Solid form of an isoquinolinone derivative, a method for producing the same, a composition containing the same, and a method for using the same.

Abstract

To provide a solid form of a PI3K inhibitor.SOLUTION: A solid form containing a compound of the formula (I) or its salt, or solvation, or a mixture thereof, as well as the compound for treating diseases and states relating to the kinase activity containing PI3 kinase activity, a pharmaceutical composition, and a method are provided. Furthermore, a method of preparing polymorph of the compound, cocrystal, and amorphous form, as well as a method of preparing these pharmaceutical compositions is provided.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This application, filed on September 14, 2015, is incorporated herein by reference in its entirety. U.S. Provisional Application No. 62 / 218,486 and U.S. Provisional Application No. 62 / 218,493 filed on September 14, 2015 They claim priority. [Background technology]

[0002] (1. Background) Cellular activity can be regulated by external signals that stimulate or inhibit intracellular events. The process by which stimulative or inhibitory signals are transmitted into and within cells to induce intracellular responses is This is called signal transduction. Over the past few decades, the cascade of signal transduction events has been revealed. It was found to play a central role in various biological responses. Deficiencies in various components of the pathway can lead to numerous forms of cancer, inflammatory disorders, metabolic disorders, and vascular and nerve damage. It has been found to be the cause of numerous diseases, including disease (Gaestel et al., Curren t Medicinal Chemistry (2007) 14: 2214-2234).

[0003] Kinases are a class of important signaling molecules. Kinases are generally... They can be classified into protein kinases and lipid kinases, and certain types of kinases are bispecific. Protein kinases exhibit phosphorylation (i.e., phosphorylation) of other proteins and / or themselves. It is an enzyme that performs autophosphorylation. Protein kinases are generally based on their substrate utilization. Next, there are three main groups: tyrosine kinases, which primarily phosphorylate substrates on tyrosine residues. (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl), mainly serine and / or Serine / threonine kinases that phosphorylate substrates on threonine residues (e.g., mTorC1, mT (orC2, ATM, ATR, DNA-PK, Akt), and on tyrosine, serine, and / or threonine residues It can be classified as a bispecific kinase that phosphorylates the substrate of [the substance].

[0004] Lipid kinases are enzymes that catalyze the phosphorylation of lipids. These enzymes, as well as the resulting Phosphorylated lipids and lipid-derived bioactive organic molecules are involved in cell proliferation, migration, adhesion, and differentiation. They play a role in many different physiological processes, including membrane-related processes. Certain lipid kinases are involved in membrane processes. These processes involve the phosphorylation of lipids contained within or associated with the cell membrane. It catalyzes. An example of such an enzyme is phosphoinositide kinase (e.g., PI3-kinase). -ase, PI4-kinase), diacylglycerol kinase, and sphingosine kinase It can be listed.

[0005] Phosphoinositide 3-kinase (PI3K) is derived from phosphatidylinositol or phosphoinositide. A unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on citides. The PI3K family consists of molecules with different substrate specificities, expression patterns, and regulatory mechanisms. It contains 15 types of kinases. Class I PI3K (p110α, p110β, p110δ, and p110γ) are commonly used. Normally activated by tyrosine kinase or G protein-coupled receptors, it is called PIP3. Lipid products are produced, which are then used in downstream effects, such as those in the Akt / PDK1 pathway. This involves mTOR, Tec family kinases, and Rho family GTPases. Class II PI3K of and III plays an important role in intracellular transport through the synthesis of PI(3)P and PI(3,4)P2. To accomplish.

[0006] The PI3K signaling pathway is one of the most highly mutated systems in human cancer. PI3K signaling is also an important factor in many other human diseases. Signal transduction is involved in allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease. Disorders related to chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, and complications of diabetes, and It is involved in many disease conditions, including inflammatory complications of the cardiovascular system such as acute coronary artery syndrome. .

[0007] Many PI3K inhibitors have been developed. Such compounds are often soluble in solution. When this occurs, its activity is the first thing to be evaluated, but solid-state characteristics such as polymorphism are important. It plays a role. The polymorphisms of the active pharmaceutical ingredient, for example, the PI3K inhibitor, include crystallinity, melting point, and chemical reactivity. , various chemical properties including solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. And may have physical properties. These properties may be used when processing or manufacturing the active pharmaceutical ingredient and drug product. It can have a direct effect on the manufacturing ability. Furthermore, polymorphism can be obtained from various manufacturers. Polymorphism is often a factor that is subject to regulatory review regarding the "identity" of drug products. Compounds such as rufarin sodium, famotidine, and ranitidine have been evaluated. Polymorphism can affect the quality, safety, and / or efficacy of drug products, such as kinase inhibitors. Therefore, polymorphisms of PI3K inhibitors and methods for producing polymorphisms of PI3K inhibitors can be developed. Research on elephants is a remarkably useful area of ​​research in the development of active pharmaceutical ingredients (APIs).

[0008] Furthermore, PI3K inhibitors have been shown to treat various human diseases and disorders (for example, in clinical trials). It is used for the production of active pharmaceutical ingredients intended for human use, the latest pharmaceuticals. Good Manufacturing Practices (GMP) apply. The procedure controls the level of impurities and conforms to the specified specifications. It is necessary to ensure that API products that consistently meet these criteria are produced. Therefore, it is particularly suitable for human use on a commercial scale, that is, above all, safe, P is scalable, efficient, economically feasible, and / or has other desirable characteristics. There is a significant need for methods to manufacture I3K inhibitors. Among several entities, In particular, disclosed herein addresses these needs and offers exemplary advantages. This is a polymorph of the PI3K inhibitor provided. [Overview of the project]

[0009] (2. Overview) Provided herein is a compound of formula (I) (also referred to herein as compound 1): [ka] or its salt, or solvate (e.g., hydrate), or solvate of the salt, or these This specification provides a solid form containing a mixture of the following. It is a method.

[0010] The solid forms provided herein include the hydrate, anhydrous, and solvate of compound 1, and the solid forms thereof. This includes, but is not limited to, salts and cocrystals of these compounds. Solid forms provided herein It is useful as an active pharmaceutical ingredient for the preparation of formulations used in animals or humans. Therefore, the embodiments described herein include the use of these solid forms as the final drug product. In some embodiments, the manufacture, processing, formulation, and / or storage of the final drug product are among the applications. Improved properties required, such as powder flowability, compression properties, tableting properties, and stability. To provide a solid form useful in preparing a final dosage form with specific properties and excipient compatibility characteristics. Some embodiments herein describe a single-component crystalline form and / or multi-component compound comprising the compound of formula (I). We propose a crystalline form and a pharmaceutical composition containing a diluent, excipient, or carrier that is acceptable as a pharmaceutical. To provide.

[0011] In one embodiment, the solid form is crystalline. The state further includes co-formations. In one embodiment, the solid state containing compound 1 and co-formations In one embodiment, the solid state is cocrystalline. In another embodiment, the solid state is amorphous.

[0012] Also provided herein are pharmaceutical compositions including amorphous forms provided herein. These are single-unit dosage forms, administration regimens, and kits.

[0013] This specification also provides for the composition and amorphous form provided herein. This is a method for treating, preventing, and managing various disorders. The method is a method for treating or managing such disorders. To administer a therapeutically effective amount of the compound provided herein to a patient in need of treatment. This includes. Furthermore, methods for preventing various diseases and disorders are provided, such To patients in need of prophylactic treatment, administer a prophylactically effective amount of the compound provided herein. This is a method that includes the following.

[0014] Furthermore, provided herein are compounds of formula (I), or salts or solvates thereof (e.g. For example, a hydrate, or a solvate of a salt thereof, or a method for preparing a mixture thereof. ru.

[0015] Furthermore, this specification provides for the presence or quantity of solid forms provided herein. A method for analyzing a material, wherein the compound of formula (I), or its salt or solvate (for example) The material provides a solvate of a salt thereof (a hydrate), or a mixture thereof. and; and feature analysis methods are used to compare the features obtained from the material with the reference signature features. This includes determining whether signature features associated with the solid form are present in the material. Here, the presence of a feature substantially identical to the reference signature feature is the presence of the solid form in the material. This is a method to demonstrate that.

[0016] (3. Incorporation by citation) All publications, patents, and patent applications referred to herein are entirely and individually published. It is not permissible to include a work, patent, or patent application as if it were specifically and individually incorporated by reference. It is incorporated herein by reference to the same extent as indicated. [Brief explanation of the drawing]

[0017] (4. Brief explanation of the drawing) [Figure 1] Figure 1 shows a typical X-ray powder diffraction (XRPD) pattern of compound 1, form 1.

[0018] [Figure 2]Figure 2 shows a typical overlay of the thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of compound 1, form 1.

[0019] [Figure 3] Figure 3 shows a typical gravitational vapor deposition (GVS) isotherm plot for form 1 of compound 1.

[0020] [Figure 4] Figure 4 shows a typical XRPD pattern of compound 1, form 2.

[0021] [Figure 5] Figure 5 shows typical overlays of TGA and DSC thermograms for compound 1, form 2.

[0022] [Figure 6] Figure 6 shows a typical GVS isotherm plot for form 2 of compound 1.

[0023] [Figure 7] Figure 7 shows another representative overlay of the TGA and DSC thermograms of compound 1, form 2.

[0024] [Figure 8] Figure 8 shows another representative XRPD pattern of compound 1, form 2.

[0025] [Figure 9] Figure 9 shows a typical XRPD pattern of compound 1, form 3.

[0026] [Figure 10] Figure 10 shows typical overlays of TGA and DSC thermograms for compound 1, form 3.

[0027] [Figure 11] Figure 11 shows a typical XRPD pattern of form 4 of compound 1.

[0028] [Figure 12] Figure 12 shows typical overlays of TGA and DSC thermograms for form 4 of compound 1.

[0029] [Figure 13] Figure 13 shows a typical XRPD pattern of form 5 of compound 1.

[0030] [Figure 14] Figure 14 shows typical overlays of TGA and DSC thermograms for compound 1, form 5.

[0031] [Figure 15] Figure 15 shows a typical XRPD pattern of compound 1, form 6.

[0032] [Figure 16] Figure 16 shows typical overlays of TGA and DSC thermograms for form 6 of compound 1.

[0033] [Figure 17] Figure 17 shows a typical GVS isotherm plot for form 6 of compound 1.

[0034] [Figure 18] Figure 18 shows a typical XRPD pattern of form 7 of compound 1.

[0035] [Figure 19] Figure 19 shows typical overlays of TGA and DSC thermograms for form 7 of compound 1.

[0036] [Figure 20] Figure 20 shows a typical XRPD pattern of compound 1, form 8.

[0037] [Figure 21] Figure 21 shows a typical ORTEP plot for form 2 of compound 1.

[0038] [Figure 22] Figure 22 shows a typical XRPD pattern of the cocrystal morphology P1C3 of compound 1 and L-tartaric acid.

[0039] [Figure 23] Figure 23 shows representative TGA and DSC analyses of the cocrystal morphology P1C3 of compound 1 and L-tartaric acid.

[0040] [Figure 24] Figure 24 shows a typical XRPD of the cocrystal morphology P1C9 of compound 1 and salicylic acid.

[0041] [Figure 25] Figure 25 shows a representative TGA vs. DSC analysis of the cocrystal morphology P1C9 of compound 1 and salicylic acid.

[0042] [Figure 26] Figure 26 shows a representative XRPD analysis of the P2C9 morphology of the cocrystal of compound 1 and salicylic acid.

[0043] [Figure 27] Figure 27 shows representative TGA and DSC analyses of the P2C9 morphology of the cocrystal of compound 1 and salicylic acid.

[0044] [Figure 28] Figure 28 shows a typical GVS analysis of the cocrystal morphology P1C3 of compound 1 and L-tartaric acid.

[0045] [Figure 29] Figure 29 shows the solubility of compound 1 in ethanol / water and the corresponding ethanol content in isolated compound 1.

[0046] [Figure 30] Figure 30 shows a typical crystal structure of Form 1 of Compound 1, obtained by heating 13.5 mg / ml of Compound 1 in 80% ethanol / water to 60°C and then cooling to room temperature.

[0047] [Figure 31] Figure 31 shows a typical TGA analysis of spray-dried compound 1.

[0048] [Figure 32] Figure 32 shows representative TGA analyses of spray-dried compounds 1 and PVP / VA 64.

[0049] [Figure 33] Figure 33 shows representative TGA analyses of spray-dried compounds 1 and HPMC-AS.

[0050] [Figure 34] Figure 34A shows the conversion (% area) after 2 hours for the coupling reaction between 4-iodo-1-methyl-1H-pyrazole and trimethylsilylacetylene; Figure 34B shows the reaction conversion (% area) after 24 hours; Figure 34C shows the product / diyne ratio (% area) after 24 hours; and Figure 34D shows the diyne content (% area) after 24 hours. [Modes for carrying out the invention]

[0051] (5. Detailed explanation) (5.1 Definition) Unless otherwise defined, all technical and scientific terms used herein are defined as those of the art. It has the same meaning as it is generally understood to mean.

[0052] As used herein and in the claims, the singular forms "one (a)" and "one (an)" are used. ) and “the” are plural unless the context clearly indicates otherwise. Includes the target of the instruction.

[0053] Regarding physical properties such as molecular weight or chemical properties such as chemical formula, the range used herein is defined as the range of physical properties or chemical properties. If so, the scope and all combinations and partial combinations of specific embodiments within it are included. It is intended to be used as such. When used herein, "about" and "approximate" are used. The term "ely)" is used in combination with a numerical value or a range of values, and refers to the range of values. If the range is, for example, within the range of experimental variability (or within the range of statistical experimental error), It may deviate to an extent that is considered reasonable, and therefore the range of the numerical value or value may, for example, , 1% to 15%, 1% to 10%, 1% to 5%, 0.5% to 5%, and 0. This means that there may be a difference of 5% to 1%. As disclosed herein, the range of numerical or value. When the term "about" precedes a given value, it includes all embodiments of that value. For example, "about 3°C" discloses an embodiment in which the temperature is "3°C". The term "approximately" is used interchangeably throughout this disclosure. The term "between" includes the number of endpoints at both ends of the range. For example, "3-5 The range described by "" includes the numbers "3" and "5". A tilde (i.e., "~") before a number, a number, or a range of values ​​means "about" or "about This indicates "(relatively)".

[0054] As used herein, unless otherwise specified, "drug" or "biological agent" or "Second activator" refers to a biological, pharmaceutical, or chemical compound or other part of a compound. Non-limiting examples include simple or complex organic or inorganic molecules, peptides, and tannins. Proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamin derivatives, carbohydrates Examples include toxins or chemotherapy compounds. Various compounds, such as small molecules and oligonucleotides. Mers (e.g., oligopeptides and oligonucleotides), as well as based on various core structures. Synthetic organic compounds can be synthesized. Furthermore, various natural sources, such as plants or Animal extracts and the like can provide compounds for screening. Those skilled in the art will find this opening It can be easily recognized that there are no restrictions regarding the structural properties of the indicated drug.

[0055] As used herein, unless otherwise specified, the term "agonist" is a mark of a mark. Whether by enhancement or induction of the activity of the target protein, or by enhancement of the expression of the target protein or It has the ability to induce or enhance the biological function of a target protein, whether through inducement. It refers to a compound. Therefore, the term "agonist" refers to the biological role of the target protein. Defined in relation to the target. The agonists provided herein are specifically interacting with the target. It can act (for example, bind) but the target protein is not a member. By interacting with other members of the signaling pathway, it enhances the biological activity of target proteins. Compounds that induce or enhance sexuality are also specifically included in this definition.

[0056] As used herein, unless otherwise specified, "antagonist" and "inhibitor" refer to the same term. The terms are used interchangeably and refer to the inhibition of the activity of the target protein. Whether it is due to the inhibition of the expression of the target protein, the biological effects of the target protein This refers to compounds that have the ability to inhibit a function. Therefore, the terms "antagonist" and "inhibitor" are used. The term "agent" is defined in relation to the biological role of the target protein. The antagonists provided in the book interact specifically with (e.g., bind to) the target. Yes, but the target protein may interact with other members of the signaling pathway in which it is a member. Compounds that inhibit the biological activity of target proteins by acting upon them are also specifically included in this definition. In one embodiment, the biological activity inhibited by the antagonist is the development of tumors. The birth, growth, or transmission of, or, for example, undesirable, such as in autoimmune diseases. It is related to the immune response.

[0057] As used herein, unless otherwise specified, the terms "anticancer agent," "antitumor agent," or "Chemotherapy agents" refer to any drug that is useful in treating tumor conditions. One type of anticancer drug is... Lass contains chemotherapeutic agents. When used herein, unless otherwise specified, "chemotherapeutic agents" The "method" involves administering one or more chemotherapy drugs and / or other drugs intravenously, orally, intramuscularly, intraperitoneally, or bladder-administered. By various methods including internal, subcutaneous, transdermal, oral, or inhalation, or in the form of suppositories, This means administering it to cancer patients.

[0058] As used herein, unless otherwise specified, the term “cell proliferation” refers to cells. This refers to the phenomenon in which the number of cells changes as a result of cell division. In one embodiment, this term refers to cell morphology. This also includes cell growth that has changed in accordance with proliferative signals (e.g., increased size).

[0059] Where used herein, unless otherwise specified, "co-administration" and "in combination with administration" are used. The terms "to be given" and their grammatical equivalents refer to the administration of two or more drugs simultaneously or sequentially. This includes administering the drug to an animal in one of the following ways. In one embodiment, both drugs and / Or their metabolites are present simultaneously in the animal. In one embodiment, co-administration is performed separately. Simultaneous administration in the composition, administration at different time points in separate compositions, or both drugs present This includes administration in one composition.

[0060] As used herein, unless otherwise specified, “effective dose” or “therapeutic effective dose” The term includes, but is not limited to, disease treatment as defined herein. i. The amount of the compound described herein that is sufficient to achieve the intended use or effect. This refers to the therapeutically effective dose, which is the dose used for the intended purpose (in vitro or in vivo), or the dose used to treat the condition. The subject and disease state, for example, the subject's weight and age, the severity of the disease, the mode of administration, etc. This can vary depending on the circumstances, and this can be determined by those skilled in the art. The word induces specific responses in target cells, such as a decrease in platelet adhesion and / or cell migration. It can also be applied to the dosage to be derived. The specific dosage depends on the specific compound selected. The dosage regimen to follow, and whether it is administered in combination with other compounds. The timing of administration, the tissue to which it is administered, and the physical delivery system through which it is transported all depend on these factors. They are different.

[0061] As used herein, unless otherwise specified, "treat," "treat," and "reduce" are used. The terms “to do” and “to improve” are used interchangeably herein and are not limited to… However, it refers to a method for obtaining beneficial or desired results, including therapeutic benefits. One embodiment In this context, therapeutic benefit means the eradication or improvement of the underlying disease being treated. In this case, the therapeutic benefit is that the patient may still have an underlying condition. To achieve improvement in the patient, one or more physiological symptoms associated with the underlying disease are addressed. It is obtained by eliminating or improving it.

[0062] As used herein, unless otherwise specified, the terms "prevention" and "prevent" The term refers, but is not limited to, any method for obtaining beneficial or desired results, including preventative benefits. In one embodiment, the preventive benefit is the delay or disappearance of the onset of a disease or illness. , delay or disappearance of the onset of symptoms of a disease or illness, slowing down the progression of a disease or illness, This includes stopping, reversing, or any combination thereof. To gain a preventative benefit, The composition may be administered to patients at risk of developing a specific disease, or to those with physiological symptoms of the disease. Even if a diagnosis of this disease can be made in a patient who is complaining of one or more symptoms, It can be administered even if a diagnosis of the disease cannot be made.

[0063] As used herein, unless otherwise specified, “signaling” means irritant or This is a process in which inhibitory signals enter and are transmitted within cells, triggering intracellular responses. A modulator of a signaling pathway is located within the same specific signaling pathway. This refers to compounds that regulate the activity of the cellular proteins mentioned above. Modulators are signal transduction compounds. It can either enhance (agonist) or inhibit (antagonist) the activity of a molecule.

[0064] When used herein, unless otherwise specified, the term "selective" applies to biological agents. The terms "inhibit" or "selectively inhibit" refer to direct or interactive interactions with the target. By using this method, target signaling activity is selected compared to off-target signaling activity. This refers to the ability of a drug to effectively reduce something.

[0065] As used herein, unless otherwise specified, the term "in vivo" refers to the subject matter. This refers to events that occur within the body.

[0066] As used herein, unless otherwise specified, the term "in vitro" refers to the case of This refers to events that occur outside the body of an elephant. For example, an in vitro assay is performed outside the target assay. It includes any assay that is performed. In vitro assays utilize living or dead cells. This includes cell-based assays. In one embodiment, the in vitro assay involves intact cells. This also includes cell-free assays that do not utilize cells.

[0067] The "targets" for administration include humans (i.e., men or women of any age group). For example, targeting children (e.g., infants, children, adolescents) or adults (e.g., young adults, middle-aged adults) Humans or elderly people), and / or other primates (e.g., crab-eating macaques, rhesus macaques); This includes commercial mammals such as crickets, pigs, horses, sheep, goats, cats, and / or dogs. Mammals; and / or chickens, ducks, geese, quail, and / or turkeys, etc. This includes, but is not limited to, birds, including commercial birds.

[0068] As used herein, unless otherwise specified, “radiotherapy” means treating a patient. Using routine methods and compositions known to the public, a radiation emitter, for example, alpha-particles Emitted radionuclides (e.g., actinium and thorium radionuclides), low-energy transitions (L ET) Radiation emitters (i.e., beta emitters), conversion electron emitters (e.g., strontium-8) 9 and samarium-153-EDTMP, or, but not limited to, high radiation including X-rays, gamma rays, and neutrons. This means exposure to energy radiation.

[0069] As used herein, the term “combining” means one or more chemical entities. This refers to associating one or more chemical entities with another. Combining means combining one or more compounds a mixture of one or more compounds (the same or different chemical entities) in solid, liquid, or gaseous form. This includes methods of adding to a liquid solution or a multiphase liquid mixture. The act of combining is , one or more compounds that react with one or more compounds (the same or different chemical entities) Methods (e.g., bond formation or cleavage; salt formation, solvate formation, chelation, or other non- This includes binding and alteration (association). The act of combining is, for example, isomerization (e.g., tautomerism). The transformation of one or more compounds by (formation, separation of one isomer from another isomer, or racemization) It can include.

[0070] When used herein, unless otherwise specified, the “one-pot” method refers to the desired raw A method for preparing a product, wherein all reactants are added simultaneously or sequentially, and the desired result is obtained. Before the formation of the product is substantially complete, separate, isolate, and / or remove any intermediates formed. This refers to a method in which purification is not performed. The "one-pot" method is performed in a single container. Preferably, this may be carried out in multiple containers.

[0071] As used herein, the term “recover” refers to the method and process disclosed herein. The act of obtaining one or more compounds by collection during and / or thereafter, as disclosed herein. In the method for separating one or more compounds from one or more other chemical entities during and / or thereafter Therefore, it includes, but is not limited to, the act of obtaining one or more compounds. The term "collection" This refers to any act known in the art for this purpose, including filtration, solidification of mother liquor, etc. Decanting from a body to obtain one or more compounds, and liquid media in solutions or other mixtures This includes evaporating the mixture to obtain a solid, oily substance, or other residue containing one or more compounds. However, it is not limited to these. Among the characteristics known in the art, solids are particularly crystalline and non-crystalline. Crystalline (acrystalline), partially crystalline, amorphous, containing one or more polymorphs, powder, granules They can have various particle sizes or uniform particle sizes. Oily substances have different colors and viscosities. It is possible to make one or more solid forms non-uniform, and among the features known in the art, one or more solid forms are made non-uniform. It can be included as a mixture. The term "separation" is used in the art for this purpose. This refers to any publicly known action, which includes, for example, seeding or seedless actions. (dless) Crystallization or other precipitation techniques (e.g., adding a poor solvent to the solution to induce precipitation of the compound) To do; to heat the solution and then cool it to induce the precipitation of the compound; the surface of the solution (By scratching with an instrument to induce the precipitation of a compound), and using distillation techniques, one or more This includes, but is not limited to, isolating compounds from solutions or mixtures. 1 or more The recovery of the compound allows for the preparation of its salts, solvates, hydrates, chelates, or other complexes. This may include collecting or separating the data as described above.

[0072] When used herein, “medically acceptable form” of the disclosed formula (I) means Salts, hydrates, solvates, chelates, non-covalent complexes, isomers, and plutons that are pharmacopoeias acceptable. This includes, but is not limited to, drug-like substances and isotope-labeled derivatives, as well as mixtures thereof. It is not defined. Therefore, "chemical entity" and "chemical entity (chemical The term "entities" refers to the medicinally acceptable salts, hydrates, solvates, and chelates of those entities. non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives, and these This also includes mixtures of the same. In some embodiments, the disclosed formula (I) is acceptable as a pharmaceutically acceptable substance. Possible forms include its salts, solvates, or hydrates.

[0073] In one embodiment, a form that is acceptable as a medicine is a salt that is acceptable as a medicine. Where used herein, the term “medically acceptable salt” means a reliable medical Within the bounds of academic judgment, contact with the target tissue without causing excessive toxicity, irritation, or allergic reactions. This refers to a salt that is suitable for contact use and has a reasonable benefit / risk ratio. Salts that are acceptable as medicines are well known in this field. For example, Berge et al. have found that salts that are acceptable as medicines are The acceptable salts are described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Suitable inorganic and organic acids are suitable as pharmaceutically acceptable salts of the compounds provided in the details. Examples include salts derived from bases. Inorganic acids that can derive salts include hydrochloric acid. Examples include, but are not limited to, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids that can be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, Oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, Cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, Examples include licylic acid, but are not limited to these. Examples of salting include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, and These include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Use with organic acids, or by other methods used in the art, such as ion exchange. It is a salt of the amino group formed by [the following]. Other salts that are acceptable as pharmaceuticals include [the following]. Ascorbate, alginate, ascorbate, aspartate, benzenesulfonate, Besilates, benzoates, bisulfates, borates, butyrates, camphorates, camphor sulfone Salts, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, Ethanolate, formate, fumarate, glucoheptanate, glycerophosphate, Luconic acid, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy - Ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, li Ngo salts, maleates, malons, methanesulfonates, 2-naphthalenesulfonates Nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectorate Zinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate , propionate, stearate, succinate, sulfate, tartrate, thiocyanate, Examples include p-toluenesulfonate, undecanoate, and valerate. Several implementations In this embodiment, examples of organic acids that can induce salt formation include acetic acid and propionic acid. Glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, Tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfone Examples include acids, p-toluenesulfonic acid, and salicylic acid.

[0074] Suitable salts that can be derived from appropriate bases and are acceptable as pharmaceuticals include alkali metal salts, and alkali metal salts. Earth metal salts, ammonium salts, and N + (C 1-4 Alkyl)4 salts are an example. Deriving the salt Inorganic bases that can be used include sodium, potassium, lithium, ammonium, and calcium. Examples include zinc, magnesium, iron, zinc, copper, manganese, and aluminum, but These are not the only organic bases that can induce salts, including primary, secondary, and tertiary bases. Amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange trees Examples include fats, but are not limited to these; other examples include isopropylamine and trimester. Tylamine, diethylamine, triethylamine, tripropylamine, and ethanol Examples include, but are not limited to, amines. In some embodiments, as a pharmaceutical The acceptable base addition salts are ammonium salts, potassium salts, sodium salts, and calcium salts. , or magnesium salts. Typical alkali metal salts and alkaline earth metal salts include Sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese Examples include aluminum, etc. Further salts that may be acceptable as pharmaceuticals include appropriate In some cases, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and lower alkyl Non-toxic aryl sulfonates are formed using counterions such as aryl sulfonates. Examples include ammonium cations, quaternary ammonium cations, and amine cations. Examples of organic bases that can induce this include primary, secondary, and tertiary amines, and naturally occurring ones. Examples include substituted amines, cyclic amines, and basic ion exchange resins containing existing substituted amines. Isopropylamine, trimethylamine, diethylamine, triethylamine, trip Examples include ropylamine and ethanolamine. In some embodiments, pharmaceuticals Acceptable base addition salts include ammonium salts, potassium salts, sodium salts, and calcium salts. Selected from bis(i.e., two counterions) and more Higher-order salts (e.g., three or more counterions) fall within the scope of what constitutes a medicinally acceptable salt. It is included.

[0075] Furthermore, when the compound disclosed herein is obtained as an acid addition salt, the free base is used to salt the solution of the acid salt. It can be obtained by basement. Conversely, if the product is a free base, an acid addition salt is obtained. In particular, conventional methods for preparing pharmaceutically acceptable addition salts from base compounds to acid addition salts By following the procedure, the free base is dissolved in a suitable organic solvent, and the solution is treated with acid. It can be produced. Those skilled in the art can prepare an addition salt that is acceptable as a non-toxic pharmaceutical. They are likely aware of the various synthesis methods that can be used for this purpose.

[0076] In one embodiment, the pharmaceutically acceptable form is a "solvate" (e.g., hydrate). Yes. As used herein, the term “solvate” refers to non-covalent intermolecular forces. This refers to a compound that further contains stoichiometric or nonstoichiometric amounts of solvent bonded by a compound. The solvate is made of the disclosed compound or a pharmaceutically acceptable salt thereof is made. When the solvent is water, the solvate is a "hydrate". A pharmaceutically acceptable sol vate and hydrate may be, for example, a complex containing from 1 to about 100, or 1 to about 10, or 1 to about 2, 3, or 4 solvent molecules or water molecules. In some embodiments, the solvate can be a channel solvate. As used herein, the term "compound" is understood to include the compound and the solvate of the compound, as well as mixtures thereof will be.

[0077] As used herein, unless otherwise specified, a "prodrug" is converted to a bioactive compound described herein under physiological conditions or by solvolysis. Thus, the term "prodrug" is intended to refer to a precursor of a pharmaceutically acceptable bioactive compound. A prodrug may be inactive when administered to a subject but, for example, is converted to an active compound in vivo by hydrolysis . In some embodiments, prodrug compounds often provide advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, the literature of Bundgard, H . Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Consideration of prodrugs is incorporated herein by reference in its entirety, both the literature of Higuchi, T. et al., "Prodrugs as a Novel Delivery System" . (Design of Prodrugs) (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam) should be referred to). The consideration of prodrugs is incorporated herein by reference in its entirety, both the literature of Higuchi, T. et al., "Prodrugs as a Novel Delivery System" "ugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Drug Design Bioreversible carriers in drug design, Edward B. Provided to Roche (ed.), American Pharmaceutical Association and Pergamon Press, 1987. The term "prodrug" refers to the administration of such prodrugs to mammalian subjects. When this occurs, it contains any covalently bonded carrier that releases the active formula (I) in vivo. It is also intended that the prodrugs of active compounds described herein are modified in a rudimentary manner. The active formula is such that it can be cleaved either by an operation or in vivo to become a parenteral compound. (I) It can be prepared by modifying the functional groups present in it. Prodrugs are This includes compounds in which a hydroxy, amino, or mercapto group is bonded to any group, and this is appropriate. The basis of the meaning is that when an active prodrug of formula (I) is administered to a mammalian subject, it is cleaved. These then form free hydroxyl, free amino, or free mercapto groups, respectively. Examples of lags include acetic acid esters, formic acid esters, and benzoic acid esters of alcohols. Acetamide, formamide, and benzur of amine functional groups in derivatives or active compounds Examples of prodrugs include, but are not limited to, mido derivatives. Examples include compounds containing -NO, -NO2, -ONO, or -ONO2 moieties. Prodrugs are typically, Well-known methods, for example, Burger's Medicinal Chemistry and Drug Discovery. Drug Discovery), 172-178, 949-982 (edited by Manfred E. Wolff, 5th edition, 1995), and Prodra Described in "Design of Products" (edited by H. Bundgaard, Elselvier, New York, 1985). It can be prepared using the following method.

[0078] For example, if the disclosed compound or a pharmaceutically acceptable form of said compound is carboxylic acid functional If a group is present, the prodrug is composed of a hydrogen atom of the acid group and (C1-C8) alkyl, (C2-C 12 )a Alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4-9 carbon atoms, 5 1-methyl-1-(alkanoyloxy)-ethyl with ~10 carbon atoms, 3~6 carbon atoms Alkoxycarbonyloxymethyl having 4 to 7 carbon atoms, 1-(alkoxy Carbonyloxyethyl, 1-methyl-1-(alkoxycarbonyl) having 5-8 carbon atoms (Oxy)ethyl, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 4 1-(N-(alkoxycarbonyl)amino)ethyl, 3-phthalidyl, having ~10 carbon atoms 4-Crotonolactonyl, gamma-butyrolactone-4-yl, di-N,N-(C1-C2)alkylamino (C2-C3) alkyl (e.g., β-dimethylaminoethyl), carbamoyl-(C1-C2) alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl, and piperidino-, pyrrolidino- or as a pharmaceutically acceptable pharmaceutically acceptable pharmaceutically, formed by substitution with groups such as morpholino(C2-C3)alkyl. It may include esters that can be included.

[0079] Similarly, when the disclosed compound or a pharmaceutically acceptable form of the compound contains an alcohol functionality group, the prodrug is formed by substitution of the hydrogen atom of the alcohol group with a group such as (C1-C6) alkanoyloxymethyl, 1-((C1-C6) alkanoyloxy)ethyl, 1-methyl-1-((C1-C6) alkanoyloxy)ethyl, (C1-C6) alkoxycarbonyloxymethyl, N-(C1-C6) alkoxycarbonylaminomethyl, succinoyl, (C1-C6) alkanoyl, α-amino (C1-C4) alkanoyl, arylacyl, and α-aminoacyl, or α-aminoacyl-α-aminoacyl (where each α-aminoacyl group is independently selected from naturally occurring L-amino acids ), P(O)(OH)2, -P(O)(O(C1-C6) alkyl)2, or a radical obtained by removal of the hydroxyl group of a glycosyl (hemicacetal form of a carbohydrate ). (where each α-aminoacyl group is independently selected from naturally occurring L-amino acids ), P(O)(OH)2, -P(O)(O(C1-C6) alkyl)2, or a radical obtained by removal of the hydroxyl group of a glycosyl (hemicacetal form of a carbohydrate ).

[0080] When the disclosed compound or a pharmaceutically acceptable form of formula (I) incorporates an amine functionality , the prodrug is formed by substitution of the hydrogen atom in the amine group with R-carbonyl, RO-carbonyl, NRR'-carbonyl (where R and R' are each independently (C1-C ) alkyl, (C3-C7) cycloalkyl, benzyl, natural α-aminoacyl, or natural α-aminoacyl-natural α-aminoacyl 10 ), -C(OH)C(O)OY (where Y is H, (C1-C6) alkyl, or benzyl), -C 1 (OY 1 )Y (where Y 2 is (C1-C4) alkyl and Y 3 is (C1-C4) alkyl), or -C 2 (OY 3 ​​is (C1-C6) alkyl, carboxy(C 1-C6) alkyl, amino(C1-C4) alkyl, or mono-N- or di-N,N-(C1-C6) alkyl aminoalkyl), -C(Y 4 )Y 5 (wherein Y 4 is H or methyl, and Y 5 is mono-N- or di-N,N-(C1-C6) alkylamino), morpholino, piperidin-1-yl, or pi rolidin-1-yl and the like can be formed by substitution with a group such as.

[0081] In certain embodiments, the pharmaceutically acceptable forms are isomers. An "isomer" is a different compound having the same molecular formula. A "stereoisomer" is an isomer that differs only in the way the atoms are arranged in space. As used herein, the term "isomer" includes any and all geometric and stereoisomers. For example, "isomers" include double bond cis- and trans-geometric isomers, also known as E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof are included within the scope of the present disclosure.

[0082] mixtures thereof as being included within the scope of the present disclosure. Alternatively, substituents around a carbon-carbon double bond can be referred to as "cis" or "trans", in which case "cis" represents substituents on the same side of the double bond and "trans" represents substituents on the opposite side of the double bond. The configuration of substituents around a carbocyclic ring can also be represented as "cis" or "trans". The term "cis" represents substituents on the same side of the plane of the ring, and the term "trans" represents substituents on the opposite side of the plane of the ring. When a substituent is represented as "cis" or "trans", the term "cis" represents substituents on the same side of the plane of the ring, and the term "trans" represents substituents on the opposite side of the plane of the ring. When a substituent A compound mixture where compounds are located on both the same side and opposite sides of the ring's plane is called "cis / trans". It is expressed as ".

[0083] An "enantiomer" is a pair of stereoisomers that are mirror images of each other but cannot be superimposed. It is a compound. A mixture of any proportion of a pair of enantiomers is known as a "racemic" mixture. It may also be the case that the term "(±)" is used to represent a racemic mixture, where appropriate. Diastereoisomers are compounds that have at least two chiral atoms, but are mirror images of each other. It is a stereoisomer. Absolute stereochemistry is Cahn-Ingold-prelog. -Prelog) Defined in accordance with the RS system. When formula (I) is an enantiomer, each of the k The stereochemistry of chirogenic carbon is defined by either R or S. This is possible. For divided compounds whose absolute configuration is unknown, they can be found at the wavelength of the sodium D line. Planar polarization can be represented as (+) or (-) depending on the direction of rotation (dextrorotatory or levorotatory). Some of the compounds described herein contain one or more chiral centers, and therefore each Regarding the absolute stereochemistry of an asymmetric atom, the enantitis can be defined as (R)- or (S)-. This chemical experiment can produce omers, diastereomers, and other stereoisomer forms. The body, pharmaceutical composition, and method are racemic mixtures, optically substantially pure forms, and intermediates. It is intended to include all such possible isomers, including mixtures. Optically active The (R)- and (S)-isomers can be prepared, for example, using chiral synthons or chiral reagents. It can be done, or it can be divided using conventional techniques.

[0084] As used herein, unless otherwise specified, the term “stereoisomerically pure” means The term includes one stereoisomer of the compound and substantially includes other stereoisomers of that compound. This refers to compositions or substances that do not have a chiral center. For example, stereoisomerism of a compound having one chiral center. A pure composition of the compound is substantially free of the opposite enantiomer. A stereoisomerically pure composition of a compound having a rifle center is a stereoisomer of the compound (for example). diastereoisomers or enantiomers, or synes or antiisomers, It substantially does not contain cis or trans isomers. A typical stereoisomerically pure compound. This includes more than 80% by weight of one stereoisomer of the compound and less than 20% by weight of the other stereoisomer of the compound. stereoisomers, one stereoisomer of the compound in more than approximately 90% by weight, and less than approximately 10% by weight of the compound. Other stereoisomers, more than 95% by weight of one stereoisomer of the compound, and less than 5% by weight of the compound Other stereoisomers of the substance, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight This includes other stereoisomers of the compound.

[0085] As used herein, unless otherwise specified, the term “mirror-isometrically pure” means The term refers to a stereoisomerically pure composition of a compound having one or more chiral centers.

[0086] As used herein, unless otherwise specified, "enantiomer excess" and " The term “diastereomer excess rate” is used interchangeably herein. In this embodiment, compounds having a single stereocenter exist in an "enantiomer excess." It can be said that compounds having at least two stereocenters are "diastereotypes". It can be said that it exists in terms of the "enantiomeric excess rate". For example, the "enantiomeric excess rate" and The term is well known in this art and is defined as follows:

number

[0087] Therefore, in the sense that both are measures of the same phenomenon, "enantiomer excess rate" and The term is related to the term "optical purity." The value of ee is a number from 0 to 100, where 0 is... It is a racemic mixture, and 100% is enantiomerically pure. In the past, it was considered 98% optically pure. The compound that was previously known as such is now more accurately characterized as 96%ee. %ee is a compound in which 95% of the material consists of one enantiomer and 5% of the other enantiomer. To indicate existence.

[0088] Some compositions described herein contain at least about 50%, 75%, 90%, 95%, and It contains S enantiomers with an enantiomer excess of 99%. In other words, the composition contains R Includes an enantiomeric excess of S-enantiomers relative to the enantiomer. Other embodiments In this specification, some compositions contain at least about 50%, 75%, 90%, The set contains R-enantiomers with an enantiomer excess of 95% or 99%. In other words, the set The resulting product contains an enantiomer excess of the R enantiomer relative to the S enantiomer.

[0089] For example, in some embodiments, isomers / enantiomers are the corresponding enantiomers. It can be provided in a manner that substantially does not contain OMER, and is also used interchangeably in this specification. To that end, "optically concentrated," "enantiomerically concentrated," "enantiomerically pure" It can also be called "stylish" and "non-racemic." These terms refer to one enan. The weight percentage of the thiomer is that of one enantiomer in the control mixture of the racemic composition. This refers to a composition in an amount exceeding (for example, more than approximately 1:1 by weight). For example, S enantiomer The enantiomerally concentrated preparation contains more than approximately 50% by weight relative to the R enantiomer, for example. For example, at least about 75% by weight, and even more, for example, at least about 80% by weight of S enantiomer This refers to a preparation of a compound having [the specified characteristic]. In some embodiments, the concentration is about 80% by weight. Far beyond that, "substantially mirror-isomerized," "substantially mirror-isomerized pure" It may provide a preparation of "a" or "substantially non-racemic compounds," and this They contain at least about 85% by weight, for example, at least about 90% by weight, compared to other enantiomers. Preparation of a composition having, for example, at least 95% by weight of one enantiomer. It refers to a substance. In one embodiment, the compound provided herein is at least about 90% by weight. It consists of % of one enantiomer. In other embodiments, formula (I) is less Each is composed of approximately 95%, 98%, or 99% by weight of a single enantiomer.

[0090] Enantiomers are analyzed by chiral high-pressure liquid chromatography (HPLC), chiral salt formation, and bonding. Isolate the racemic mixture by any method known to those skilled in the art, including crystallization, or asymmetrically. They can be prepared by synthesis. For example, enantiomers, racemic compounds, and resolution compounds. (Enantiomers, Racemates and Resolutions), edited by Jacques, Wiley Interscience, New York , 1981); Wilen et al., Tetrahedron 33: 2725 (1977); Stereochemistry of carbon compounds (Stereoch (Emistry of Carbon Compounds) (Ed. E.L. Eliel, McGraw-Hill, NY, 1962); and resolving agents and Tables of Resolving Agents and Optical Resolutions, p. 268 (EL E) See Liel (ed.), Univ. of Notre Dame Press, Notre Dame, IN, 1972.

[0091] In one embodiment, the pharmaceutically acceptable form is a tautomer. When used, the term "tautomer" refers to a compound in which at least one formal transfer of a hydrogen atom occurs. At least one change in dynamic and valency (e.g., from a single bond to a double bond, from a triple bond to a single bond) It is an isomer of the type that contains two or more interconvertible compounds obtained from (or vice versa). "Tautomerism" is considered a type of acid-base chemical reaction, specifically a prototropic or prototropic reaction. Includes proton-shift type tautomerism. "Prototropic type tautomerism" or "proton-shift type Tautomerism involves the transfer of protons accompanied by a change in bond order. The exact ratio of tautomers. This is determined by several factors, including temperature, solvent, and pH. It is possible to bring the chemical equilibrium of the tautomers to a state (for example, in solution). In other words, the reaction that provides tautomer pairs can be catalyzed by an acid or a base. This can occur, or it can occur without the action or presence of external drugs. Exemplary tautomutations. In terms of chemical transformation, keto to enol; amide to imide; lactam to lactim; enamine Examples include rhimines; and tautomerism from one enamine to another, but these include Not limited to this. An example of keto-enol tautomerization is the pentane-2,4-dione tautomer and 4-H This is the interconversion of droxypenta-3-en-2-one tautomers. Another example of tautomerization is f This is phenol-keto tautomerization. Another example of phenol-keto tautomerization is pyridine-4- This is the interconversion between all tautomers and pyridine-4(1H)-one tautomers.

[0092] When used herein, unless otherwise specified, the structures illustrated herein are 1 It is also intended that the compounds may differ only in the presence of the above isotopic enriched atoms. For example, this structure Compounds having this structure are formed by the substitution of hydrogen with deuterium or tritium, or 13 C- also or 14 Carbon substitution with C-enriched carbon, or 13 N- or 15 Nitrogen replacement with N-concentrated nitrogen , or 14 O-, 15 O-, 17 O-, or 18 Oxygen replacement with O-concentrated oxygen, or 35 Cl-, 36 Cl-, or 37 Except for chlorine substitution with Cl-concentrated chlorine, this falls within the scope of this disclosure.

[0093] In one embodiment, the compound disclosed herein is one of the atoms constituting such a compound. The compound may also contain one or more atomic isotopes in unnatural proportions. For example, the compound For example, tritium ( 3 H), Iodine-125( 125 I), or carbon-14 ( 14 Radioactive isotopes such as C) It can be radioactively labeled in the body. A disclosed isotope-labeled compound (e.g., 3 H and 14 Those labeled with 1C are useful in compound and / or substrate tissue distribution assays. . Tritium-labeled isotope (i.e., 3 H) and carbon-14 isotopes (i.e., 14 C) Preparation This makes it possible to enable simplicity and detectability. Furthermore, heavier isotopes, for example, di Eutherium (that is, 2 Substitution with H) for certain therapeutic effects resulting from greater metabolic stability It can provide certain advantages (e.g., extension of the in vivo half-life or reduction of the required dosage). The disclosed isotope-labeled compounds are typically isotopes labeled in place of unlabeled reagents. It can be prepared by using a self-labeled reagent. In some embodiments... Provided herein are one or more atoms among those constituting such compounds. The compound may also contain atomic isotopes in non-natural proportions in terms of number. All variations of the body, whether radioactive or not, are included within the scope of this disclosure.

[0094] As used herein, unless otherwise specified, "solvent," "organic solvent," or " The term "inert solvent" refers to a solvent that is inert under the conditions of the reaction described in relation to it. This refers to a solvent, and this includes, but is not limited to, benzene, toluene, acetonitrile ("M eCN, ethyl acetate (SiO), isopropyl acetate (IPAc), hexane, heptane, Dioxane, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), dimethyl Acetamide ("DMA"), chloroform, methylene chloride ("DCM"), diethyl ether, Butanol ("MeOH"), butanol ("1-BuOH"), methyl t-butyl ether ("MTBE") or It contains "TBME", 2-butanone ("MEK"), N-methylpyrrolidone ("NMP"), pyridine, etc. Unless otherwise specified, the solvents used in the reactions described herein are inert. It is an organic solvent. Unless otherwise specified, 1 cc (or mL) of each gram of the limiting reagent. The solvent is equivalent by volume.

[0095] As used herein, unless otherwise specified, “a pharmaceutically acceptable carrier” or "Pharmacopoeia-acceptable excipients" include any and all solvents, dispersion media, and coatings. This includes antimicrobial agents, antibacterial and antifungal agents, isotonic agents, and absorption retarders. The use of such media and agents for this purpose is known in the art. Any conventional media or Unless the drug is incompatible with the active ingredient, its use in the therapeutic composition of this disclosure is intended. It is also possible to incorporate auxiliary active ingredients into the composition.

[0096] As used herein, unless otherwise specified, the term “solid form” and related terms The term primarily refers to physical forms that are neither liquid nor gaseous. Solid forms include crystalline and non-crystalline. It may be crystalline or a mixture thereof. In certain embodiments, the solid form is liquid crystal. That's fine.

[0097] In some embodiments, the solid forms provided herein are single-component or multi-component. It is in solid form. A "single-component" solid form containing a compound of a certain formula is essentially derived from the compound of that formula. To become a target. A "multicomponent" solid form containing a compound of a certain formula is one or more in significant amounts. It contains species, such as ions and / or molecules, in solid form. For example, it contains a compound of a certain formula. The crystalline multicomponent solid form further contains one or more species non-covalently bonded at fixed positions within the crystal lattice. The multi-component solid forms provided herein may be cocrystals.

[0098] As used herein, unless otherwise specified, the term "crystalline" and related terms When a word is used to describe a substance, modifier, material, component, or product, the substance, If the modification, material, component, or product is determined by X-ray diffraction, then it is substantially crystalline. This means that. For example, Remington: The Science and Practice of Pharmacy (Remington: T Science and Practice of Pharmacy), 21st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23rd edition, 1843-184 See 4(1995).

[0099] As used herein, unless otherwise specified, the term “crystal morphology” and related terms The term refers to a crystalline solid form. Crystallized forms include single-component crystals and multi-component crystals. This includes, but is not limited to, morphologies such as polymorphs, solvates, hydrates, cocrystals, and other molecular complexes. Compounds, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and their polymorphs It is included. In one embodiment, the crystalline form of the substance is amorphous and / or other crystalline forms. It may substantially contain no form. In one embodiment, the crystalline form of the substance is by weight Based on the percentages, approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, and 25%. , one or more amorphous forms and / or other crystalline forms less than 30%, 35%, 40%, 45%, or 50% It may include. In one embodiment, the crystalline form of the substance is physically and / or chemically pure. It is possible. In one embodiment, the crystalline form of the substance is approximately 99%, 98%, 97%, 96%, and 95%. It may be 94%, 93%, 92%, 91%, or 90% physically and / or chemically pure.

[0100] As used herein, unless otherwise specified, "polymorph" and "polymorph" are used herein. The term "state" and related terms refer to the same molecule, molecule, or ion. It refers to two or more crystalline forms that are essentially different crystalline forms. Different polymorphs, as well as different crystalline forms, are crystalline polymorphs. As a result of the arrangement or conformation of molecules or ions in the lattice, for example, the melting temperature, heat of fusion, It may have different physical properties such as solubility, dissolution rate, and / or vibrational spectrum. The differences in properties include storage stability, compressibility, and density (important in formulation and product manufacturing), and This also affects pharmaceutical parameters such as dissolution rate (an important factor in bioavailability). This can have an effect. Differences in stability can be due to changes in chemical reactivity (for example, if the dosage form is composed of a certain polymorph). (Differential oxidation, which, when performed, causes a more rapid discoloration than when composed of other polymorphs.) Alternatively, mechanical changes (for example, tablets undergo thermodynamic polymorphisms during storage that are kinetically favorable) (It disintegrates as it converts to a stable polymorph) or both (for example, a tablet of a certain polymorph) This can result from differences in solubility / solubility, which can lead to extreme decomposition. In some cases, the transition to the solid state may result in a lack of efficacy, or in other extreme cases, toxicity. This can also lead to... Furthermore, physical properties can be important in processing (for example... In some cases, certain polymorphs may be more likely to form solvates, or impurities may be washed away by filtration. (This may be difficult, and the particle shape and particle size distribution may differ between polymorphs.) .

[0101] As used herein, unless otherwise specified, “solvate” and “solvated” The term refers to the crystalline form of a substance containing a solvent. The term refers to a solvate in which the solvent is water. "Polymorph of a solvate" refers to a specific solvate composition. This refers to the existence of multiple crystalline forms. Similarly, "polymorphism of a hydrate" refers to a specific hydrate composition. This refers to the existence of multiple crystalline forms of a substance. The term "desolvated solvation" as used herein refers to a desolvated solvation. The term "substance" refers to the crystalline form of a substance that can be prepared by removing the solvent from a solvate. It refers to.

[0102] As used herein, unless otherwise specified, "amorphous" as used herein The term "amorphous form" and related terms refer to the state in which a substance, component, or product is diffracted by X-ray diffraction. If determined, it essentially means that it is not crystalline. In particular, "amorphous form" The term refers to a disordered solid state, that is, a solid state lacking long-range crystalline order. Let me explain. In one embodiment, the amorphous form of a substance is other amorphous forms and / or crystalline. It may substantially lack form. In other embodiments, the amorphous form of the substance is Based on weight, approximately 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% It may include one or more other amorphous and / or crystalline forms in amounts less than %, 45%, or 50%. In some embodiments, the amorphous form of a substance may be physically and / or chemically pure. In this embodiment, the amorphous form of the material is approximately 99%, 98%, 97%, 96%, 95%, 94%, and 93%. It may be 92%, 91%, or 90% physically and / or chemically pure.

[0103] Techniques for analyzing the characteristics of solid morphology include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), gravimetric vapor deposition (GVS), single-crystal X-ray diffraction, vibrational spectroscopy, for example, infrared (IR) spectroscopy. ) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hotspot Tegei optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PS) A) Surface area analysis, solubility measurement, dissolution measurement, elemental analysis, and Karl Fischer analysis are These are some examples, but are not limited to them. Characteristic unit cell parameters are not limited, but simple The determination is made using one or more techniques, including crystal diffraction and powder diffraction, such as X-ray diffraction and neutron diffraction. This is possible. Useful techniques for analyzing powder diffraction data include, for example, analyzing multiple solids. It can be used to analyze a single phase and associated diffraction peak in a sample containing a body phase, Examples include profile refinement, such as belt refinement. Another useful method is for those skilled in the art to determine unit cell parameters from a sample containing crystalline powder. One example that makes this possible is unit cell indexing.

[0104] In some embodiments, the solid forms described herein, for example, the crystalline forms, It is substantially pure, that is, substantially free of other solid forms and / or other chemical compounds. Approximately 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, and 0.75%. %, 0.5%, 0.25%, or less than 0.1% by weight of one or more other solid forms and / or other Contains chemical compounds.

[0105] The solid form is unique to a particular solid form, such as the crystalline form described herein. Physical feature analysis data can be presented. These feature analysis data can be obtained, for example, from X-ray powder diffraction. Various methods known to those skilled in the art, including differential scanning calorimetry, thermogravimetric analysis, and nuclear magnetic resonance spectroscopy. This can be obtained through techniques. Using the data provided by these techniques, specific The solid form can be identified. Those skilled in the art can implement one of these feature analysis techniques. The data obtained is identified as characteristic of a particular solid form, as provided herein. By determining whether the solid form "matches" the reference data specified herein, the solid form is determined to match the reference data specified herein. It is possible to determine whether it is one of the forms described. Characteristics of the reference solid form. Feature analysis data that "match" feature analysis data corresponds to the same solid morphology as the reference solid morphology. This is understood by those skilled in the art. When analyzing whether the data "matches", those skilled in the art will understand that Certain feature analysis data points may be compromised due to, for example, experimental errors and routine sample-by-sample analysis. They may differ to a certain extent, but it is important to understand that they still describe a particular solid form. It is.

[0106] The solid forms provided herein are crystalline or intermediate forms (for example, crystalline and amorphous forms). It may be a mixture of forms. The crystalline forms described herein are therefore of varying degrees It may have a degree of crystallinity or lattice order. The solid forms described herein are any particular crystal It is not limited by the degree of crystallinity or lattice order, and can be 0-100% crystalline. The method of determination is known to those skilled in the art, and this is, for example, fully described herein by reference. The literature by Suryanarayanan, R., is incorporated, X-ray powder diffraction, analysis of the physical characteristics of pharmaceutical salts (X- Ray Power Diffractometry, Physical Characterization of Pharmaceutical Salts), H. As described in G. Brittain (ed.), Mercel Dekkter, Murray Hill, NJ, 1995, pp. 187-199. There are some. In some embodiments, the solid forms described herein are about 0 , 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or It is 100% crystalline.

[0107] The specific definitions of functional groups and chemical terms are described in more detail below. For the purpose of this, chemical elements are found in the Periodic Table of Elements, the CAS edition, and the Handbook of Chemistry and Physics (Periodic Table of Elements). Table of the Elements, CAS version, Handbook of Chemistry and Physics), 75th edition They are identified according to the inside cover, and the specific functional groups are usually defined as described therein. It is understood that the general principles of organic chemistry, as well as specific functional parts and reactivity, are organic. Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 19 99; Smith and March's literature, March's Advanced Organic Chemistry (try), 5th edition, John Wiley & Sons, New York, 2001; Larock's literature, Comprehensive Organic Transformation (C omprehensive Organic Transformations), VCH Publishers, New York, 1989; Carruth ers' literature, Some Modern Methods of Organic Synthes This is described in (is), 3rd edition, Cambridge University Press, Cambridge, 1987.

[0108] As used herein, the term "alkyl" refers to a compound formed by the removal of one hydrogen atom. 6 carbon atoms (for example, C 1-6 A saturated, straight moiety derived from an aliphatic moiety containing alkyl. Refers to a hydrocarbon radical optionally substituted in a chain or branched chain. In some embodiments, The alkyl group used contains 1 to 5 carbon atoms. In another embodiment, The alkyl group used contains 1 to 4 carbon atoms. In yet another embodiment, The alkyl group contains 1 to 3 carbon atoms. In another embodiment, the alkyl group is It contains 1-2 carbon atoms. Examples of alkyl radicals include methyl, ethyl, and n-propyl Isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n - Examples include octyl, n-decyl, n-undecyl, and dodecyl, but are not limited to these. do not have.

[0109] As used herein, the term "alkenyl" refers to a compound formed by the removal of one hydrogen atom. A linear or branched aliphatic moiety having at least one carbon-carbon double bond. It represents a monovalent group derived from the carbon. In one embodiment, the alkenyl group is composed of 2 to 6 carbon atoms. Elementary atoms (for example, C) 2-6 It contains an alkenyl group. In one embodiment, the alkenyl group is It contains 2 to 5 carbon atoms. In some embodiments, the alkenyl group contains 2 to 4 carbon atoms. It contains carbon atoms. In another embodiment, the alkenyl group used has 2 to 3 carbon atoms. It contains atoms. Examples of alkenyl groups include ethenyl, propenyl, butenyl, 1- Examples include methyl-2-buten-1-yl.

[0110] As used herein, the term "alkynyl" refers to a compound formed by the removal of one hydrogen atom. A linear or branched chain with at least one carbon-carbon triple bond, optionally substituted aliphatic portion. It refers to a monovalent group derived from . In one embodiment, the alkynyl group is composed of 2 to 6 carbon atoms. Elementary atoms (for example, C) 2-6 It contains an alkynyl group. In one embodiment, the alkynyl group is It contains 2 to 5 carbon atoms. In some embodiments, the alkynyl group contains 2 to 4 carbon atoms. It contains carbon atoms. In another embodiment, the alkynyl group contains 2 to 3 carbon atoms. Typical alkynyl groups include ethynyl, 2-propynyl (propargyl), and 1-prop. Examples include pinyl, but the work is not limited to these.

[0111] Used alone, or as "aralkyl," "aralkoxy," or "aryloxyalkyl" The term "aryl," as seen in "[...]," is used as part of a larger part. This refers to any substituted ring systems of monocyclic and bicyclic rings having a total of 5 to 12 ring members, where At least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. It has. In some embodiments, the "aryl" has a total of 6 to 12 ring members (e.g., C6 -12 This refers to any substituted monocyclic and bicyclic ring systems having an aryl group, where in the system At least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring." In one embodiment, "aryl" may support one or more substituents, but is not limited to, This refers to aromatic ring systems, including those containing nyl, biphenyl, naphthyl, and anthracyl. When used in writing, the term "aryl" includes, for example, Indian Lu, phthalimidyl, naphthymidyl, phenantriidinyl, or tetra These are groups such as lahydronaphthyl, in which an aromatic ring is condensed with one or more non-aromatic rings.

[0112] In isolation, or as part of a larger term, for example, "heteroaralkyl" or "heteroaral" The term "heteroaryl," used as part of "coxy," refers to a group of 5-10 ring atoms. Preferably, it has 5, 6, or 9 ring atoms; and 6, 10, or 14 π atoms shared in a cyclic configuration. This refers to any substituted group that has electrons and, in addition to carbon atoms, has 1 to 5 heteroatoms. In some embodiments, the term "heteroaryl" refers to a group of 6-10 ring atoms. For example, C 6-12This refers to any substituted group as defined above, having a heteroaryl group. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and any of nitrogen or sulfur. This includes oxidized forms and any quaternized forms of basic nitrogen. As for heteroaryl groups, Nyl, furanil, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, Oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thi Asiazolyl, pyridyl, pyridazinil, pyrimidinil, pyrazinil, indolidinil, Examples include, but are not limited to, prinyl, naphthilidinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaryl-" refer to heteroaryl compounds. This also includes groups in which the fragrance ring is condensed with one or more aryl, alicyclic, or heterocyclyl rings, and In this case, the radical or bond site is located on a heteroaromatic ring. A non-limiting example is India. Lyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazo Lyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl Phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, A Cridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinone Linyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one Examples include: The heteroaryl group can be monocyclic or bicyclic. "heteroaryl" The terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic" are used in this context. These terms can be used interchangeably, and all of these terms include rings which are arbitrarily substituted. The term "heteroaryl" refers to an alkyl group substituted with a heteroaryl. Here, the alkyl and heteroaryl portions are independently and arbitrarily substituted.

[0113] As described herein, the compounds provided herein are "optionally substituted". It may contain the part "ta". Generally, the term "substituted" is used with the term "arbitrarily". Whether preceding or not, one or more hydrogen atoms in the specified portion are replaced with suitable substituents. This means that it is obtained. Unless otherwise indicated, "arbitrarily substituted" bases are each of the bases. It may have suitable substituents at various substituted positions, and multiple positions in any given structure may be specific If the group can be substituted with multiple substituents selected from the group, the substituents are the same at all positions. However, they may be different. The combinations of substituents envisioned in this application are: Preferably, the combination results in the formation of a stable or chemically feasible compound. As used in this document, the term “stable” refers to its generation, detection, and, in certain embodiments. This allows for its recovery, purification, and use for one or more purposes disclosed herein. This refers to a compound that remains substantially unchanged when subjected to conditions that enable its function.

[0114] Preferred monovalent substituents on the substituted carbon atoms of the "arbitrarily substituted" group are, independently, halo Gen; -(CH2) 0-4 R ○ ; -(CH2) 0-4 Ure ○ -O-(CH2) 0-4 C(O)OR ○ ; -(CH2) 0-4 CH(OR ○ )2; -(CH 2) 0-4 SR ○ ; -(CH2) 0-4 Ph (This is R ○which may be replaced by); -(CH2) 0-4 O(CH2) 0-1 Ph (which is R ○ which may be replaced by); -CH=CHPh (which is R ○ which may be replaced by); -NO2; -CN; -N3; -(CH2)0 -4 N(R ○ )2; -(CH2) 0-4 N(R ○ )C(O)R​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​0-4 C(O)NR ○ 2; -C(S)NR ○ 2; -C(S)SR ○ ; -SC(S)SR ○ 、-(CH2) 0-4 OC(O)NR ○ 2; -C(O)N(OR ○ )R ○ ; -C(O)C(O)R ○ ; -C(O)CH2C(O)R ○ ; -C(NOR ○ ) R ○ ; -(CH2) 0-4 SSR ○ ; -(CH2) 0-4 S(O)2R ○ ; -(CH2) 0-4 S(O)2OR ○ ; -(CH2) 0-4 OS(O)2R ○ ; -S(O)2NR ○ 2; -(CH2) 0-4 S(O)R ○ ; -N(R ○ )S(O)2NR ○ 2; -N(R ○ )S(O)2R ○ ; -N(OR ○ )R ○ ; -C(NH)NR ○ 2; -P(O)2R ○ ; -P(O)R ○ 2; -OP(O)R ○ 2; -OP(O)(OR ○ )2; SiR ○ 3; -(C 1-4 linear or branched alkylene)O-N(R ○ )2; or -(C 1-4 linear or branched alkylene)C(O)O- N(R ○ )2, where each R ○ can be substituted as defined below and is independently , hydrogen, C1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 pH, or independently of nitrogen, oxygen, or sulfur A 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 selected heteroatoms. Or, despite the above definition, two independently occurring R ○ The intervening atom Together with, they can be substituted as defined below, independently of nitrogen, oxygen, or sulfur. A 3-12 member saturated, partially unsaturated, or aryl monopolymer having 0-4 heteroatoms selected for this purpose. It forms a ring or a biring ring.

[0115] R ○ (or two independently occurring R ○ Formed by combining it with the intervening atom Suitable monovalent substituents on the ring are, independently, halogens, -(CH2) 0-2 R ● ,-(HaroR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 Ure ● ,-(CH2) 0-2 CH(OR ● )2; -O(HaroR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● ,-(CH2) 0-2 SR ● ,-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -( CH2) 0-2 NHR ● ,-(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3, -C(O)SR ●,-(C 1-4 Linear chain (K is a branched alkylene) C(O)OR ● , or -SSR ● And here, each R ● It is replaced If none are present, or if "halo" precedes it, it is replaced by only one or more halogens, and Independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 pH, or independently of nitrogen, oxygen, or sulfur A 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 selected heteroatoms. Selected from R. ○ Suitable divalent substituents on the saturated carbon atom include =O and =S. It can be done.

[0116] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S- is given, and here, R appears independently in each case. * is hydrogen, C 1-6 fat aliphatic (which can be substituted as defined below), or nitrogen, oxygen, or sulfur Unsubstituted 5-6 member saturated, partially unsaturated, and also have 0-4 heteroatoms that are independently selected. Alternatively, it is selected from the aryl ring. The substituted carbon adjacent to the "arbitrarily substituted" group Suitable divalent substituents to be bonded include: -O(CR * 2) 2-3 O- is mentioned, and here, each independently Appearing R * is hydrogen, C 1-6 Aliphatic (which can be substituted as defined below), or Unsubstituted 5 having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur Selected from saturated, partially unsaturated, or aryl rings with up to 6 members.

[0117] R * Suitable substituents on the aliphatic group include halogens and -R ● ,-(HaroR ● ), -OH, -OR ● , -O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, are examples. Here, each R ● If it is not substituted, or if "halo" is preceding it, then one or more halos It is substituted only in Gen, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or nitrogen , a saturated 5-6 member having 0-4 heteroatoms independently selected from oxygen or sulfur, It is partially unsaturated or an aryl ring.

[0118] A suitable substituent on the substituted nitrogen of the "arbitrarily substituted" group is -R † , -NR † 2. -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S )NR † 2, -C(NH)NR † 2, or -N(R †)S(O)2R † These are listed; here, each R † Independently, Hydrogen, C 1-6 Aliphatic (which can be substituted as defined below), unsubstituted -OPh, or nitrogen Unsubstituted 5-6 heteroatoms having 0-4 heteroatoms independently selected from element, oxygen, or sulfur. Whether the member is saturated, partially unsaturated, or an aryl ring, or not, despite the above definition , two independently appearing R † Together with the intervening atom, it forms nitrogen, oxygen, or sulfur Unsubstituted 3-12 member saturated, partially unsaturated, or having 0-4 heteroatoms independently selected. These form aryl monocyclic or bicyclic rings.

[0119] R † Preferred substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, Here, each R ● If it is not substituted, or if "halo" is preceding it, then one or more halos It is substituted only in Gen, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or nitrogen , a saturated 5-6 member having 0-4 heteroatoms independently selected from oxygen or sulfur, It is partially unsaturated or an aryl ring.

[0120] (5.2 Solid form) Potential pharmaceutical solids include crystalline and amorphous solids. Amorphous solids are suitable for long-distance transport. While pharmaceuticals are characterized by a lack of structural order, crystalline solids are characterized by periodicity of structural planes. The preferred class of solid is determined by the specific application; amorphous solids, for example, are improved. While crystalline solids may be selected based on their dissolution profile, for example, It may be desirable for properties such as physicochemical stability (for example, S.R. Vippagunta et al.) References, Adv. Drug. Deliv. Rev., (2001) 48:3-26; References, Adv. Drug. Deliv. Rev., L. Yu. (See 2001) 48:27-42). Changes in solid form affect various physical and chemical properties. This may lead to other important pharmaceutical properties, particularly processing, formulation, and stabilization. This may result in benefits or disadvantages in terms of sex and bioavailability.

[0121] Whether crystalline or amorphous, potential solid forms of pharmaceutical compounds include single-component solids and Multi-component solids may be present. Single-component solids are essentially pharmaceutical compounds in the absence of other compounds. It becomes a target. The diversity within single-component crystalline materials is a tertiary factor for specific pharmaceutical compounds. This can potentially arise from the phenomenon of polymorphism, where the original sequence exists (for example, the sentence by S.R. Byrn et al.). References, Solid State Chemistry of Drugs (1999), SSCI, West Lafayet (See te).

[0122] Further diversity in the potential solid forms of pharmaceutical compounds stems from the possibility of multi-component solids. It is possible. A crystalline solid containing two or more ionic species is called a salt (for example, "a hand of pharmaceutical salts"). Book: Properties, Selection, and Uses (Handbook of Pharmaceutical Salts: Properties, Selection, and Uses) See "Condition and Use" edited by P.H. Stahl and C.G. Wermuth (2002), Wiley, Weinheim. Further types of multi-component solids that may potentially impart other property improvements to pharmaceutical compounds or their salts include: For example, these include hydrates, solvates, cocrystals, and inclusion compounds (e.g., S R. Byrn et al., Solid State Chemistry of Drugs (1999), SSC (See I, West Lafayette). Compound 1 and its polymorphs are also provided herein. The crystalline form may be potentially susceptible to polymorphism, in which case, given polymorphism The component composition may exist in multiple three-dimensional crystal arrangements. The discovery of the solid form is safe and effective. This is extremely important in the development of stable and marketable pharmaceutical compounds.

[0123] The solid forms provided herein are active for the preparation of formulations for use in animals or humans. It is useful as a pharmaceutical ingredient. Therefore, the embodiments described herein are used as the final drug product. This includes the use of these solid forms. One embodiment involves the manufacture, processing, and production of the final drug product. Improved properties required for formulation and / or storage, such as, in particular, powder flowability. To produce a final dosage form with properties, compressibility, tableting properties, stability properties, and excipient compatibility properties. To provide a solid form useful when doing so. Some embodiments herein provide a compound of formula (I) and Single-component crystalline form and / or multi-component form including a pharmaceutically acceptable diluent, excipient, or carrier. The present invention provides a pharmaceutical composition including a crystalline form.

[0124] Solid states and related terms primarily refer to physical forms that are neither liquid nor gaseous. The form may be crystalline or a mixture of crystalline and amorphous forms. Certain compounds include A "single-component" solid form is essentially composed of its compound. A "multi-component" solid contains a specific compound. The compound is composed of the compound and one or more further species in significant amounts, such as ions and / or fractions. The solid form contains the child. The solid form provided herein is crystalline or an intermediate form (for example) It may be a mixture of crystalline and amorphous forms. The crystalline forms described herein are Therefore, it may have varying degrees of crystallinity or lattice order. Solid form described herein The state is not limited to any specific degree of crystallinity or lattice order, and can be 0 to 100% crystalline. The method for determining the degree of crystallinity is known to those skilled in the art, and this includes, for example, the complete method by reference. The literature of Suryanarayanan, R., X-ray powder diffraction, pharmaceutical solids, is incorporated herein in full. Physical Characterization of Pharm (X-Ray Powder Diffractometry) aceutical Solids), edited by HG Brittain, Marcel Dekkter, Murray Hill, NJ, 1995, pp. Some are described in pp. 187-199. In some embodiments, as described herein... The solid forms are approximately 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, It is 80, 85, 90, 95, or 100% crystalline.

[0125] The solid form is unique to a particular solid form, such as the crystalline form described herein. Physical feature analysis data can be presented. These feature analysis data can be obtained, for example, from X-ray powder diffraction. Various methods known to those skilled in the art, including differential scanning calorimetry, thermogravimetric analysis, and nuclear magnetic resonance spectroscopy. This can be obtained through techniques. Using the data provided by these techniques, specific The solid form can be identified. Those skilled in the art can implement one of these feature analysis techniques. The data obtained is identified as characteristic of a particular solid form, as provided herein. By determining whether the solid form is "substantially similar" to the reference data being used, the solid form is determined to be It can be determined whether it is one of the forms described herein. Feature analysis data of body morphology and feature analysis data that are "substantially similar" are the same as the reference solid morphology. It is understood by those skilled in the art that this corresponds to the same solid form. The data is "substantially similar". When analyzing whether or not, a person skilled in the art can determine that certain feature analysis data points are, for example, experimental error and rule Although the analysis of each sample of Chin may vary to a reasonable extent, it still represents a given solid form. I understand that it is meant to be an explanation.

[0126] In some embodiments, compounds of formula (I) are provided herein: [ka] or its salts, solvates (e.g., hydrates), or solvates of salts, or mixtures thereof. It is a solid form containing the compound of formula (I). In one embodiment, the solid form containing the compound of formula (I) is crystalline. It can be in the form of a partially crystalline form, or a mixture of a crystalline form and an amorphous form. In one embodiment, the Specified herein provides a solid form including a crystalline form of the compound of formula (I). The state, or its salt, solvate (e.g., hydrate), or solvate of its salt, or these It is a mixture of. In one embodiment, the solid form further comprises co-formations. In this embodiment, the solid form containing compound 1 and the co-form is a cocrystal. In another embodiment, And the solid form is amorphous. In one embodiment, the solid form is substantially pure Yes, there is a compound of formula (I) called (S)-2-amino-N-(1-(8-((1-methyl-1H-pyrazole-4-yl)ethyl (Nyl)-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3-yl)ethyl)pyrazolo[1,5-a] It has the chemical name pyrimidine-3-carboxamide. The compound of formula (I) is cited as a whole. As incorporated herein by reference, as described in US2015 / 011874.

[0127] In some embodiments, formula (I) is a racemic mixture of (S)-isomers and (R)-isomers. In other embodiments, provided herein, the individual compounds of the mixture are (S)-different It is a mixture of compounds that mainly exist in a primordial configuration or (R)-isomer configuration. For example, the compound mixture The blended blends are approximately 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, and 95%. Approximately 96%, 97%, 98%, 99%, over 99.5%, or exceeding (S)-enantiomer It has a surplus. In other embodiments, the compound mixture is about 55% to over 99.5%, and about 60% ~Over approximately 99.5%, approximately 65%~over approximately 99.5%, approximately 70%~over approximately 99.5%, approximately 75%~over approximately 99.5%, approximately 80% ~Over approximately 99.5%, approximately 85%~over approximately 99.5%, approximately 90%~over approximately 99.5%, approximately 95%~over approximately 99.5%, approximately 96% ~Over approximately 99.5%, approximately 97%~over approximately 99.5%, approximately 98%~over approximately 99.5%, approximately 99%~over approximately 99.5%, or It has a higher (S)-enantiomer excess rate.

[0128] In other embodiments, the compound mixture is approximately 55%, approximately 60%, approximately 65%, approximately 70%, and approximately 75%. , about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, more than about 99.5%, or It has a higher (R)-enantiomer purity. In some other embodiments, the Compound mixtures are approximately 55% to over 99.5%, approximately 60% to over 99.5%, approximately 65% ​​to over 99.5%, and approximately 70%. %~over approximately 99.5%, approximately 75%~over approximately 99.5%, approximately 80%~over approximately 99.5%, approximately 85%~over approximately 99.5%, approximately 90 %~over approximately 99.5%, approximately 95%~over approximately 99.5%, approximately 96%~over approximately 99.5%, approximately 97%~over approximately 99.5%, approximately 98 (R)-enantiomer excess rates exceeding % to approximately 99.5%, approximately 99% to approximately 99.5%, or above. To possess.

[0129] (5.2.1. Solid form of compound 1) Provided herein are compounds of formula (I): [ka] or its salt, or solvate (e.g., hydrate), or solvate of the salt, or these It is a solid form containing a mixture of [these elements].

[0130] In one embodiment, the following is provided herein: a free base of compound 1, or its solvent. It is a solid form containing a hydrate (for example, a hydrate). In one embodiment, provided herein This is a solid form containing anhydrous free base of compound 1. In one embodiment, this specification Provided is a solid form containing the solvate of the free base of compound 1. In one embodiment, In this specification, the solid form provided is one containing the hydrate of the free base of compound 1. .

[0131] Compound 1, or its salt, or solvate (e.g., hydrate), or solvate of the salt, Alternatively, these mixtures can be assumed to exist in various solid forms. Solid forms such as crystalline solids (e.g., polymorphs of compound 1 anhydride, polymorphs of compound 1 hydrate) Forms (and polymorphs of the solvate of compound 1), amorphous solids, or mixtures of crystalline and amorphous solids. This includes. In one embodiment, the solid form is substantially crystalline. In one embodiment, Furthermore, the solid form is crystalline.

[0132] In some embodiments, the molar ratio of compound 1 to solvent / water in the solid form is approximately 10:1 to approximately The ratio is in the range of 1:10. In some embodiments, the molar ratio of compound 1 in solid form to solvent / water is... The ratio is in the range of approximately 5:1 to approximately 1:5. In some embodiments, compound 1 in solid form The molar ratio of solvent to water is in the range of approximately 3:1 to approximately 1:3. In some embodiments, solid In one embodiment, the molar ratio of compound 1 to solvent / water is in the range of approximately 2:1 to approximately 1:2. The molar ratio is approximately 1:2 (i.e., bissolvate / hydrate). In another embodiment, The molar ratio is approximately 1:1 (i.e., monosolvate / hydrate). In another embodiment, The molar ratio is approximately 2:1 (i.e., hemi-solvate / hydrate).

[0133] (5.2.1.1 Form 1 of Compound 1) In some embodiments, the first form of the compound of formula (I) is provided herein. In one embodiment, form 1 of compound 1 is a crystalline nonsolvated anhydrous free base of compound 1. Yes. In some embodiments, form 1 of compound 1 substantially comprises amorphous compound 1. No. In some embodiments, form 1 of compound 1 is another crystalline form of compound 1 (that is, It substantially does not contain polymorphs. In some embodiments, form 1 of compound 1 is chemical It substantially does not contain a salt of compound 1. In some embodiments, form 1 of compound 1 is a compound It is provided as a substantially pure form 1 of object 1. In some embodiments, one or more residues Distillation solvent (e.g., a small amount of EtOH or i PrOH) may be present in form 1 of compound 1, but the residual solvent It does not form a solvate of compound 1.

[0134] A representative XRPD pattern of compound 1, form 1, is provided in Figure 1.

[0135] In one embodiment, form 1 has peaks at 16.8, 23.6, and 25.6 ± 0.2 degrees 2θ. It has an X-ray powder diffraction (XRPD) pattern. In one embodiment, form 1 is described in 14.6 and 21.2 The XRPD pattern further includes at least one peak selected from 2θ of ±0.2 degrees. In one embodiment, form 1 is a pin at 2θ of 14.6, 16.8, 21.2, 23.6, and 25.6 degrees. The 2 degrees are 11.3, 15.4, 16.2, 18.4, 20.5, 22.6, 24.3, 26.6, 27.1, and 29.5±0.2 degrees. It has an XRPD pattern that includes at least one peak selected from θ.

[0136] In one embodiment, Form 1 is located at the following positions: 11.3, 14.6, 15.4, 16.2, 16.8, 18.4, 2 2θ of 0.5, 21.2, 22.6, 23.6, 24.3, 25.6, 26.6, 27.1, and 29.5±0.2 degrees, No. 1, 2 XRPD peaks located at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of them It is characterized by the following. In one embodiment, the solid form is characterized by three of the peaks Characterized. In one embodiment, the solid form is characterized by five of the peaks. It is characterized by seven of the peaks. In one embodiment, the solid form is characterized by seven of the peaks. It is attached. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by 11 of the peaks. In one embodiment, the solid form is characterized by 13 of the peaks. In one embodiment, the solid form is characterized by all of the peaks. ru.

[0137] In some embodiments, the above XRPD peak (degree 2θ peak) is obtained by using copper Kα radiation. It is observed when it is analyzed.

[0138] In one embodiment, form 1 has an XRPD pattern generally as shown in Figure 1.

[0139] Thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of compound 1, form 1. A typical overlay is provided in Figure 2.

[0140] In one embodiment, when the features of form 1 were analyzed by DSC, the starting temperature was approximately 255°C and It exhibits an endothermic event with a peak temperature of approximately 257°C. In one embodiment, form 1 is A DSC thermogram, as generally shown in Figure 2, It is characterized by... In another embodiment, when form 1 is feature-analyzed by DSC, it is approximately This exhibits an endothermic event with an onset temperature of 242°C and / or a peak temperature of approximately 251°C. In this embodiment, when the features of Embodiment 1 are analyzed by DSC, the starting temperature is approximately 242°C to approximately 255°C. It exhibits an endothermic phenomenon.

[0141] In one embodiment, Form 1 exhibits a weight loss of approximately 0.6% when heated from approximately 230°C to approximately 310°C. This indicates a failure. In one embodiment, form 1 is generally as shown in the TGA thermogram presented in Figure 2. Characterized by a TGA thermogram as shown. In another embodiment, Form 1 showed a weight loss of approximately 0.4% when heated from approximately 25°C to approximately 70°C, and from approximately 200°C to approximately 2 When heated to 80°C, it exhibits a weight loss of approximately 1.1%.

[0142] A typical gravitational vapor deposition (GVS) isotherm for Embodiment 1 is shown in Figure 3. And when form 1 is subjected to an increase in relative humidity from approximately 0% relative humidity to approximately 90% relative humidity, It shows a weight increase of 0.5%. In one embodiment, form 1 is the GVS thermo shown in Figure 3. It is characterized by a GVS thermogram, which is generally shown in the gram.

[0143] In one embodiment, form 1 is approximately: a=11.1 Å, b=12.8 Å, c=16.1 Å, α=90 It has unit cell dimensions of °, β=90°, and γ=90°. In one embodiment, form 1 is near Similar to: a=11.14 Å, b=12.76 Å, c=16.13 Å, α=90°, β=90°, and γ=90°. It has globular dimensions. In one embodiment, form 1 is approximately: a=11.140 Å, b=12.758 Å It has unit cell dimensions of Å, c=16.131Å, α=90°, β=90°, and γ=90°. In this embodiment, form 1 has a unit cell of the space group P212121. State 1 is approximately 2292.5 Å 3 / Has a cell volume. In one embodiment, form 1 has a Z value of 4. In one embodiment, Form 1 is approximately 1.279 g / cm³. 3 It has a density of .

[0144] In one embodiment, form 1 is anhydrous. In one embodiment, form 1 is nonhygroscopic. In one embodiment, Form 1 is used at 40°C / 75%RH or 25°C / 96%RH for longer than 9 months. It remains stable after storage.

[0145] All combinations of the above embodiments are encompassed by this application.

[0146] (5.2.1.2 Form 2 of Compound 1) In some embodiments, the following forms of the compound of formula (I) are provided herein: In one embodiment, form 2 of compound 1 is a crystalline solvate of the free base of compound 1. In some embodiments, form 2 of compound 1 substantially does not contain amorphous compound 1. In some embodiments, form 2 of compound 1 is another crystalline form of compound 1 (that is, It substantially does not contain polymorphs. In some embodiments, form 2 of compound 1 is a compound It substantially does not contain a salt of compound 1. In some embodiments, form 2 of compound 1 is compound 1 It is provided as a substantially pure form 2 of the same.

[0147] In one embodiment, the molar ratio of compound 1 to solvent in form 2 is in the range of approximately 1:0.5 to approximately 1:2. In one embodiment, the molar ratio of compound 1 to solvent in form 2 is in the range of about 1:0.75 to about 1:1.25. In one embodiment, the molar ratio of compound 1 to solvent in form 2 is approximately 1:0.75 to approximately 1:1 This is within the range. In one embodiment, the molar ratio of compound 1 to solvent in form 2 is approximately 1:0.85. In one embodiment, the molar ratio of compound 1 to solvent in form 2 is approximately 1:1.

[0148] In one embodiment, form 2 is the acetone / DCM solvate of the free base of compound 1. In this embodiment, the molar ratio of compound 1:acetone:DCM in Form 2 is approximately 1:0.1:0.75. In another embodiment, form 2 is the 1-propanol solvate of the free base of compound 1. In one embodiment, the molar ratio of compound 1 to 1-propanol in form 2 is approximately 1:0.85. In another embodiment, form 2 is the DCM solvate of the free base of compound 1. In this case, the molar ratio of compound 1 to DCM in form 2 is approximately 1:1.

[0149] A typical XRPD pattern of compound 1, form 2, is provided in Figure 4. Another representative XRPD pattern is provided in Figure 8.

[0150] In one embodiment, form 2 has peaks at 13.6, 14.9, and 21.0 ± 0.2 degrees at 2θ. It has an XRPD pattern including. In one embodiment, form 2 has 2θ of 7.4 and 16.7±0.2 degrees The XRPD pattern further includes at least one peak selected from the above. In one embodiment, In this configuration, form 2 has peaks at 7.4, 13.6, 14.9, 16.7, and 21.0 degrees 2θ, and 9.5, 18 Selected from 2θ of 0.1, 18.4, 19.7, 20.8, 22.4, 23.2, 24.5, 26.2, and 26.8 ± 0.2 degrees. It has an XRPD pattern that includes at least one peak.

[0151] In one embodiment, form 2 is located at the following positions: 7.4, 9.5, 13.6, 14.9, 16.7, 18.1, 18. 4, 19.7, 20.8, 21.0, 22.4, 23.2, 24.5, 26.2, and 26.8±0.2 degrees 2θ (Nagoya 1, 2, 3) , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of the XRPD peaks are special It is characterized by three of the peaks. In one embodiment, the solid form is characterized by three of the peaks. It is attached. In one embodiment, the solid form is characterized by five of the peaks. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by 11 of the peaks. In one embodiment, the solid form is characterized by 13 of the peaks. In one embodiment, the solid morphology is characterized by all of the peaks.

[0152] In some embodiments, the above XRPD peak (degree 2θ peak) is obtained by using copper Kα radiation. It is observed when it is analyzed.

[0153] In one embodiment, form 2 has an XRPD pattern generally as shown in Figure 4. In another embodiment, form 2 has an XRPD pattern generally as shown in Figure 8.

[0154] Thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of compound 1, form 2. A typical overlay is provided in Figure 5.

[0155] In one embodiment, when the features of form 2 were analyzed by DSC, the starting temperature was approximately 168°C and It exhibits an endothermic event with a peak temperature of approximately 182°C. In one embodiment, form 2 is A DSC thermogram, as generally shown in Figure 5, is used. It is characterized by this.

[0156] In one embodiment, form 2 exhibits a weight loss of approximately 12.9% when heated from approximately 80°C to approximately 240°C. This indicates a failure. In one embodiment, form 2 is generally as shown in the TGA thermogram presented in Figure 5. Characterized by a TGA thermogram as shown.

[0157] Thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of compound 1, form 2. Another representative overlay is provided in Figure 7.

[0158] In one embodiment, when feature analysis is performed by DSC, the form 2 has a starting temperature of approximately 25°C. Endothermic events, endothermic events with an onset temperature of approximately 151°C, exothermic events with an onset temperature of approximately 179°C This represents an endothermic event with an onset temperature of approximately 244°C. In one embodiment, form 2 is DS When feature analysis was performed using C, an endothermic event with an onset temperature of approximately 25°C and an onset temperature of approximately 151°C were observed. It has an endothermic event, an exothermic event with an onset temperature of approximately 179°C, and an onset temperature of approximately 244°C. This shows an endothermic phenomenon. In one embodiment, form 2 is the DSC thermogram shown in Figure 7. It is characterized by a DSC thermogram, which is generally shown here.

[0159] In one embodiment, form 2 exhibits a weight loss of approximately 0.9% when heated from approximately 25°C to approximately 75°C. This shows that when heated from approximately 75°C to approximately 250°C, it exhibits a weight loss of approximately 8.5%. In one embodiment, And form 2 is a TGA thermogram as generally shown in Figure 7. Characterized by a mogram.

[0160] A typical gravitational vapor deposition (GVS) isotherm for Embodiment 2 is shown in Figure 6. And when form 2 is subjected to an increase in relative humidity from approximately 0% relative humidity to approximately 90% relative humidity, It shows a weight increase of 1.3%. In one embodiment, form 2 is the GVS thermo shown in Figure 6. It is characterized by a GVS thermogram, which is generally shown in the gram.

[0161] In one embodiment, form 2 is non-hygroscopic.

[0162] In one embodiment, form 2 is approximately: a=8.7Å, b=13.2Å, c=26.0Å, α=90 It has unit cell dimensions of °, β=90°, and γ=90°. In one embodiment, form 2 is near Similar to: a=8.73 Å, b=13.22 Å, c=25.96 Å, α=90°, β=90°, and γ=90°. It has globular dimensions. In one embodiment, form 2 is approximately: a = 8.729 Å, b = 13.222 Å It has unit cell dimensions of c = 25.955 Å, α = 90°, β = 90°, and γ = 90°. One embodiment In this embodiment, form 2 has a unit cell of the space group P212121. 2 is approximately 2995.6 Å 3 / It has a cell volume. In one embodiment, form 2 has a Z value of 4. In one embodiment, form 2 is approximately 1.360 Mg / m³ 3 It has a density of .

[0163] All combinations of the above embodiments are encompassed by this application.

[0164] (5.2.1.3 Form 3 of Compound 1) In some embodiments, the following is provided herein: In one embodiment, form 3 of compound 1 is a crystalline solvate of the free base of compound 1. In some embodiments, form 3 of compound 1 substantially does not contain amorphous compound 1. In some embodiments, form 3 of compound 1 is another crystalline form of compound 1 (that is, It substantially does not contain polymorphs. In some embodiments, form 3 of compound 1 is a compound It substantially does not contain a salt of compound 1. In some embodiments, form 3 of compound 1 is compound 1 It is provided as a substantially pure form 3 of the same.

[0165] In one embodiment, the molar ratio of compound 1 to solvent in form 3 is in the range of approximately 1:0.2 to approximately 1:1. In one embodiment, form 3 is a 2-methyl-1-propanol solvent of the free base of compound 1. It is a dimethyl compound. In one embodiment, the molars of compound 1 and 2-methyl-1-propanol in form 3. The ratio is approximately 1:0.79. In another embodiment, form 3 is a MEK solvent of the free base of compound 1. It is a mixed compound. In one embodiment, the molar ratio of compound 1 to MEK in form 3 is approximately 1:0.25. .

[0166] A representative XRPD pattern of form 3 of compound 1 is provided in Figure 9.

[0167] In one embodiment, form 3 has peaks at 17.9, 20.6, and 25.8 ± 0.2 degrees at 2θ. It has an XRPD pattern. In one embodiment, form 3 has 2θ of 11.7 and 23.5 ± 0.2 degrees. The XRPD pattern further includes at least one peak selected from. One embodiment In this configuration, form 3 has peaks at 11.7, 17.9, 20.6, 23.5, and 25.8 degrees 2θ, and 7.4 Selected from 2θ of 10.2, 13.5, 19.3, 19.5, 21.0, 21.5, 22.4, 23.7, and 26.5 ± 0.2 degrees. It has an XRPD pattern that includes at least one peak combined with the following.

[0168] In one embodiment, form 3 is located at the following positions: 7.4, 10.2, 11.7, 13.5, 17.9, 19.3, 19 0.5, 20.6, 21.0, 21.5, 22.4, 23.5, 23.7, 25.8, and 26.5±0.2 degrees 2θ. (Nagoya 1, 2) XRPD peaks located at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of them Characterized. In one embodiment, the solid form is characterized by three of the peaks. It is characterized by five of the peaks. In one embodiment, the solid form is characterized by five of the peaks. It is attached. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by 11 of the peaks. In one embodiment, the solid form is characterized by 13 of the peaks. In one embodiment, the solid form is characterized by all of the peaks. .

[0169] In some embodiments, the above XRPD peak (degree 2θ peak) is obtained by using copper Kα radiation. It is observed when it is analyzed.

[0170] In one embodiment, form 3 has an XRPD pattern generally as shown in Figure 9.

[0171] Thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of compound 1, form 3. A typical overlay is provided in Figure 10.

[0172] In one embodiment, when feature analysis is performed by DSC, the form 3 has a starting temperature of approximately 29°C. Endothermic events, endothermic events with an onset temperature of approximately 126°C, endothermic events with an onset temperature of approximately 148°C The phenomenon exhibits either an exothermic event with an initiation temperature of approximately 181°C, or an endothermic event with an initiation temperature of approximately 246°C. In one embodiment, when feature analysis was performed by DSC, the starting temperature was approximately 29°C. Endothermic events, endothermic events with an onset temperature of approximately 126°C, endothermic events with an onset temperature of approximately 148°C The events include an exothermic event with an onset temperature of approximately 181°C and an endothermic event with an onset temperature of approximately 246°C. As shown, in one embodiment, form 3 is generally shown in the DSC thermogram presented in Figure 10. It is characterized by a DSC thermogram that looks like this.

[0173] In one embodiment, when feature analysis is performed by DSC, the form 3 has a starting temperature of approximately 30°C. Endothermic events, endothermic events with an onset temperature of approximately 127°C, endothermic events with an onset temperature of approximately 137°C An exothermic event with an onset temperature of approximately 169°C, an endothermic event with an onset temperature of approximately 207°C, or approximately This exhibits an endothermic event with an onset temperature of 250°C. In one embodiment, form 3 is obtained by DSC When feature analysis was performed, an endothermic event with an onset temperature of approximately 30°C and an endothermic event with an onset temperature of approximately 127°C were found. Thermal events, endothermic events with an onset temperature of approximately 137°C, exothermic events with an onset temperature of approximately 169°C, This shows an endothermic event with an initiation temperature of 207°C and an endothermic event with an initiation temperature of approximately 250°C.

[0174] In one embodiment, when heated from approximately 25°C to approximately 75°C, form 3 exhibits a weight loss of approximately 0.8%. This shows that when heated from approximately 75°C to approximately 300°C, it exhibits a weight loss of approximately 10.4%. In one embodiment, In this case, form 3 is a TGA as generally shown in the TGA thermogram presented in Figure 10. Characterized by thermograms.

[0175] In one embodiment, form 3 exhibits a weight loss of approximately 2.0% when heated from approximately 25°C to approximately 80°C. It exhibits a weight loss of approximately 3.4% when heated from approximately 80°C to approximately 175°C.

[0176] All combinations of the above embodiments are encompassed by this application.

[0177] (5.2.1.4 Form 4 of Compound 1) In some embodiments, the following forms of the compound of formula (I) are provided herein: In one embodiment, form 4 of compound 1 is a crystalline solvate of the free base of compound 1. In some embodiments, form 4 of compound 1 substantially does not contain amorphous compound 1. In some embodiments, form 4 of compound 1 is another crystalline form of compound 1 (that is, It substantially does not contain polymorphs. In some embodiments, form 4 of compound 1 is a compound It substantially does not contain a salt of compound 1. In some embodiments, form 4 of compound 1 is compound 1 It is provided as a substantially pure form 4.

[0178] In one embodiment, the molar ratio of compound 1 to solvent in form 4 is in the range of approximately 1:0.75 to approximately 1:1. Yes. In one embodiment, the molar ratio of compound 1 to solvent in form 4 is approximately 1:0.83 to approximately 1:0.9. This is the range. In one embodiment, form 4 is the isopropyl alcohol of the free base of compound 1. It is a solvate of compound 1 in form 4 and isopropyl alcohol. The molar ratio is approximately 1:0.9. In another embodiment, compound 1 in form 4 and isopropyl The molar ratio of ethanol is approximately 1:0.83.

[0179] A representative XRPD pattern of form 4 of compound 1 is provided in Figure 11.

[0180] In one embodiment, form 4 includes peaks at 7.4, 18.0, and 20.7 ± 0.2 degrees 2θ. It has an XRPD pattern. In one embodiment, form 4 has 2θ of 11.9 and 13.6±0.2 degrees The XRPD pattern further includes at least one peak selected from the above. In one embodiment, In this configuration, form 4 has peaks at 7.4, 11.9, 13.6, 18.0, and 20.7 degrees 2θ, and 10.3, 1 Selected from 2θ of 9.3, 19.6, 19.8, 21.0, 21.8, 23.6, 23.8, 26.0, and 26.6 ± 0.2 degrees. It has an XRPD pattern that includes at least one peak in combination with the following.

[0181] In one embodiment, form 4 is located at the following positions: 7.4, 10.3, 11.9, 13.6, 18.0, 19.3, 19 0.6, 19.8, 20.7, 21.0, 21.8, 23.6, 23.8, 26.0, and 26.6±0.2 degrees, one or two of the 2θ values. XRPD peaks located at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of them Characterized. In one embodiment, the solid form is characterized by three of the peaks. It is characterized by five of the peaks. In one embodiment, the solid form is characterized by five of the peaks. It is attached. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by 11 of the peaks. In one embodiment, the solid form is characterized by 13 of the peaks. In one embodiment, the solid form is characterized by all of the peaks. .

[0182] In some embodiments, the above XRPD peak (degree 2θ peak) is obtained by using copper Kα radiation. It is observed when it is analyzed.

[0183] In one embodiment, form 4 has an XRPD pattern generally as shown in Figure 11. .

[0184] Thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of compound 1, form 4. A typical overlay is provided in Figure 12.

[0185] In one embodiment, when feature analysis is performed by DSC, the form 4 has a starting temperature of approximately 30°C. Endothermic events, endothermic events with an onset temperature of approximately 156°C, exothermic events with an onset temperature of approximately 190°C This represents an endothermic event with an onset temperature of approximately 245°C. In one embodiment, form 4 is DS When feature analysis was performed using C, an endothermic event with an onset temperature of approximately 30°C and an onset temperature of approximately 156°C were observed. It has an endothermic event, an exothermic event with an onset temperature of approximately 190°C, and an onset temperature of approximately 245°C. This shows an endothermic event. In one embodiment, form 4 is the DSC thermogram shown in Figure 12. It is characterized by a DSC thermogram, which is generally shown here.

[0186] In one embodiment, when feature analysis is performed by DSC, the form 4 has a starting temperature of approximately 28°C. Endothermic events, endothermic events with an onset temperature of approximately 156°C, exothermic events with an onset temperature of approximately 201°C This represents an endothermic event with an onset temperature of approximately 247°C. In one embodiment, form 4 is DS When feature analysis was performed using C, an endothermic event with an onset temperature of approximately 28°C and an onset temperature of approximately 156°C were observed. It has an endothermic event, an exothermic event with an onset temperature of approximately 201°C, and an onset temperature of approximately 247°C. It exhibits an endothermic phenomenon.

[0187] In one embodiment, form 4 exhibits a weight loss of approximately 0.7% when heated from approximately 25°C to approximately 75°C. This shows that when heated from approximately 75°C to approximately 225°C, it exhibits a weight loss of approximately 9.3%. In one embodiment, And form 4 is a TGA thermogram as generally shown in Figure 12. Characterized by an omogram.

[0188] In one embodiment, form 4 exhibits a weight loss of approximately 0.8% when heated from approximately 25°C to approximately 75°C. It exhibits a weight loss of approximately 8.6% when heated from approximately 75°C to approximately 250°C.

[0189] All combinations of the above embodiments are encompassed by this application.

[0190] (5.2.1.5 Form 5 of Compound 1) In some embodiments, the following forms of the compound of formula (I) are provided herein: In one embodiment, form 5 of compound 1 is a crystalline solvate of the free base of compound 1. In some embodiments, form 5 of compound 1 substantially does not contain amorphous compound 1. In some embodiments, form 5 of compound 1 is another crystalline form of compound 1 (that is, It substantially does not contain polymorphs. In some embodiments, form 5 of compound 1 is a compound It substantially does not contain a salt of compound 1. In some embodiments, form 5 of compound 1 is compound 1 It is provided as a substantially pure form 5.

[0191] In one embodiment, the molar ratio of compound 1 to solvent in form 5 is in the range of about 1:0.1 to about 1:0.2. Yes. In one embodiment, form 5 is the anisole solvate of the free base of compound 1. In one embodiment, the molar ratio of compound 1 to anisole in form 5 is approximately 1:0.12.

[0192] A representative XRPD pattern of form 5 of compound 1 is provided in Figure 13.

[0193] In one embodiment, form 5 has peaks at 2θ of 21.0, 22.1, and 25.2±0.2 degrees. It has an XRPD pattern. In one embodiment, form 5 has 2θ of 14.5 and 19.2 ± 0.2 degrees. The XRPD pattern further includes at least one peak selected from. One embodiment In this configuration, form 5 shows peaks at 2θ degrees of 14.5, 19.2, 21.0, 22.1, and 25.2 degrees, and 7.9 Select from 2θ of 11.0, 12.7, 16.6, 18.0, 23.3, 27.7, 28.5, 29.1, and 29.2 ± 0.2 degrees. It has an XRPD pattern that includes at least one peak combined with the following.

[0194] In one embodiment, form 5 is located at the following positions: 7.9, 11.0, 12.7, 14.5, 16.6, 18.0, 19 0.2, 21.0, 22.1, 23.3, 25.2, 27.7, 28.5, 29.1, and 29.2±0.2 degrees 2θ Miya1, 2 XRPD peaks located at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of them Characterized. In one embodiment, the solid form is characterized by three of the peaks. It is characterized by five of the peaks. In one embodiment, the solid form is characterized by five of the peaks. It is attached. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by 11 of the peaks. In one embodiment, the solid form is characterized by 13 of the peaks. In one embodiment, the solid form is characterized by all of the peaks. .

[0195] In some embodiments, the above XRPD peak (degree 2θ peak) is obtained by using copper Kα radiation. It is observed when it is analyzed.

[0196] In one embodiment, form 5 has an XRPD pattern generally as shown in Figure 13. .

[0197] Thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of compound 1, form 5. A typical overlay is provided in Figure 14.

[0198] In one embodiment, when the features of form 5 were analyzed by DSC, the starting temperature was approximately 126°C. This describes an endothermic event having or an endothermic event having a starting temperature of approximately 254°C. In one embodiment, When form 5 was characterized by DSC analysis, it was found to be an endothermic event with an onset temperature of approximately 126°C and approximately 254 This shows an endothermic event with a starting temperature of °C. In one embodiment, form 5 is shown in Figure 14. Characterized by a DSC thermogram, which is generally as shown in the DSC thermogram. ru.

[0199] In one embodiment, form 5 exhibits a weight loss of approximately 2.1% when heated from approximately 175°C to approximately 300°C. This indicates a failure. In one embodiment, form 5 is roughly the same as the TGA thermogram shown in Figure 14. Characterized by a TGA thermogram as shown.

[0200] All combinations of the above embodiments are encompassed by this application.

[0201] (5.2.1.6 Form 6 of Compound 1) In some embodiments, the following forms of the compound of formula (I) are provided herein: In one embodiment, form 6 of compound 1 is the crystalline hydrate of the free base of compound 1. In some embodiments, form 6 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 6 of compound 1 is another crystalline form of compound 1 (i.e. It substantially does not contain (polymorphs). In some embodiments, form 6 of compound 1 is compound 1 It is substantially free of salts of compound 1. In some embodiments, form 6 of compound 1 is a salt of compound 1. It is provided as essentially a pure form 6.

[0202] In one embodiment, the molar ratio of compound 1 to water in form 6 is in the range of approximately 1:2 to approximately 1:4. In one embodiment, the molar ratio of compound 1 to water in form 6 is approximately 1:3.3.

[0203] A representative XRPD pattern of compound 1, form 6, is provided in Figure 15.

[0204] In one embodiment, form 6 includes peaks at 4.8, 19.9, and 26.7 ± 0.2 degrees 2θ. It has an XRPD pattern. In one embodiment, form 6 has 2θ of 11.9 and 24.8±0.2 degrees The XRPD pattern further includes at least one peak selected from the above. In one embodiment, In this configuration, form 6 has peaks at 4.8, 11.9, 19.9, 24.8, and 26.7 degrees 2θ, and 12.2, 1 Selected from 2θ of 2.4, 14.1, 16.0, 17.7, 18.1, 18.9, 20.9, 24.0, and 27.1 ± 0.2 degrees. It has an XRPD pattern that includes at least one peak in combination with the following.

[0205] In one embodiment, form 6 is located at the following positions: 4.8, 11.9, 12.2, 12.4, 14.1, 16.0, 17 0.7, 18.1, 18.9, 19.9, 20.9, 24.0, 24.8, 26.7, and 27.1±0.2 degrees, 1 or 2 of the 2θ values. XRPD peaks located at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of them Characterized. In one embodiment, the solid form is characterized by three of the peaks. It is characterized by five of the peaks. In one embodiment, the solid form is characterized by five of the peaks. It is attached. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by 11 of the peaks. In one embodiment, the solid form is characterized by 13 of the peaks. In one embodiment, the solid form is characterized by all of the peaks. .

[0206] In some embodiments, the above XRPD peak (degree 2θ peak) is obtained by using copper Kα radiation. It is observed when it is analyzed.

[0207] In one embodiment, form 6 has an XRPD pattern generally as shown in Figure 15. .

[0208] Thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of compound 1, form 6. A typical overlay is provided in Figure 16.

[0209] In one embodiment, when the features of form 6 are analyzed by DSC, the starting temperature is approximately 46°C. An endothermic event having an endothermic temperature of approximately 154°C, or an endothermic event having an endothermic temperature of approximately 243°C This shows thermal phenomena. In one embodiment, when form 6 is characterized by DSC analysis, it is approximately 46°C. Endothermic events with a starting temperature, endothermic events with a starting temperature of approximately 154°C, and starting temperature of approximately 243°C It exhibits an endothermic event with a degree. In one embodiment, form 6 is a DSC shown in Figure 16. It is characterized by a DSC thermogram, which is generally shown in the chromatogram.

[0210] In one embodiment, form 6 exhibits a weight loss of approximately 10.3% when heated from approximately 30°C to approximately 100°C. This indicates a failure. In one embodiment, form 6 is generally as shown in the TGA thermogram presented in Figure 16. Characterized by a TGA thermogram as shown.

[0211] A typical gravitational vapor deposition (GVS) isotherm of Embodiment 6 is shown in Figure 17. And when form 6 is subjected to an increase in relative humidity from approximately 0% relative humidity to approximately 90% relative humidity, It shows a 14% weight increase. In one embodiment, form 6 is the GVS thermo shown in Figure 17. It is characterized by a GVS thermogram, which is generally shown in the gram.

[0212] All combinations of the above embodiments are encompassed by this application.

[0213] (5.2.1.7 Form 7 of Compound 1) In some embodiments, the following forms of the compound of formula (I) are provided herein: In some embodiments, form 7 of compound 1 substantially does not contain amorphous compound 1. In some embodiments, form 7 of compound 1 is another crystalline form of compound 1 (that is, It substantially does not contain polymorphs. In some embodiments, form 7 of compound 1 is a compound It is substantially free of a salt of compound 1. In some embodiments, form 7 of compound 1 is compound 1 It is provided as a substantially pure form 7.

[0214] A representative XRPD pattern of form 7 of compound 1 is provided in Figure 18.

[0215] In one embodiment, form 7 includes peaks at 7.5, 12.3, and 20.7 ± 0.2 degrees 2θ. It has an XRPD pattern. In one embodiment, form 7 has 2θ of 13.7 and 17.2 ± 0.2 degrees The XRPD pattern further includes at least one peak selected from the above. In one embodiment, In this configuration, form 7 has peaks at 7.5, 12.3, 13.7, 17.2, and 20.7 degrees 2θ, and 11.8, 1 Selected from 2θ of 4.9, 18.0, 18.4, 19.6, 20.2, 21.1, 23.5, 23.6, and 25.9 ± 0.2 degrees. It has an XRPD pattern that includes at least one peak in combination with the following.

[0216] In one embodiment, form 7 is located at the following positions: 7.5, 11.8, 12.3, 13.7, 14.9, 17.2, 18 1 or 2 of the 2θ values ​​of 0.0, 18.4, 19.6, 20.2, 20.7, 21.1, 23.5, 23.6, and 25.9±0.2 degrees, XRPD peaks located at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of them Characterized. In one embodiment, the solid form is characterized by three of the peaks. It is characterized by five of the peaks. In one embodiment, the solid form is characterized by five of the peaks. It is attached. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by 11 of the peaks. In one embodiment, the solid form is characterized by 13 of the peaks. In one embodiment, the solid form is characterized by all of the peaks. .

[0217] In some embodiments, the above XRPD peak (degree 2θ peak) is obtained by using copper Kα radiation. It is observed when it is analyzed.

[0218] In one embodiment, form 7 has an XRPD pattern generally as shown in Figure 18. .

[0219] Thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of compound 1, form 7. A typical overlay is provided in Figure 19.

[0220] In one embodiment, when the features of form 7 are analyzed by DSC, the starting temperature is approximately 30°C. Endothermic events, endothermic events with an onset temperature of approximately 127°C, endothermic events with an onset temperature of approximately 137°C An exothermic event with an onset temperature of approximately 169°C, an endothermic event with an onset temperature of approximately 207°C, or approximately This exhibits an endothermic event with an onset temperature of 250°C. In one embodiment, form 7 is obtained by DSC When feature analysis was performed, an endothermic event with an onset temperature of approximately 30°C and an endothermic event with an onset temperature of approximately 127°C were found. Thermal events, endothermic events with an onset temperature of approximately 137°C, exothermic events with an onset temperature of approximately 169°C, This shows an endothermic event with an initiation temperature of 207°C and an endothermic event with an initiation temperature of approximately 250°C. In this embodiment, form 7 is generally shown in the DSC thermogram presented in Figure 19. Characterized by a DSC thermogram like this.

[0221] In one embodiment, form 7 exhibits a weight loss of approximately 2.0% when heated from approximately 10°C to approximately 90°C. This shows that when heated from approximately 90°C to approximately 190°C, it exhibits a weight loss of approximately 3.4%. In one embodiment, And form 7 is a TGA thermogram as generally shown in Figure 19. Characterized by an omogram.

[0222] All combinations of the above embodiments are encompassed by this application.

[0223] (5.2.1.8 Form 8 of Compound 1) In some embodiments, provided herein are eight forms of the compound of formula (I). In some embodiments, form 8 of compound 1 substantially does not contain amorphous compound 1. In some embodiments, form 8 of compound 1 is another crystalline form of compound 1 (that is, It substantially does not contain polymorphs. In some embodiments, form 8 of compound 1 is a compound It is substantially free of a salt of compound 1. In some embodiments, form 8 of compound 1 is compound 1 It is provided as a substantially pure form 8.

[0224] A representative XRPD pattern of compound 1, form 8, is provided in Figure 20.

[0225] In one embodiment, form 8 has peaks at 18.8, 20.8, and 24.5 ± 0.2 degrees 2θ. It has an XRPD pattern. In one embodiment, form 8 has 2θ of 16.0 and 17.9 ± 0.2 degrees. The XRPD pattern further includes at least one peak selected from. One embodiment In this configuration, form 8 has peaks at 16.0, 17.9, 18.8, 20.8, and 24.5 degrees 2θ, 5.4 At least one of the 2θ values ​​selected from 9.4, 11.0, 12.3, 12.7, 14.2, 16.4, and 22.0 ± 0.2 degrees. It also has an XRPD pattern that includes a combination of one peak.

[0226] In one embodiment, form 8 is located at the following positions: 5.4, 9.4, 11.0, 12.3, 12.7, 14.2, 16. Among the 2θ values ​​of 0, 16.4, 17.9, 18.8, 20.8, 22.0, and 24.5±0.2 degrees, 1, 2, 3, 4, 5, 6, 7 Characterized by XRPD peaks located at 8, 9, 10, 11, 12, 13, 14, or all of them. In one embodiment, the solid morphology is characterized by three of the peaks. In one embodiment, the solid morphology is characterized by five of the peaks. In this embodiment, the solid morphology is characterized by seven of the peaks. In one embodiment, the solid morphology is characterized by nine of the peaks. In one embodiment, the solid form is characterized by 11 of the peaks. In this embodiment, the solid form is characterized by 13 of the peaks. In this case, the solid form is characterized by all of the peaks.

[0227] In some embodiments, the above XRPD peak (degree 2θ peak) is obtained by using copper Kα radiation. It is observed when it is analyzed.

[0228] In one embodiment, form 8 has an XRPD pattern generally as shown in Figure 20. .

[0229] In one embodiment, form 8 is the non-solvated solid form of compound 1.

[0230] In one embodiment, when the features of form 8 were analyzed by DSC, the starting temperature was approximately 156°C. It exhibits an endothermic phenomenon.

[0231] All combinations of the above embodiments are encompassed by this application.

[0232] In one embodiment, the solid forms provided herein (for example, Form 1, Form 2, Form 3, The diameter of particles in Form 4, Form 5, Form 6, Form 7, or Form 8 is approximately 0.1 μm to approximately 150 μm. μm ~ approx. 125 μm, approx. 0.1 μm ~ approx. 100 μm, approx. 0.1 μm ~ approx. 75 μm, approx. 0.1 μm ~ approx. 50 μm, approx. 1 μm The thickness ranges are approximately 50 μm, 0.1 μm to 10 μm, 0.1 μm to 7 μm, or 0.5 μm to 5 μm. In one embodiment, the diameter is approximately 0.5 μm to approximately 5 μm. In another embodiment, the diameter is The size ranges from approximately 0.6 μm to approximately 4.8 μm.

[0233] In one embodiment, the Specified Specified Material provides a solid form of a compound of formula (I), or the A composition comprising a salt of, or a solvate of, or a solvate of a salt, or a mixture thereof. In this composition, the compound has a purity of over approximately 98.0% as determined by HPLC. Yes. In one embodiment, the compound of formula (I) is approximately 98.5%, approximately 99.0%, approximately 99.5%, and approximately 99.6%. It has a purity of %, approximately 99.9%, or approximately 99.91%.

[0234] (5.2.2. Method for preparing the solid form of compound 1) Provided herein is a method for preparing a compound of formula (I), wherein the compound is of formula ( I) The compound, or its salt or solvate, or solvate of the salt, or mixture thereof A method which is a polymorphic form 1 of a compound; the method is: (i) A compound of formula (I), or a salt or solvate thereof, or a solvate of a salt, or A composition containing at least one non-morphological polymorph of these mixtures is mixed in one or more solvents. Exposure for a period of time sufficient to convert at least about 50% of the total amount of form to form 1 of the compound of formula (I) to; and (ii) Recover the polymorphic form 1. Includes.

[0235] In one embodiment, a non-polymorph of the compound of formula (I) is exposed to one solvent. In one embodiment, a non-polymorph of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, a non-polymorph of the compound of formula (I) is exposed to one or more solvents. In this embodiment, the solvent is an organic solvent. In one embodiment, the solvent is an alcohol. In one embodiment, the solvent is ethanol, 2-methoxyethanol, methanol, ethylethanol The solvent is acetic acid or isopropyl alcohol. In one embodiment, the solvent is acetic acid. Ethyl, methyl isobutyl ketone, toluene, 1,2-dimethoxyethane, N,N-dimethylform It is humamide, acetonitrile, ethylene glycol, anisole, or water. In this example, the solvent is ethanol. In one embodiment, the solvent system is a mixture of two solvents. It contains a mixture. In one embodiment, the solvent system is a mixture of two solvents. The mixture of the two solvents is a mixture of anisole and isopropyl alcohol, anisole A mixture of ethanol and anisole, a mixture of toluene and anisole, a mixture of acetonitrile and water A mixture of toluene and ethanol, a mixture of acetone and water, isopropyl alcohol and water A mixture of ethanol and water, a mixture of N,N-dimethylformamide and water, N,N-acetate A mixture of toamide and water, a mixture of dimethyl sulfoxide and water, or anisole and methanol It is a mixture of two solvents. In one embodiment, the mixture of the two solvents is isopropyl alcohol It is a mixture of isopropyl alcohol and water. In one embodiment, the volume ratio of isopropyl alcohol to water is approximately The ratio is approximately 1:4 to 4:1. In one embodiment, the volume ratio of isopropyl alcohol to water is approximately 1: It is 1 or about 3:2. In one embodiment, the volume ratio of isopropyl alcohol to water is about 1: 2. In one embodiment, the mixture of the two solvents is a mixture of acetone and water. In this embodiment, the mixture of the two solvents is a mixture of ethanol and water. In this embodiment, the mixture of the two solvents is a mixture of acetonitrile and water. In one embodiment, the volume ratio of acetonitrile to water is approximately 1:4 to approximately 8:1. The volume ratio of acetonitrile to water is approximately 4:1. In one embodiment, acetonitrile and water The volume ratio is approximately 2:3. In one embodiment, the solvent system includes a mixture of three solvents. In this embodiment, the mixture of the three solvents is a mixture of ethanol, water, and DCM.

[0236] In one embodiment, the non-morphological polymorph is an amorphous compound of formula (I). Therefore, non-morphological polymorph 1 is morphological 2 of the compound of formula (I). In one embodiment, non-morphological polymorph 1 The time required to convert at least about 50% of the total amount to form 1 of the compound of formula (I) is about 1 hour. Approximately 2 hours, approximately 5 hours, approximately 10 hours, approximately 12 hours, approximately 20 hours, approximately 24 hours, approximately 30 hours, approximately 40 hours, It is approximately 48 hours, or approximately 72 hours.

[0237] In one embodiment, the non-polymorph of the compound of formula (I) is, for example, in a 1:1 volume ratio, iso It is exposed to propyl alcohol and water. The final volume ratio of isopropyl alcohol to water is 1: Another volume of water is added at approximately 60°C to make a ratio of 2. The mixture is then heated at approximately 60°C for approximately 30 minutes, then 1 hour. Intervals: approximately 2 hours, 5 hours, 10 hours, 12 hours, 20 hours, 24 hours, 30 hours, 40 hours Let it rest for approximately 48 hours, or approximately 72 hours.

[0238] In one embodiment, the non-form polymorph of the compound of formula (I) is, for example, about 50 in a volume ratio of 4:1. It is exposed to acetone and water at temperatures ranging from ℃ to approximately 60℃. The solvent is acetone / water to isopropyl alcohol. The mixture is then replaced with 100% alcohol until it reaches a final volume of approximately 30%. The mixture is then heated at approximately 60°C for approximately 30 minutes, then 1 hour. Approximately 2 hours, approximately 5 hours, approximately 10 hours, approximately 12 hours, approximately 14 hours, approximately 20 hours, approximately 24 hours, approximately 30 hours, Let it rest for approximately 40 hours, 48 ​​hours, or 72 hours.

[0239] In one embodiment, Form 1 is the crystallization or recrystallization of a compound of formula (I) from one or more solvents. It is prepared by chemical reaction. In one embodiment, the solvent is ethanol, 2-methoxyethanol The alcohol is methanol, ethylene glycol, or isopropyl alcohol. One embodiment In this, the solvents are ethyl acetate, methyl isobutyl ketone, toluene, and 1,2-dimethoxyethyl acetate. Tan, N,N-dimethylformamide, acetonitrile, ethylene glycol, anisole, Or water. In one embodiment, the solvent is ethanol.

[0240] In one embodiment, Form 1 is the crystallization of a compound of formula (I) from a solvent containing an alcohol or It is prepared by recrystallization. In one embodiment, the solvent is isopropyl alcohol. Yes, it exists. In one embodiment, the solvent is ethanol.

[0241] In one embodiment, Embodiment 1 is a compound of formula (I) from a solvent containing a mixture of two solvents. It is prepared by crystallization or recrystallization. In one embodiment, a mixture of two solvents is prepared. A mixture of anisole and isopropyl alcohol, a mixture of anisole and ethanol, anisole A mixture of sole and toluene, a mixture of acetonitrile and water, a mixture of toluene and ethanol Substances, mixtures of acetone and water, mixtures of isopropyl alcohol and water, mixtures of ethanol and water Compound, mixture of N,N-dimethylformamide and water, mixture of N,N-acetamide and water, dimethyl A mixture of sulfoxide and water, or a mixture of anisole and methanol. One embodiment In this case, the mixture of the two solvents is a mixture of isopropyl alcohol and water. In this embodiment, the volume ratio of isopropyl alcohol to water is approximately 1:4 to approximately 4:1. In this case, the volume ratio of isopropyl alcohol to water is approximately 1:1 or approximately 3:2. In this embodiment, the volume ratio of isopropyl alcohol to water is approximately 1:2. The mixture of the two solvents is a mixture of acetone and water. In one embodiment, the two solvents The medium mixture is a mixture of ethanol and water. In one embodiment, a mixture of the two solvents The substance is a mixture of acetonitrile and water.

[0242] In one embodiment, form 1 is a compound of formula (I) from a solvent containing a mixture of alcohol and water. It is prepared by crystallization or recrystallization of a substance. In one embodiment, the solvent is about 30% water It is a mixture of alcohols, approximately 90%. In one embodiment, the solvent is approximately 40% of the water. It is a mixture of 80% alcohols. In one embodiment, the solvent is isopropyl alcohol. It is a mixture of isopropyl alcohol and water. In one embodiment, the solvent is isopropyl alcohol and water in a ratio of about 3:2. It is a mixture of water. In one embodiment, the solvent is a mixture of ethanol and water. In one embodiment, the solvent is a mixture of about 20% to about 90% ethanol in water. In this embodiment, the solvent is a mixture of approximately 40% to approximately 80% ethanol in water. The solvent is a mixture of approximately 40% ethanol in water. In one embodiment, the solvent is water It is a mixture of about 60% ethanol. In one embodiment, the solvent is about 80% ethanol in water. It is a mixture of nols. In one embodiment, the solvent further comprises DCM. In one embodiment Crystallization or recrystallization is performed by heating and cooling one or more times (for example, 1, 2, 3, 4, 5, or 6 times). Includes a cooling cycle. In one embodiment, crystallization or recrystallization is performed in three heating and cooling steps. Includes Ikul. In one embodiment, crystallization or recrystallization is performed in four heating and cooling cycles. Includes. In one embodiment, the heating stage is performed at approximately 50°C to approximately 60°C for a certain period of time (for example, approximately 1 hour). This includes heating for approximately 6 hours (for example, approximately 3 hours). In one embodiment, the cooling step is This includes keeping it at room temperature for a certain period of time (for example, about 1 hour to about 6 hours, for example, about 2 hours).

[0243] In one embodiment, form 1 is a solvent containing a mixture of acetonitrile and water, and formula (I) It is prepared by crystallization or recrystallization of the compound. In one embodiment, acetonitrile The volume ratio of acetonitrile to water is approximately 1:4 to approximately 8:1. In one embodiment, the volume of acetonitrile to water The ratio is approximately 4:1. In one embodiment, the volume ratio of acetonitrile to water is approximately 2:3. .

[0244] Provided herein is a method for preparing a compound of formula (I), wherein the compound is of formula ( I) The compound, or its salt or solvate, or solvate of the salt, or mixture thereof A method which is a polymorphic form 2 of the compound; the method is: (i) A compound of formula (I), or a salt or solvate thereof, or a solvate of a salt, or A composition containing at least one non-morphological polymorph of these mixtures is prepared in one or more solvents, Exposure for a sufficient time to convert at least about 50% of the total amount of form to form 2 of the compound of formula (I) to; and (ii) Recover the polymorphic form 2. Includes.

[0245] In one embodiment, the non-morphological polymorph of the compound of formula (I) is exposed to one solvent. In one embodiment, a non-form 2 polymorph of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, the non-morphological polymorph of the compound of formula (I) is exposed to one or more solvents. In this embodiment, the solvent is an organic solvent. In one embodiment, the solvent is dichloromethane, The substances are acetone, tetrahydrofuran, water, 1-propanol, or chloroform. In one embodiment, the mixture of two solvents is a mixture of dichloromethane and acetone, tetrahydr A mixture of rofuran and water, a mixture of dichloromethane and ethanol, or dichloromethane and ethanol. It is a mixture of tanols. In one embodiment, the mixture of two solvents is dichloromethane. It is a mixture of and acetone. In one embodiment, the non-morphological polymorph of the compound of formula (I) is three It is exposed to a mixture of solvents. In one embodiment, a mixture of three solvents is dichloromethyl It is a mixture of tan, ethanol, and water. In one embodiment, the non-form 2 polymorph is the non-form (I) It is a crystalline compound. In one embodiment, at least about 50% of the total amount of non-morphological polymorphs is of formula (I). The time required to convert the compound to form 2 is approximately 1 hour, 2 hours, 5 hours, and 10 hours. The duration is approximately 12 hours, 20 hours, 24 hours, 30 hours, 40 hours, 48 ​​hours, or 72 hours.

[0246] In one embodiment, form 2 is, for example, 1-propanol, acetone, or dichloro A mixture of chloromethane, or dichloromethane and acetone, or a mixture of tetrahydrofuran and water. It is obtained from maturation in a compound. In one embodiment, form 2 is obtained at about 5°C in dichloromethane It is obtained from.

[0247] Provided herein is a method for preparing a compound of formula (I), wherein the compound is of formula ( I) The compound, or its salt or solvate, or solvate of the salt, or mixture thereof The method is a polymorphic form 3 of the compound; the method is: (i) A compound of formula (I), or a salt or solvate thereof, or a solvate of a salt, or A composition containing at least one non-morphological polymorph of these mixtures is mixed with one or more solvents. Exposure for a sufficient time to convert at least about 50% of the total amount of form to form 3 of the compound of formula (I) to; and (ii) Recover the polymorphic form 3. Includes.

[0248] In one embodiment, the non-morphological trimorph of the compound of formula (I) is exposed to one solvent. In one embodiment, the non-morphological trimorph of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, the non-morphological trimorph of the compound of formula (I) is exposed to one or more solvents. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is methyl ethyl ketol , tert-butyl methyl ether, 2-methyl-1-propanol, 2-methyltetrahydrofur N, isopropyl alcohol, ethanol, toluene, 1-propanol, acetone, or It is acetonitrile. In one embodiment, the mixture of the two solvents is 2-methyltetranitrile. A mixture of tetrahydrofuran and isopropyl alcohol, 2-methyltetrahydrofuran and ethanol A mixture of 2-methyltetrahydrofuran and toluene, or acetonitrile and water It is a mixture of the following. In one embodiment, the non-morphological polymorph is an amorphous compound of formula (I). In this embodiment, at least about 50% of the total amount of non-form 3 polymorphs is converted to form 3 of the compound of formula (I). The appropriate time for replacement is approximately 1 hour, 2 hours, 5 hours, 10 hours, 12 hours, or 20 hours. These are approximately 24 hours, 30 hours, 40 hours, 48 ​​hours, or 72 hours.

[0249] In one embodiment, form 3 is obtained from maturation in one solvent or a mixture of one or more solvents. In one embodiment, form 3 can be obtained at approximately 5°C.

[0250] Provided herein is a method for preparing a compound of formula (I), wherein the compound is of formula ( I) The compound, or its salt or solvate, or solvate of the salt, or mixture thereof The method is a polymorphic form 4 of the compound; the method is: (i) A compound of formula (I), or a salt or solvate thereof, or a solvate of a salt, or A composition containing at least one non-morphological polymorph of these mixtures is prepared in one or more solvents, Exposure for a sufficient time to convert at least about 50% of the total amount of form to form 4 of the compound of formula (I) to; and (ii) Recover the polymorphic form 4. Includes.

[0251] In one embodiment, the non-morphological 4 polymorphs of the compound of formula (I) are exposed to one solvent. In one embodiment, a non-morphological polymorph of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, the non-morphological polymorph of the compound of formula (I) is exposed to one or more solvents. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is 1-propanol. Acetone, 2-methyl-1-propanol, 1,4-dioxane, chloroform, tetrahydrofoam Lan, 2-methoxyethanol, isopropyl alcohol, water, anisole, toluene, or It is dimethyl sulfoxide. In one embodiment, a mixture of the two solvents is aniso A mixture of toluene and tetrahydrofuran, a mixture of toluene and tetrahydrofuran, toluene and It is a mixture of isopropyl alcohol, or a mixture of isopropyl alcohol and water. In one embodiment, the non-morphological polymorph is an amorphous compound of formula (I). Sufficient time to convert at least about 50% of the total amount of non-form 4 polymorphs to form 4 of the compound of formula (I) The intervals are approximately 1 hour, 2 hours, 5 hours, 10 hours, 12 hours, 20 hours, 24 hours, and 30 hours. The interval is approximately 40 hours, 48 ​​hours, or 72 hours.

[0252] In one embodiment, form 4 is obtained from maturation in one solvent or a mixture of one or more solvents. In one embodiment, form 4 can be obtained at approximately 5°C.

[0253] Provided herein is a method for preparing a compound of formula (I), wherein the compound is of formula ( I) The compound, or its salt or solvate, or solvate of the salt, or mixture thereof A method which is a polymorphic form of the compound; the method is: (i) A compound of formula (I), or a salt or solvate thereof, or a solvate of a salt, or A composition containing at least one non-morphological polymorph of these mixtures is mixed with one or more solvents. Exposure for a sufficient time to convert at least about 50% of the total amount of form to form 5 of the compound of formula (I) to; and (ii) To recover the polymorphic form 5. Includes.

[0254] In one embodiment, the non-morphological polymorphs of the compound of formula (I) are exposed to one or more solvents. In this embodiment, the solvent is an organic solvent. In one embodiment, the solvent is anisole. In one embodiment, the non-morphological polymorph is an amorphous compound of formula (I). And, to convert at least about 50% of the total amount of non-form 5 polymorphs into form 5 of the compound of formula (I) The durations are approximately 1 hour, 2 hours, 5 hours, 10 hours, 12 hours, 20 hours, and 24 hours. It is approximately 30 hours, 40 hours, 48 ​​hours, or 72 hours.

[0255] In one embodiment, form 5 is obtained from maturation in one solvent or a mixture of one or more solvents. In one embodiment, form 5 can be obtained at approximately 5°C.

[0256] Provided herein is a method for preparing a compound of formula (I), wherein the compound is of formula ( I) The compound, or its salt or solvate, or solvate of the salt, or mixture thereof A method which is a polymorphic form 6 of the compound; the method is: (i) A compound of formula (I), or a salt or solvate thereof, or a solvate of a salt, or A composition containing at least one non-morphological polymorph of these mixtures is prepared in one or more solvents, Exposure for a sufficient time to convert at least about 50% of the total amount of form to form 6 of the compound of formula (I) to; and (ii) Recover the polymorphic form 6. Includes.

[0257] In one embodiment, the non-morphological 6 polymorphs of the compound of formula (I) are exposed to one solvent. In one embodiment, a non-form 6 polymorph of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, the non-morphological polymorph of the compound of formula (I) is exposed to one or more solvents. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is nitromethane, The solvent is cetonitrile or water. In one embodiment, the solvent is nitromethane. In one embodiment, the mixture of two solvents is a mixture of nitromethane and water or acetonitrile and It is a mixture of water. In one embodiment, the mixture of two solvents is acetonitrile and water It is a mixture. In one embodiment, the volume ratio of acetonitrile to water is 1:1. In one embodiment, the non-morphological polymorph is an amorphous compound of formula (I). A sufficient period to convert at least about 50% of the total amount of form 6 polymorphs to form 6 of the compound of formula (I). These are approximately 1 hour, 2 hours, 5 hours, 10 hours, 12 hours, 20 hours, 24 hours, and 30 hours. These are approximately 40 hours, 48 ​​hours, or 72 hours.

[0258] In one embodiment, form 6 is obtained from maturation in one solvent or a mixture of one or more solvents. In one embodiment, form 6 can be obtained at approximately 5°C.

[0259] Provided herein is a method for preparing a compound of formula (I), wherein the compound is of formula ( I) The compound, or its salt or solvate, or solvate of the salt, or mixture thereof The method is a polymorphic form of the compound 7; the method is: (i) A compound of formula (I), or a salt or solvate thereof, or a solvate of a salt, or A composition containing at least one non-morphological polymorph of these mixtures is mixed with one or more solvents. Exposure for a sufficient time to convert at least about 50% of the total amount of form to form 7 of the compound of formula (I) to; and (ii) To recover the polymorph 7. Includes.

[0260] In one embodiment, seven non-polymorphs of the compound of formula (I) are exposed to one solvent. In one embodiment, the non-polymorph of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, the non-polymorphs of the compound of formula (I) are exposed to one or more solvents. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is methyl ethyl ketol The ether is 1-propanol, acetone, or tert-butyl methyl ether. In one embodiment, In this embodiment, the non-morphological polymorph is an amorphous compound of formula (I). The time required to convert at least about 50% of the total amount of form 7 of the compound of formula (I) is about 1 Duration: Approximately 2 hours, 5 hours, 10 hours, 12 hours, 20 hours, 24 hours, 30 hours, 40 hours The interval is approximately 48 hours, or approximately 72 hours.

[0261] Provided herein is a method for preparing a compound of formula (I), wherein the compound is of formula ( I) The compound, or its salt or solvate, or solvate of the salt, or mixture thereof A method which is a polymorphic form of the compound; the method is: (i) A compound of formula (I), or a salt or solvate thereof, or a solvate of a salt, or A composition containing at least one non-morphological 8 polymorph of these mixtures, with a small total amount of non-morphological 8 polymorphs. Exposure to heating for a sufficient time to convert at least 50% of the compound of formula (I) to form 7; and (ii) Recover the polymorphic form 8. Includes.

[0262] In one embodiment, the non-morphological polymorph is morphological polymorph 6 of the compound of formula (I). And, to convert at least about 50% of the total amount of non-form 8 polymorphs into form 8 of the compound of formula (I) The durations are approximately 1 hour, 2 hours, 5 hours, 10 hours, 12 hours, 20 hours, and 24 hours. It is approximately 30 hours, 40 hours, 48 ​​hours, or 72 hours.

[0263] (5.2.3. Solid form including compound 1 and co-forms) In one embodiment, the solid form provided herein further comprises a co-formation. In one embodiment, the compound of formula (I) is provided herein: [ka] or its salt, or solvate (e.g., hydrate), or solvate of the salt, or these It is a solid form containing a mixture of and co-formations.

[0264] In one embodiment, the following is provided herein: a free base of compound 1, or its solvent. This is a solid form containing a hydrate (for example, a hydrate) and a co-form. In one embodiment, the present invention Provided in the details is a non-solvated solid form containing compound 1 and its co-formations. In this specification, the compound 1 and the co-formation are provided in an anhydrous solid form. In one embodiment, the following is provided herein: a solvent comprising compound 1 and a co-formation. It is in solid form. In one embodiment, compound 1 and conformate are provided herein. It is a hydrated solid form containing mature compounds.

[0265] Compound 1, or its salt, or solvate (e.g., hydrate), or solvate of the salt, Alternatively, these mixtures and co-formations can exist in various solid forms. It is conceivable. Such solid forms include crystalline solids or mixtures of crystalline and amorphous solids. It includes. In one embodiment, the solid form is substantially crystalline. In one embodiment, the solid state is crystalline.

[0266] In some embodiments, the molar ratio of compound 1 to solvent / water in the solid form is approximately 10:1 to approximately The ratio is in the range of 1:10. In some embodiments, the molar ratio of compound 1 in solid form to solvent / water is... The ratio is in the range of approximately 5:1 to approximately 1:5. In some embodiments, compound 1 in solid form The molar ratio of solvent to water is in the range of approximately 3:1 to approximately 1:3. In some embodiments, solid In one embodiment, the molar ratio of compound 1 to solvent / water is in the range of approximately 2:1 to approximately 1:2. The molar ratio is approximately 1:2 (i.e., bissolvate / hydrate). In another embodiment, The molar ratio is approximately 1:1 (i.e., monosolvate / hydrate). In yet another embodiment... The molar ratio is approximately 2:1 (i.e., hemi-solvate / hydrate).

[0267] The ratio of compound 1 to the co-form may be stoichiometric or non-stoichiometric. In one embodiment... In one embodiment, the ratio of compound 1 to the co-form is in the range of approximately 5:1 to approximately 1:5. The ratio of compound 1 to co-formed compounds is approximately 5:1, 4:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, and 1:2. The ratio is 5, 1:3, 1:4, or 1:5. In one embodiment, the ratio of compound 1 to the co-form is approximately 1:1. Yes. In one embodiment, the cocrystal includes a plurality of co-formations. The crystal contains two co-formations.

[0268] In one embodiment, the co-formed product is citric acid, L-malic acid, L-tartaric acid, fumaric acid, succinate. Citric acid, maleic acid, sorbic acid, ketoglutaric acid, salicylic acid, benzoic acid, 3-hydroxy Benzoic acid, 2,4-dihydroxybenzoic acid, 4-aminobenzoic acid, orotic acid, urea, nicotine Nicotinic acid, isonicotinic acid, nicotinamide, isonicotinamide, saccharin, L-lactic acid, L- Serine, L-proline, glycine, maltol, succinimide, sulfacetamide, and It is one or more of the p-toluenesulfonic acid monohydrates.

[0269] In one embodiment, the co-form is L-tartaric acid. In another embodiment, the co-form is It is salicylic acid.

[0270] (5.2.3.1 Solid form containing compound 1 and L-tartaric acid P1C3) In some embodiments, the herein provides compound 1 and L-tartaric acid This is the solid form P1C3. In one embodiment, form P1C3 is compound 1 and L-tartaric acid It is a crystalline hydrate solid form containing [the substance]. In some embodiments, form P1C3 is amorphous It substantially does not contain compound 1. In some embodiments, form P1C3 of compound 1 is a compound Substantially does not include other crystalline forms (i.e., polymorphs) of substance 1. In some embodiments, Therefore, form P1C3 is provided as substantially pure form P1C3.

[0271] In one embodiment, the molar ratio of compound 1 to L-tartaric acid in form P1C3 is in the range of approximately 1:2 to 2:1. In one embodiment, the molar ratio of compound 1 to L-tartaric acid in form P1C3 is approximately 1:1. In one embodiment, form P1C3 further contains water. In one embodiment, in form P1C3 The molar ratio of compound 1 to water is in the range of approximately 1:2 to 2:1. In one embodiment, in form P1C3 The molar ratio of compound 1 to water is approximately 1:1. In one embodiment, compound 1 in form P1C3:L-alcohol The molar ratio of nitrate to water is approximately 1:1:1.

[0272] A typical XRPD pattern for morphology P1C3 is provided in Figure 22.

[0273] In one embodiment, form P1C3 has peaks at 11.2, 17.4, and 17.7±0.2 degrees 2θ. It has an XRPD pattern that includes . In one embodiment, form P1C3 has 21.2 and 22.5 ± 0.2 degrees The XRPD pattern further includes at least one peak selected from 2θ. In this embodiment, form P1C3 has peaks at 2θ of 11.2, 17.4, 17.7, 21.2, and 22.5 degrees. 2θ of 10.7, 11.6, 17.0, 20.6, 20.8, 21.4, 22.2, 23.2, 23.6, and 24.2±0.2 degrees It has an XRPD pattern that includes at least one peak selected from the above.

[0274] In one embodiment, form P1C3 is located at the following positions: 10.7, 11.2, 11.6, 17.0, 17.4, 17.7 , 20.6, 20.8, 21.2, 21.4, 22.2, 22.5, 23.2, 23.6, and 24.2±0.2 degrees 2θ Town1 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of the XRPD peaks It can be characterized as follows. In one embodiment, the solid form is characterized by three of the peaks It is characterized by the following. In one embodiment, the solid form is characterized by five of the peaks Characterized. In one embodiment, the solid form is characterized by seven of the peaks. It is characterized by nine of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. It is attached. In one embodiment, the solid form is characterized by 11 of the peaks. In one embodiment, the solid form is characterized by 13 of the peaks. In one embodiment, the solid form is characterized by all of the peaks. It can be done.

[0275] In some embodiments, the above XRPD peak (degree 2θ peak) is obtained by using copper Kα radiation. It is observed when it is analyzed.

[0276] In one embodiment, form P1C3 has an XRPD pattern as generally shown in Figure 22. ru.

[0277] Thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of compound 1, form P1C3. A typical overlay for RAM is provided in Figure 23.

[0278] In one embodiment, when morphology P1C3 is characterized by DSC analysis, the starting temperature is approximately 129°C. And / or exhibits an endothermic event with a peak temperature of approximately 149°C. In one embodiment, form P1C3 This is a DSC thermogram that is generally as shown in Figure 23. Therefore, it can be characterized.

[0279] In one embodiment, form P1C3, when heated from approximately 30°C to approximately 100°C, has a weight of approximately 0.5% It shows a loss, and when heated from approximately 100°C to approximately 160°C, it shows a weight loss of approximately 1.9%, and at approximately 170°C... When heated to approximately 260°C, it exhibits a weight loss of approximately 15.9%. In one embodiment, form P1C3 This is a TGA thermogram that is generally as shown in Figure 23. Therefore, it can be characterized.

[0280] A typical gravitational vapor deposition (GVS) isotherm for morphology P1C3 is shown in Figure 28. One embodiment In this case, morphology P1C3 was used to increase relative humidity from approximately 0% relative humidity to approximately 90% relative humidity. At that time, it shows a weight increase of approximately 3.7%. In one embodiment, form P1C3 is shown in Figure 28. Characterized by a GVS thermogram, which is generally shown in the GVS thermogram. .

[0281] In one embodiment, the preparation of form P1C3 is carried out by mixing compound 1 and L-tartaric acid in the presence of a solvent. This includes grinding. In one embodiment, the solvent is nitromethane. In one embodiment, In this context, nitromethane is not anhydrous; that is, it contains a certain amount of water (for example, about 5%). In one embodiment, the preparation of form P1C3 involves compound 1 and L-tartaric acid in the presence of nitromethane. This involves grinding a 1:1 mixture of the two.

[0282] In one embodiment, the preparation of form P1C3 involves slowly dissolving compound 1 and L-tartaric acid in a solvent. This includes cooling. In one embodiment, the solvent is nitromethane. In one embodiment, Furthermore, nitromethane is not anhydrous; that is, it contains a certain amount of water (for example, about 5%). In this embodiment, the preparation of form P1C3 involves mixing compound 1 in a 1:1 ratio in nitromethane containing about 5% water. and includes slow cooling of the L-tartaric acid solution. In one embodiment, the solution is about 0.1 It cools from approximately 50°C to approximately 5°C at a rate of about 0.25°C / minute.

[0283] All combinations of the above embodiments are encompassed by this application.

[0284] (5.2.3.2 Solid form containing Compound 1 and salicylic acid P1C9) In some embodiments, the following are provided herein: Compound 1 and salicylic acid This is a solid form P1C9 containing compound 1 and salicy It is a crystalline hydrate solid form containing ruic acid. In some embodiments, form P1C9 is non It is substantially free of crystalline compound 1. In some embodiments, form P1C9 of compound 1 is Substantially does not contain other crystalline forms (i.e., polymorphs) of compound 1. In some embodiments, In this context, form P1C9 is provided as substantially pure form P1C9.

[0285] In one embodiment, the molar ratio of compound 1 to salicylic acid in form P1C9 is in the range of approximately 1:1 to 3:1. In one embodiment, the molar ratio of compound 1 to salicylic acid in form P1C9 is approximately 2:1. Yes. In one embodiment, form P1C9 further contains water. In one embodiment, form P1C9 The molar ratio of compound 1 to water is in the range of approximately 1:3 to 1:5. In one embodiment, form P1C9 The molar ratio of compound 1 to water is approximately 1:4. In one embodiment, compound 1 in form P1C9: The molar ratio of salicylic acid to water is approximately 1:0.5:4.

[0286] A typical XRPD pattern for morphology P1C9 is provided in Figure 24.

[0287] In one embodiment, form P1C9 has peaks at 6.9, 10.1, and 12.0 ± 0.2 degrees 2θ. It has an XRPD pattern that includes . In one embodiment, form P1C9 has 17.8 and 20.0 ± 0.2 degrees The XRPD pattern further includes at least one peak selected from 2θ. In this embodiment, form P1C9 has peaks at 6.9, 10.1, 12.0, 17.8, and 20.0 degrees 2θ. Select from 2θ of 4.7, 6.0, 12.7, 13.7, 15.0, 16.2, 24.2, 24.6, 26.1, and 28.3±0.2 degrees. It has an XRPD pattern that includes at least one selected peak.

[0288] In one embodiment, form P1C9 is located at the following positions: 4.7, 6.0, 6.9, 10.1, 12.0, 12.7, 1 Among the 2θ values ​​of 3.7, 15.0, 16.2, 17.8, 20.0, 24.2, 24.6, 26.1, and 28.3±0.2 degrees, 1 and 2 XRPD peaks located at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of them It is characterized by the following. In one embodiment, the solid form is characterized by three of the peaks Characterized. In one embodiment, the solid form is characterized by five of the peaks. It is characterized by seven of the peaks. In one embodiment, the solid form is characterized by seven of the peaks. It is attached. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by 11 of the peaks. In one embodiment, the solid form is characterized by 13 of the peaks. In one embodiment, the solid form is characterized by all of the peaks. ru.

[0289] In some embodiments, the above XRPD peak (degree 2θ peak) is obtained by using copper Kα radiation. It is observed when it is analyzed.

[0290] In one embodiment, form P1C9 has an XRPD pattern as generally shown in Figure 24. ru.

[0291] Thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of compound 1, form P1C9. A typical overlay for RAM is provided in Figure 25.

[0292] In one embodiment, when the form P1C9 is characterized by DSC analysis, the starting temperature is approximately 43°C. and / or an endothermic event with a peak temperature of approximately 75°C or an onset temperature of approximately 120°C and / or This exhibits an endothermic event with a peak temperature of approximately 127°C. In one embodiment, form P1C9 is DSC When feature analysis was performed, an absorbent with an initial temperature of approximately 43°C and / or a peak temperature of approximately 75°C was found. This exhibits a thermal event and an endothermic event with an onset temperature of approximately 120°C and / or a peak temperature of approximately 127°C. In one embodiment, form P1C9 is generally shown in the DSC thermogram presented in Figure 25. It is characterized by a DSC thermogram that looks like this.

[0293] In one embodiment, when form P1C9 is heated from about 30°C to about 100°C, it is about 10.15% of its weight. This shows quantitative loss. In one embodiment, form P1C9 is a TGA thermograph shown in Figure 25. It is characterized by a TGA thermogram, which is generally shown in the image.

[0294] In one embodiment, the preparation of form P1C9 involves a mixture of compound 1 and salicylic acid in the presence of a solvent. This includes sonication below. In one embodiment, the solvent is a mixture of acetonitrile and water. It is a mixture. In one embodiment, the solvent is a 1:1 mixture of acetonitrile and water. In this embodiment, the preparation of form P1C9 involves a 1:1 mixture of compound 1 and salicylic acid, and acetonite This includes ultrasonic treatment in the presence of a 1:1 mixture of ru and water. This further includes allowing the material derived from the ultrasonic treatment process to stand for a certain period of time. In one embodiment, The standing period is less than approximately 2 hours. In one embodiment, the standing period is approximately 30 minutes. .

[0295] All combinations of the above embodiments are encompassed by this application.

[0296] (5.2.3.3 Solid form containing compound 1 and salicylic acid P2C9) In some embodiments, the following are provided herein: Compound 1 and salicylic acid This is the solid form P2C9. In one embodiment, form P2C9 is compound 1 and salicy It is a crystalline solvate solid containing ruic acid. In one embodiment, form P2C9 is compound 1 and a solid form of crystalline acetonitrile solvate containing salicylic acid. Several embodiments In some embodiments, form P2C9 substantially does not contain amorphous compound 1. Furthermore, form P2C9 of compound 1 substantially contains other crystalline forms (i.e., polymorphs) of compound 1. No. In some embodiments, form P2C9 is provided as substantially pure form P2C9. It can be done.

[0297] In one embodiment, the molar ratio of compound 1 to salicylic acid in form P2C9 is in the range of approximately 1:2 to 2:1. In one embodiment, the molar ratio of compound 1 to salicylic acid in form P2C9 is approximately 1:1. Yes. In one embodiment, form P2C9 further comprises acetonitrile. Therefore, the molar ratio of compound 1 to acetonitrile in form P2C9 is in the range of approximately 1:1 to 3:1. In this embodiment, the molar ratio of compound 1 to acetonitrile in form P2C9 is approximately 1:0.5. In this embodiment, the molar ratio of compound 1:salicylic acid:acetonitrile in form P2C9 is approximately 1:1 : 0.5.

[0298] A typical XRPD pattern for morphology P2C9 is provided in Figure 26.

[0299] In one embodiment, form P2C9 has peaks at 11.4, 13.4, and 24.0 ± 0.2 degrees 2θ. It has an XRPD pattern that includes . In one embodiment, form P2C9 is 25.1 and 26.9 ± 0.2 degrees. The XRPD pattern further includes at least one peak selected from 2θ. In this embodiment, form P2C9 has peaks at 2θ of 11.4, 13.4, 24.0, 25.1, and 26.9 degrees. , 8.5, 12.7, 16.0, 16.8, 18.7, 19.9, 21.7, 23.6, 28.3, and 28.7 ± 0.2 degrees of 2θ It has an XRPD pattern that includes at least one peak selected from the above.

[0300] In one embodiment, form P2C9 is located at the following positions: 8.5, 11.4, 12.7, 13.4, 16.0, 16.8 , 1 of 2θ degrees: 18.7, 19.9, 21.7, 23.6, 24.0, 25.1, 26.9, 28.3, and 28.7±0.2 degrees , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of the XRPD peaks It can be characterized as follows. In one embodiment, the solid form is characterized by three of the peaks It is characterized by the following. In one embodiment, the solid form is characterized by five of the peaks Characterized. In one embodiment, the solid form is characterized by seven of the peaks. It is characterized by nine of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. It is attached. In one embodiment, the solid form is characterized by 11 of the peaks. In one embodiment, the solid form is characterized by 13 of the peaks. In one embodiment, the solid form is characterized by all of the peaks. It can be done.

[0301] In some embodiments, the above XRPD peak (degree 2θ peak) is obtained by using copper Kα radiation. It is observed when it is analyzed.

[0302] In one embodiment, form P2C9 has an XRPD pattern as generally shown in Figure 26. ru.

[0303] Thermogravimetric analysis (TGA) thermogram and differential scanning calorimetry (DSC) thermogram of compound 1, form P2C9. A typical overlay for RAM is provided in Figure 27.

[0304] In one embodiment, when morphology P2C9 is characterized by DSC analysis, the starting temperature is approximately 78°C. and / or exhibit an endothermic event with a peak temperature of approximately 96°C. In one embodiment, form P2C9 This is a DSC thermogram that is generally as shown in Figure 27. Therefore, it can be characterized.

[0305] In one embodiment, form P2C9, when heated from about 30°C to about 130°C, loses about 5.6% of its weight. This shows the loss. In one embodiment, form P2C9 is shown in the TGA thermogram presented in Figure 27. It is characterized by a TGA thermogram, which is generally shown here.

[0306] In one embodiment, the preparation of form P2C9 involves a mixture of compound 1 and salicylic acid in the presence of a solvent. This includes sonication below. In one embodiment, the solvent is a mixture of acetonitrile and water. It is a mixture. In one embodiment, the solvent is a 1:1 mixture of acetonitrile and water. In this embodiment, the preparation of form P2C9 involves mixing compound 1 and salicylic acid in a 1:1 ratio using acetonitrile. This includes ultrasonic treatment in the presence of a 1:1 mixture of ru and water. This further includes allowing the material derived from the ultrasonic treatment process to stand for a certain period of time. In one embodiment, The standing period is at least about 2 hours.

[0307] All combinations of the above embodiments are encompassed by this application.

[0308] In one embodiment, a solid form provided herein (for example, form P1C9, form P1C9, Alternatively, the diameter of particles of form P2C9), where the diameter of the particles of the compound is approximately 0.1 μm to approximately 150 μm. Approximately 0.1μm to approximately 125μm, approximately 0.1μm to approximately 100μm, approximately 0.1μm to approximately 75μm, approximately 0.1μm to approximately 50μm, approximately 1 μm to approximately 50 μm, approximately 1 μm to approximately 50 μm, approximately 0.1 μm to approximately 10 μm, approximately 0.1 μm to approximately 7 μm, or approximately 0.5 μm The diameter is approximately 0.5 μm to 5 μm. In one embodiment, the diameter is approximately 0.5 μm to 5 μm. In this case, the diameter is approximately 0.6 μm to approximately 4.8 μm.

[0309] In one embodiment, provided herein are compounds of formula (I), or salts thereof, if A composition comprising a solvate, a solvate of a salt, or a solid form of a mixture thereof. Here, the compound has a purity of over 98.0% as determined by HPLC. In one embodiment, the compound of formula (I) is approximately 98.5%, approximately 99.0%, approximately 99.5%, approximately 99.6%, and approximately 9 It has a purity of 9.9%, or approximately 99.91%.

[0310] (5.2.4 Methods for analyzing materials) In some embodiments, provided herein are solids provided herein. A method for analyzing a material in terms of the presence or quantity of a compound of formula (I), or a salt thereof, Alternatively, a solvate (e.g., hydrate), or a solvate of its salt, or a mixture thereof. To provide a material containing; and to provide a reference signature for the features obtained from the material using a feature analysis method. By comparing it with signature features, it is possible to determine whether signature features associated with the solid form are present in the material. This includes determining whether the presence of a feature substantially identical to the reference signature feature is the material This is also a method for demonstrating the presence of the solid form in the material.

[0311] In one embodiment, the method determines the batch as a result of a decision based on comparison with a reference standard. Further including making a selection. In one embodiment, the method makes a decision regarding the quality of the material. The method further includes lowering. In one embodiment, the method involves using materials in the manufacture of a pharmaceutical composition. The method further includes making a decision on whether or not to use the material. In one embodiment, the method is This further includes making a decision on whether to use the drug to treat PI3K-mediated disorders.

[0312] In one embodiment, the feature analysis method is one of the following: XRPD, TGA, DSC, GVS, FT-IR, or NMR. There is one or more.

[0313] (5.2.5. Method for preparing the amorphous form of compound 1) Provided herein is a method for preparing an amorphous form of a compound of formula (I), This method involves the creation of an amorphous form through a crystalline form. In one embodiment, this specification Provided in this book is a method for preparing an amorphous form of a compound of formula (I), the amorphous form The state is a compound of formula (I), or a salt or solvate thereof, or a solvate of a salt, This method is produced via polymorphic form 1 of these mixtures.

[0314] In one embodiment, the method is: (i) A compound of formula (I), or a salt or solvate thereof, or a solvate of a salt, or The solid form containing polymorphs of these mixtures is dissolved in one or more solvents to form a solution. thing; and (ii) Remove the solvent from the solution to obtain the amorphous form of the compound of formula (I). Includes.

[0315] In one embodiment, the polymorphic form is polymorphic form 1.

[0316] In one embodiment, the solid form further includes an amorphous form of the compound of formula (I).

[0317] In one embodiment, the method is: (i) A compound of formula (I), or a salt or solvate thereof, or a solvate of a salt, or The solid form containing polymorph 1 of these mixtures is dissolved in one or more solvents to form a solution. thing; and (ii) Remove the solvent from the solution to obtain the amorphous form of the compound of formula (I). Includes.

[0318] In one embodiment, the method is: (i) A compound of formula (I), or a salt or solvate thereof, or a solvate of a salt, or One or more compositions containing at least one amorphous polymorph or amorphous form of these mixtures In the solvent, convert at least about 50% of the total amount of non-form 1 polymorphs to form 1 of the compound of formula (I). To be exposed for a sufficient period of time; (ii) To recover the polymorph 1; (iii) Dissolve the polymorph 1 in one or more solvents to form a solution; and (iv) Remove the solvent from the solution to obtain the amorphous form of the compound of formula (I). Includes.

[0319] In one embodiment, the solvent of the solution is removed by freeze-drying. In another embodiment... Then, the solvent in the solution is removed by spray drying.

[0320] In one embodiment, a non-polymorph of the compound of formula (I) is exposed to one solvent. In one embodiment, a non-polymorph of the compound of formula (I) is exposed to a mixture of two solvents. In one embodiment, a non-polymorph of the compound of formula (I) is exposed to one or more solvents. In this embodiment, the solvent is an organic solvent. In one embodiment, the solvent is an alcohol. In one embodiment, the solvent is ethanol, 2-methoxyethanol, methanol, ethylethanol The solvent is acetic acid or isopropyl alcohol. In one embodiment, the solvent is acetic acid. Ethyl, methyl isobutyl ketone, toluene, 1,2-dimethoxyethane, N,N-dimethylform It is humamide, acetonitrile, ethylene glycol, anisole, or water. In this embodiment, the solvent is ethanol. In one embodiment, a mixture of two solvents is A A mixture of nisol and isopropyl alcohol, a mixture of anisole and ethanol, aniso A mixture of ethanol and toluene, a mixture of acetonitrile and water, a mixture of ethanol and ethanol , a mixture of acetone and water, or a mixture of isopropyl alcohol and water. One embodiment In this case, the mixture of the two solvents is a mixture of isopropyl alcohol and water. In one embodiment, the volume ratio of isopropyl alcohol to water is 1:1 or 3:2. In this embodiment, the volume ratio of isopropyl alcohol to water is 1:2. One solvent mixture is a mixture of acetone and water. In one embodiment, non-polymorphic is an amorphous compound of formula (I). In one embodiment, at least the total amount of non-morphological polymorphs The time required to convert approximately 50% to form 1 of the compound of formula (I) is approximately 1 hour, approximately 2 hours, and approximately 5 hours. Between approximately 10 hours, 12 hours, 20 hours, 24 hours, 30 hours, 40 hours, 48 ​​hours, or approximately It is 72 hours.

[0321] In one embodiment, the non-polymorph of the compound of formula (I) is, for example, in a 1:1 volume ratio, iso It is exposed to propyl alcohol and water. The final volume ratio of isopropyl alcohol to water is 1: Another volume of water is added at approximately 60°C so that the ratio becomes 2. The mixture is then heated at approximately 60°C for approximately 30 minutes. Duration: Approximately 2 hours, 5 hours, 10 hours, 12 hours, 20 hours, 24 hours, 30 hours, 40 hours Allow it to rest for approximately 48 hours or 72 hours.

[0322] In one embodiment, the non-form polymorph of the compound of formula (I) is, for example, about 50 in a volume ratio of 4:1. It is exposed to acetone and water at temperatures ranging from ℃ to approximately 60℃. The solvent is acetone / water to isopropyl alcohol. The mixture is then replaced with 100% alcohol until it reaches a final volume of approximately 30%. The mixture is then heated at approximately 60°C for approximately 30 minutes, then 1 hour. Approximately 2 hours, approximately 5 hours, approximately 10 hours, approximately 12 hours, approximately 14 hours, approximately 20 hours, approximately 24 hours, approximately 30 hours, Let it rest for approximately 40 hours, 48 ​​hours, or 72 hours.

[0323] In one embodiment, the solvent for dissolving the compound of formula (I) is DCM, an alcohol, or the same It is a mixture of these. In one embodiment, the alcohol is MeOH. In one embodiment The alcohol is 2-propanol. In another embodiment, the polymer is spray-dried. It is added beforehand. In another embodiment, the polymer is PVP / VA 64. In another embodiment In this case, the polymer is HPMC-AS.

[0324] (5.3 Method for preparation) In one embodiment, a compound of formula (I) is provided herein: [ka] Alternatively, prepare a salt thereof, a solvate thereof, a solvate of the salt, or a mixture thereof. A method for which compound C of the following formula: [ka] The carboxylic acid of formula G: [ka] The method includes coupling with to provide a compound of formula (I).

[0325] In one embodiment, coupling is performed in the presence of a coupling reagent. In this embodiment, the coupling reagent is carbodiimide, triazine, phosphonium, uro It is anium, or a mixture of anhydrous substances, or a mixture thereof. In one embodiment, cup The ring reagent is N,N'-dicyclohexylcarbodimide (DCC), N ,N'-Diisopropylcarbodiimide (DIC), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Bodiimide (EDCI), hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzo Triazole (HOAt), 2-propanephosphonic anhydride (T3P), 1-[(dimethylamino)(morpho [Lino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxidehexaful Olophosphate (HDMA), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl) Uronium hexafluorophosphate (HBTU), (1-cyano-2-ethoxy-2-oxoethili Dimethylamino-morpholino-carbenium-hexafluorophosphate COMU, benzotriazole-1-yloxy-tris(dimethylamino)phosphonium Xafluorophosphate (BOP), (benzotriazole-1-yloxy)tripyrrolidinophosphate Suphonium hexafluorophosphate (PyBOP), 1-[bis(dimethylamino)methylene]-1H -1,2,3-Triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) Diethyl phosphorocyanidate (DECP), diethyl phosphorochloride (DEPC), dimethyl Azide phosphate (DPPA), bis(2-oxazolidide) chloride phosphate (BOPCl), chlorodimethyl Toxytriazine or its N-methylmorpholinium adduct, 3-(diethoxyphosphory Luoxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT), bromotris(dimethylamino) Phosphonium hexafluorophosphate (BroP), (EtO)2P(O)-Cl,(EtO)2P(O)-oxima , pivaloyl chloride, isobutyl chloroformate, 2-chloro-4,6-dimethoxy-1,3,5- Triazine (CDMT), or 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpho Linium chloride (DMTMM) or its BF4 analogue, or a mixture thereof. In one embodiment, the coupling reagent is EDCI. It is DMTMM.

[0326] In one embodiment, the coupling is carried out in the presence of an activator. The activators are HOBt, HB triazinon, and ethyl 2-cyano-2-(hydroxyimino)acetate. Tate (oxima), NHS, or ethyl (hydroxyimino)cyanoacetate potassium salt (K- It is an oxima. In one embodiment, the activator is HOBt.

[0327] In one embodiment, the coupling is performed in the presence of a base. The base is Et3N, DIPEA, pyridine, NMM, DBU, NaOH, or DMAP. In one embodiment... In one embodiment, the base is Et3N.

[0328] In one embodiment, the coupling is carried out in the presence of a solvent. The solvent is DMF, NMP, acetonitrile, EtOH, acetone, DCM, MeOH, or water. These are mixtures.

[0329] In one embodiment, the coupling is performed in the presence of a carbodiimide coupling reagent. In one embodiment, carbodiimide is 1-ethyl-3-(3-dimethylaminopropyl (L)Carbodiimide. In one embodiment, the coupling is hydroxybenzo The coupling is carried out in the presence of a riazole (HOBt). In one embodiment, the coupling is carried out in the presence of a base. It is carried out under the supervision of a base. In one embodiment, the base is DIPEA. This is in DMF. In one embodiment, coupling is performed under an inert atmosphere. It can be done.

[0330] In one embodiment, the coupling is performed in the presence of a triazine coupling reagent. In one embodiment, the triazine is DMTMM. In one embodiment, the coupling The process is carried out in the presence of a base. In one embodiment, the base is Et3N, DIPEA, pyridine. The base is NMM, DBU, NaOH, or DMAP. In one embodiment, the base is Et3N. In this case, coupling is performed with acetonitrile, EtOH, acetone, DCM, MeOH, or The process is carried out in water or a mixture thereof as a solvent. In one embodiment, the solvent is acetonitrile A mixture of ethanol and water (e.g., 4:1 v / v), a mixture of ethanol and water (e.g., 3:1 v / v), ethanol and water and DC A mixture of M (e.g., 14.4:4.8:1 v / v / v), a mixture of acetone and water (e.g., 4:1 v / v), DCM A mixture of DCM and MeOH (e.g., 4:1 v / v), a mixture of DCM and EtOH (e.g., 4:1 v / v), or DCM In one embodiment, the solvent is a mixture of acetonitrile and water. The volume ratio of acetonitrile to water is approximately 4:1.

[0331] In one embodiment, coupling is performed in the presence of T3P and DIPEA in DMF.

[0332] In one embodiment, a compound of formula (I) is provided herein: [ka] Alternatively, prepare a salt thereof, a solvate thereof, a solvate of the salt, or a mixture thereof. A method for which compound C of the following formula: [ka] The ester of formula D: [ka] The method includes coupling with to provide a compound of formula (I).

[0333] In one embodiment, the coupling is carried out in the presence of one or more solvents. In this embodiment, the coupling is carried out in the presence of a base and one or more solvents. In this example, the base is an amine. In one embodiment, the amine is N,N-diisopropylethyl It is diamine (DIPEA). In one embodiment, the solvent is an organic solvent. The organic solvents are acetonitrile, dimethylformamide, tetrahydrofuran, and 2-methylformamide. Selected from tyltetrahydrofuran, dichloromethane, or a mixture thereof. In one embodiment, the organic solvent is acetonitrile. In one embodiment, the organic solvent is It is a mixture of DCM and ethanol. In one embodiment, the volume ratio of DCM to ethanol is The ratio is approximately 8:1 to 2:1. In one embodiment, the volume ratio of DCM to ethanol is approximately 4:1. In one embodiment, the coupling is carried out in the presence of a mixture of two solvents. In one embodiment, the solvent mixture is water and acetonitrile. The volume ratio of to acetonitrile is approximately 1:4. In one embodiment, the coupling is approximately 3 The process is carried out at temperatures of 0°C to approximately 80°C, approximately 40°C to approximately 70°C, or approximately 55°C to approximately 65°C. In one embodiment... And the temperature is approximately 60°C.

[0334] In one embodiment, the compound C of the following formula is provided herein: [ka] A method for preparing compound A of the following formula: [ka] The alkyne of formula E: [ka] This method includes coupling with [another component].

[0335] In one embodiment, the coupling involves a catalyst, ligand, or catalyst / ligand complex; a base; and This is carried out in the presence of a solvent.

[0336] In one embodiment, the catalyst is a palladium (Pd) catalyst, a nickel (Ni) catalyst, a copper (Cu) catalyst, or a mixture thereof. In one embodiment, the catalyst is a Pd catalyst. In one embodiment, The Pd catalyst is Pd-G3, Pd2(dba)3, PdCl2(MeCN)2, Pd(OAc)2, Pd(PPh3)4, or PdCl2(P The pH is 3)2. In one embodiment, the palladium catalyst is PdCl2(MeCN)2. In this case, the palladium catalyst is Pd2(dba)3.

[0337] In one embodiment, the catalyst is a Ni catalyst. In one embodiment, the Ni catalyst is (Ph3P)2NiC It is l2.

[0338] In one embodiment, the catalyst is a Cu catalyst. In one embodiment, the Cu catalyst is CuI. .

[0339] In one embodiment, the ligand is a phosphine ligand or a bisphosphine ligand. In one embodiment, the ligands are XPhos, PCy3, PCy2Ph, P i Pr3, PCy2 t Bu, Cataclinium A, P(MeOC6H4)3, PPh2(C6H4CO2H), PPh2(C6H4SO3H), SPhos, JohnPhos, DavePhos, MePhos, cBRIDP, Cy-vBRIDP, Cy-cBRIDP, i Bu triple cage, P t Bu2Cy, P t Bu3, CataCXium PICy , P tBu2(PhNMe2), PPh3, dppp, dppe, dppb, BINAP, DPEPhos, dppf, dbpf, XantPhos, N - t Bu2P azetin, dppm, dmpe, dippe, DIPAMP, Chiraphos, SPANphos, SEGPHOS, Me-DuPh It is os or Josiphos. In one embodiment, the ligand is XPhos, CataCXium A, JohnPh This includes os, DavePhos, MePhos, cBRIDP, CataCXium PICy, or dbpf. In one embodiment Here, the ligand is XPhos(2-dicyclohexylphosphino-2',4',6'-triisopropyl It is biphenyl. In one embodiment, the ligand is cBRIDP.

[0340] In one embodiment, the molar ratio of ligand to catalyst is approximately 5:1 to approximately 1:5. The molar ratio of ligand to catalyst is approximately 2:1 to approximately 1:2. In one embodiment, ligand and catalyst The molar ratio of the medium is approximately 2:1 to approximately 1:1. In one embodiment, the ligand is a monodentate ligand. The molar ratio of ligand to catalyst is approximately 2:1. In one embodiment, the ligand is a monodentate ligand. The molar ratio of ligand to catalyst is approximately 1:1. In one embodiment, the ligand is a bidentate ligand. The ligand is a ligand, and the molar ratio of ligand to catalyst is approximately 1:1. In one embodiment, the ligand is two It is a acetal ligand, and the molar ratio of ligand to catalyst is approximately 1:2.

[0341] In one embodiment, the amount of catalyst added is approximately 0.5% to approximately 10%, approximately 1% to approximately 10%, or approximately 1% ~Approximately 5%. In one embodiment, the amount of catalyst added is approximately 5%. In one embodiment, the amount of catalyst added is approximately 4%. In one embodiment, the amount of catalyst added is approximately 2%. The amount included is approximately 1%.

[0342] In one embodiment, the amount of ligand added is approximately 0.5% to approximately 20%, approximately 0.5% to approximately 15%, and approximately 0.5%. The percentages are approximately 10%, 1% to 10%, 1% to 5%, or 1% to 3%. In one embodiment... In one embodiment, the amount of catalyst added is approximately 10%. Yes. In one embodiment, the amount of catalyst added is approximately 4%. In one embodiment, the catalyst The amount of the additive is approximately 3%. In one embodiment, the amount of the catalyst added is approximately 2%. In this embodiment, the amount of catalyst added is approximately 1%.

[0343] In one embodiment, the base is an inorganic base. In one embodiment, the base is an alkali metal It is a group salt. In one embodiment, the base is an alkaline earth metal salt. The base is Cs2CO3, K2CO3, or K3PO4. In one embodiment, the base is Cs2CO3. In one embodiment, the base is K2CO3. In another embodiment, the base is K3PO4. .

[0344] In one embodiment, the base is an organic base.

[0345] In one embodiment, the Pd catalyst is Pd2(dba)3, the ligand is Xphos, and the base is K2CO3. In one embodiment, the Pd catalyst is Pd2(dba)3, the ligand is Xphos, and the base is It is K3PO4. In one embodiment, the Pd catalyst is PdCl2(MeCN)2 and the ligand is Xphos. The base is K2CO3. In one embodiment, the Pd catalyst is Pd(OAc)2 and the ligand is Xphos. Yes, and the base is K2CO3.

[0346] In one embodiment, the solvent is MeCN, i PrOAc, n-propyl acetate, 2-MeTHF, EtCN The solvent is MEK or toluene. In one embodiment, the solvent is MeCN.

[0347] In one embodiment, the coupling is performed in the presence of PdCl2(MeCN)2. In this case, the coupling is further carried out in the presence of XPhos. In one embodiment, The plucking is further carried out in the presence of a base. In one embodiment, the base is Cs2CO3. In one embodiment, the coupling is carried out in the presence of a solvent. The solvent is an organic solvent. In one embodiment, the organic solvent is acetonitrile.

[0348] In one embodiment, coupling is performed in the presence of Pd2(dba)3. Furthermore, coupling is performed in the presence of XPhos. In one embodiment, The pulling is further carried out in the presence of a base. In one embodiment, the base is K3PO4. In one embodiment, the coupling is carried out in the presence of a solvent. The solvent is an organic solvent. In one embodiment, the organic solvent is acetonitrile.

[0349] In one embodiment, the alkyne of formula E is provided herein: [ka] A method for preparing a compound of formula F: [ka] This method includes deprotecting the system.

[0350] In one embodiment, deprotection is carried out in the presence of a base and a solvent.

[0351] In one embodiment, the base is an inorganic base. In one embodiment, the base is an alkali metal It is a group salt. In one embodiment, the base is KOH, NaOH, NaHCO3, K3PO4, or K2CO3. In one embodiment, the base is an organic base. In one embodiment, the base is pyridine. That is the case.

[0352] In one embodiment, deprotection is carried out in the presence of an acid. In one embodiment, the acid is These are HCl, AcOH, p-TsOH, and camphor sulfonic acid.

[0353] In one embodiment, deprotection is carried out in the presence of a fluoride source. The fluoride source is tetra-n-butylammonium fluoride (TBAF). In one embodiment, In this case, the fluoride source is pyridine-HF.

[0354] In one embodiment, deprotection is carried out in the presence of a phase transfer catalyst. The phase transfer catalyst is tetrabutylammonium hydroxide.

[0355] In one embodiment, the solvent is an organic solvent. In one embodiment, the organic solvent is MeOH. In one embodiment, the solvent is a mixture of water and a water-immiscible solvent. In this embodiment, the water-immiscible solvent is MTBE or DCM. In one embodiment, deprotection is about 10 watts. The process is carried out in the presence of a mixture of t% KOH aqueous solution and MTBE. In one embodiment, the solvent is acetonite It's a trill.

[0356] In one embodiment, a compound of formula F is provided herein: [ka] A method for preparing a product, wherein 4-iodo-1-methyl-1H-pyrazole is converted to trimethylsilylacetyl This method involves coupling with Len.

[0357] In one embodiment, the coupling is carried out in the presence of a Cu catalyst, a Pd catalyst, and a base. .

[0358] In one embodiment, the Cu catalyst is CuI.

[0359] In one embodiment, the Pd catalyst is Pd-G3, Pd2(dba)3, PdCl2(MeCN)2, Pd(OAc)2, Pd(PPh 3)4, or PdCl2(PPh3)2. In one embodiment, the Pd catalyst is PdCl2(PPh3)2.

[0360] In one embodiment, the molar ratio of Pd catalyst to Cu catalyst is approximately 1:20 to approximately 10:1, approximately 1:10 to approximately 5:1. The molar ratio is approximately 1:7.5 to 1:1, and approximately 1:6 to 1:2. In one embodiment, the molar ratio of the Pd catalyst to the Cu catalyst is Approximately 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, or 2 :1. In one embodiment, the molar ratio of Pd catalyst to Cu catalyst is approximately 1:6. In this case, the molar ratio of Pd catalyst to Cu catalyst is approximately 1:2.

[0361] In one embodiment, the amount of Pd catalyst added is approximately 0.0005 equivalents to approximately 0.1 equivalents, and approximately 0.001 equivalents to approximately This is 0.05 equivalents, approximately 0.002 equivalents to approximately 0.02 equivalents, or approximately 0.003 equivalents to approximately 0.01 equivalents. One embodiment In this case, the amount of Pd catalyst added is approximately 0.003 equivalents. In one embodiment, the amount of Pd catalyst added The quantity is approximately 0.01 equivalents.

[0362] In one embodiment, the amount of Cu catalyst added is approximately 0.001 equivalents to approximately 0.2 equivalents, and approximately 0.005 equivalents to approximately 0. This is 0.1 equivalent, approximately 0.01 equivalents to approximately 0.05 equivalents, or approximately 0.0175 equivalents to approximately 0.02 equivalents. In one embodiment... In this embodiment, the amount of Cu catalyst added is approximately 0.0175 equivalents. This is approximately 0.02 equivalents.

[0363] In one embodiment, the amount of Pd catalyst added is approximately 0.01 equivalents, and the amount of Cu catalyst added is approximately 0. It is 0.02 equivalents. In one embodiment, the amount of Pd catalyst added is about 0.003 equivalents, and the amount of Cu catalyst is The amount added is approximately 0.0175 equivalents.

[0364] In one embodiment, the base is DIPA, DIPEA, or N-methylmorpholine (NMM). In one embodiment, the base is DIPA. In another embodiment, the base is DIPEA. In one embodiment, the base is NMM. In one embodiment, the base (e.g., DIPA) is the solvent. It is also used as such.

[0365] In one embodiment, the coupling is DCM, toluene, and 2-methyltetrahydrofuran. The process is carried out in a solvent of , or DIPA, or a mixture thereof. In one embodiment, cup The ring is formed in the solvent of DCM. In one embodiment, the coupling is performed in toluene. The process is carried out in a solvent. In one embodiment, the coupling is performed on 2-methyltetrahydrofur. It is carried out in a solvent.

[0366] In one embodiment, the compound of formula F is used in the preparation of the alkyne compound of formula E without purification. In one embodiment, the compound of formula F is purified and then prepared as an alkyne compound of formula E. Used in manufacturing.

[0367] In one embodiment, the coupling is less than approximately 5%, less than approximately 4%, less than approximately 3%, and less than approximately 2%. The following formulas apply to percentages less than approximately 1%, less than approximately 0.5%, less than approximately 0.3%, less than approximately 0.2%, or less than approximately 0.1%. [ka] It produces by-products.

[0368] In one embodiment, the carboxylic acid of formula G is described in PCT publications WO 2011 / 003065 and WO 2015 / It is prepared according to the method described in No. 073267. An exemplary synthesis scheme is shown below. The overall average yield is approximately 10% to 25%. [ka]

[0369] In one embodiment, the following is provided herein for the preparation of carboxylic acids of formula G This is an alternative method. An exemplary synthesis scheme is shown below. This alternative method is This yields an overall yield of approximately 40-45%, and the product is obtained in an off-white color. [ka]

[0370] In one embodiment, the carboxylic acid of formula G is a compound of formula H: [ka] It is prepared by a method that includes hydrolysis.

[0371] In one embodiment, hydrolysis is carried out in the presence of a base. In one embodiment, salt The group is LiOH, NaOH, or KOH. In one embodiment, the base is LiOH.

[0372] In one embodiment, the compound of formula H is the compound of formula J: [ka] It is prepared by a method that includes reacting with 1,1,3,3-tetramethoxypropane.

[0373] In one embodiment, the reaction of the compound of formula J with 1,1,3,3-tetramethoxypropane is performed with AcOH The process is carried out in the solvent. In one embodiment, the compound of formula H is prepared after the removal of the solvent AcOH. Without further purification, it is used in the preparation of the compound of formula G.

[0374] In one embodiment, the reaction of the compound of formula J with 1,1,3,3-tetramethoxypropane is carried out in the presence of HCl. It will be done under the influence.

[0375] In one embodiment, the compound of formula J is provided herein: [ka] A method for preparing a compound of formula K: [ka] This method involves cyclizing the product.

[0376] In one embodiment, cyclization is carried out under reflux in a solvent of 1-propanol for approximately 2 to 4 days. This is carried out by the following. In one embodiment, the cyclization is carried out in a solvent of 1-propanol for about several days. This is done by allowing the water to recirculate.

[0377] In one embodiment, cyclization is carried out under reflux in a solvent of 1-butanol for approximately 24 to 48 hours. This is carried out by [doing something]. In one embodiment, cyclization is performed in a solvent of 1-butanol for about 36 hours. This is done by allowing the water to recirculate.

[0378] In one embodiment, the compound of formula K is the compound of formula L: [ka] It is prepared by a method that includes reacting it with hydrazine or hydrated hydrazine.

[0379] In one embodiment, the reaction of the compound of formula L with hydrazine or hydrated hydrazine is 1-Pro This is done by refluxing in a Panol solvent.

[0380] In one embodiment, the reaction of the compound of formula L with hydrazine or hydrated hydrazine is performed by 1-but This is done by heating in a solvent of gnoll at approximately 60°C to 80°C.

[0381] In one embodiment, the compound of formula L is the compound of formula M: [ka] It is prepared by a method that includes reacting with NH3 or NH4OH.

[0382] In one embodiment, the reaction of the compound of formula M with NH3 or NH4OH is carried out at room temperature.

[0383] In one embodiment, the preparation of the compound of formula L, the compound of formula K, and the compound of formula J is done in one step. It will be held at the venue.

[0384] In one embodiment, the compound of formula M is ethyl 2-cyanoacetate with 2-chloroethyl acetate. It is prepared by a method that includes reacting it with roloformate.

[0385] In one embodiment, the reaction of 2-cyanoacetate and 2-chloroethyl chloroformate This is carried out in the presence of a base. In one embodiment, the base is an inorganic base. In this embodiment, the base is an alkali metal salt. In one embodiment, the base is an alkaline earth metal It is a salt. In one embodiment, the base is LiOH, NaOH, or KOH. And the base is NaOH.

[0386] In one embodiment, the reaction of 2-cyanoacetate and 2-chloroethyl chloroformate This is carried out in MeCN solvent.

[0387] In one embodiment, the compound of formula M is purified by recrystallization from MeOH. In one embodiment, the compound of formula M is purified by reslurrying in 1-propanol. In one embodiment, the compound of formula M is purified by crystallization from 1-butanol. ru.

[0388] (5.4. Pharmaceutical Compositions) In some embodiments, provided herein are compounds of formula (I), or the same A solid form containing a salt, or a solvate, or a solvate of a salt, or a mixture thereof. A pharmaceutical composition comprising a filler (bulking agent or carrier), and optionally a disintegrant and a lubricant. In some embodiments, the solids provided herein are Form, or its salt, or solvate, or solvate of a salt, or mixture thereof, Also, inert solid diluents and expanders, sterile aqueous solutions and various organic solvents, permeation enhancers, soluble Includes pharmaceutically acceptable excipients, diluents, or carriers, including activating agents and adjuvants. It is a pharmaceutical composition. In one embodiment, provided herein is a pharmaceutical composition provided herein. This is a pharmaceutical composition comprising a solid form and excipients that are acceptable as pharmaceuticals. In this specification, what is provided is essentially from the solid form provided herein. This is a pharmaceutical composition. In one embodiment, the solid form contains at least about It is present in an amount of 80% by weight. In one embodiment, the solid form is present in the composition in at least It also exists in an amount of approximately 90% by weight.

[0389] In one embodiment, the solid form in the pharmaceutical composition is the polymorphic form provided herein or It is a cocrystalline form. In one embodiment, the solid form is form 1, form 2, and form 3 of compound 1. These are form 4, form 5, form 6, form 7, form 8, form P1C3, form P1C9, or form P2C9. In this embodiment, the solid form is form 1.

[0390] In one embodiment, the solid form in the pharmaceutical composition is the amorphous form of compound 1. In one embodiment, the amorphous form of compound 1 is prepared by the method provided herein. In one embodiment, the amorphous form of compound 1 is dissolved in one or more solvents. Allow to form a solution; and remove the solvent from the solution to obtain the amorphous form of compound 1. It is prepared by providing the solvent. In one embodiment, the solvent is removed by spray drying. .

[0391] In one embodiment, the pharmaceutical composition comprises a filler (or bulking agent), a disintegrant, a lubricant, and a cap. It comprises one or more excipients selected from cell shells. In one embodiment, the filler is man The disintegrant is nitrol or pregelatinized starch. In another embodiment, the disintegrant is croscarmellose. It is sodium cellulose. In another embodiment, the lubricant is magnesium stearate. Yes. In one embodiment, the capsule shell is an HPMC capsule shell. In this pharmaceutical composition, mannitol, pregelatinized starch, croscarmellose sodium One or more excipients selected from um, magnesium stearate, and HPMC capsule shells Contains the agent.

[0392] In one embodiment, the amount of compound 1 in the pharmaceutical composition is approximately 1 mg to approximately 100 mg, and approximately 1 mg to approximately 75 mg. , about 1 mg to about 50 mg, about 1 mg to about 40 mg, about 5 mg to about 50 mg, about 5 mg to about 30 mg, about 5 mg to about 10 mg, about 5 The amount is mg, or approximately 30 mg. In one embodiment, the amount is approximately 5 mg, 10 mg, 15 mg, 20 mg, or 30 mg. The amount is 40 mg, 50 mg, 75 mg, or 100 mg. In one embodiment, the amount is approximately 5 mg or 30 mg. Yes. In one embodiment, the amount of compound 1 in the pharmaceutical composition is about 1.5% to about 25% w / w, about 1.5 %~approximately 15% w / w, approximately 1.5%~approximately 10% w / w, approximately 1%~approximately 25% w / w, approximately 1%~approximately 15% w / w, or approximately 1% It is approximately 10% w / w. In one embodiment, the amount of compound 1 in the pharmaceutical composition is approximately 1% to approximately 10% It is %w / w. In one embodiment, the amount of compound 1 in the pharmaceutical composition is about 1, 1.5, 2, 2.5. The values ​​are 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10% w / w. In one embodiment, the amount of compound 1 in the pharmaceutical composition is approximately 1.9% or approximately 9.4%. In this case, the amount of compound 1 is approximately 1.92% or approximately 9.38%.

[0393] In one embodiment, a filler (or bulking agent) in a pharmaceutical composition (for example, starch and man) The nitrole content is approximately 80% to 95% w / w, 85% to 95% w / w, or 90% to 95% w / w. In one embodiment, the filler (or bulking agent) in the pharmaceutical composition (for example, starch and manifold) The concentration (Thor) is approximately 80%, 85%, 90%, or 95% w / w. In one embodiment, pharmaceutical The fillers (or bulking agents) in the composition (e.g., starch and mannitol) make up about 93% w / w, about 8 It is 6% w / w, approximately 92.3% w / w, or approximately 85.1% w / w. In one application, the filler is approximately 93% It is w / w. In one embodiment, the filler is about 85% w / w. In one embodiment, The filler is starch, mannitol, or a mixture thereof. In one embodiment, The filler is a mixture of starch and mannitol. In one embodiment, starch and mannitol The weight ratio of nitrol is approximately 1:3 to approximately 3:1. In one embodiment, the filler is starch and It is a mixture of mannitol in a ratio of approximately 1:1. In one embodiment, the starch is gelatinized starch. It is.

[0394] In one embodiment, a disintegrant in the pharmaceutical composition (e.g., croscarmellose sodium) These range from approximately 1% to 20% w / w, approximately 1% to 15% w / w, approximately 1% to 10% w / w, and approximately 2.5% to 7.5% w / w. It is approximately 1% to approximately 5% w / w, or approximately 5% w / w. In one instance, the disintegrant is approximately 1%, approximately 2%. The percentages are approximately 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w / w. In this case, the disintegrant is approximately 5% w / w.

[0395] In one embodiment, the lubricant in the pharmaceutical composition (e.g., magnesium stearate) is The w / w concentration is approximately 0.1% to 10%, approximately 0.1% to 5%, or approximately 0.1% to 1%. In one embodiment, In this case, the lubricant is present in approximately 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, and 0.7% concentrations. The concentration is approximately 0.8%, 0.9%, or 1% w / w. In one embodiment, the lubricant is approximately 0.5% w / w. That is the case.

[0396] In one embodiment, the pharmaceutical composition provided herein is A method for preparing a solid form containing the compound of formula (I) as a pharmaceutically acceptable excipient. or including mixing with a carrier; wherein the solid form is form 1, form 2, form 3, form 4, The method is of form 5, form 6, form 7, form 8, form P1C3, form P1C9, or form P2C9. In one embodiment, provided herein are pharmaceutical compounds prepared by the above method. It is a finished product.

[0397] In one embodiment, provided herein are compounds of formula (I), or salts thereof, if or solvates, or solvates of salts, or amorphous forms of mixtures thereof, and fillers A pharmaceutical composition comprising (a bulking agent or carrier), and optionally a disintegrant and a lubricant. In this specification, what is provided is a compound of formula (I) in an amount of about 1% to about 10% w / w, or the same Amorphous form of salt, or solvate, or solvate of salt, or mixture thereof, approximately 80% to approximately 95% w / w filler, approximately 2.5% to approximately 7.5% w / w disintegrant, and approximately 0.1% to approximately 1% w / w lubricant This is a pharmaceutical composition containing an augmenting agent.

[0398] In one embodiment, the following is provided herein: about 5 to 30 mg of compound 1 (for example, amorphous This is a pharmaceutical composition comprising (a substance), pregelatinized starch, and mannitol. In one embodiment... The pharmaceutical composition contains croscarmellose sodium and magnesium stearate. It also includes.

[0399] In one embodiment, the pharmaceutical composition is formulated as follows: about 5 mg of compound 1 (for example) (Amorphous), approximately 120 mg of pregelatinized starch, approximately 120 mg of mannitol, approximately 13 mg of croscarmellose Lumellose sodium and approximately 1.3 mg of magnesium stearate. In an embodiment, The pharmaceutical composition is formulated as a capsule. In one embodiment, the pharmaceutical composition is as follows: It is formulated as follows: approximately 5 mg of compound 1 (e.g., amorphous), approximately 120.35 mg of denamide gelatinide. Pun, approximately 120.35 mg of mannitol, approximately 13.00 mg of croscarmellose sodium, and approximately 1 0.3 mg of magnesium stearate. In this embodiment, the pharmaceutical composition is used as a capsule. It is formulated into a pharmaceutical product.

[0400] In one embodiment, the pharmaceutical composition is formulated as follows: about 30 mg of compound 1 (for example) (Amorphous), approximately 136 mg of pregelatinized starch, approximately 136 mg of mannitol, approximately 16 mg of cross Carmellose sodium and approximately 1.6 mg of magnesium stearate. In one embodiment, The pharmaceutical composition is formulated as follows: approximately 30 mg of compound 1 (e.g., amorphous), approximately 136 mg. 20 mg pregelatinized starch, approximately 136.20 mg mannitol, approximately 16.00 mg croscarmellol Sodium stearate and approximately 1.60 mg of magnesium stearate. In this embodiment, the pharmaceutical composition The substance is formulated as a capsule.

[0401] In some embodiments, the pharmaceutical compositions described herein, the second activator, for example For example, this includes additional therapeutic agents (e.g., chemotherapy agents).

[0402] In some embodiments, provided herein are: (a) about 5 mg of amorphous compound 1; ( b) Approximately 120.35 mg of pregelatinized starch; (c) Approximately 120.35 mg of maanitol; (d) Approximately 13 mg (e) croscarmellose sodium; and (e) an amount containing approximately 1.3 mg of magnesium stearate This is a pharmaceutical composition for oral administration (for example, a capsule).

[0403] In some embodiments, provided herein are: (a) about 30 mg of amorphous compound 1; (b) Approximately 136.2 mg of pregelatinized starch; (c) Approximately 136.2 mg of maanitol; (d) Approximately 16 mg (e) a dose containing approximately 1.6 mg of croscarmellose sodium; and (e) a dose containing approximately 1.6 mg of magnesium stearate. This is a pharmaceutical composition for oral administration (for example, a capsule).

[0404] In one embodiment, the pharmaceutical composition is in oral dosage form. In one embodiment, the oral dosage form is It is a capsule. In another embodiment, the oral dosage form is a tablet. In one embodiment The capsule shell is either Swedish orange or white.

[0405] (5.4.1. Formulation) Pharmaceutical compositions include the following: oral administration, for example, liquid drugs (aqueous or non-aqueous liquids or suspensions). ), tablets (e.g., those intended for oral, sublingual, and systemic absorption), capsules, boluses Preparations, powders, granules, pastes for application to the tongue, and duodenal pathways; for example, sterile As a liquid, suspension, or sustained-release formulation, intravenous, intraarterial, subcutaneous, intramuscular, intravascular, Parenteral administration, including intraperitoneal or injectable administration; for example, creams, ointments applied to the skin. Alternatively, topical application as a controlled-release patch or spray; for example, a pessary. Intravaginal or rectal use as a ream, stent, or foam; sublingual; intraocular; intrapulmonary; catheter Local delivery by sten or stent; including solid or liquid substances suitable for intrathecal or nasal cavity delivery. It can be specially formulated for administration in a specific form.

[0406] Suitable aqueous and non-aqueous carriers that can be used in pharmaceutical compositions include water, Tyl, polyol (e.g., glycerol, propylene glycol, polyethylene glycol) Recalls, etc.), and suitable mixtures thereof, vegetable oils, such as olive oil, and injections Possible organic esters include, for example, ethyl oleate. Appropriate fluidity is, for example, By using coating materials such as lecithin, the required particle size can be achieved in the case of dispersants. It can be maintained by maintenance and by the use of surfactants.

[0407] In one embodiment, a suitable carrier that can be used in a pharmaceutical composition is man. Nitol, pregelatinized starch, croscarmellose sodium, magnesium stearate Examples include um and HPMC capsule shells.

[0408] These compositions include auxiliary agents, such as preservatives, wetting agents, emulsifiers, dispersants, lubricants, and / or may contain antioxidants. Microbial activity of the compounds described herein Prevention involves various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenol. This can be ensured by including sorbic acid, etc. Isotonic agents, for example, sugar, It may also be desirable to include sodium chloride or similar substances in the composition. Sustained absorption of pharmaceutical forms is a concern for drugs whose absorption is delayed, such as aluminum monostearate. This can be achieved by including um and gelatin.

[0409] Methods for preparing these formulations or compositions are described herein for the compounds and / or chemicals. The process includes associating a therapeutic agent with a carrier and optionally one or more auxiliary components. Generally, formulations This method involves distributing the compounds provided herein with a liquid carrier, a finely powdered solid carrier, or both. Prepared by forming one closely related product, and then, if necessary, by shaping the product. ru.

[0410] The preparation of such pharmaceutical compositions is well known in the art. For example, Anderson, Philip O .; Knoben, James E.; Troutman, William G. (eds.), Handbook of Clinical Drug Data (k of Clinical Drug Data), 10th edition, McGraw-Hill, 2002; edited by Pratt and Taylor, Pharmacokinetics Principles of Drug Action, 3rd edition, Churchill Livingston, New York, 1990; Katzung (ed.), Basic and Clinical Pharmacology, 12th edition, McGraw H. ill, 2011; Goodman and Gilman (eds.), The Pharmacological Basis of Therapeutic Drugs f Therapeutics), 10th edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences 20th edition, Lippincott Williams & Wilkins., 2000; Martindal Reference e, The Extra Pharmacopoeia, 32nd edition (The Pharmaceutical Press, L See Ondon, 1999; all of these are fully incorporated herein by reference. For example, if it produces any undesirable biological effect, or otherwise is a drug By interacting in a detrimental manner with any other components of the acceptable composition, any Except when conventional excipient media are incompatible with the compounds provided herein, use of excipients This is assumed to be within the scope of this disclosure.

[0411] In some embodiments, one of the compounds provided in the disclosed pharmaceutical composition The concentrations of one or more are approximately 100%, 90%, 80%, 70%, 60%, 50%, 40%, and 3%. 0%, approximately 20%, approximately 19%, approximately 18%, approximately 17%, approximately 16%, approximately 15%, approximately 14%, approximately 13%, approximately 12%, approximately 1 1%, approximately 10%, approximately 9%, approximately 8%, approximately 7%, approximately 6%, approximately 5%, approximately 4%, approximately 3%, approximately 2%, approximately 1%, 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 0.01%, approximately 0.009%, approximately 0.008%, approximately 0.00 7%, 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. It is 0.0002%, or approximately 0.0001%, w / w, w / v, or v / v or less.

[0412] In some embodiments, one or more concentrations of the compounds provided herein are used. The degrees are approximately 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, and 19.75%. Approximately 19.50%, approximately 19.25%, approximately 19%, approximately 18.75%, approximately 18.50%, approximately 18.25%, approximately 18%, approximately 17.75% %, approximately 17.50%, approximately 17.25%, approximately 17%, approximately 16.75%, approximately 16.50%, approximately 16.25%, approximately 16%, approximately 15. 75%, approximately 15.50%, approximately 15.25%, approximately 15%, approximately 14.75%, approximately 14.50%, approximately 14.25%, approximately 14%, approximately 1 3.75%, approximately 13.50%, approximately 13.25%, approximately 13%, approximately 12.75%, approximately 12.50%, approximately 12.25%, approximately 12% Approximately 11.75%, approximately 11.50%, approximately 11.25%, approximately 11%, approximately 10.75%, approximately 10.50%, approximately 10.25%, approximately 10% Approximately 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, and 7%. 75%, approximately 7.50%, approximately 7.25%, approximately 7%, approximately 6.75%, approximately 6.50%, approximately 6.25%, approximately 6%, approximately 5.75%, Approximately 5.50%, approximately 5.25%, approximately 5%, approximately 4.75%, approximately 4.50%, approximately 4.25%, approximately 4%, approximately 3.75%, approximately 3.50 %, approximately 3.25%, 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 0.5%, 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 0.01%, 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 This is approximately %, 0.0003%, 0.0002%, or 0.0001%, w / w, w / v, or greater than v / v.

[0413] In some embodiments, one or more concentrations of the compounds provided herein are used. The degrees are approximately 0.0001% to 50%, 0.001% to 40%, 0.01% to 30%, and 0.02% to 29%. Approximately 0.03% to 28%, approximately 0.04% to 27%, approximately 0.05% to 26%, approximately 0.06% to 25%, approximately 0.07 %~approximately 24%, approximately 0.08%~approximately 23%, approximately 0.09%~approximately 22%, approximately 0.1%~approximately 21%, approximately 0.2%~approximately 20% Approximately 0.3% to 19%, approximately 0.4% to 18%, approximately 0.5% to 17%, approximately 0.6% to 16%, approximately 0.7% Approximately 15%, approximately 0.8% to 14%, approximately 0.9% to 12%, or approximately 1% to 10%, w / w, w / v, or v / v It is within range.

[0414] In some embodiments, one or more concentrations of the compounds provided herein are used. The percentages are approximately 0.001% to 10%, 0.01% to 5%, 0.02% to 4.5%, 0.03% to 4%, and 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to It falls within the range of approximately 1.5%, approximately 0.09% to approximately 1%, or approximately 0.1% to approximately 0.9%, w / w, w / v, or v / v.

[0415] In some embodiments, an amount of one or more of the compounds provided herein These are approximately 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, and 5.5g. g, about 5.0g, about 4.5g, about 4.0g, about 3.5g, about 3.0g, about 2.5g, about 2.0g, about 1.5g, about 1.0g, about 0.9 5g, about 0.9g, about 0.85g, about 0.8g, about 0.75g, about 0.7g, about 0.65g, about 0.6g, about 0.55g, about 0.5g, Approximately 0.45g, approximately 0.4g, approximately 0.35g, approximately 0.3g, approximately 0.25g, approximately 0.2g, approximately 0.15g, approximately 0.1g, approximately 0.09g, approximately 0 0.08g, approximately 0.07g, approximately 0.06g, approximately 0.05g, approximately 0.04g, approximately 0.03g, approximately 0.02g, approximately 0.01g, approximately 0.009g Approximately 0.008g, approximately 0.007g, approximately 0.006g, approximately 0.005g, approximately 0.004g, approximately 0.003g, approximately 0.002g, approximately 0.001g, Approx. 0.0009g, approx. 0.0008g, approx. 0.0007g, approx. 0.0006g, approx. 0.0005g, approx. 0.0004g, approx. 0.0003g, approx. 0 It is 0.0002 g, or about 0.0001 g or less. Several embodiments are provided herein. The amount of one or more of the compounds provided herein in the pharmaceutical composition is about 1 mg, about 1. 5mg, about 2mg, about 2.5mg, about 3mg, about 3.1mg, about 3.2mg, about 3.3mg, about 3.4mg, about 3.5mg, about 4mg, The dosage is approximately 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

[0416] In some embodiments, an amount of one or more of the compounds provided herein These are approximately 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, and 0.0007g. Approximately 0.0008g, approximately 0.0009g, approximately 0.001g, approximately 0.0015g, approximately 0.002g, approximately 0.0025g, approximately 0.003g, approximately 0. 0035g, approx. 0.004g, approx. 0.0045g, approx. 0.005g, approx. 0.0055g, approx. 0.006g, approx. 0.0065g, approx. 0.007g, Approximately 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g Approximately 0.025g, approximately 0.03g, approximately 0.035g, approximately 0.04g, approximately 0.045g, approximately 0.05g, approximately 0.055g, approximately 0.06g, approximately 0.065g, approximately 0.07g, approximately 0.075g, approximately 0.08g, approximately 0.085g, approximately 0.09g, approximately 0.095g, approximately 0.1g, approximately 0.15g , about 0.2g, about 0.25g, about 0.3g, about 0.35g, about 0.4g, about 0.45g, about 0.5g, about 0.55g, about 0.6g, about 0.65g, about 0.7g, about 0.75g, about 0.8g, about 0.85g, about 0.9g, about 0.95g, about 1g, about 1.5g, about 2g, about 2.5g, about 3g, about 3.5g, about 4g, about 4.5g, about 5g, about 5.5g, about 6g, about 6.5g, about 7g, about 7.5g, about 8g It is approximately 8.5g, 9g, 9.5g, or more than 10g.

[0417] In some embodiments, an amount of one or more of the compounds provided herein is about 0.0001 to about 10g, about 0.0005 to about 9g, about 0.001 to about 8g, about 0.005 to about 7g, about 0.01 to about 6g The amounts range from approximately 0.05 to 5g, 0.1 to 4g, 0.5 to 4g, or 1 to 3g.

[0418] (5.4.1.1 Compositions for oral administration) In some embodiments, the compounds provided herein are This is a pharmaceutical composition for oral administration, comprising a substance and pharmaceutical excipients suitable for oral administration. In the embodiments thereof, provided herein are: (i) an effective amount of the disclosed compound; optionally ( ii) one or more effective amounts of a second drug; and (iii) one or more pharmaceutical excipients suitable for oral administration, This is a pharmaceutical composition for oral administration. In some embodiments, the pharmaceutical composition is: (iv) effective It further contains a third quantity of the drug.

[0419] In some embodiments, the pharmaceutical composition is a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions suitable for oral administration contain a predetermined amount of the active ingredient in powder form, granule form, or dissolved form. Liquid, or suspension in an aqueous or non-aqueous liquid, oil-in-water emulsion, or water-in-oil liquid The emulsion contains individual dosage forms such as capsules, cachets, or tablets, or liquids. It can be provided as a body or an aerosol spray. Such dosage forms are subject to the dispensing regulations of the Pharmaceutical Affairs Law. It can be prepared by any of the following methods, but all methods involve the active ingredient being one or more components This includes a step of associating the constituent carrier. Generally, a pharmaceutical composition contains an active ingredient in a liquid carrier or It is mixed uniformly and densely with the pulverized solid carrier or both, and then, if necessary, the generated It is prepared by shaping the material into the desired form. For example, a tablet can be optionally made with one or more supplements. It can be prepared by compression or molding together with auxiliary ingredients. Compressed tablets can be optionally , but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersions. A freely flowing active ingredient, such as a powder or granules, mixed with an excipient such as a preparation, is preferred. They can be prepared by compression in a machine. Wet tablets are prepared by diluting with an inert liquid. It is produced by molding a mixture of powder compounds moistened with an agent in a suitable machine. It is possible.

[0420] This disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms containing an active ingredient, wherein water is This is because it can accelerate the degradation of certain compounds. For example, formulations that have a limited shelf life or have been consumed over time. Pharmaceutical technology is a means of simulating long-term storage in order to determine characteristics such as stability. Water (for example, about 5%) can be added. The anhydrous pharmaceutical composition and dosage form are anhydrous Alternatively, it can be prepared using low-moisture components and low-moisture or low-humidity conditions. In areas where substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Pharmaceutical compositions and dosage forms containing lactose can be made anhydrous. Anhydrous pharmaceutical compositions It can be prepared and stored in such a way that its anhydrous nature is maintained. Therefore, anhydrous medicine The composition is designed to prevent exposure to water so that it can be included in a suitable formulation kit. It can be packaged using materials for which this is known. A suitable example of packaging is a sealed package. Foil, plastic, etc., unit dose containers, blister packs, and strip packs These include, but are not limited to, the following:

[0421] The active ingredient is combined by closely mixing it with the pharmaceutical carrier, following conventional pharmaceutical formulation techniques. This is possible. The carrier takes on a wide variety of forms depending on the desired form of the preparation for administration. This is possible. When preparing a pharmaceutical composition for oral dosage form, an oral liquid preparation (e.g., suspension) In the case of liquids, solutions, and elixirs, or aerosols, any of the usual pharmaceutical media. For example, using water, glycol, oil, alcohol, fragrance, preservative, coloring agent, etc. as a carrier. It can be used; or in the case of oral solid preparations, in some embodiments, lact Without using -, starch, sugar, microcrystalline cellulose, diluent, granulator, lubricant, A combination agent and a disintegrant or other support can be used. For example, a suitable support is a solid In the case of orally administered preparations, examples include powders, capsules, and tablets. In some embodiments... The tablets can then be coated using standard aqueous or non-aqueous techniques.

[0422] Suitable binders for use in pharmaceutical compositions and dosage forms include corn starch and potato starch. Potato starch, or other starches, gelatin, natural and synthetic rubber, such as gum arabic. Sodium alginate, alginic acid, other alginates, tragacanth powder, guarga Cellulose, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethylcellulose) Calcium methylcellulose, sodium carboxymethylcellulose, polyvinyl Pyrrolidone, methylcellulose, pregelatinized starch, hydroxypropylmethylcellulose Examples include, but are not limited to, cellulose, microcrystalline cellulose, and mixtures thereof. .

[0423] Examples of suitable volume extenders for use in pharmaceutical compositions and dosage forms provided herein This includes talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, and powdered cellulose. Calcium, dextrose, kaolin, mannitol, silica, sorbitol, starch, Examples include, but are not limited to, fermented starch and mixtures thereof.

[0424] When a disintegrant is used in a pharmaceutical composition provided herein and exposed to an aqueous environment... We can provide disintegrating tablets. If there is too much disintegrant, the tablets may disintegrate in the bottle. Sometimes, this is generated. If there is too little, it may not be enough for collapse to occur, Therefore, the rate and extent of release of the active ingredient from the dosage form may change. a sufficient amount, neither too little nor too much, that would negatively alter the release of the active ingredient. A disintegrant can be used to form the dosage forms of the compounds provided herein. The amount of disintegrant used may vary depending on the type of formulation and the mode of administration, and is known to those skilled in the art. It can be more easily recognized. Approximately 0.5 to approximately 15 weight percent of disintegrant, or approximately 1 to approximately A disintegrant at a concentration of 5% by weight can be used in the pharmaceutical composition. Pharmaceutical composition and dosage form Disintegrants that can be used to form agar include agar-agar, alginic acid, and calcium carbonate. Microcrystalline cellulose, croscarmellose sodium, crospovidone, polaryl Potassium, sodium starch glycolate, potato starch or tapioca starch Starch, other starches, pregelatinized starch, other starches, clay, other algins, other Examples include, but are not limited to, cellulose, rubber, or mixtures thereof.

[0425] Lubricants that can be used to form pharmaceutical compositions and dosage forms include stear Calcium phosphate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitan Glycol, mannitol, polyethylene glycol, other glycols, stearic acid, lauric acid Sodium sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil) Sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, oleic acid Examples include, but are not limited to, ethyl acetate, ethyl laurate, agar, or mixtures thereof. It is not possible. Further lubricants include, for example, siloid silica gel, synthetic silica coagulation aero Examples include sols or mixtures thereof. The lubricant is present in about 1% by weight of the pharmaceutical composition. It can be added as needed, up to the maximum amount.

[0426] If an aqueous suspension and / or elixir is preferred for oral administration, the active ingredient therein The ingredients are water, ethanol, propylene glycol, glycerin, and various combinations thereof. Along with diluents such as, various sweeteners or flavorings, colorings or pigments, and for example, It can be combined with emulsifiers and / or suspending agents.

[0427] The tablets are either uncoated or coated by known techniques and are used in the gastrointestinal tract. It slows down the breakdown and absorption of the substance, thereby providing a sustained effect over a long period of time. For example, glyceryl monostearate or glyceryl distearate, which have a time delay. Expanded material can be used. For oral use formulations, the active ingredient is diluted with an inert solid. Hard gelatin mixed with an agent, such as calcium carbonate, calcium phosphate, or kaolin. As a capsule, or the active ingredient is in a water or oil medium, for example, peanut oil, liquid powder To be provided as soft gelatin capsules mixed with lafing or olive oil. It's also possible.

[0428] Surfactants that can be used to form pharmaceutical compositions and dosage forms include: Examples include, but are not limited to, aqueous surfactants, lipophilic surfactants, and mixtures thereof. No. In other words, a mixture of hydrophilic surfactants can be used, or a lipophilic interface A mixture of surfactants can be used, or at least one hydrophilic surfactant and a small Alternatively, a mixture of one lipophilic surfactant can be used.

[0429] A suitable hydrophilic surfactant typically has an HLB value of at least about 10, while a suitable lipophilic surfactant... Nonionic amphiphilic surfactants typically have an HLB value of approximately 10 or less. The experimental parameters used to characterize the relative hydrophilicity and hydrophobicity of the compound are: This is the water-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic. An interfacial activity that is oily or hydrophobic, and has higher solubility in oil, while also having a higher HLB value. The surfactant is more hydrophilic and has higher solubility in aqueous solutions. Hydrophilic surfactants are typically, Compounds with an HLB value greater than approximately 10, and anionic and cations to which the HLB standard does not usually apply. It is thought to be an ionic or zwitterionic compound. Similarly, it is lipophilic (i.e., phosphatid). Aqueous surfactants are compounds with an HLB value of approximately 10 or less. However, surfactants The HLB value enables the formulation of emulsions for industrial, pharmaceutical, and cosmetic use. It is merely a rough guideline for general use.

[0430] Hydrophilic surfactants can be either ionic or nonionic. Examples of ionic surfactants include alkylammonium salts; fusidic acid salts; amino acids, oligosaccharides. Fatty acid derivatives of peptides and polypeptides; amino acids, oligopeptides, and polypeptides Glycerides of lecithin; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin Tin; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid esters Salts; alkyl sulfate salts; fatty acid salts; sodium doxate; acylactylate (acy lactylate; monoacetylation of monoglycerides and diglycerides and diacetylated tartaric acid Esters; succinylated monoglycerides and diglycerides; monoglycerides and diglycerides Examples include, but are not limited to, citrate esters and mixtures thereof.

[0431] Among the groups mentioned above, examples of ionic surfactants include: lecithin, lysolecithin Tin, phospholipids, lysophospholipids, and their derivatives; carnitine fatty acid ester salts; Cyrulfate salts; fatty acid salts; sodium doxate; acylactylate (acylactyla) te); Monoacetylation and diacetylated tartaric acid esters of monoglycerides and diglycerides ; succinylated monoglycerides and diglycerides; monoglycerides and diglycerides Examples include nitrate esters and mixtures thereof.

[0432] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, and phosphatidylcholine. Dylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidi Lucerin, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidyl ethanolamine, lysophosphatidylcholine Phatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidyl Phatidylethanolamine, PVP-phosphatidylethanolamine, lactyl fatty acid Acid ester, stearoyl-2-lactylate, stearoyl lactylate, succinylation Monoglycerides, mono / diacetylated tartrates of mono / diglycerides, mono / diglycerides Ceride citrate, coryl sarcosine, caproate, caprylate, capre To, laurate, myristate, palmitate, oleate, lysinolate, linole , linolenate, stearate, lauryl sulfate, teracecil sulfate, Doxate, Lauroyl Carnitine, Palmitoyl Carnitine, Myristoyl Carnitine These can be ionized forms, as well as salts and mixtures thereof.

[0433] Examples of hydrophilic nonionic surfactants include alkyl glucosides; alkyl maltosides; Kilthioglucoside; Lauryl macrogol glyceride; Polyoxyalkylene alkyl Polyethylene glycol alkyl ether; polyoxyalkylene ether Cylphenols, e.g., polyethylene glycol alkylphenols; polyoxyal Chelen alkylphenol fatty acid esters, for example, polyethylene glycol fatty acid mono Esters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerides Polyglycerol fatty acid esters; polyoxyalkylene sorbita ¹ fatty acid esters, for example, polyethylene glycol sorbitan fatty acid esters; poly Among glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols, at least Another hydrophilic transesterification product with another member; polyoxyethylene sterol, its inducement Conductors and analogues; polyoxyethylated vitamins and their derivatives; polyoxyethylene-poly Oxypropylene block copolymers; and mixtures thereof; polyethylene glycol Rubitan fatty acid esters, as well as polyols, triglycerides, vegetable oils, and hydrogenated plants. A hydrophilic transesterification product with at least one member of the oil can be listed. However, it is not limited to these. Polyols include glycerol, ethylene glycol, and polyols. Polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, Alternatively, it can be a saccharide.

[0434] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, laurate, PEG-12 phosphate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, oleic acid PEG-12, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG trioleate -25 Glyceryl, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Laurate Glyceryl, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, oleic acid PEG-30 glyceryl, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 Palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, capric acid / PEG-6 Caprylate, Capric Acid / PEG-8 Caprylate, Polyurethane Laurate Glyceryl-10, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soy sterol PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, POE-23 Lauryl Ether Tel, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, Tocopheryl succinate PEG-100, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopal Mite, PEG10-100 nonylphenol series, PEG15-100 octylphenol series, and PO Loxamer is one example.

[0435] Suitable lipophilic surfactants include, to name just a few: fatty alcohols; glycerol fats. Acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; p Pylene glycol fatty acid ester; sorbitan fatty acid ester; polyethylene glycol Sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols Polyethylene glycol alkyl ethers; sugar esters; sugar esters Lactic acid derivatives of monoglycerides and diglycerides; polyols and glycerides, plants Hydrophobic with at least one member from oils, hydrogenated vegetable oils, fatty acids, and sterols. Examples include transesterification products; lipid-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, a non-exclusive example of a lipophilic surfactant is glycerol fatty acid Contains esters, propylene glycol fatty acid esters, and mixtures thereof, or poly Oal and at least one member from vegetable oil, hydrogenated vegetable oil, and triglycerides - is a hydrophobic transesterification product.

[0436] In one embodiment, the pharmaceutical composition provides good solubilization of the compounds provided herein and / or to ensure dissolution and to minimize precipitation of the compound, soluble It may contain a chemical agent. This is a pharmaceutical composition for parenteral use, for example, a pharmaceutical for injection. This can be particularly important for drug compositions. Hydrophilic drugs and / or other components, for example , to increase the solubility of surfactants, or to make pharmaceutical compositions into stable or homogeneous solutions. Alternatively, a solubilizing agent can be added to maintain the dispersion.

[0437] Suitable solubilizers include: alcohols and polyols, e.g., ethanol Isopropyl alcohol, butanol, benzyl alcohol, ethylene glyco Glue, propylene glycol, butanediol, and their isomers, glycerol, penetrant Taerythritol, sorbitol, mannitol, transktol, dimethyl isosorbate Polyethylene glycol, polypropylene glycol, polyvinyl alcohol, Droxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and Cyclodextrin derivatives; polyethylene glycol with an average molecular weight of approximately 200 to 6000. Ethers, for example, tetrahydrofurfuryl alcohol PEG ether (glycoflor) Or methoxyPEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone and 2-piperidone. ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-A Lucylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinyl Pyrrolidone; esters, e.g., ethyl propionate, tributyl citrate, acetylated Triethyl acetyl citrate, tributyl acetyl citrate, triethyl citrate, ethyl oleate Ingredients: ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate Tate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-ba Leloractone and its isomers, β-butyrolactone and its isomers; and public in the art Other solubilizers of knowledge, for example, dimethylacetamide, dimethyl isosorbide, N-methyl methyl phosphate. Examples include rolidone, monooctanoin, diethylene glycol monoethyl ether, and water. These are possible, but are not limited to these.

[0438] A mixture of solubilizing agents can also be used. For example, triacetin, tricitrate. Ethyl, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolic acid Don, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmeth Cellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol Coal 200-100, Glycoflor, Transktol, Propylene Glycol, and Dimethicone Examples include, but are not limited to, chloroisosorbide. As solubilizing agents, sorbitol, glycerol, triacetin, ethyl alcohol, Examples include PEG-400, glycoflor, and propylene glycol.

[0439] The amount of solubilizer that can be included is not particularly limited. Given the amount of solubilizer, The amount can be limited to a permissible volume, and this amount can be easily determined by those skilled in the art. In some cases, for example, to maximize the concentration of a drug, the body may exceed the acceptable level by a great deal. Including a certain amount of solubilizer, any excess solubilizer should be distilled or used before providing the pharmaceutical composition. It may be advantageous to remove it using conventional techniques such as evaporation. Therefore, in the place where it exists In combination, the solubilizer is approximately 10% by weight, 25% by weight, based on the combined weight of the drug and other excipients. The weight ratio can be %, 50% by weight, 100% by weight, or up to approximately 200% by weight. Desired In some cases, very small amounts of solubilizer are used, such as about 5%, 2%, 1%, or even less. It is also possible. Typically, the solubilizer is about 1% to about 100% by weight, more typically about It can exist in amounts ranging from 5% to approximately 25% by weight.

[0440] The pharmaceutical composition may further contain one or more pharmaceutically acceptable additives and / or excipients. Such additives and excipients include, but are not limited to, release agents (detackifiers). Antifoaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers (viscomodulato r), tonicifier, flavoring agent, coloring agent, oil, fragrance agent, emulsion agent, suspending agent, Examples include binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0441] Examples of preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, and Examples include glycolic preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants Examples of agents include alpha-tocopherol, ascorbic acid, ascorbyl palmitate, and b Chilled hydroxyanisole, butylated hydroxytoluene, monothioglycerol, Potassium bicarbonate, propionic acid, propyl gallate, sodium ascorbate, Examples include sodium bisulfite, sodium metabisulfite, and sodium sulfite, This list is not limited to these. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA). Citric acid monohydrate, disodium edetate, dipotassium edetate, edetate, fumaric acid, Examples include malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate. Examples of antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, and benzalkonium chloride. Diyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine Chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl Ingredients: Glycerin, Hexetidine, Idomideurea, Phenoxyethanol , phenylethyl alcohol, phenylmercury nitrate, propylene glycol, and thimero Examples of antifungal preservatives include, but are not limited to, butyl. Parabens, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxy Benzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, propionic acid Examples include, but are not limited to, sodium and sorbic acid. Examples of chemical preservatives include ethanol, polyethylene glycol, phenol, and phenolic compounds. Compound, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethylamine Examples of acidic preservatives include, but are not limited to, alcohols. Vitamin A, Vitamin C, Vitamin E, Beta-carotene, Citric acid, Acetic acid, Dehydroacetic acid, A Examples include, but are not limited to, scorbic acid, sorbic acid, and phytoic acid. As preservatives, tocopherol, tocopherol acetate, deteroxime mesylate, ceto Limid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (hydroxyt (BHT), ethylenediamine, sodium lauryl sulfate (SLS), lauryl ether sulfur Sodium bisulfite (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite Potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Ger Examples include, but are not limited to, maben II, Neolone, Kathon, and Euxyl. In one embodiment, the preservative is an antioxidant. In another embodiment, the preservative is a chelating agent. That is the case.

[0442] Examples of suitable oils include almond oil, apricot kernel oil, avocado oil, and babassu oil. Bergamot oil, blackcurrant seed oil, borage oil, cade oil, chamomile oil, ca Nora oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter oil, coconut Oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, moon viewing Grass oil, fish oil, linseed oil, geraniol oil, gourd oil, grape seed oil, hazelnut Oil, hyssop oil, isopropyl myristate oil, jojoba oil, kukui nut oil, lavandin Oil, lavender oil, lemon oil, litsea cubeba oil, macadamia nut oil, mallow oil, man Gorgonian seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, Orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed Pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood Soybean oil, sasquana oil, savory oil, sea buckthorn oil, sesame oil, shea butter oil, siris Corn oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, Examples of oils include, but are not limited to, lum oil and wheat germ oil. Butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethyl Thycone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, oc Other examples include chyldodecanol, oleyl alcohol, silicone oil, and combinations thereof. However, it is not limited to these.

[0443] Furthermore, to accelerate processing, to enhance stability, or for other reasons, acid or Bases can be incorporated into pharmaceutical compositions. Examples of pharmaceutically acceptable bases include: , amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide M, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, Magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, water Magnesium aluminum oxide, diisopropylethylamine, ethanolamine, eth Didiamine, triethanolamine, triethylamine, triisopropyl alcohol Examples include amines, trimethylamine, and tris(hydroxymethyl)aminomethane (TRIS). Also suitable are pharmaceutically acceptable acids, such as acetic acid, acrylic acid, and adipine. Acids, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, Butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid (hydroquinosulfonic acid), isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-brom Mophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearin Acids, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc. It is a base that is a salt of a polybasic acid, such as sodium phosphate and disodium hydrogen phosphate. Um and sodium dihydrogen phosphate can also be used. If the base is a salt, cation ON is any convenient and pharmacopoeially acceptable cation, such as ammonium, ammonium, ammonium These can be potassium metals, alkaline earth metals, etc. Examples include sodium and potassium. Examples include um, lithium, magnesium, calcium, and ammonium. , but not limited to these.

[0444] Suitable acids are organic or inorganic acids that are acceptable as pharmaceuticals. Examples of suitable inorganic acids include... Examples include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, and phosphoric acid. Suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, and alkansul. Fonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids Formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoacid Ascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenyl Sulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succin Examples include acids, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. ru.

[0445] (5.4.1.2 Preparations for parenteral administration) In some embodiments, the compounds provided herein are This is a pharmaceutical composition for parenteral administration, comprising a substance and a pharmaceutical excipient suitable for parenteral administration. In some embodiments, provided herein are: (i) an effective amount of the disclosed compound; (ii) one or more effective doses of a second drug; and (iii) one or more pharmaceutical excipients suitable for parenteral administration. The pharmaceutical composition includes, for parenteral administration. In some embodiments, the pharmaceutical composition is (iv) Further containing an effective dose of a third drug.

[0446] The disclosed pharmaceutical composition can be incorporated into the following forms for administration by injection: Aqueous or oily suspension containing sesame oil, corn oil, cottonseed oil, or peanut oil. Liquid or emulsion, as well as elixir, mannitol, dextrose, or sterile water. Examples include solutions and similar pharmaceutical vehicles.

[0447] Aqueous solutions in physiological saline are also used for injection as before. Ethanol, glycerol, pro Pyrene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclamine Rodextrin derivatives and vegetable oils can also be used.

[0448] Aqueous solutions in physiological saline are also used for injection as before. Ethanol, glycerol, pro Pyrene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclamine Rodextrin derivatives and vegetable oils can also be used. Appropriate fluidity is, for example, In the case of dispersants, a coating agent, such as lecithin, is used to maintain the required particle size. This can be maintained by the use of surfactants. Prevention of microbial action is possible in various ways. Various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbin. This can be achieved by acids, thimerosal, etc.

[0449] A sterile injection solution is prepared by dissolving the required amount of the compound provided herein in a suitable solvent as needed. Accordingly, it is incorporated along with the other various components listed above, and then filtered and sterilized. Therefore, it is prepared. Typically, the dispersion contains various sterilizing active ingredients as a base dispersion medium and the above-listed components. It is prepared by incorporating it into a sterile vehicle containing other suitable components derived from the same material. In the case of sterile powders for the preparation of sterile injection solutions, the specific preparation method involves the active ingredient and optional Vacuum drying and freezing techniques are used to produce the powder with additional components from a solution that has been pre-sterilized and filtered. This is a drying technique.

[0450] Injectable preparations are, for example, filtered by passing them through a bacterial-retaining filter, or used A sterile solid that can be dissolved or dispersed in sterile water or other sterile injection medium beforehand. Sterilization can be achieved by incorporating a sterilizing agent in the form of a body composition. Injectable composition The substance may contain approximately 0.1 to approximately 5% w / w of the compounds disclosed herein.

[0451] (5.4.1.3 Preparations for local administration) In some embodiments, the compounds provided herein are A pharmaceutical composition for topical (e.g., transdermal) administration comprising a substance and a pharmaceutical excipient suitable for topical administration. Yes. In some embodiments, the following are provided herein: (i) an effective amount disclosed (ii) a compound; optionally (ii) one or more effective amounts of a second drug; and (iii) one or more pharmacokinetics suitable for topical administration. A pharmaceutical composition for topical administration, comprising a formant. In some embodiments, the pharmaceutical composition The substance: (iv) further contains an effective amount of a third drug.

[0452] The pharmaceutical compositions provided herein are solids suitable for local or topical administration. Preparations in semi-solid or liquid form, such as gels, water-soluble jellies, creams, and lotions. , suspension, foam, powder, slurry, ointment, solution, oil, paste, suppository, spray, It can be formulated into a marion, saline solution, or dimethyl sulfoxide (DMSO)-based solution. Generally, high-density carriers allow a site to be exposed to the active ingredient for a longer period of time. In contrast... Furthermore, solution formulations allow for immediate exposure of the active ingredient to a selected site.

[0453] The pharmaceutical composition enhances the permeability or delivery of therapeutic molecules across the permeability barrier of the stratum corneum of the skin. It may also contain a suitable solid or gel phase carrier or excipient, which is a compound that enables assistance. There are many such permeation-promoting molecules that are known to those skilled in the art of topical formulations. Examples of bodies and excipients include humectants (e.g., urea), glycols (e.g., propylene glycol) Glycols, alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants Sexual agents (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, gu Ricerol monolaurate, sulfoxide, terpene (e.g., menthol), amine, Mido, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, Polymers such as cellulose derivatives, gelatin, and polyethylene glycol These are some examples, but are not limited to them.

[0454] Another exemplary formulation for use in the disclosed manner utilizes a transdermal delivery device ("patch") To use. Using such a transdermal patch, with or without another drug, control It is possible to provide continuous or discontinuous injection of the specified amount of the compound provided herein. ru.

[0455] The construction and use of transdermal patches for drug delivery are well known in the art. For example, See National Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceuticals. Cut.

[0456] Suitable for use in the delivery of pharmaceutically acceptable intradermal compositions described herein. As for the apparatus, a short needle apparatus, for example, U.S. Patent Nos. 4,886,499; 5,190,521; 5,328, No. 483; No. 5,527,288; No. 4,270,537; No. 5,015,235; No. 5,141,496; and No. 5,417,662 Examples of the devices described above include: an intradermal composition, a device that limits the effective penetration length of a needle into the skin, For example, administration by the device and its functional equivalent described in PCT Publication WO 99 / 34850. It can reach the dermis via a liquid jet syringe and / or by penetrating the stratum corneum. A jet injection device that delivers liquid vaccine to the dermis via a needle that generates a jet is preferred. Jet injection devices are, for example, U.S. Patent Nos. 5,480,381; 5,599,302; 5,334, No. 144; No. 5,993,412; No. 5,649,912; No. 5,569,189; No. 5,704,911; No. 5,383,851; No. 5, No. 893,397; No. 5,466,220; No. 5,339,163; No. 5,312,335; No. 5,503,627; No. 5,064,413; Nos. 5,520,639; Nos. 4,596,556; Nos. 4,790,824; Nos. 4,941,880; Nos. 4,940,460; and PCT It is described in public WO 97 / 37705 and WO 97 / 13537. Vaccine in powder form is applied to the skin. A ballistic powder / particle delivery device that uses compressed gas to accelerate the particles from the dermis to the dermis is preferred. Alternatively, or in addition to that, conventional syringes can be used in the classic Mantoh method for intradermal administration. It is possible.

[0457] For locally administered formulations, for example, the amount of the active ingredient is approximately 1% to approximately 10% (w / w) of the total weight of the formulation. The formulation may include the compounds provided in the Specified Specification, but the compounds provided in the Specified Specification may include the compounds provided in the Specified Specification. The concentration can be as high as the solubility limit of the compound in the solvent. In that embodiment, the locally administrative formulation is, for example, about 1% to about 9% (w / w) of the specified The compounds provided are, for example, about 1% to about 8% (w / w), and further, for example, about 1% to about 7% (w / w), For example, approximately 1% to approximately 6% (w / w), for example, approximately 1% to approximately 5% (w / w), for example, Approximately 1% to approximately 4% (w / w), and further, for example, approximately 1% to approximately 3% (w / w), and further, for example, approximately 1% to approximately 2% This specification may contain %(w / w) of the compounds provided herein. Formulations for topical administration are provided herein. It further contains one or more of the further pharmacopoeias permissible excipients listed in the details. It is possible.

[0458] (5.4.1.4 Formulations for inhalation administration) In some embodiments, the compounds provided herein are This is a pharmaceutical composition for inhalation administration, comprising a substance and pharmaceutical excipients suitable for topical administration. In the embodiments thereof, provided herein are: (i) an effective amount of the disclosed compound; optionally ( ii) one or more effective amounts of a second drug; and (iii) one or more pharmaceutical excipients suitable for inhalation administration, It is a pharmaceutical composition for administration. In some embodiments, the pharmaceutical composition is: (iv) effective It further contains a third amount of the drug.

[0459] Pharmaceutical compositions for inhalation or inhalation may contain pharmaceutically acceptable aqueous or organic solvents, or This includes solutions and suspensions in mixtures of these, as well as powders. Liquid or solid pharmaceutical compositions are included in this The specification may include excipients that are acceptable as suitable pharmaceutically acceptable agents as described in the specification. In this embodiment, the pharmaceutical composition is administered orally or via nasal respiration for topical or systemic effects. It is administered by [method]. Pharmaceutical compositions in pharmacopoeia that are pharmacopoeia acceptable are those that use an inert gas. Therefore, it can be sprayed. The sprayed solution can be directly inhaled from the spraying device. Alternatively, the spraying device can be attached to a face mask tent or an intermittent positive airway pressure (PAP) respirator. Yes, it is possible. Pharmaceutical compositions in solution, suspension, or powder form can be delivered from a device that delivers the formulation in an appropriate manner. For example, it can be administered orally or nasally.

[0460] (5.4.1.5 Preparations for intraocular administration) In some embodiments, this disclosure provides pharmaceutical compositions for treating ophthalmic disorders. Provides an effective amount of the compound provided herein, and suitable for intraocular administration. Pharmaceutical excipients may be included. Pharmaceutical compositions suitable for intraocular administration are available in individual dosage forms, for example, Each eye drop or spray, liquid, or aqueous or non-aqueous preparation containing a predetermined amount of the active ingredient. To be provided as a suspension agent in liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. This is possible. Other forms of administration include intraocular injection, intravitreal injection, topical administration, or drug dissolution. Examples include placement, microcapsules, implants, or the use of microfluidic devices. In some examples, the compounds provided herein are surrounded by an interfacial film. Intraocular penetration of compounds such as oil-water emulsions containing colloidal particles with a rare oily core into the eye. It is administered with a carrier or excipient that increases the amount of the substance. Locally, subconjunctivally, periophthalmosally, posteriorly. This includes administration under the sheath of the eyeball, in the anterior chamber, in the vitreous, in the eyeball, subretinal, near the sclera, and on the choroid. It is considered that all local routes to the drug can be used. Systemic or parenteral administration is possible. These methods include, but are not limited to, intravenous, subcutaneous, and oral delivery. Exemplary methods of administration include intravitreal or subocular injection of the solution or suspension, or in vivo. Intravitreal or subocular placement of erosive or non-biological erosive devices, or solutions or suspensions. This is done by local intraocular administration of a turbid solution, or by administration of a gel or cream formulation near the retrosclera. .

[0461] Eye drops contain an active ingredient dissolved in a sterile aqueous solution, such as physiological saline or a buffer solution. It is prepared by either doing so, or by combining and dissolving powder compositions before use. It is possible to select other vehicles, such as those known in the art. This can be: an equilibrium salt solution, a saline solution, a water-soluble polyether, for example, a polyethylene glycoside. Polyethylene glycol, polyvinyl, for example, polyvinyl alcohol and povidone, Lulurose derivatives, for example, methylcellulose and hydroxypropylmethylcellulose, Petroleum derivatives, such as mineral oil and white petrolatum; animal fats, such as lanolin and acrylics. Acid polymers, e.g., carboxypolymethylene gel; vegetable fats, e.g., peanuts. Oils, and polysaccharides, such as dextran, and glycosaminoglycans, such as hyaluronic acid. This includes, but is not limited to, sodium phosphate. In some embodiments, eye drops are used. Commonly used additives can be added to the drug. Such additives include isotonic ones. Reacting agents (e.g., sodium chloride), buffering agents (e.g., boric acid, sodium monohydrogen phosphate) (e.g., sodium dihydrogen phosphate), preservatives (e.g., benzalkonium chloride, benzeth chloride) (e.g., chlorobutanol), thickeners (e.g., saccharides, e.g., lactose, methyl phosphates) Initol, maltose, etc.; for example, hyaluronic acid or its salts, for example, hyaluronic acid Sodium, potassium hyaluronate, etc.; for example, mucopolysaccharides, for example, chondroitin sulfur Acids, etc.; for example, sodium polyacrylate, carboxyvinyl polymer, cross-linked polyacrylate Relate, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydrox hydroxyethylcellulose, carboxymethylcellulose Examples include hydroxypropylcellulose, or other agents known to those skilled in the art.

[0462] In some examples, the colloidal particles consist of at least one cationic agent and at least one One nonionic surfactant, for example, poloxamer, tyroxapole, polysorbate, Polyoxyethylene castor oil derivatives, sorbitan esters, or polyoxy stearate It contains . In some examples, the cationic agent is alkylamine, tertiary alkylamine. N, quaternary ammonium compounds, cationic lipids, amino alcohols, biguanidine salts, A cationic compound, or a mixture thereof. In some examples, the cationic agent is Biguanidine salts, for example, chlorhexidine, polyaminopropyl biguanidine, fen Formin, alkyl biguanidine, or a mixture thereof. In some examples, Quaternary ammonium compounds include benzalkonium halides and lauryl halides. Mu, Cetrimid, Hexadecyltrimethylammonium halogen, Tetradecyltrimethylammonium halogen Siltrimethylammonium, dodecyltrimethylammonium halogenated, halogenated Cetrimonium, benzethonium halide, benzalkonium halide, halogenated Cetalkonium, cetethyldimonium halide, cetylpyridinium halide, halo Benzododecinium ionide, chlorarylmethenamine halogenate, myristalcoholic acid halogenate Myristalkonium halide, stearalkonium halide, or two or more of these It is a mixture. In some examples, the cationic agent is benzalkonium chloride, lau chloride. Larkonium, benzododecinium bromide, benzethenium chloride Hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide , dodecyltrimethylammonium bromide, or a mixture of two or more of these. In this example, the oil phase consists of mineral oil and light mineral oil, medium-chain triglycerides (MCT), coconut oil; and water. Hydrogenated oils including hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated castor oil, or hydrogenated soybean oil; Polyoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oil, or polyoxy This is a polyoxyethylene hydrogenated castor oil derivative containing sil-100 hydrogenated castor oil.

[0463] (5.4.1.6 Formulations for controlled-release administration) In some embodiments, the compounds provided herein are This is a pharmaceutical composition for controlled-release administration, comprising a substance and a pharmaceutical excipient suitable for controlled-release administration. In some embodiments, the following are provided herein: (i) an effective amount of the disclosed compound (ii) one or more effective doses of a second drug; and (iii) one or more pharmaceutical excipients suitable for controlled-release administration. This is a pharmaceutical composition for controlled-release administration, comprising an agent. In some embodiments, the pharmaceutical composition The product further contains: (iv) an effective amount of a third drug.

[0464] The activators, for example, the compounds provided herein, are released by controlled release means, or by means of the art of the art It can be administered by a delivery device that is well known. For example, each of them is cited in U.S. Patents No. 3,845,770; No. 3,916,899; No. 3,536,809 are more incorporated herein by reference. Nos. 3,598,123; and 4,008,719; Nos. 5,674,533; Nos. 5,059,595; Nos. 5,591,767; Nos. 5,12 No. 0,548; No. 5,073,543; No. 5,639,476; No. 5,354,556; No. 5,639,480; No. 5,733,566; No. No. 5,739,108; No. 5,891,474; No. 5,922,356; No. 5,972,891; No. 5,980,945; No. 5,993,855 No. 6,045,830; No. 6,087,324; No. 6,113,943; No. 6,197,350; No. 6,248,363; No. 6,264 ,970;No.6,267,981;No.6,376,461;No.6,419,961;No.6,589,548;No.6,613,358;No.6 Examples of such agents include, but are not limited to, those listed in publications 699 and 500. Using the form, for example, hydroxypropyl methylcellulose, or other polymer matrices. Gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres A, or a combination thereof, provides slow release or controlled release of one or more activators, It is possible to provide desired emission profiles with various proportions as described herein. Suitable controlled-release formulations known to those skilled in the art, including those provided herein, in combination with the activators. It can be easily selected for use. Therefore, the pharmaceutical compositions provided are limited Tablets, capsules, gel caps, and caplets suitable for controlled release are not specified. This includes single-unit dosage forms suitable for oral administration, such as iodine tablets.

[0465] All controlled-release pharmaceutical products achieve a level of drug therapy that is greater than that achieved by their uncontrolled counterparts. They share the common objective of improvement. In some embodiments, in medical procedures The use of controlled-release preparations is intended to cure or control a disease, disorder, or condition in the shortest possible time. It is characterized by the use of a minimum amount of active pharmaceutical ingredient (API) to achieve this. The advantages of controlled-release formulations include: These benefits include prolonged drug activity, reduced medication frequency, and improved adherence to medication among patients. Furthermore, Controlled-release formulations can be used to influence the onset time or other characteristics of the drug, such as the level of the drug in the blood. It can have an effect, and therefore influence the occurrence of side effects (e.g., adverse effects). It is possible.

[0466] In some embodiments, the controlled-release formulation contains an amount that appropriately produces the desired therapeutic effect. The compound provided in the specification is initially released, and this level of treatment or Designed to gradually and continuously release other amounts of the compound to maintain its preventative effect. To maintain this constant level of the compound in the body, the compound is metabolized and removed from the body. The drug should be released from the dosage form at a rate that replenishes the amount of drug being excreted. Control of the activator. Release may include, but is not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds. It can be stimulated by various conditions.

[0467] In one embodiment, the pharmaceutical composition is administered intravenously, via an implantable osmotic pump, and through It can be administered using a skin patch, liposomes, or other methods of administration. In one embodiment, In this case, a pump can be used (Sefton's literature, CRC Crit. Ref. Biomed. Eng. 1) 4: 201 (1987); Buchwald et al., Surgery 88: 507 (1980); Saudek et al., N. Engl. See J. Med. 321: 574 (1989). In another embodiment, a polymer material is used. This is possible. In yet another embodiment, the controlled discharge system is appropriately determined by those skilled in the art. It can be placed within the target area, meaning that only a small portion of the total systemic dose is needed. Not required (for example, Goodson's literature, Medical Applications of C See controlled release, pp. 115-138 (Vol. 2, 1984). Other controlled release systems are described by Langer. This is discussed in a review article (Science 249: 1527-1533 (1990)). One or more activators are present inside the solid. Trix, for example, polymethyl methacrylate, polybutyl methacrylate, plasticizer or This includes unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, and natural Rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene - Vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate Hydrocopolymers, hydrophilic polymers, for example, esters of acrylic acid and methacrylic acid. Drogel, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate It can be dispersed within the tate, and this inner matrix is ​​insoluble in body fluids. Polymer membranes, for example, polyethylene, polypropylene, ethylene / propylene copolymer, Ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone Polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, Vinyl chloride copolymer of vinyl acetate, vinylidene chloride, ethylene, and propylene. Ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethyl Vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol copolymer , and is surrounded by an ethylene / vinyloxyethanol copolymer. As a result One or more activators diffuse through the outer polymer membrane during the step of controlling the release rate. The proportion of activators in such parenteral compositions varies greatly depending on their specific properties and the needs of the target audience. It depends on the situation.

[0468] (5.4.2 Dosage) The compounds described herein are one or more compounds described herein in a therapeutically effective amount. , and / or one or more additional excipients which are formulated together with one or more pharmaceutically acceptable excipients. Therapeutic agents, for example, can be delivered in the form of a pharmaceutically acceptable composition including chemotherapeutic agents. Yes, it is possible. In some cases, the compounds and additional therapeutic agents described herein are used separately. Administered in the pharmaceutical composition, different (for example, due to different physical and / or chemical properties) It can be administered via a route (for example, one drug is administered orally, but the other is administered via a route The therapeutic agent is administered intravenously. In other examples, the compounds and additional compounds described herein The therapeutic agents are administered via the same route, although they are different (for example, both orally or both intravenously). It is possible to do so. In other examples, the compounds and additional therapeutic agents described herein may also be used. It can be administered in the same pharmaceutical composition.

[0469] The selected dosage level is determined by various factors, including, for example, the use of The activity of a specific compound, the route of administration, the timing of administration, and the excretion of the specific compound being used. This relates to the rate of metabolism, the rate and degree of absorption, the duration of treatment, and the combination with specific compounds used. Other drugs, compounds, and / or materials used, age, sex, weight, and condition of the patient being treated. This includes general health, past medical history, and similar factors well known in the medical field.

[0470] In general, what is the preferred daily dose of the compounds and / or chemotherapeutic agents described herein? In that embodiment, the minimum dose that is effective in producing a therapeutic effect may be the This refers to the amount of the compound. Such an effective dose is usually determined by the factors mentioned above. Typically, the patient The dosage of the compounds described herein for a person is when used to achieve the indicated effect. Approximately 0.0001 mg to approximately 100 mg per day, or approximately 0.001 mg to approximately 100 mg per day, or approximately 0.01 mg to approximately 100 mg, or approximately 0.1 mg to approximately 100 mg per day, or approximately 0.0001 mg to approximately 500 mg per day , or approximately 0.001 mg to approximately 500 mg per day, or approximately 0.01 mg to 1000 mg, or approximately 0.01 mg to per day Approximately 500 mg, or approximately 0.1 mg to approximately 500 mg per day, or approximately 1 mg to 50 mg per day, or approximately 5 mg to 40 mg The range is g. An exemplary dosage is approximately 10-30 mg per day. In some embodiments... For a person weighing 70 kg, the appropriate dosage is approximately 0.05 to 7 g / day, for example, approximately 0.05 to 2.5 g / day. It will be a day. Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein. It is formulated to be toxic to patients and suitable for specific patients, compositions, and modes of administration. This involves altering the amount of the active ingredient to obtain the amount that is effective in achieving the desired therapeutic response. This is possible. In some cases, a dosage level below the lower limit of the aforementioned range is sufficient. In some cases, however, even larger doses have been used, for example, such larger doses By dividing the dose into several smaller doses to administer throughout the day, It can be used without causing any harmful side effects.

[0471] In some embodiments, the daily dose of the compounds described herein is approximately 0.0001 mg / kg ~ approx. 1000mg / kg, approx. 0.001mg / kg ~ approx. 1000mg / kg, approx. 0.01mg / kg ~ approx. 1000mg / kg, approx. 0.1mg / kg ~1000mg / kg, approx. 0.0001mg / kg~approx. 500mg / kg, approx. 0.001mg / kg~approx. 500mg / kg, approx. 0.01mg / kg ~100mg / kg, about 0.01mg / kg to about 100mg / kg, about 0.1mg / kg to about 100mg / kg, about 0.01mg / kg to 50mg / k g can be in the range of approximately 0.05 mg / kg to 20 mg / kg, or approximately 0.05 mg / kg to 10 mg / kg. For example In that case, the daily dose is approximately 10 mg / kg, 5 mg / kg, 1.5 mg / kg, 0.5 mg / kg, 0.15 mg / kg, or approximately 0.05 mg / kg It can be in kg. For example, the daily dose could be about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, approx. 3 mg / kg, approx. 3.1 mg / kg, approx. 3.2 mg / kg, approx. 3.3 mg / kg, approx. 3.4 mg / kg, approx. 3.5 mg / kg, approx. 4 The concentration should be mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, or approximately 10 mg / kg. It is possible.

[0472] In some embodiments, the compound is administered daily, every other day, three times a week, twice a week, and It can be administered once a week or once every two weeks. The administration schedule is based on the "drug-free period". This can include, for example, a drug taken for 2 weeks, not taken for 1 week, or taken for 3 weeks, 1 week Intermittent administration, or administration for 4 weeks followed by 1 week of non-administration, or continuous administration without a drug-free period. The compound can be administered orally, intravenously, intraperitoneally, topically, percutaneously, intramuscularly, subcutaneously, or nasally. It can be administered sublingually or by any other route.

[0473] In some embodiments, the compounds provided herein are administered in multiple doses. The drug can be administered approximately once, twice, three times, four times, five times, six times, or seven or more times per day. The medication should be administered approximately once a month, once every two weeks, once a week, or once every other day. This is possible. In another embodiment, the compounds and other agents provided herein are used daily They are administered together approximately once to six times a day. In another embodiment, as described herein The administration of the compound and drug is continued for less than approximately 7 days. In another embodiment... The administration period is approximately 6 days, 10 days, 14 days, 28 days, 2 months, 6 months, or longer than 1 year. It continues for as long as necessary. In some cases, continuous administration is implemented and maintained as long as necessary. ru.

[0474] The administration of the pharmaceutical compositions provided herein can be continued for as long as necessary. In a few embodiments, the agents provided herein last for about 1 day, about 2 days, about 3 days, about 4 days, It is administered for a period of approximately 5 days, 6 days, 7 days, 14 days, 21 days, or longer than 28 days. In that embodiment, the agent provided herein lasts for approximately 28 days, approximately 21 days, approximately 14 days, and approximately 7 days. It is administered for approximately 6 days, 5 days, 4 days, 3 days, 2 days, or less than 1 day. In the manner of application, the agents provided herein are approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, It is administered for about 14, about 21, or about 28 days. Several embodiments are provided herein. The drugs being administered are, for example, given on a chronic basis for the treatment of chronic conditions.

[0475] The compounds described herein may be used in other treatments (e.g., additional chemotherapy drugs, radiotherapy, Since it can be administered in combination with (or surgical procedures), the dosage of each drug or therapy is The dose can be lower than the corresponding dose for monotherapy. For example, the dose for monotherapy is: Approximately 0.0001 to 200 mg per kg of body weight per day, or approximately 0.001 to 100 mg, or approximately 0.01 to 100 mg. Alternatively, the amount can be in the range of approximately 0.1 to 100 mg, or approximately 1 to 50 mg.

[0476] The compounds provided herein are administered in a pharmaceutical composition containing one or more agents, and If a drug has a shorter half-life than the compounds provided herein, the drug and this specification The unit dose form of the compounds provided in the book can be adjusted accordingly.

[0477] (5.4.3 Kit) In some embodiments, what is provided herein is a kit. The kit is In suitable packaging, the compounds or pharmaceutical compositions described herein, and instructions for use, The kit may include materials such as a detailed explanation of clinical trials and a list of side effects. The t indicates or specifies the activity and / or benefits of the pharmaceutical composition, and / or the application Include information on dosage, administration, side effects, drug interactions, or other information useful to healthcare providers. This includes scientific references, package inserts, clinical trial results, and / or these. It can also include information such as summaries. Such information can be used in various studies, for example, in vivo Based on the results of studies using experimental animals, including models, and human clinical trials. can.

[0478] In some embodiments, the memory aid is, for example, a number next to a tablet or capsule. In form, provided in the kit, the number indicates that the tablet or capsule designated as such is taken. It corresponds to the date of the treatment plan to be performed. Another example of such memory aids is, for example, the following: "Week 1, Monday, Tuesday... etc., ..., Week 2, Monday, Tuesday... etc.," the card says. It is a calendar printed on it. Other variations of memory aids are easily apparent. It will be. "Daily dose" is the single tablet or capsule to be taken on a given day. Alternatively, it may be in the form of several tablets or capsules.

[0479] The kit may further contain other drugs. In some embodiments, this specification The compounds and drugs provided in this book are separate pharmaceutical compositions in separate containers within the kit. Provided as follows. In some embodiments, the compounds and agents provided herein It is provided as a single pharmaceutical composition in one container within the kit. Suitable packaging, and And additional items for use (e.g., measuring cup for liquid preparations, minimizing exposure to air) Methods such as foil w...

Claims

1. Compound of formula (I): 【Chemistry 1】 or a salt thereof, or a solvate thereof, or a solvate of a salt thereof, or a method for preparing a mixture thereof, Compound C in the following formula: 【Chemistry 2】 The carboxylic acid of formula G: 【Transformation 3】 This includes coupling with to form a compound of formula (I), Compound C is compound A with the following formula: 【Transformation 8】 The alkyne of formula E: 【Chemistry 9】 The method described above is prepared by coupling with [the specified element].

2. The method according to claim 1, wherein the coupling of compound C with the carboxylic acid of formula G is carried out in the presence of a coupling reagent.

3. The method according to claim 2, wherein the coupling reagent is carbodiimide, triazine, phosphonium, uronium, or a mixed anhydride, or a mixture thereof.

4. The coupling reagents include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 2-propanephosphonic anhydride (T3P), and 1-[(dimethylamino)(morpholino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridine-1-ium. 3-Oxidohexafluorophosphate (HDMA), N,N,N',N'-Tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), Benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxydohexafluorophosphate (HATU), diethylphosphocyanidate (DECP), diethylphosphochloride (DEPC), diphenyl phosphate azide (DPPA), bis(2-oxazolidide)chloride phosphate (BOPCl), chlorodimethoxytriazine or its N-methylmorpholinium adduct, 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT), bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), (EtO) 2 P(O)-Cl, (EtO) 2 P(O)-Oxima, pivaloyl chloride, isobutyl chloroformate, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), or 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM) or its BF 4 The method according to claim 2, wherein the analogue is a mixture thereof.

5. The method according to claim 4, wherein the coupling reagent is EDCI.

6. The method according to claim 4, wherein the coupling reagent is DMTMM.

7. The method according to any one of claims 1 to 6, wherein the coupling of compound C with the carboxylic acid of formula G is carried out in the presence of an activator.

8. The method according to claim 7, wherein the activator is HOBt, HB triazinon, ethyl 2-cyano-2-(hydroxyimino)acetate (oxima), NHS, or ethyl (hydroxyimino)cyanoacetate potassium salt (K-oxima).

9. The method according to claim 8, wherein the activator is HOBt.

10. The method according to any one of claims 1 to 9, wherein the coupling of compound C with the carboxylic acid of formula G is carried out in the presence of a base.

11. The aforementioned base, Et 3 The method according to claim 10, wherein the member is N, DIPEA, pyridine, NMM, DBU, NaOH, or DMAP.

12. The method according to any one of claims 1 to 11, wherein the coupling of compound C with the carboxylic acid of formula G is carried out in the presence of a solvent of DMF, NMP, acetonitrile, EtOH, acetone, DCM, MeOH, or water, or a mixture thereof.

13. Compound of formula (I): 【Chemistry 4】 A method for preparing a salt thereof, a solvate thereof, a solvate of a salt thereof, or a mixture thereof, comprising compound C of the following formula: 【Transformation 5】 The ester of formula D: 【Transformation 6】 This includes coupling with to form a compound of formula (I), Compound C is compound A with the following formula: 【Transformation 8】 The alkyne of formula E: 【Chemistry 9】 The method described above is prepared by coupling with [the specified element].

14. The method according to claim 13, wherein the coupling of compound C with the ester of formula D is carried out in the presence of a base and a solvent.

15. The method according to claim 14, wherein the base is an amine.

16. The method according to claim 15, wherein the amine is N,N-diisopropylethylamine.

17. The method according to any one of claims 14 to 16, wherein the solvent is an organic solvent.

18. The method according to claim 17, wherein the organic solvent is acetonitrile.

19. The method according to claim 17, wherein the organic solvent is a mixture of DCM and ethanol.

20. The method according to any one of claims 13 to 19, wherein the coupling of compound C with the ester of formula D is carried out at a temperature of about 30°C to about 80°C, about 40°C to about 70°C, about 55°C to about 65°C, or about 60°C.

21. The ester of formula D is the carboxylic acid of formula G: 【Transformation 7】 The method according to any one of claims 13 to 20, wherein the method is prepared by a method comprising coupling with N-hydroxysuccinimide.

22. Compound C in the following formula: 【Chemistry 10】 A method for preparing compound A of the following formula: 【Chemistry 11】 The alkyne of formula E: 【Chemistry 12】 The method, which includes coupling with

23. The method according to any one of claims 1 to 22, wherein the coupling of compound A with the alkyne of formula E is carried out in the presence of a catalyst and ligand, or a catalyst / ligand complex; a base; and a solvent.

24. The method according to claim 23, wherein the catalyst is a Pd catalyst.

25. wherein the Pd catalyst is Pd-G3, Pd 2 (dba) 3 , PdCl 2 (MeCN) 2 , Pd(OAc) 2 , Pd(PPh 3 ) 4 , or PdCl 2 (PPh 3 ) 2 ; the method according to claim 24

26. The palladium catalyst is PdCl 2 (MeCN) 2 The method according to claim 25.

27. The palladium catalyst is Pd 2 (dba) 3 The method according to claim 25.

28. The palladium catalyst is Pd(OAc) 2 The method according to claim 25.

29. The method according to claim 23, wherein the catalyst is a Ni catalyst or a Cu catalyst.

30. The method according to any one of claims 23 to 29, wherein the ligand is a phosphine ligand or a bisphosphine ligand.

31. The ligands are XPhos, PCy 3 PCy 2 Ph, P i Pr 3 PCy 2 t Bu, CataCXium A, P(MeOC) 6 H 4 ) 3 PPh 2 (C 6 H 4 CO 2 H), PPh 2 (C 6 H 4 SO 3 H), SPhos, JohnPhos, DavePhos, MePhos, cBRIDP, Cy-vBRIDP, Cy-cBRIDP, i Bu triple cage, P t Bu 2 Cy, P t Bu 3 CataCXium PICy, P t Bu 2 (PhNMe 2 ), PPh 3 , dppp, dppe, dppb, BINAP, DPEPhos, dppf, dbpf, XantPhos, N- t Bu 2 The method according to claim 30, wherein the method is P-azetine, dppm, dmpe, dippe, DIPAMP, Chiraphos, SPANphos, SEGPHOS, Me-DuPhos, or Josiphos.

32. The method according to claim 31, wherein the ligand is XPhos, CataCXium A, JohnPhos, DavePhos, MePhos, cBRIDP, CataCXium PICy, or dbpf.

33. The method according to claim 32, wherein the ligand is XPhos.

34. The method according to any one of claims 23 to 33, wherein the molar ratio of the ligand to the catalyst is about 5:1 to about 1:

5.

35. The method according to claim 34, wherein the molar ratio of the ligand to the catalyst is about 2:1 to about 1:

1.

36. The method according to any one of claims 23 to 35, wherein the amount of catalyst added is about 0.5% to about 10%, and the amount of ligand added is about 0.5% to about 20%.

37. The aforementioned base is Cs 2 CO 3 , K 2 CO 3 , or K 3 PO 4 The method according to any one of claims 23 to 36.

38. The solvent is MeCN, i The method according to any one of claims 23 to 37, wherein the substance is PrOAc, n-propyl acetate, 2-MeTHF, EtCN, MEK, or toluene.

39. The method according to claim 38, wherein the solvent is MeCN.

40. The alkyne of formula E is the compound of formula F: 【Chemistry 13】 The method according to any one of claims 1 to 39, which is prepared by a method including deprotecting.

41. The method according to claim 40, wherein the compound of formula F is prepared by a method comprising coupling 4-iodo-1-methyl-1H-pyrazole with trimethylsilylacetylene.

42. The carboxylic acid of formula G is a compound of formula H: 【Chemistry 14】 The method according to any one of claims 1 to 12 or 21, which is prepared by a method comprising hydrolyzing.

43. The compound of formula H is the compound of formula J: 【Chemistry 15】 The method according to claim 42, which is prepared by a method comprising reacting with 1,1,3,3-tetramethoxypropane.

44. The compound of formula J is the compound of formula K: 【Chemistry 16】 The method according to claim 43, which is prepared by a method comprising cyclizing.

45. The compound of formula K is the compound of formula L: 【Chemistry 17】 The method according to claim 44, which is prepared by a method comprising reacting with hydrazine or hydrated hydrazine.

46. The compound of formula L is the compound of formula M: [Chemistry 18] NH 3 or NH 4 The method according to claim 45, which is prepared by a method comprising reacting with OH.

47. The method according to claim 46, wherein the compound of formula M is prepared by a method comprising reacting ethyl 2-cyanoacetate with 2-chloroethyl chloroformate.

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