Compounds containing amide functional groups with stable heavy isotopes and their applications

Abstract

The present invention provides a compound containing a stable heavy isotope-enriched amide functional group as shown in formula (I), which is used to adjust the pharmacokinetic properties, metabolic properties and / or delivery efficiency of a drug or prodrug, as well as its therapeutic and preventive effects. The present invention also relates to the use of drugs and prodrugs containing isotope-enriched amides in the treatment or prevention of disease conditions and symptoms.

Description

Technical Field

[0001] The present invention relates to compounds containing a stable heavy isotope-enriched amide functional group, and their use in adjusting the pharmacokinetic properties, metabolic properties and / or delivery efficiency of compounds (such as drugs or prodrugs), as well as to the therapeutic and preventive applications of the compounds. Background Art

[0002] Amide compounds, also known as acid amine compounds, are compounds having the formula R m E(O) n NR 1 R 2 A compound wherein R, R 1 and R 2 is hydrogen (H) or an organic group. The most common amide is formamide (organic amide), where m is 1, E is carbon (C) and n is 1. Many other important types of amides are known, including phosphoramides (e.g., where m is 1, E is phosphorus (P) and n is 2, and related compounds) and sulfonamides (e.g., where m is 1, E is sulfur (S) and n is 2, and related compounds) (see, see IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"), 1997). Another type of amide is phosphoamide.

[0003] Structurally, the amide bond in a molecule can be shown as follows:

[0004]

[0005] refers to carboxamide, phosphoramide, phosphonamide and sulfonamide, respectively, wherein R, R 1 , R 2 and R 3 is independently hydrogen or a substituted or unsubstituted organic group such as an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a combination thereof.

[0006] In common nomenclature, the term "amide" is added to the backbone of the parent acid. For example, an amide derived from acetic acid is called acetamide (CH3CONH2). IUPAC recommends the name acetamide for this compound, but this and related formal names are rarely used in practice. When an amide is derived from a primary or secondary amine, the substituent on the nitrogen should be indicated first in the name. Thus, the amide formed from dimethylamine and acetic acid is N,N-dimethylacetamide (CH3CONMe2). Cyclic amides are called lactams, which are necessarily secondary or tertiary amides. 1 R 2 and –SO2NR 1 R2 The compounds with functional groups are phosphonamide and sulfonamide (Organic Chemistry IUPAC Nomenclature. Rules C-821. Amides http: / / www.acdlabs.com / iupac / nomenclature / 79 / r79_540.htm).

[0007] Amides are important functional groups present in various types of drugs (such as local anesthetics, antiarrhythmic drugs, etc.). Amides are also key connecting parts in protein and peptide drug products (DeRuiter, J., Principles of Drug Action 1, Spring 2005, Amides, http: / / www.auburn.edu / ~deruija / pdal_amides.pdf). In addition, many drugs developed in the last century are prodrugs of amines, highlighting their importance in the pharmaceutical field. It is now widely accepted that amine prodrugs can play an important role in drug targeting, and they are usually the initial compounds that deliver drugs to the target site in a stable form. Amine prodrugs are usually classified by the connection of nitrogen atoms to nearby atoms. Amine-containing prodrugs have a variety of basic functional groups and linkages, such as amide prodrugs, azo-linked prodrugs, lipid peptide prodrugs (Chandy, A., et al., Med. Chem. Drug Discov., 2013, 4 (2), 108-126; Simplício, AL, et al., Molecules, 2008, 13, 519-547). For example, a large number of anticancer agents have amide bonds in their molecules (see, for example, Mohammed, YHE and Khanum, SA, Int. J. of Pharma and Bio Sci. (2018), 9 (2), 94-124; Wang, B, et al., Drug Delivery, 2nd Ed., 2016, 475-502.). As a specific example, Alpelisib (formerly BYL719, or N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl)-2-thiazolyl)aminocarbonyl-L-prolineamide) is an α-specific PI3K (phosphoinositide 3-kinase) inhibitor, an experimental drug for certain cancers under development (https: / / www.cancertherapyadvisor.com / breast-cancer / novel-agents-for-endocrine-resistant-breast-cancer / article / 508600 / ). It involves late-stage clinical trials for certain types of breast cancer, including the SOLAR-1 trial for metastatic breast cancer with PIK3CA changes. The compound is being used clinically in patients with advanced solid tumors (Ando, ​​Y., et al., Cancer Science, 2019, 1-11).

[0008] One of the key reactions of carboxylic acid amides (also called carboxamides or amides) with peptides is the hydrolysis of the amide bond. The hydrolysis can be acid-catalyzed, base-catalyzed, or enzyme-catalyzed, and generally produces the corresponding carboxylic acid and amine or ammonia. The hydrolysis involves the production of a tetrahedral intermediate centered on the carbon atom after the C=O double bond is converted into a CO single bond (see http: / / research.cm.utexas.edu / nbauld / teach / ch610bnotes / ch18.htm, East, ALL, Int. J. Chem. Kinet., 2018; 1–5). The acid-catalyzed hydrolysis is shown below:

[0009]

[0010]

[0011] The rate-determining step is step 2 (see figure above), in which the C=O double bond is converted into a CO single bond through the cleavage of the π-bond, which directly affects the rate of amide bond cleavage. Summary of the invention

[0012] The object of the present invention is to provide an amide moiety with an improved amide bond cleavage rate to alter the pharmacokinetic properties of amide bond-containing drugs and prodrugs, thereby adjusting their therapeutic and preventive effects and / or side effects.

[0013] The present invention is based, at least in part, on the inventors' recognition that stable heavy isotopes ( 17 O and / or 18 O; 13 C; and / or 15 N) and the isotope with natural abundance ( 16 O. 12 C and 14 N), the rate of amide bond cleavage can be changed, thereby improving the pharmacokinetic properties of amide-bonded drugs and prodrugs, and further adjusting the therapeutic and preventive effects and / or side effects of amide-bonded drugs and prodrugs.

[0014] Therefore, using heavy stable oxygen isotopes ( 17 O or 18 O) replaces the naturally abundant isotope of oxygen atoms ( 16 O) will have a significant isotope effect on the rate of amide bond cleavage. Without wishing to be bound by theory, it is believed that the use of heavy stable oxygen isotopes ( * O or O * ,express 17 O and / or 18 O) Replacement 16O will change the rate of amide bond cleavage. This change can improve the pharmacokinetic properties of drugs and prodrugs containing amide bonds, thereby adjusting the treatment, preventive effect and / or side effects of drugs and prodrugs. It is also noted that the carboxylic acid amide center directly involves three atoms, that is, a carbon atom, an oxygen atom and a nitrogen atom. Therefore, the isotopes of carbon and / or nitrogen can also directly affect the rate of amide bond cleavage, and therefore affect the treatment, preventive effect and / or side effects of drugs and prodrugs containing amide bonds.

[0015] Thus, the present invention provides drugs and prodrugs containing amide bonds having one or more stable heavy isotopes, wherein the one or more stable heavy isotopes replace the carboxylic acid amide functional group ((C(=O)-N or ) in naturally occurring isotopes.

[0016] In a first general aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, ester, hydrate, chelate or solvate thereof:

[0017]

[0018] Where n is an integer from 1 to 5. refers to an isotopically enriched amide functional group (also referred to as “isotopically enriched amide”); R is an organic moiety; R 1 and R 2 is independently hydrogen or an organic moiety; and the structure of Formula I comprises an isotopically enriched molecule of a drug and / or prodrug containing at least one carboxamide bond or is included in an isotopically enriched molecule of a drug and / or prodrug containing at least one carboxamide bond; provided that -NR 1 R 2 The moiety is not a 3-sulfo-1-propylamino moiety.

[0019] It should be noted that, in the above formula I, the n amide groups may be located at any position of R and are not limited to being located on the same atom.

[0020] As used herein, the terms "isotopically enriched" and "heavy isotopically enriched" are used interchangeably to refer to a substance enriched with one or more heavy stable isotopes ( 18 O. 17 O. 13 C and / or 15 N) enrichment. It should be understood that two or more atoms in a molecule can be enriched, and the atoms can be enriched with the same or different isotopes. For example, they can be enriched with two different isotopes of the same element, or alternatively with isotopes of two different elements. There may be a variety of such combinations and arrangements.

[0021] In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, ester, hydrate, chelate or solvate thereof, wherein the heavy isotope-enriched amide functional group is replaced by one or more stable heavy oxygen isotopes ( 18 O and 17 O) enriched in one or both; wherein n, R, R 1 and R 2 As defined above.

[0022] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, ester, hydrate and / or solvate thereof, wherein the heavy isotope-enriched amide functional group is replaced by one or more stable heavy carbon isotopes ( 13 C) enrichment; where n, R, R 1 and R 2 As defined above.

[0023] In another embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, ester, hydrate and / or solvate thereof, wherein the heavy isotope-enriched amide functional group is replaced by one or more stable diazo isotopes ( 15 N) enrichment; among them, n, R, R 1 and R 2 As defined above.

[0024] In one embodiment, the isotopically enriched amide is enriched in a single isotope of a single element, such as 18 O-enriched, 17 O-enriched, 13 C-enriched or 15 N-enriched.

[0025] In another embodiment, the isotopically enriched amide is enriched with two or more isotopes of one or more elements, such as 17 O- and 18 O-enriched, 18 O- and 13 C-enriched, 18 O- and 15 N-enriched or 13 C- and 15 N-enriched.

[0026] In one embodiment, n is an integer from 1 to 3; in another embodiment, n is equal to 1.

[0027] In a second general aspect, the present invention provides isotopically enriched amides. As described herein, amides are part of a drug or prodrug. Amides are important functional groups present in various types of drug molecules (e.g., local anesthetics, antiarrhythmic drugs, etc.), and are also key linking moieties in protein and peptide drug products (DeRuiter, J., Principles of Drug Action 1, Spring 2005, Amides). A large number of drug molecules include at least one amide bond or amine moiety, and many drugs developed in the last century are prodrugs of amines.

[0028] Alpelisib is an amide-containing drug with the following structure:

[0029]

[0030] It has an amide functionality, the proline amide group shown at the right end of the molecule derived from the proline moiety.

[0031] It has been demonstrated that Alpelisib is metabolized primarily at the proline amide group to form the corresponding proline derivative, the carboxylic acid (shown below). Unfortunately, however, the acid metabolite is biologically inactive.

[0032] (M4, the major metabolite of Alpelisib).

[0033] In an embodiment, an isotopically enriched amide as described herein is provided, wherein the isotopically enriched amide structure is contained in the molecule of Alpelisib. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt, ester and / or solvate thereof is provided, wherein R is an N-((4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl)-2-thiazolyl)aminocarbonyl)-pyrrolidin-2-yl organic moiety shown below:

[0034]

[0035] Among them, R 1 and R 2 and R is independently hydrogen or a protecting group, thereby providing an Alpelisib derivative having an isotopically enriched amide functionality.

[0036] In another embodiment, a compound of Formula I is provided, which is a compound of Formula II or a pharmaceutically acceptable salt, ester, hydrate, chelate and / or solvate thereof:

[0037]

[0038] in, R 1 and R 2 As defined above.

[0039] In some embodiments, in the compound of Formula II, the isotopically enriched amide functional group or is monoisotopically enriched, e.g. 18 O-enriched, 17 O-enriched, 13 C-enriched or 15 N-enriched; and R 1 and R 2 The same definitions apply as above.

[0040] In another embodiment, in the compound of formula II, the isotopically enriched amide functional group or is enriched in two or more isotopes of one or more elements, e.g. 17 O- and 18 O-enriched, 18 O- and 13 C-enriched, 18 O- and 15 N-enriched or 13 C- and 15 N-enriched.

[0041] In other embodiments, drug molecules containing isotopically enriched amide functional groups include Niraparib and Mefuparib. Both are PARP inhibitors used for cancer treatment. Among them, the organic part of Niraparib is The organic part of furupriol is Their corresponding isotopically enriched amide functional group drug molecular structures are as follows:

[0042]

[0043] in, isotopically enriched with one element, e.g. 17 O-, or 18 O-, or 13 C-, or 15 N-enriched; or enriched with two or more isotopes of one or more elements, e.g. 18 O- and 13 C-enriched, 18 O- and 15 N-enriched or 13 C- and 15 N-enriched.

[0044] Other examples of amide-containing drugs are the drugs developed by Actelion for the treatment of pulmonary arterial hypertension (PAH), Selexipag or ). Celexa and its active metabolite, ACT-333679 (or MRE-269, free carboxylic acid) are agonists of prostacyclin receptors, which cause vasodilation in the pulmonary circulation (Sitbon, O.; Morrell, N., Eur. Respir. Rev., 2012, 21(126):321–327). Celexa is a prodrug that hydrolyzes to release the following active substances:

[0045]

[0046] Another example of an amide-containing drug is Midodrine, which is an N-glycyl derivative of deglycine diazines. The former is deprotected by peptidase to give the latter, as shown below:

[0047]

[0048] Examples can be extended to many drugs and prodrugs. Other examples are NSAID prodrugs disclosed by Husain A et al. (Husain A., et al., Sch. Acad. J. Pharm., 2015; 4(3): 145-152), whose common structures are shown below:

[0049]

[0050] Among them, NSAIDs include but are not limited to aceclofenac, diclofenac, fenbufen, indomethacin, mefenamic acid and 4-biphenylacetic acid.

[0051] In another embodiment, a compound of Formula III, or a pharmaceutically acceptable salt, ester and / or solvate thereof is provided:

[0052]

[0053] in, As defined above; and NSAID is the residual part of a non-steroidal anti-inflammatory drug (the residue after removing the carboxyl group), the carboxyl group of the non-steroidal anti-inflammatory drug participates in the formation of the heavy isotope-enriched amide functional group, that is, NSAID and the carboxyl group together form a non-steroidal anti-inflammatory drug molecule.

[0054] Other examples of compounds include Rapastinel (GLYX-13, an N-methyl-D-aspartate receptor modulator), safinamide (a monoamine oxidase inhibitor), and BPN14770 (2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acetamide, a phosphodiesterase-4 (PDE4) allosteric modulator). Their non-isotopically enriched molecular structures are as follows:

[0055]

[0056] In addition, the oxygen, nitrogen, and carbon atoms in the amide groups of the following compounds can also be enriched or labeled with their respective stable heavy isotopes:

[0057]

[0058] In a specific embodiment, a compound of Table 1 or a pharmaceutically acceptable salt, ester, hydrate, chelate or solvate thereof is provided.

[0059] Table 1: Examples of compounds of the present invention

[0060]

[0061]

[0062]

[0063]

[0064]

[0065] Many examples of specific compounds of drugs and prodrugs having amide bonds at strategic positions in the molecule can be provided.

[0066] As shown below, other types of amides and their pharmaceutically acceptable salts, esters and / or solvates are also within the scope of the present invention. Therefore, in another embodiment, the following compounds or their pharmaceutically acceptable salts, esters, hydrates, chelates and solvates are provided:

[0067]

[0068] Among them, O * is the stable heavy oxygen isotope ( 17 O and / or 18 O)-enriched amide oxygen atoms; R, R 1 and R 2 As defined above; R 3represents an organic group with or without a substitution group, such as an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, etc.; and an isotopically enriched structure is present in the O of a drug and / or prodrug containing at least one amide bond (for example, but not limited to a phosphoamide, a phosphoramide and / or a sulfonamide bond). * -enriched molecules, or provide drugs and / or prodrugs containing at least one amide bond (such as but not limited to phosphoamide, phosphoramide and / or sulfonamide bonds) * -Enriched molecules.

[0069] In a third general aspect, the invention provides a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, ester, hydrate, chelate or solvate thereof, and a pharmaceutically acceptable carrier.

[0070] In a fourth general aspect, the invention provides methods for modifying or improving the pharmacokinetic properties of a drug or prodrug by replacing one or more of the three naturally occurring atoms in the amide bond (C(=O)-N) with one or more stable heavy isotope atoms.

[0071] In one embodiment, compared with using compounds with only natural abundance isotopic atoms (i.e., compounds without isotopic enrichment), the compounds described in the present invention (e.g., compounds of Formula I, Formula II or Formula III, or compounds of Table 1) and / or pharmaceutical compositions can be used to regulate the metabolic pathways of drugs or prodrugs in subjects, reduce the metabolism of drugs or prodrugs, regulate the pharmacokinetic properties of drugs or prodrugs, and / or improve or increase the therapeutic effect of drugs or prodrugs. In some embodiments, compared with using compounds with only natural abundance isotopic atoms (i.e., compounds without isotopic enrichment), provided herein are compounds and pharmaceutical compositions for reducing the therapeutic toxicity and / or side effects of compounds in subjects, increasing the tolerance of drugs, and / or improving or increasing the therapeutic or preventive effects of compounds. In some embodiments, compared with using compounds with only natural abundance isotopic atoms (i.e., compounds without isotopic enrichment), provided herein are compounds and pharmaceutical compositions for improving the biodistribution of compounds and / or enhancing the therapeutic and / or preventive effects of compounds in subjects.

[0072] In one embodiment, a method for adjusting the metabolism or pharmacokinetic properties of a compound containing an amide bond in a subject is provided, comprising administering an isotopically enriched compound or pharmaceutical composition as described herein to a subject, wherein, compared to administering the same compound having only natural abundance isotopic atoms (i.e., a compound that has not been isotopically enriched), the metabolism and pharmacokinetic properties of the amide bond-containing compound of the present invention are adjusted. In some embodiments, a method for reducing compound metabolism, reducing the therapeutic toxicity of a compound, reducing the side effects of a compound, increasing the tolerance of a compound, improving the biodistribution of a compound, and / or increasing the therapeutic or preventive effect of a compound in a subject is provided, the method comprising administering an isotopically enriched compound or pharmaceutical composition as described herein to a subject, wherein, compared to administering a compound having only natural abundance isotopic atoms (i.e., a compound that has not been isotopically enriched), the metabolism of the compound is reduced, the therapeutic toxicity is reduced, the side effects are reduced, the tolerance is increased, the biodistribution is improved, and / or the therapeutic or preventive effect is increased.

[0073] In other general aspects, kits are provided that include one or more compounds or pharmaceutical compositions described herein. The kits may further include one or more other therapeutic agents, and / or instructions, such as instructions for using the kit to treat subjects suffering from the same disease or condition treated by the parent compound (non-isotopically enriched compound). BRIEF DESCRIPTION OF THE DRAWINGS

[0074] In order to better understand the present invention and to more clearly show how to implement the present invention, reference will now be made by way of example to the accompanying drawings which illustrate aspects and features of embodiments according to the present invention, wherein:

[0075] Figure 1 It is shown that when Alpelisib and Alpelisib- 18 In O1 SD rats, the plasma levels of Alpelisib and Alpelisib- 18 Drug concentration-time curve of O1;

[0076] Figure 2 It is shown that when Alpelisib and Alpelisib- 18 In O1 ICR mice, plasma levels of Alpelisib and Alpelisib- 18 Drug concentration-time curve of O1;

[0077] Figures 3a to 3d Figure 2 shows the incubation of Alpelisib and Alpelisib- 18M4 and M4- generated after O1 18 O1: (a) monkey liver S9, (b) pooled human liver S9, (c) mini pig liver S9, and (d) male Wistar rat liver S9. In each figure, M4: -x-; M4- 18 O: -o-. DETAILED DESCRIPTION

[0078] definition

[0079] In order to provide a clear and consistent understanding of the terms used in the specification of the present invention, some definitions are provided below. In addition, unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0080] When used in conjunction with the term "comprising" in the claims and / or the specification, the use of the word "a" can mean "one", but it also means "one or more", "at least one" and "one or more than one". Similarly, the word "another" can mean at least a second or many.

[0081] As used herein, the term "natural abundance of oxygen" refers to oxygen atoms in their natural isotopic abundance, which typically have an isotopic composition close to that of oxygen atoms in the Earth's atmosphere: 16 O, 99.759%; 17 O, 0.037%; and 18 O, 0.204%. However, it should be understood that naturally occurring compounds may have slight variations in the isotopic composition of oxygen atoms.

[0082] The terms "heavy oxygen atom", "heavy oxygen isotope", "stable heavy oxygen", " * O" and "O * " are used interchangeably in this article and mean 17 O and / or 18 O is the stable oxygen atom, excluding any radioactive and non-naturally occurring heavy isotopes. 17 O and 18 O occurs naturally but relative to the major isotope 16 O exists in very low ratios. The terms "heavy carbon isotope", "stable heavy carbon isotope", "carbon-13", 13 C" and " * C" is used interchangeably in this article to refer to 13 C isotope. Similarly, the terms "diazo isotope", "stable diazo isotope", "nitrogen-15", " 15 N" and " * N" is used interchangeably in this article to refer to 15N isotope.

[0083] As used herein, the terms "oxygen atoms enriched with stable heavy oxygen isotopes", "stable heavy oxygen enriched", "heavy oxygen enriched", " * O-enriched" and "O * "-enriched" are used interchangeably herein to refer to heavy oxygen atoms that do not have their natural isotopic composition but have a higher stable heavy oxygen isotope than the naturally occurring isotopic composition. "Heavy oxygen enriched", "stable heavy oxygen enriched", " * O-enriched" and "O * "-enriched" means that the oxygen atoms at specific sites of the compound are enriched with stable heavy oxygen isotopes, specifically, 17 O and 18 One or both of O are enriched.

[0084] Similarly, for carbon or nitrogen atoms enriched with stable heavy atomic isotopes, 13 C-enriched or 15 N-enrichment refers to the presence of heavy isotopes in carbon or nitrogen atoms in the compound that do not have their natural isotopic composition. 13 C or 15 The proportion of N is higher than that found in naturally occurring carbon or nitrogen, respectively.

[0085] Isotopic enrichment is a process of changing the relative abundance of the isotopes of a given element, thereby producing a form of the element that is enriched (i.e., increased) in a particular isotope and reduced or depleted in other isotopes. As used herein, a "heavy isotopically enriched" compound or derivative refers to a compound that is enriched (i.e., increased) in a particular isotope, i.e., oxygen-17 or oxygen-18, or both and / or carbon-13, and / or nitrogen-15, at a particular position or site of an amide bond.

[0086] For carbon and nitrogen, the most abundant isotope with a molar fraction of 0.9893 12 C and the most abundant isotope of 0.99636 14 Compared with N, the most abundant heavy isotope 13 C and 15 The mole fractions of N are 0.0107 and 0.00364 respectively. Under normal conditions, the most abundant isotope with a mole fraction of 0.99757 16 O, oxygen-18 ( 18 O) and oxygen-17( 17 The mole fractions of O) are 0.00204 and 0.00037 respectively.

[0087] As used herein, an "isotopically enriched" compound or derivative has an isotopic form with a content higher than its natural abundance. The enrichment of an isotope varies depending on the change in the natural abundance of a particular isotopic form. In some embodiments, the isotopic enrichment level of a compound or element in a compound may be from about 2 mole percent to about 100 mole percent (%), for example, about 2%, about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 98%, greater than about 98%, about 99% or 100%. In one embodiment, the isotopic enrichment of the isotopically enriched compounds of the present invention (e.g., compounds in Formula I to Formula III or compounds in Table 1, etc.) is about 5% or more, or about 10% or more. In another embodiment, the isotopic enrichment of the isotopically enriched compounds of the present invention (e.g., compounds in Formula I to Formula III and compounds described herein) is about 20% or more, or about 50% or more. In another embodiment, the isotopic enrichment in the isotopically enriched compounds of the invention (e.g., compounds of Formula I to Formula III and compounds described herein) is about 75% or more, or about 90% or more. In another embodiment, the isotopic enrichment level in the isotopically enriched compounds of the invention (e.g., compounds of Formula I to Formula III and compounds described herein) is about 95% or more, about 98% or more, or 100%. It should be understood that the isotopic enrichment level of a particular compound, or a particular oxygen isotope of a compound, will be selected based on several properties including the chemical, pharmacokinetic and therapeutic properties of the compound to enhance the therapeutic or preventive effect, therapeutic biodistribution, bioavailability, metabolism, stability and / or pharmacokinetic properties of the compound.

[0088] As used herein, a "non-isotopically enriched" compound refers to a compound in which all atoms or elements are isotopes of natural abundance, i.e., a compound in which all atoms or elements have the most abundant atomic mass in nature. This non-isotopically enriched compound is completely different from an isotopically enriched compound in which one or more elements are enriched in one or more specific isotopic forms rather than naturally abundant isotopes. Compounds that are isotopically enriched are not encompassed by the compounds of the invention provided herein.

[0089] As used herein, the terms "compounds of the present invention" and "compounds of the present invention" and equivalent expressions refer to the isotopically enriched compounds provided herein that can be used for at least one purpose of the present invention, for example, those compounds covered by structural formulas such as Formula I to Formula III, as well as the specific compounds mentioned herein, and pharmaceutically acceptable salts, esters, chelates, hydrates and / or solvates thereof.

[0090] Without being limited by theory, these two heavy oxygen isotopes, viz.18 O and 17 O has different isotope effects on the rate of amide bond breakage, such as hydrolysis. 18 O has a higher 17 O (atomic weight 17) isotope effect. 18 O or 17 O was enriched, or at different ratios 18 O and 17 O mixtures are enriched to achieve the desired biological and pharmaceutical effects.

[0091] Similarly, heavy isotopes can be selected 13 C and / or 15 N is enriched to achieve the desired biological and pharmaceutical effects of isotopically enriched compounds.

[0092] As described herein, an isotopically enriched compound can be isotopically enriched with one or more isotopes of a single element, or isotopically enriched with isotopes of one or more elements.

[0093] As used herein, "drug" or "prodrug" or "parent compound" refers to a compound having natural isotopic abundance at the amide site of interest. The present invention provides such compounds, compositions, preparation methods and uses in "heavy isotope enriched" form, thereby regulating or improving the pharmaceutical properties of the parent compound, and enhancing or regulating the effect of disease treatment. In some embodiments, "drug" or "prodrug" or "parent compound" refers to a compound having natural oxygen, carbon and / or nitrogen abundance at each amide oxygen, carbon and / or nitrogen position of interest; the present invention provides compounds, compositions, preparation methods and uses of "heavy oxygen", "heavy carbon" and / or "heavy nitrogen" enriched forms of such compounds, thereby regulating or improving the pharmaceutical properties of the parent compound, and enhancing or regulating the effect of disease treatment.

[0094] As used herein, "organic moiety" or "organic fragment" refers to a group of atoms that form part of the overall molecule or structure of a compound. The moiety, amide bond or functional group, protecting group or substituent (if present) are linked together via covalent bonds to form the molecule or structure of the compound.

[0095] As used herein, the term "protecting group" has a well-known meaning in the art, and in the present application, especially an amino protecting group, for example, tert-butyloxycarbonyl, acetyl, (tert-butyldimethylsilyl)oxy, benzyloxycarbonyl, p-toluenesulfonyl, etc.

[0096] In one embodiment, when substitution is possible, the compounds of the invention may be further substituted with one or more substituents. In some embodiments, the substituted form of the compound is a prodrug; in these embodiments, the substituents may be cleaved, or the compound may be otherwise transformed so as to release the active ingredient or drug molecule from the prodrug form after administration to a subject.

[0097] The term "administering" or "administration" refers to delivering a compound to a subject and includes all dosing and drug delivery methods known in the art.

[0098] As used herein, the words "comprising" (and any forms of comprising, such as "including" and "comprising"), "having" (and any forms of having, "having", "including" and "containing") used in the specification and claims are inclusive and open-ended, and do not exclude additional, unrecited elements or processing steps.

[0099] The term "about" is used to indicate that the value includes the error resulting from the equipment and method employed in determining the value.

[0100] The term "derivative" as used in the present invention refers to a substance that is structurally similar to another compound but differs in some minor structural details.

[0101] This specification refers to many chemical terms and abbreviations used by those skilled in the art. However, for the sake of clarity and consistency, definitions of selected terms are provided.

[0102] As used herein, the term "substituted" or "having a substituent" means that the parent compound or part has at least one substituent group. The term "unsubstituted" or "having no substituents" means that the parent compound or part has no other substituents except that the undefined valence is chemically saturated by hydrogen atoms.

[0103] As used herein, "substituent" or "substituent group" refers to a group selected from halogen (F, Cl, Br or I), hydroxy, thiol, amino, nitro, carbonyl, carboxyl, alkyl, alkoxy, alkylamino, aryl, aryloxy, arylamino, acyl, sulfinyl, sulfonyl, phosphonyl, and other organic moieties conventionally used and accepted in organic chemistry.

[0104] As used herein, the term "alkyl" refers to a saturated hydrocarbon having 1 to 12 carbon atoms, including straight chain, branched chain and cyclic alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term alkyl includes unsubstituted alkyl and substituted alkyl. The term "C1-C n"alkyl" (wherein n is an integer from 2 to 12) means an alkyl group having from 1 to the indicated "n" carbon atoms. The alkyl residue can be substituted or unsubstituted. In some embodiments, for example, the alkyl group can be substituted with groups such as hydroxyl, amino, carboxyl, carboxylate, amide, carbamate or aminoalkyl.

[0105] Unless the carbon number is limited, the "lower" in "lower aliphatic", "lower alkyl", "lower alkenyl" and "lower alkynyl" used in this article means that the part has at least one (at least two for alkenyl and alkynyl) and equal to or less than 6 carbon atoms.

[0106] The terms "cycloalkyl", "alicyclic", "carbocycle" and equivalent expressions refer to a group containing a saturated or partially unsaturated carbocycle in a monocyclic, spirocyclic (sharing one atom) or fused (sharing at least one bond) carbocyclic ring system, wherein the carbocyclic ring system has 3 to 15 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonyl, norbornyl, and the like. The term cycloalkyl includes unsubstituted cycloalkyl and substituted cycloalkyl. The term "C3-C n "Cycloalkyl" wherein n is an integer from 4 to 15, refers to a cycloalkyl group having from 3 to the indicated "n" number of carbon atoms in the ring structure. Unless otherwise specified, a "lower cycloalkyl" group as used herein refers to a group having at least 3 and equal to or less than 8 carbon atoms in its ring structure.

[0107] "Cycloalkyl residues" may be saturated or contain one or more double bonds in the ring system. In particular, they may be saturated or contain one double bond in the ring system. In unsaturated cycloalkyl residues, the double bonds may be present in any suitable position. Monocyclic alkyl residues include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl or cyclotetradecyl, which may also be substituted with C 1-4 Alkyl. Examples of substituted cycloalkyl residues are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl. Examples of parent structures of bicyclic ring systems are norbornane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.1]octane.

[0108] The term "heterocycloalkyl" and equivalent expressions used in the present invention refer to a group containing a saturated or partially unsaturated carbocyclic ring in a monocyclic, spirocyclic (sharing one atom) or fused (sharing at least one bond) carbocyclic ring system, a group having 3 to 15 carbon atoms, including 1 to 6 heteroatoms (e.g., N, O, S, P) or a group containing heteroatoms (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO2, SO, SO2, etc.). The heterocycloalkyl group can be connected to C or to a heteroatom (e.g., through a nitrogen atom). Examples of heterocycloalkyl include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrodithienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxolanyl, thiolanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolidine, 2-pyrrolidine, 3-pyrrolidine, 4-pyrrolidine, 5-pyrrolidine, 6-pyrrolidine, 7-pyrrolidine, 8-pyrrolidine, 9-pyrrolidine, 10-pyrrolidine, 11-pyrrolidine, 12-pyrrolidine, 13-pyrrolidine, 14-pyrrolidine, 15-pyrrolidine, 16-pyrrolidine, 17-pyrrolidine, 18-pyrrolidine, 19-pyrrolidine, 19-pyrrolidine, 19-pyrrolidine, 11-pyrrolidine, 12-pyrrolidine The term heterocycloalkyl includes unsubstituted heterocycloalkyl and substituted heterocycloalkyl. The term "C3-C n "Heterocycloalkyl", wherein n is an integer from 4 to 15, means a heterocycloalkyl having from 3 to "n" atoms in the ring structure, including at least one hetero group or atom as defined above. Unless otherwise specified, "lower heterocycloalkyl" used in the present invention refers to a heterocyclic alkyl having at least 3 and equal to or less than 8 carbon atoms in its ring structure.

[0109] The terms "aryl" and "aryl ring" used in the present invention refer to an aromatic group having "4n+2" (π) electrons and 6 to 14 ring atoms in a conjugated monocyclic or polycyclic system (fused or non-fused), wherein n is an integer from 1 to 3. The polycyclic system includes at least one aromatic ring. The aryl group can be directly connected or connected through a C1-C3 alkyl group (also referred to as an arylalkyl group or aralkyl group). Examples of aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthenyl, fluorenyl, phenanthrenyl, anthracenyl, etc. The term aryl includes unsubstituted aryl and substituted aryl. The term "C6-C n "Aryl" (wherein n is an integer from 6 to 15) means an aromatic group having from 6 to the indicated "n" carbon atoms in the ring structure, including at least one heterocyclic group or atom as defined above.

[0110] The terms "heteroaryl" and "heteroaryl ring" used in the present invention refer to aromatic groups having "4n+2" (π) electrons in a conjugated monocyclic or polycyclic system (fused or non-fused), wherein n is an integer from 1 to 3 and includes one to six heteroatoms (e.g., N, O, S, P) or groups including heteroatoms (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO2, SO, SO2, etc.). The polycyclic system includes at least one heteroaromatic ring. The heteroaryl group can be directly connected or connected through a C1-C3 alkyl group (also called heteroarylalkyl or heteroaralkyl). The heteroaryl group can be connected to carbon or to a heteroatom (e.g., through a nitrogen atom). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl; isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolidinyl, quinolyl, isoquinolyl, indolyl, isoindolyl, chromenyl, isochromenyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyrid ... The term heteroaryl includes unsubstituted heteroaryl and substituted heteroaryl. The term "C5-C 5-C 5-H 2 O" includes 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol, 4-(4-oxo)-4-nitro-2-ol n "Heteroaryl", wherein n is an integer from 6 to 15, means a heteroaryl having from 5 to the indicated "n" atoms in the ring structure, including at least one heterocyclic group or atom as defined above.

[0111] As used herein, the term "heterocycle" or "heterocyclic" includes heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, acridinyl, azinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, 4αH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofurano[2,3-b]tetrahydrofuran, furanyl, 1,2-dihydrofurano[2,3-b]tetrahydrofuran ... furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, dihydroindolinyl, 3H-indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrol phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridinyl, pyrrolyl, pyrrolyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, quinuclidine, tetrahydrofuranyl, tetrahydroisoquinolyl, Tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 3,4-triazolyl, xanthenyl, and the like. The term heterocycle includes unsubstituted heterocyclic groups and substituted heterocyclic groups.

[0112] The term "amine" or "amino" as used herein refers to an unsubstituted or substituted group of the general formula -NR a R b A fragment, where R a and R b are each independently hydrogen, alkyl, aryl or heterocyclic, or R a and R bTogether with the nitrogen atom to which they are attached, they form a heterocycle. The term amino refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to a nitrogen atom. Therefore, the terms "alkylamino" and "dialkylamino" used in the present invention refer to an amine group having one and at least two C1-C6 alkyl groups attached to a nitrogen atom, respectively. The terms "arylamino" and "diarylamino" include at least one or two aryl-bound groups attached to a nitrogen atom. The term "amide" or "aminocarbonyl" refers to a structure in which the carbon of a carbonyl or thiocarbonyl group of a compound or fragment is attached to a nitrogen atom. The term "acylamino" refers to a structure in which an amino group is directly attached to an acyl group.

[0113] The term "alkylmercapto" refers to an alkyl group having a mercapto group attached thereto. Suitable alkylmercapto groups include groups having 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms. The term "alkylcarboxy" as used herein refers to an alkyl group having a carboxyl group attached thereto.

[0114] The term "alkoxy" or "lower alkoxy" used in the present invention refers to a structure in which an alkyl group is connected to an oxygen atom. Representative alkoxy groups include groups having 1 to about 6 carbon atoms, such as methoxy, ethoxy, propoxy, tert-butoxy, etc. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, pentyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc. The term "alkoxy" includes unsubstituted or substituted alkoxy groups, as well as perhalogenated alkoxy groups, etc.

[0115] As used herein, the term "carbonyl" or "carboxyl" refers to compounds and fragments containing a carbon connected to an oxygen atom via a double bond. Examples of moieties containing a carbonyl group include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, and the like.

[0116] The term "acyl" as used herein refers to a carbonyl structure in which the carbon atom of the carbonyl group is connected to hydrogen (i.e., formyl), an aliphatic group (C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, such as acetyl), a cycloalkyl group (C3-C8 cycloalkyl), a heterocyclic group (C3-C8 heterocyclic alkyl and C5-C6 heteroaryl), or an aryl group (C6 aryl, such as benzoyl). The acyl group may be unsubstituted or substituted (e.g., salicyl).

[0117] The term "solvate" refers to the physical association of a compound with one or more solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In some cases, the solvate can be isolated, for example when one or more solvent molecules are incorporated into the lattice of a crystal. "Solvate" includes both solution-phase solvates and isolatable solvates. Examples of "solvates" include, but are not limited to, hydrates, ethanolates, methanolates, hemiethanolates, and the like. The term "hydrate" refers to the physical association of a compound with water molecules.

[0118] A "pharmaceutically acceptable salt" of a compound refers to a salt of a pharmaceutically acceptable compound. The desired salt of the compound (basic, acidic or charged functional group) can retain or improve the biological activity and properties of the parent compound as defined in the present invention and is not biologically undesirable. Pharmaceutically acceptable salts may be those mentioned by Berge et al. in "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977). Including but not limited to:

[0119] (1) Salts formed by adding an acid to a basic or positively charged functional group. Inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, nitric acid, phosphoric acid, carbonates, etc. Organic acids include acetic acid, propionic acid, lactic acid, oxalic acid, glycolic acid, pivalic acid, tert-butylacetic acid, β-hydroxybutyric acid, valeric acid, caproic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, cyclohexylaminosulfonic acid, benzene Sulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, laurylsulfonic acid, laurylsulfonic acid, oleic acid, palmitic acid, stearic acid, lauric acid, pamoic acid (pamoic acid), pamoic acid, pantothenic acid, lactobionic acid, alginic acid, galactaric acid, galacturonic acid, gluconic acid, glucoheptonic acid, glutamic acid, naphthoic acid, hydroxynaphthoic acid, salicylic acid, ascorbic acid, stearic acid, muconic acid, etc.

[0120] (2) When acidic protons exist in the parent compound or are replaced by metal ions, a base can be added to obtain a salt. The metal ions include alkaline metal ions (such as lithium, sodium, potassium), alkaline earth metal ions (magnesium, calcium, barium) or other metal ions such as aluminum, zinc, iron, etc. Organic bases include but are not limited to N, N'-dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, piperazine, chloroprocaine, procaine, choline, lysine, etc.

[0121] Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic fragments by conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with an equistoichiometric amount of a base or acid in water or an organic solvent or in a mixture of the two. Salts can be prepared in situ during the final separation or purification of the medicament, or by reacting the purified compound of the present invention in the form of a free acid or base with the desired corresponding base or acid and separating the salt thus formed. The term "pharmaceutically acceptable salt" also includes zwitterionic compounds containing a cationic group covalently bonded to an anionic group, which are referred to as "inner salts". The compounds of the present invention include all acids, salts, bases and other ionic and non-ionic forms. For example, if the compound in the present invention is an acid, the salt form of the compound is also included. Similarly, if the compound in the present invention is a salt, the acid and / or base form of the compound is also included.

[0122] As used herein, the term "effective amount" refers to the amount or dosage of a therapeutic agent (e.g., a compound) that provides the desired therapeutic, prophylactic, diagnostic, or prognostic effect in a subject after being administered to the subject in a single dose or multiple doses. The effective amount can be readily determined by the attending physician or diagnostician by known techniques and by observing the results obtained under similar circumstances. In determining the effective amount or dosage of the compound to be administered, many factors are considered, including, but not limited to: the weight, age, and general health of the subject; the specific disease involved; the degree of involvement or severity of the disease or condition to be treated; the response of the individual subject; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosage regimen; the use of concomitant drugs; and other relevant considerations.

[0123] "Pharmaceutically acceptable" means that the drug, medicine, inert ingredient, etc. described by the term is suitable for contact with cells or tissues of humans and animals without abnormal toxicity, incompatibility, instability, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. It usually refers to a compound or composition approved or approvable by a regulatory agency of the Federal or state government, or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, more particularly in humans.

[0124] "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, carrier or vehicle with which the compound is administered. The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable carrier" are used interchangeably herein.

[0125] "Pharmaceutical composition" means a composition comprising a compound as described herein and at least one component, depending on the mode of administration and dosage form requirements, including a pharmaceutically acceptable carrier, diluent, adjuvant, excipient or vehicle, such as a preservative, filler, disintegrant, wetting agent, emulsifier, suspending agent, sweetener, flavoring agent, fragrance, antibacterial agent, antifungal agent, lubricant and dispersant, etc. "Prevention" or "prevention" is used to mean at least reducing the likelihood of acquiring a disease or condition (or susceptibility) to acquire a disease or disorder (i.e., preventing the clinical symptoms of at least one disease from developing in a patient who may be exposed to or susceptible to the disease but has not yet experienced or displayed symptoms of the disease).

[0126] In some embodiments, "treating" or "treating" any disease or condition refers to the alleviation of at least one disease or condition. In certain embodiments, "treating" or "treatment" refers to the alleviation of at least one physical parameter, which may be discernible or indiscernible to the patient. In certain embodiments, "treating" or "treatment" refers to the inhibition of a disease or condition physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters) or both. In certain embodiments, "treating" or "treatment" refers to improving the quality of life or side effects of a disease in a subject in need. "Therapeutically effective amount" refers to the amount of a compound administered to a subject for the treatment or prevention of a disease sufficient to achieve the effect of treating or preventing the disease. "Therapeutically effective amount" will vary depending on the compound; the disease and its severity; the age, weight, etc. of the subject to be treated or prevented from having the disease. As used herein, "therapeutically effective amount" refers to a compound or composition sufficient to prevent, treat, inhibit, reduce, alleviate or eliminate one or more causes, symptoms or complications of a disease, such as cancer.

[0127] The term "subject" refers to animals including mammals and humans, and particularly refers to humans.

[0128] The term "prodrug" or its equivalent refers to an agent that is directly or indirectly converted into an active form in vitro or in vivo (see, for example, RB Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), "Design of Prodrugs". 360 pp. Elsevier, Amsterdam; Stella, V.; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J. (Eds.) (2007), "Prodrugs: Challenges and Rewards, XVIII, 1470p. Springer). Prodrugs can be used to change the biodistribution of a particular drug (e.g., so that the agent does not normally enter the protease reaction site) or pharmacokinetics. A variety of groups have been used to modify compounds to form prodrugs, such as esters, ethers, phosphates / salts, etc. When the prodrug is administered to a subject, the group is cleaved off enzymatically or non-enzymatically, reduced, oxidatively or hydrolytically, or otherwise releases the active compound. As used herein, "prodrugs" include pharmaceutically acceptable salts or esters, or pharmaceutically acceptable solvates or chelates, and any crystalline forms of the above. Prodrugs are generally (although not necessarily) pharmaceutically inactive until they are converted to an active form.

[0129] The term "ester" refers to a compound represented by the formula RCOOR (carboxylate) or RSO3R' (sulfonate), which is typically formed by the reaction between a carboxylic acid or sulfonic acid, respectively, and an alcohol (elimination of one molecule of water).

[0130] The term "amino acid" generally refers to an organic compound that contains both a carboxylic acid group and an amino group. The term "amino acid" includes "natural" and "unnatural" amino acids. In addition, the term amino acid includes O-alkylated amino acids or N-alkylated amino acids, as well as amino acids with nitrogen-, sulfur- or oxygen-containing side chains (e.g., Lys, Cys or Ser), wherein the nitrogen, sulfur or oxygen atom may or may not be acylated or alkylated. The amino acid may be a pure L-isomer or D-isomer, or a mixture of L-isomers and D-isomers, including (but not limited to) a racemic mixture.

[0131] The term "natural amino acid" and equivalent expressions refer to L-amino acids commonly found in naturally occurring proteins. Examples of natural amino acids include, but are not limited to, alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-Ala) and γ-aminobutyric acid (GABA).

[0132] The term "non-natural amino acid" refers to any derivative of a natural amino acid, including D-amino acids, and α- and β-amino acid derivatives. The terms "non-natural amino acid" and "non-natural amino acid" are used interchangeably herein. It should be noted that certain amino acids (e.g., hydroxyproline) that can be classified as non-natural amino acids in the present invention may also exist in certain biological tissues or specific proteins in nature. Amino acids with many different protecting groups suitable for direct application in solid phase peptide synthesis are commercially available. In addition to the twenty most common natural amino acids, the following exemplary non-natural amino acids and amino acid derivatives (common abbreviations in brackets) can be used according to the present invention: 2-aminoadipic acid (Aad), 3-aminoadipic acid (β-Aad), 2-aminobutyric acid (2-Abu), α, β-dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC), aminoisobutyric acid (Aib), 3-aminoisobutyric acid (β-Aib), 2-amino-thiazoline-4- Carboxylic acids, 5-aminopentanoic acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 2-aminoheptanoic acid (Ahe), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid (4-Abz), 4-amino-3-hydroxy-6-methylheptanoic acid (Sta), aminooxyacetic acid (Aoa), 2-aminotetralin-2-carboxylic acid (ATC), 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), p-aminophenylalanine (4-NH2-Phe), 2-aminopimelic acid (Apm), biphenylalanine (Bip), p-bromophenylalanine (4-Br-Phe), o-chlorophenylalanine (2-Cl-Phe), m-chlorophenylalanine (3-Cl-Phe), p-chlorophenylalanine (4-Cl-Phe), m-chlorotyrosine (3-C l-Tyr), p-benzoylphenylalanine (Bpa), tert-butylglycine (TLG), cyclohexylalanine (Cha), cyclohexylglycine (Chg), desmosine (Des), 2,2-diaminopimelic acid (Dpm), 2,3-diaminopropionic acid (Dpr), 2,4-diaminobutyric acid (Dbu), 3,4-dichlorophenylalanine (3,4-Cl2-Phe), 3,4-difluorophenylalanine (3,4-F2-Phe), 3,5-diiodotyrosine (3,5-I2-Tyr), N-ethylglycine (EtGly), N-ethylasparagine (EtAsn), o-fluorophenylalanine (2-F-Phe), m-fluorophenylalanine (3-F-Phe), p-fluorophenylalanine (4-F-Phe), m-fluorotyrosine (3-F-Tyr), homoserine (Hse), homophenylalanine (Hfe), homotyrosine (Htyr), hydroxylysine (Hyl), isohydroxylysine (aHyl), 5-hydroxytryptophan (5-OH-Trp), 3- or 4-hydroxyproline (3- or 4-Hyp), p-iodophenylalanine-isotrosine (3-I-Tyr), indoline-2-carboxylic acid (Idc), isoiduromicin (Ide), isoleucine (α-Ile), isopenepic acid (Inp), N-methylisoleucine (M eLys), m-methyltyrosine (3-Me-Tyr), N-methylvaline (MeVal), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), p-nitrophenylalanine (4-NO2-Phe), 3-nitrotyrosine (3-NO2-Tyr), norleucine (Nle), norvaline (Nva), ornithine (Orn), o-phosphotyrosine (H2PO3-Tyr), octahydroindole-2-carboxylic acid (Oic), penicillamine (Pen), pentafluorophenylalanine (F5-Phe), phenylglycine (Phg), pipecolic acid (Pip), propargylglycine (Pra), pyroglutamic acid (PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic), thiazolidine-4-carboxylic acid (thioproline, Th). ,

[0133] For the compounds provided herein, in some embodiments, salts thereof, pharmaceutically acceptable salts are also included. Those skilled in the art will be aware of a variety of possible salt forms (e.g., TFA salts, tetrazolium salts, sodium salts, potassium salts, etc.), and suitable salts may also be selected based on considerations known in the art. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base (including inorganic acids and bases and organic acids and bases). For example, for compounds containing basic nitrogen, salts thereof can be prepared by pharmaceutically acceptable non-toxic acids (including inorganic acids and organic acids). Pharmaceutically acceptable acids suitable for use in the present invention include, but are not limited to, acetic acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, ethylenesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. When the compound contains an acidic side chain, pharmaceutically acceptable bases suitable for use in the present invention include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

[0134] Composition

[0135] In one embodiment, a pharmaceutical composition is provided, which includes a compound of the present invention, such as a compound shown in Formula I to Formula III and a compound of Table 1 or a pharmaceutically acceptable salt, ester, chelate, hydrate or solvate thereof, and a pharmaceutically acceptable carrier. In yet another embodiment, a pharmaceutical composition including a compound shown in Formula I to Formula III and a compound of Table 1 or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier is provided.

[0136] Example

[0137] The present invention will be more readily understood by reference to the following examples, which are provided to illustrate the present invention and are not to be construed as limiting the scope of the present invention in any way.

[0138] Unless otherwise defined or the context clearly dictates otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. It should be understood that any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.

[0139] Example 1: N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridine)-2-thiazole)aminocarbonyl-L-proline- 18O-amide (compound 1 or Alpelisib- 18 Preparation of O1)

[0140] Under nitrogen protection, (S)-1-N-Boc-2-pyrrolidinecarbonitrile (100 mg, 0.51 mmol), palladium acetate (12 mg, 0.051 mmol), 2,2-bipyridine (8 mg, 0.051 mmol) were added to H2 18 O (98% oxygen-18 abundance, 0.5 mL), the reaction solution was stirred at 60 ° C for 24 hours in a sealed tube. The reaction solution was cooled to room temperature and transferred to a flask, concentrated under vacuum, and the residue was purified by column chromatography (mobile phase, dichloromethane: methanol = 100 / 0 to 50 / 1) to finally obtain N-Boc-L-proline- 18 O-amide (48 mg; oxygen-18 abundance, 97.3%).

[0141] N-Boc-L-proline- 18 O-amide (48 mg, 0.22 mmol) was dissolved in dichloromethane (0.5 mL), and then hydrochloric acid / dioxane solution (4 M, 0.5 mL) was added, and the reaction was stirred at 25 ° C for 1 hour, and then the reaction solution was spin-dried under an oil pump to obtain L-proline- 18 O-amide hydrochloride (35 mg).

[0142] N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl)-2-thiazole)aminocarbonyl-[1H]-imidazole ester (79 mg, 0.2 mmol) was added to DMF (1 mL), followed by the addition of L-proline- 18 O-amide hydrochloride (33 mg, 0.22 mmol), triethylamine (80 mg, 0.8 mmol), the reaction solution was stirred at 30°C for 16 hours. The reaction solution was spin-dried by an oil pump, and the residue was purified by column chromatography (mobile phase, dichloromethane: methanol = 100 / 0 to 30 / 1) to obtain compound 1 (70 mg, oxygen-18 abundance 97.34%, yield 81.87%).

[0143] 1 H NMR (500MHz, DMSO-d6): δppm 10.96(s,1H),8.60(d,J=5.0Hz,1H),7.55(s,1H),7.41(s,2H),6.97(s,1H),4.26(s,0 .48H),3.60(s,1H),3.46(s,1H),2.42(s,4H),2.09(s,1H),1.87(s,3H),1.61(s,6H).

[0144] 13 C NMR (125MHz, DMSO-d6): δppm 174.36,159.87,158.99,152.99,149.58,145.69,141.44,129.94,127 .69,121.80,120.78,60.36,55.40,46.92,46.71,30.43,21.93,16.89.

[0145] m / z(ESI + ): 443.7; m / z (ESI - )441.5.

[0146] Example 2: N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridine)-2-thiazole)aminocarbonyl-L-proline- 17 O-amide (compound 2 or Alpelisib- 17 Preparation of O1)

[0147] In addition to using O 17 - Water (H2 17 O) to replace the H2 used in Example 1 18 Compound 2 was obtained in the same manner as in Example 1 except for O.

[0148] Example 3: N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridine)-2-thiazole)aminocarbonyl-L-proline- 13 C1-amide (compound 4 or Alpelisib- 13 Preparation of C1)

[0149] In addition to using proline- 13 Compound 4 was obtained in a similar manner to Example 1 except that C1-amide hydrochloride was used as the starting material.

[0150] Example 4: N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridine)-2-thiazole)aminocarbonyl-L-prolinamide 15 N (compound 5 or Alpelisib- 15 Preparation of N)

[0151] L-proline (5 g, 43.4 mmol, 1.0 eq.) and triethylamine (6.6 g, 65.2 mmol, 1.5 eq.) were dissolved in 50 ml of methanol, (Boc)2O (9.5 g, 43.5 mmol, 1 eq.) was slowly added, and the mixture was stirred at 50°C for 2 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: MeOH / DCM=1 / 50) to obtain N-tert-butyloxycarbonyl-L-proline (6 g, 64.2%).

[0152] The N-tert-butyloxycarbonyl-L-proline (1.5 g, 6.97 mmol, 1.0 eq.) obtained in the previous step was dissolved in 1,4-dioxane (27 mL), and pyridine (0.36 mL, 4.20 mmol, 0.6 eq.) was added. 15 N-ammonium sulfate (1.19 g, 8.87 mmol, 1.3 eq.), (Boc)2O (1.98 g, 8.87 mmol, 1.3 eq.), the reaction mixture was stirred at 25°C overnight. After the reaction solution was concentrated, the residue was purified by column chromatography (eluent: MeOH / DCM = 100 / 0 to 50 / 1) to obtain N-tert-butyloxycarbonyl-L-proline- 15 N-amide (0.29 g; 15 N abundance, 99.4%).

[0153] The N-tert-butyloxycarbonyl-L-proline- 15 N-Proline (0.29 g, 1.347 mmol, 1.0 eq.) was dissolved in DCM (3 mL), and 4 M HCl / dioxane solution (1.4 mL, 5.6 mmol, 4.16 eq.) was added and stirred at room temperature for 0.5 h. A white solid was precipitated, which was filtered and dried in vacuo to obtain L-proline- 15 N-Amide hydrochloride (0.16 g; 15 N abundance, 99.4%).

[0154] 4-Methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine (0.5 g, 1.66 mmol, 1.0 eq.) was dissolved in DCM (25 mL), CDI (0.4 g, 2.46 mmol, 1.5 eq.) was added, and stirred at 40°C for 4 h. A large amount of white solid was precipitated, which was filtered and dried in vacuo to obtain N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridine)-2-thiazole)aminocarbonyl-[1H]-imidazole ester (0.5 g, yield 76.9%).

[0155] L-proline- 15N-amide hydrochloride (0.16 g, 1.06 mmol, 1.05 eq.), N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridine)-2-thiazole)aminocarbonyl-[1H]-imidazole ester (400 mg, 1.01 mmol, 1.0 eq.) were dissolved in pyridine (5 mL), and DMAP (3 mg, 0.016 mmol, 0.023 eq.) was added, and stirred at 25° C. overnight. After the reaction solution was concentrated, the residue was purified by column chromatography (eluent: DCM / MeOH=100 / 0 to 30 / 1) to obtain compound 5 (240 mg, 15 N-abundance 99.4%, yield 53.7%).

[0156] 1 H NMR (500MHz, DMSO-d6): δppm 1.64(s,6H),1.90(s,3H),2.12(s,1H),2.44(s,3H),3.50(s,1H),3.63(s,1H), 4.31(s,1H),6.99(m,1H),7.42(m,2H),7.58(s,1H),8.63(s,1H),10.96(s,1H).

[0157] 13 C NMR (125MHz, DMSO-d6): δppm 16.78,21.91,24.39,30.41,46.72,46.92,60.38,120.68,121.71,125 .39,127.65,129.90,132.15,141.42,149.53,159.00,174.21,174.32.

[0158] m / z(ESI - )440.6; m / z(ESI + )442.8.

[0159] Example 5: Comparative study of the pharmacokinetics of compound 1 and Alpelisib in SD rats

[0160] A group of 6 SD rats were used in the experiment. 18O1) was mixed with Alpelisib in a molar ratio of 1:1 to obtain a dosing solution, wherein the concentration of both in the dosing solution was 1.25 mg / mL. The dosing solution was administered to the animal by gavage at a dose of 2.5 mg / kg. After administration, blood samples were collected at a series of preset time points (the time points were 0.167, 0.5, 1, 2, 3, 4, 6, 8 and 24 hours after administration). The blood samples were converted into plasma samples using a general method, and the concentrations of compound 1 and Alpelisib in the samples were analyzed by LC-MS / MS. The data obtained are shown in Tables 2 and Figure 1 . Figure 1 In the figure, the symbols -○- and --Δ-- respectively represent the drug concentration-time curves of Compound 1 and Alpelisib in plasma after oral administration of equal doses.

[0161] Table 2. PK parameters of Compound 1 and Alpelisib in SD rats.

[0162] parameter unit Compound 1 Alpelisib <![CDATA[AUC 0-t ]]> ug / L*h 28719 26405 <![CDATA[AUC 0-∞ ]]> ug / L*h 28798 26476 Tmax H 3 3 Vz / F L / kg 1.655 1.798 CLz / F L / h / kg 0.434 0.472 Cmax ug / L 2390 2297

[0163] Example 6: Comparative study of the pharmacokinetics of compound 1 and Alpelisib in ICR mice

[0164] 48 ICR mice were randomly divided into 6 groups (8 mice in each group). Compound 1 (Alpelisib- 18 O1) and Alpelisib in a molar ratio of 1:1 to obtain a dosing solution, wherein the concentration of both in the dosing solution is 1.25 mg / mL. The dosing solution was administered to animals by gavage at a dose of 2.5 mg / kg. After administration, blood samples were collected at a series of preset time points (the time points were 0.5, 1, 2, 4, 8 and 12 hours after administration), and samples were collected from a group of animals at each time point. The blood samples were converted into plasma samples using a general method, and the concentrations of compound 1 and Alpelisib in the samples were analyzed by LC-MS / MS. The data obtained are shown in Tables 3 and Figure 2 . Figure 2 In the figure, the symbols -○- and --Δ-- respectively represent the drug concentration-time curves of Compound 1 and Alpelisib in plasma after oral administration of equal doses.

[0165] Table 3. PK parameters of Compound 1 and Alpelisib in ICR mice.

[0166] parameter unit Compound 1 Alpelisib AUC(0-t) ug / L*h 27845 26212 AUC(0-∞) ug / L*h 32554 30597 Tmax h 2 2 Vz / F L / kg 2.236 2.37 CLz / F L / h / kg 0.384 0.409 Cmax ug / L 4519 4208

[0167] Example 7: Metabolites M4 and M4- 18 O1 generation in liver S9 medium.

[0168] The mixture stock solution (50 μL) containing equimolar amounts of compound 1 and Alpelisib was diluted to a working solution with a compound concentration of 4.5 μM using 0.1 M Tris-acetate buffer preheated in a 37°C water bath. To each incubation well, the above working solution (50 μL) and liver S9 solution (50 μL) were added and mixed evenly. After 5 minutes of preincubation, β-NADPH solution (100 μL) was added to each incubation well. Then, the incubation plate was placed at 37°C for incubation, and incubation samples were collected and analyzed at 0, 15, 30, 60, and 240 minutes.

[0169] Sample analysis method: Three samples were collected at each time point. After adding the stop solution (800 μL) to the sample at each preset time point, the mixture was mixed evenly (Vertex), centrifuged at 12000 rpm for 5 minutes, and the supernatant was transferred to the analysis sample tube. The M4 and M4- 18 The concentration of O1 was analyzed.

[0170] Under the same experimental conditions, the following two experiments were carried out in parallel: (1) M4 and M4- 18 The mixture solution of O1 was serially diluted, and the M4 and M4- 18 O1 was analyzed by LC-MS / MS, which showed that M4 and M4- 18 O1 has the same response value under this condition and is linear; (2) When only compound 1 is incubated, no M4 is produced, only M4- 18 O1 is generated.

[0171] The liver S9 used in the experiment were (a) monkey liver S9, (b) mixed human liver S9, (c) mini pig liver S9, and (d) male Wistar rat liver S9. Figures 3a to 3d ) is a summary of the experimental results.

[0172] Although the present invention has been described in detail with reference to the embodiments of the present invention, these embodiments are provided to illustrate rather than limit the present invention. Other embodiments that can be obtained according to the principles of the present invention all belong to the scope defined by the claims of the present invention.

[0173] The contents of all documents and references cited herein are incorporated by reference in their entirety.

Claims

1. A compound represented by the following formula or a pharmaceutically acceptable salt thereof:

2. A compound according to claim 1, wherein The level of heavy isotope enrichment in the compound is 5% or more.

3. A compound according to claim 1, wherein The level of heavy isotope enrichment in the compound is 10% or more.

4. A compound according to claim 1, wherein The level of heavy isotope enrichment in the compound is 20% or more.

5. A compound according to claim 1, wherein The level of heavy isotope enrichment in the compound is 50% or more.

6. A compound according to claim 1, wherein The level of heavy isotope enrichment in the compound is 75% or more.

7. A compound according to claim 1, wherein The level of heavy isotope enrichment in the compound is 90% or more.

8. A compound according to claim 1, wherein The level of heavy isotope enrichment in the compound is 95% or more.

9. A compound according to claim 1, wherein The level of heavy isotope enrichment in the compound is 100%.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier.

11. Use of the compound of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 in the preparation of a PI3K inhibitor for treating a disease condition or symptom associated with the activity of phosphoinositide 3-kinase.

12. The use according to claim 11, wherein The disease condition or symptom is a solid tumor.

13. The use according to claim 11, wherein The disease condition or symptom is cancer.

14. The use according to claim 13, wherein The cancer is breast cancer, melanoma, colon cancer, pancreatic cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, Kaposi's sarcoma, rectal cancer, renal cell carcinoma or glioblastoma.

15. A kit comprising a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10, and instructions for use thereof.

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