range of ±0.2 for the above 2θ values.

[0162] After testing, the error range of the 2θ value can also be ±0.2. Those skilled in the art should understand that these diffraction peaks do not represent the details of the diffraction peaks of the free base and fumarate crystal forms of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I). The 2θ values ​​of the X-ray powder diffraction pattern are The stated value may vary slightly depending on the measuring device, sample preparation conditions, and batch differences. These values ​​are not considered absolute values. Furthermore, it should be understood that the absolute intensity of the peak can also change due to orientation effects. Therefore, the intensities shown in this invention are illustrative and should not be used for absolute comparison.

[0163] Example 5.1 Biological activity of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) Using ODYSSEY CLx(LI-COR), phosphorylation of ATM protein using MCF-7 cells was detected. Approximately 25 μl of cells were seeded into each blank 384-well plate. After 24 hours, proportionally diluted compounds and etoposide were added using a pin tool, and incubated at 37°C for 1 hour. Cells were then fixed at room temperature for 20 minutes by adding 25 μl of 8% paraformaldehyde. Cells were permeabilized with 1XPBS containing 0.1% Triton X-100, blocked by adding 50 μl of Odyssey blocking buffer, and shaken at room temperature for 1.5 hours. The blocking buffer was removed, and 20 μl of anti-pKAP1 antibody was added. Shake gently The samples were incubated overnight at 4°C. 20 μl of secondary antibody (IRDye 800CW Goat anti-Rabbit IgG antibody) solution containing DNA stain DRAQ5 (1 / 4,000) was added to each plate well, diluted with blocking buffer containing 0.1% Tween-20 (1 / 5,000), and the secondary antibody was incubated for 1 hour. The solution was washed off. Phosphorylation of ATM protein. To evaluate inhibition Using ODYSSEY CLx (LI-COR) right away I scanned the plate. In cell-based inhibition of ATM phosphorylation, the compounds of the present invention are effective in inhibiting pATM signaling on MCF-7 (<1 nM), and therefore the ATM protein by For DNA damage repair Caused by It has the potential to overcome resistance to radiotherapy or chemotherapy.

[0164] Example 6.1 Blood-brain barrier permeability of (I) 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative To determine whether quinazoline derivative (I) can cross the blood-brain barrier (BBB), the test compound was orally administered to rats. Four hours after administration, the rats were killed, and blood and brain tissue were collected and the concentrations of the test compound were analyzed. Brain permeability is defined as the ratio of the concentration of the compound in brain tissue to the concentration in plasma. Crossing the blood-brain barrier is the ratio of the free concentration of the drug in brain tissue to the concentration of the drug in plasma. Unbound type It is a ratio of concentrations. P-glycoprotein crosses the blood-brain barrier. It exists It is a leaked protein, the substrate To the neurosurgery department To excrete. Breast cancer resistance protein (BCRP) is the blood-brain barrier It exists It is a leaked protein, the substrate To the neurosurgery department It is excreted. Table 4 shows the ability of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) to cross the blood-brain barrier.

[0165] [Table 4]

[0166] In detecting the rate at which compound (I) crosses the blood-brain barrier, Unbound type Circuits and plasma Unbound type The concentration ratio is higher than 30%, and it is not a substrate of P-glycoprotein or BCRP. It can cross the blood-brain barrier, It may be possible to achieve effective drug concentrations in the brain. It is used for the treatment and prevention of central nervous system diseases such as gliomas, cancer brain metastases, meningeal metastases, and brain cancer. ExtracranialIt may reduce the risk of dose-limiting toxicity.

[0167] Example 7. Pharmacological efficacy of 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) in combination with radiotherapy for glioma in an intracranial pdx mouse model. Patient's primary tumor tissue (brain tumor, approximately 100,000 cells) of The mice were implanted intracranially, and one week later, 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) (5 mg / kg or 10 mg / kg, QD) was orally administered for 5 days 15 minutes before radiation (2 Gy). Group 1 was the control group. No drugs were administered. The second group received radiation therapy (2 Gy). Only this will be done for 5 days. The third group was administered 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) (5 mg / kg, orally, once daily) 15 minutes before radiotherapy (2 Gy) for 5 days. The fourth group was administered 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) (10 mg / kg, orally, once daily) 15 minutes before radiotherapy (2 Gy) for 5 days. As shown in Figure 3, Groups 3 and 4: Combination therapy with drug and radiotherapy Compared to the first group (control group) and the second group (radiation only, 2 Gy for 5 days), Lifespan statistically significant Extend (P<0.01), dose-dependent in animal models sex This was shown.

[0168] Example 8.1 Equilibrium solubility of the derivative (I) of the salt crystal form of (3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one and its salt crystal form. Experimental method: Approximately 10 mg of solid samples (free base and various salt and crystalline forms) were weighed, 1.5 mL of water was added, and the mixture was equilibrated at room temperature for 24 hours. Then, 0.3 mL of the turbid solution was taken out, and the lower solid layer and the supernatant were separated by centrifugation. The supernatant was filtered through a 0.45 μm (PTFE) filter, and then the free base was extracted. base The concentration was tested.

[0169] [Table 5]

[0170] From Table 5 Karu Thus, the free base crystalline form and the fumarate crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention have good equilibrium solubility in water. Preferably, the fumarate crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention has an equilibrium solubility in water greater than 5 mg / mL. This is very beneficial for drug absorption.

[0171] Example 9. Stability study The free base crystalline form and fumarate crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention exhibit one-week physical and chemical stability. When stored for one week at 25°C / 60%RH and 40°C / 75%RH, they are stable in terms of physical and chemical properties. During the heating process, the TGA chart showed no significant change in the crystalline form of Example 4. The DSC chart showed that the free base crystalline form and fumarate crystalline form exhibited good stability. As shown in Figures 4A and 4B, the free base crystalline form showed no significant weight loss during the heating process and had a melting point of approximately 206°C. As shown in Figures 5A and 5B, the fumarate crystalline form showed no significant weight loss during the heating process and had a melting point of approximately 220°C. Such properties are useful for the preparation and processing of tablets.

[0172] Example 10. Good bioavailability of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention. In rat pharmacokinetic studies, the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention was used. Three rats in Group 1 were administered 1-2 mg / kg intravenously, and three rats in Group 2 were administered 5-10 mg / kg orally. Blood samples were collected at 7 time points after administration: 0.25, 0.5, 1, 2, 4, 8, and 16 hours.The concentration of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention in blood was measured, and the peak area and half-life were calculated. The method for calculating bioavailability was as follows: (Peak area when drug is administered orally / Oral dose) / (Peak area when drug is administered intravenously / Intravenous dose) × 100% Therefore, the free base crystalline form and fumarate crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative (I) of the present invention have good bioavailability, both of which are >35% compared to the amorphous form (oral bioavailability <35% and half-life <10 hours), and have a longer half-life (>10 hours), and are better. Con Priance and Better medication compliance and lower medication burden (Rat half-life of free base crystalline form: 22 hours, fumarate crystalline form: 11.2 hours) is provided. Furthermore, the compound of the present invention is human aldehyde oxidase ( (hAOX) It is not a substrate Furthermore, because it has a long half-life (>20 hours), For the treatment and / or prevention of cancer brain metastases, meningeal metastases, gliomas, glioblastomas, DIPG and other central nervous system diseases, It exhibits low metabolic clearance, potentially allowing for effective drug concentrations / efficacy in the brain.

[0173] Human aldehyde oxidase (hAOX) is a cytosolic drug-metabolizing enzyme expressed in the human liver. Similar to CYP enzymes, it significantly contributes to the oxidation of a considerable amount of quinoline derivatives, but acts only in the absence of NADPH cofactor. Drugs that are substrates of AOX often exhibit high metabolic clearance, resulting in low exposure and, consequently, reduced efficacy in humans (Lepri et al. PNAS, 2017, pp. E3178). ~ E3187).

[0174] The free base crystalline form and fumarate crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of the present invention have good solubility in water, do not undergo changes in crystalline form during heating, and have good stability.

[0175] The free base crystalline form and fumarate crystalline form of the 1-(3,3-difluoropiperidine-4-yl)-imidazo[4,5-c]quinoline-2-one derivative of the present invention possess unexpectedly excellent physicochemical properties and are beneficial for use in pharmaceutical processing and pharmaceutical compositions. This can be applied to the treatment of cancer, cancer with CNS metastasis, brainstem tumors, primary brain cancer, DIPG, or gliomas, particularly when combined with DNA double-strand break inducers. At the same time, providing qualitative and quantitative information regarding efficacy and safety is crucial for further research on the efficacy and safety of such solid drugs.

[0176] The specific embodiments of the present invention have been described above. Those skilled in the art should understand that the present invention is not limited to the above-described embodiments, and that various modifications and alterations can be made within the scope of the claims without affecting the essence of the invention.

Claims

1. The crystalline form of the free base of the 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivative of the present invention, wherein the derivative is represented by formula (I): 【Chemistry 1】 ， wherein the XRPD pattern of said crystalline form has major characteristic peaks at 10.2, 16.9, 20.3, 25.6 2θ and secondary characteristic peaks at 10.8, 12.6, 13.5, 14.8, 16.1, 20.6, 21.2, 23.3 2θ, the error range of said 2θ values ​​being ±0.

2.

2. A process for preparing a crystalline form of the free base of a 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivative, comprising the steps of: adding an amorphous form of the 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivative sample of formula (I) to an organic solvent (50-150 mg / mL), wherein formula (I) is represented as follows: 【Chemistry 2】 and, and agitating at 50° C. and centrifuging to separate the bottom solid to obtain the free base crystalline form, wherein 50-150 mg of the amorphous derivative of formula (I) is added per ml of the organic solvent, the first organic solvent being methyl tert-butyl ether / water (1:10, v / v).

3. A crystalline form of a fumarate salt of a 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivative represented by formula (I): 【Chemistry 3】 wherein the XRPD pattern of said crystalline form has major characteristic peaks at 2θ of 6.8, 8.6, 12.2, 13.7, 17.3, 19.4, 26.1, and said secondary characteristic peaks are at 6.1, 11.0, 14.6, 16.1, 16.5, 18.0, 20.2, 22.1, 26.8, and the error range of said 2θ values ​​is ±0.

2.

4. A method for producing a crystalline form of the fumarate salt of the 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivative according to claim 3, comprising the steps of: 【Chemistry 4】 and 2-2.5 equivalents of fumaric acid to the organic solvent, stirring the mixture at 22-28° C. and collecting the solid by centrifugation, wherein 10-200 mg of the 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivative of formula (I) is added per ml of organic solvent, and the first organic solvent is dichloromethane / methanol (1:1, v / v).

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