Compound containing stable heavy isotope amide functional group and application thereof

Abstract

The invention provides a compound containing stable heavy isotope enriched amide functional groups as shown in a formula (I), which is used for adjusting pharmacokinetic characteristics, metabolic characteristics and / or delivery efficiency of drugs or prodrugs, as well as therapeutic and prophylactic effects of the drugs or prodrugs. The invention also relates to the use of drugs and prodrugs containing isotopically enriched amides in the treatment or prevention of disease conditions and symptoms. # imgabs0 #

Description

[0001] This application is a divisional application of the application with the application number 201910447749.3, the application date of May 27, 2019, and the invention title of "Compounds Containing Amide Functional Groups with Stable Heavy Isotopes and Their Applications". Technical Field

[0002] The present invention relates to compounds containing amide functional groups enriched with stable heavy isotopes, and their use for adjusting the pharmacokinetic properties, metabolic properties, and / or delivery efficiency of compounds (such as drugs or prodrugs), as well as the therapeutic and prophylactic applications of such compounds. Background Art

[0003] Amide compounds, also known as acid amide compounds, are compounds having the formula R m E(O) n NR 1 R 2 wherein R, R 1 and R 2 are hydrogen (H) or organic groups. 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 IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"), 1997). Another class of amides is phosphonamides.

[0004] Structurally, the amide bond in a molecule can be shown as follows:

[0005]

[0006] respectively refer to carboxamide, phosphoramide, phosphonamide, and sulfonamide, wherein R, R 1 , R 2 and R 3 are independently hydrogen or an organic group with or without substituents, such as alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a combination thereof.

[0007] In the common nomenclature, the term "amide" is added to the stem of the parent acid. For example, the amide derived from acetic acid is called acetamide (CH3CONH2). The IUPAC recommends naming this compound as ethanamide, but this and related formal names are rarely used in practice. When the amide is derived from a primary or secondary amine, the substituents 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 and are necessarily secondary or tertiary amides. Compounds containing the –P(O)2NR 1 R 2 and –SO2NR 1 R 2 functional groups are phosphonamides and sulfonamides respectively (Organic Chemistry IUPAC Nomenclature.Rules C-821.Amideshttp: / / www.acdlabs.com / iupac / nomenclature / 79 / r79_540.htm).

[0008] Amides are important functional groups present in many types of drugs, such as local anesthetics, antiarrhythmic drugs, etc. Amides are also key linkages in protein and peptide drug products (DeRuiter, J., Principles of Drug Action 1, Spring 2005, Amides, http: / / www.auburn.edu / ~deruija / pda1_amides.pdf). In addition, many drugs developed in the last century are prodrugs of amines, highlighting their importance in the field of pharmacy. 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 in a stable form to the target site. Amine prodrugs are generally classified by the linkage of the nitrogen atom to a nearby atom. 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, A.L., et al., Molecules, 2008, 13, 519-547). For example, a large number of anticancer agents have amide bonds in their molecules (e.g., see Mohammed, Y.H.E. and Khanum, S.A., 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 (previously BYL719, or N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl)-2-thiazolyl)aminocarbonyl-L-proline amide) is an α-specific PI3K (phosphoinositide 3-kinase) inhibitor, an experimental drug in development for certain cancers (https: / / www.cancertherapyadvisor.com / breast-cancer / novel-agents-for-endocrine-resistant-breast-cancer / article / 508600 / ). It is involved in late-stage clinical trials for certain types of breast cancer, including the SOLAR-1 trial for PIK3CA-altered metastatic breast cancer. This compound is being used clinically in patients with advanced solid tumors (Ando, Y., et al., Cancer Science, 2019, 1-11).

[0009] One of the key reactions of carboxylic acid amides (also known as carboxamides or amides) with peptides is the hydrolysis of the amide bond. Hydrolysis can be acid-catalyzed, base-catalyzed, or enzyme-catalyzed, and generally produces the corresponding carboxylic acid and amine or ammonia. Hydrolysis involves the formation of a tetrahedral intermediate centered on the carbon atom after the C=O double bond becomes a C-O single bond (see

[0010] http: / / research.cm.utexas.edu / nbauld / teach / ch610bnotes / ch18.htm, East, A. L. L., Int. J. Chem. Kinet., 2018; 1–5). Acid-catalyzed hydrolysis is shown below:

[0011]

[0012]

[0013] The rate-determining step is step 2 (see the above equation), where the process of the C=O double bond becoming a C-O single bond through the cleavage of the π-bond directly affects the rate of amide bond cleavage. SUMMARY OF THE INVENTION

[0014] An object of the present invention is to provide an amide moiety with an improved rate of amide bond cleavage to alter the pharmacokinetic properties of drugs and prodrugs containing amide bonds, thereby adjusting their therapeutic and prophylactic effects and / or side effects.

[0015] The present invention is at least partially based on the inventors' recognition that stable heavy isotopes ( 17 O and / or 18 O; 13 C; and / or 15 N) can change the rate of amide bond cleavage compared to isotopes of natural abundance ( 16 O, 12 C, and 14 N), thereby improving the pharmacokinetic properties of drugs and prodrugs containing amide bonds, and further adjusting the therapeutic and prophylactic effects and / or side effects of drugs and prodrugs containing amide bonds.

[0016] Therefore, replacing the oxygen atom isotope of natural abundance ( 17 O or 18 O) with a stable heavy oxygen isotope ( 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 replacing the oxygen atom isotope of natural abundance with a stable heavy oxygen isotope ( * O or O * , representing 17 O and / or 18 O) to replace 16O can alter the rate of amide bond cleavage. This alteration can improve the pharmacokinetic properties of drugs and prodrugs containing amide bonds, and thus modulate the therapeutic, prophylactic effects and / or side effects of the drugs and prodrugs. It has also been noted that the carboxylic acid amide center directly involves three atoms, namely, a carbon atom, an oxygen atom, and a nitrogen atom. Therefore, isotopes of carbon and / or nitrogen can also directly affect the rate of amide bond cleavage, and thus the therapeutic, prophylactic effects and / or side effects of drugs and prodrugs containing amide bonds.

[0017] Accordingly, 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 naturally occurring isotopes in the carboxylic acid amide functional group ((C(=O)-N or )) of the drugs and prodrugs containing amide bonds.

[0018] 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:

[0019]

[0020] wherein n is an integer from 1 to 5, refers to an isotope-enriched amide functional group (also referred to as "isotope-enriched amide"); R is an organic moiety; R 1 and R 2 are independently hydrogen or an organic moiety; and the structure of Formula I includes an isotope-enriched molecule of a drug and / or prodrug containing at least one carboxamide bond or is included in an isotope-enriched molecule of a drug and / or prodrug containing at least one carboxamide bond; provided that the -NR 1 R 2 moiety is not a 3-sulfo-1-propylamino moiety.

[0021] It should be understood that in Formula I above, the n amide groups can be located at any position of R and are not limited to the same atom.

[0022] As used herein, the terms "isotope-enriched" and "heavy isotope-enriched" are used interchangeably and mean enriched with one or more stable heavy isotopes ( 18 O, 17 O, 13 C, and / or 15 N). It should be understood that two or more atoms in the 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 can be many such combinations and arrangements.

[0023] 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 enriched with one or more stable heavy oxygen isotopes ( 18 O and 17 O, one or both); wherein n, R, R 1 and R 2 are as defined above.

[0024] 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 enriched with one or more stable heavy carbon isotopes ( 13 C); wherein n, R, R 1 and R 2 are as defined above.

[0025] In yet 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 enriched with one or more stable heavy nitrogen isotopes ( 15 N); wherein n, R, R 1 and R 2 are as defined above.

[0026] In one embodiment, the isotope-enriched amide is enriched with a single isotope of a single element, such as 18 O-enriched, 17 O-enriched, 13 C-enriched or 15 N-enriched.

[0027] In another embodiment, the isotope-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.

[0028] In one embodiment, n is an integer from 1 to 3; in another embodiment, n is equal to 1.

[0029] 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 many types of drug molecules (such as 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.

[0030] Alpelisib is an amide-containing drug having the following structure:

[0031]

[0032] It has an amide functional group, a prolinamide group derived from a proline moiety shown at the right end of the molecule.

[0033] It has been shown that Alpelisib is mainly metabolized on this prolinamide group to form the corresponding proline derivative, i.e., carboxylic acid (shown below). However, unfortunately, this acid metabolite is biologically inactive.

[0034]

[0035] In an embodiment, there is provided an isotopically enriched amide as described herein, wherein the isotopically enriched amide structure is incorporated into the molecule of Alpelisib. In one embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt, ester, and / or solvate thereof, wherein R is the N-((4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl)-2-thiazolyl)aminocarbonyl)-pyrrolidin-2-yl organic moiety shown below:

[0036]

[0037] wherein R 1 and R 2 are independently hydrogen or a protecting group, thereby providing an Alpelisib derivative having an isotopically enriched amide functional group.

[0038] In another embodiment, there is provided a compound of formula I, which is a compound of formula II or a pharmaceutically acceptable salt, ester, hydrate, chelate, and / or solvate thereof:

[0039]

[0040] wherein, R 1and R 2 As defined above.

[0041] In some embodiments, in the compounds of Formula II, the isotope-enriched amide functional group or is singly isotope-enriched, e.g., 18 O-enriched, 17 O-enriched, 13 C-enriched or 15 N-enriched; and R 1 and R 2 have the same definition as above.

[0042] In another embodiment, in the compounds of Formula II, the isotope-enriched amide functional group or is two or more isotope-enriched in 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.

[0043] In other embodiments, drug molecules containing isotope-enriched amide functional groups include Niraparib and Mefuparib. Both are PARP inhibitors for cancer treatment. Among them, the organic part of Niraparib is The organic part of Mefuparib is The drug molecular structures of their corresponding isotope-enriched amide functional groups are as follows:

[0044]

[0045] Among them, is isotope-enriched by one element, e.g., 17 O-, or 18 O-, or 13 C-, or 15 N-enriched; or isotope-enriched by 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.

[0046] Other examples of amide-containing drugs are drugs developed by Actelion for the treatment of pulmonary arterial hypertension (PAH), selexipag (or ). Selexipag and its active metabolite, ACT-333679 (or MRE-269, free carboxylic acid), are agonists of the prostacyclin receptor, which cause vasodilation in the pulmonary circulation (Sitbon, O.; Morrell, N., Eur. Respir. Rev., 2012, 21(126):321–327). Selexipag is a prodrug that hydrolyzes to release the following active substance:

[0047]

[0048] Another example of an amide-containing drug is midodrine, which is an N-glycyl derivative of desglycine dazoxiben. The former is deprotected by peptidase to obtain the latter, as shown below:

[0049]

[0050] The 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), and their common structures are shown below:

[0051]

[0052] Among them, NSAIDs include but are not limited to aceclofenac, diclofenac, fenbufen, indomethacin, mefenamic acid, and 4-biphenylacetic acid.

[0053] In another embodiment, a compound of formula III, or a pharmaceutically acceptable salt, ester, and / or solvate thereof, is provided:

[0054]

[0055] Wherein, is as defined above; and NSAID is the residue of a non-steroidal anti-inflammatory drug (the residue after removing the carboxyl group), and 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.

[0056] Other examples of compounds include Rapastinel (GLYX-13, an N-methyl-D-aspartic acid receptor modulator), safinamide (a monoamine oxidase inhibitor), and BPN14770 (2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acetamide, an allosteric modulator of phosphodiesterase-4 (PDE4)). Their non-isotope-enriched molecular structures are as follows:

[0057]

[0058] 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:

[0059]

[0060] In a specific embodiment, there is provided a compound of Table 1 or a pharmaceutically acceptable salt, ester, hydrate, chelate, and solvate thereof.

[0061] Table 1: Examples of the compounds of the present invention

[0062]

[0063]

[0064]

[0065]

[0066]

[0067] Many examples of specific compounds of drugs and prodrugs having an amide bond at a key site of the molecule can be provided.

[0068] 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. Thus, in another embodiment, there is provided the following compounds or their pharmaceutically acceptable salts, esters, hydrates, chelates, and solvates:

[0069]

[0070] Wherein, O * is an amide oxygen atom enriched with stable heavy oxygen isotopes ( 17 O and / or 18 O); R, R 1 and R 2 are as defined above; R 3represents an organic group with or without substituents, such as alkyl, cycloalkyl, heterocycloalkyl, aryl, etc.; and, an isotope-enriched structure is present in a drug and / or prodrug containing at least one amide bond (such as but not limited to phosphonamide, phosphoramide, and / or sulfonamide bond) of O * -enriched molecules, or provides O * -enriched molecules of a drug and / or prodrug containing at least one amide bond (such as but not limited to phosphonamide, phosphoramide, and / or sulfonamide bond).

[0071] In a third general aspect, the present invention provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt, ester, hydrate, chelate, or solvate thereof, and a pharmaceutically acceptable carrier.

[0072] In a fourth general aspect, the present invention provides a method for modulating or improving the pharmacokinetic properties of a drug or prodrug by replacing one or more of the three naturally occurring atoms (C(=O)-N) in an amide bond with one or more stable heavy isotope atoms.

[0073] In one embodiment, compared with using a compound having only isotopic atoms of natural abundance (i.e., an un-isotope-enriched compound), the compounds (e.g., compounds of formula I, formula II, or formula III, or compounds in Table 1) and / or pharmaceutical compositions of the present invention can be used to modulate the metabolic pathway of a drug or prodrug in a subject, reduce the metabolism of the drug or prodrug, modulate the pharmacokinetic properties of the drug or prodrug, and / or improve or increase the therapeutic effect of the drug or prodrug. In some embodiments, compared with using a compound having only isotopic atoms of natural abundance (i.e., an un-isotope-enriched compound), the compounds and pharmaceutical compositions provided herein are used to reduce the therapeutic toxicity and / or side effects of the compound in a subject, increase the tolerance of the drug, and / or improve or increase the therapeutic or prophylactic effect of the compound. In some embodiments, compared with using a compound having only isotopic atoms of natural abundance (i.e., an un-isotope-enriched compound), the compounds and pharmaceutical compositions provided herein are used to improve the biodistribution of the compound and / or enhance the therapeutic effect and / or prophylactic effect of the compound in a subject.

[0074] In one embodiment, a method of modulating the metabolism or pharmacokinetic properties of an amide bond-containing compound in a subject is provided, comprising administering to the subject an isotopically enriched compound or pharmaceutical composition described herein, wherein the metabolic and pharmacokinetic properties of the amide bond-containing compound of the present invention are modulated as compared to administering the same compound having only naturally abundant isotopic atoms (i.e., a compound that is not isotopically enriched). In some embodiments, a method of 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 prophylactic effect of a compound in a subject is provided, the method comprising administering to the subject an isotopically enriched compound or pharmaceutical composition described herein, wherein as compared to administering a compound having only naturally abundant isotopic atoms (i.e., a compound that is not 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 prophylactic effect is increased.

[0075] In other general aspects, a kit comprising one or more compounds or pharmaceutical compositions described herein is provided. The kit may further comprise one or more other therapeutic agents, and / or instructions, such as instructions for using the kit to treat a subject having the same disease or disorder as that treated by the parent compound (a compound that is not isotopically enriched). BRIEF DESCRIPTION OF THE DRAWINGS

[0076] For a better understanding of the present invention and to more clearly illustrate how to practice the present invention, reference will now be made, by way of example, to the accompanying drawings, which show aspects and features of embodiments in accordance with the present invention, wherein:

[0077] Figure 1 Shows the plasma concentration-time curves of Alpelisib and Alpelisib- 18 O1 in Sprague-Dawley rats orally administered Alpelisib and Alpelisib- 18 O1 at the same dose, respectively;

[0078] Figure 2 Shows the plasma concentration-time curves of Alpelisib and Alpelisib- 18 O1 in ICR mice orally administered Alpelisib and Alpelisib- 18 O1 at the same dose, respectively;

[0079] Figures 3a to 3d Shows Alpelisib and Alpelisib- incubated in the medium of liver S9 of various different species 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 implementation mode

[0080] Definition

[0081] 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 pertains.

[0082] When used in the claims and / or the specification in conjunction with the term "comprising", the use of the word "a" can mean "one / kind", 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.

[0083] As used herein, the term "naturally abundant oxygen" refers to oxygen atoms with natural isotope abundances, which typically have an isotope 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 isotope composition of oxygen atoms.

[0084] The terms "heavy oxygen atom", "heavy oxygen isotope", "stable heavy oxygen", " * O" and "O * " are used interchangeably herein and represent 17 O and / or 18 stable oxygen atoms of O, excluding any radioactive and non-naturally occurring heavy isotopes. 17 O and 18 O occur naturally but at extremely low ratios relative to the major isotope 16 O. The terms "heavy carbon isotope", "stable heavy carbon isotope", "carbon-13", " 13 C" and " * C" are used interchangeably herein and refer to 13 the C isotope. Similarly, the terms "heavy nitrogen isotope", "stable heavy nitrogen isotope", "nitrogen-15", " 15 N" and " * N" are used interchangeably herein and refer to 15N isotope.

[0085] 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 and refer to heavy oxygen atoms that do not have their natural isotopic composition but rather have a higher stable heavy oxygen isotope compared to the naturally occurring isotopic composition. "Heavy oxygen enriched", "stable heavy oxygen enriched", " * O-enriched", and "O * -enriched" mean that the oxygen atoms at specific sites in a compound are enriched with stable heavy oxygen isotopes, specifically, enriched with 17 O and 18 O, either one or both.

[0086] Similarly, for carbon or nitrogen atoms enriched with stable heavy atomic isotopes, i.e., 13 C-enriched or 15 N-enriched respectively refer to the heavy isotopes 13 C or 15 N in carbon or nitrogen atoms in a compound that do not have the natural isotopic composition, and the proportions of

[0087] Isotope enrichment is a method of changing the relative abundances of the isotopes of a given element, resulting in a form of the element in which a specific isotope is enriched (i.e., increased) while other isotopes are decreased or depleted. As used herein, a "heavy isotope enriched" compound or derivative means that at a specific position in the compound or at the site of an amide bond, a specific isotope is enriched (i.e., increased), namely oxygen-17 or oxygen-18, or both, and / or carbon-13, and / or nitrogen-15.

[0088] For carbon and nitrogen, compared with the most abundant isotopes 12 C with a mole fraction of 0.9893 and the most abundant isotope 14 N with a mole fraction of 0.99636, the mole fractions of the most abundant heavy isotopes 13 C and 15 N are 0.0107 and 0.00364 respectively. Under normal conditions, relative to the most abundant isotope 16 O with a mole fraction of 0.99757, the mole fractions of oxygen-18 ( 18 O) and oxygen-17 ( 17 O) are 0.00204 and 0.00037 respectively.

[0089] As used herein, a "isotopically enriched" compound or derivative has a higher content of an isotopic form than its natural abundance. The degree of enrichment of the isotope varies according to the change in the natural abundance of the specific isotopic form. In some embodiments, the isotopic enrichment level of a compound or an element in a compound can 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 degree of isotopic enrichment in the isotopically enriched compounds of the present invention (e.g., the compounds in Formulas I to III or the compounds in Table 1, etc.) is about 5% or higher, or about 10% or higher. In another embodiment, the degree of isotopic enrichment in the isotopically enriched compounds of the present invention (e.g., the compounds in Formulas I to III and the compounds described herein) is about 20% or higher, or about 50% or higher. In yet another embodiment, the degree of isotopic enrichment in the isotopically enriched compounds of the present invention (e.g., the compounds in Formulas I to III and the compounds described herein) is about 75% or higher, or about 90% or higher. In yet another embodiment, the isotopic enrichment level in the isotopically enriched compounds of the present invention (e.g., the compounds in Formulas I to III and the compounds described herein) is about 95% or higher, about 98% or higher, or 100%. It should be understood that the isotopic enrichment level of a specific compound, or a specific oxygen isotope of a compound, will be selected according to several properties including the chemical properties, pharmacokinetic properties and therapeutic properties of the compound, etc., in order to improve the therapeutic or prophylactic effect, therapeutic biodistribution, bioavailability, metabolism, stability and / or pharmacokinetic properties of the compound.

[0090] As used herein, an "isotopically unenriched" compound means that all atoms or elements in the compound are isotopes of natural abundance, that is, a compound in which all atoms or elements have the most abundant atomic mass in nature. This isotopically unenriched compound is completely different from an isotopically enriched compound in which one or more elements are enriched to one or more specific isotopic forms rather than natural abundance isotopes. Isotopically unenriched compounds are not encompassed in the compounds of the present invention provided herein.

[0091] 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 Formulas I to III, and the specific compounds mentioned herein, and their pharmaceutically acceptable salts, esters, chelates, hydrates and / or solvates.

[0092] Without being bound by theory, these two heavy oxygen isotopes, namely18 O and 17 O have different isotope effects on the cleavage of amide bonds, such as the rate of hydrolysis reactions. 18 O with an atomic weight of 18 daltons has a higher isotope effect than 17 O (with an atomic weight of 17). It is possible to enrich with 18 O or 17 O, or to enrich with a mixture of 18 O and 17 O in different proportions to achieve the desired biological and pharmaceutical effects.

[0093] Similarly, it is possible to select heavy isotopes 13 C and / or 15 N for enrichment to achieve the desired biological and pharmaceutical effects of isotopically enriched compounds.

[0094] As described herein, isotopically enriched compounds can be isotopically enriched with one or more isotopes of a single element, or with isotopes of one or more elements.

[0095] As used herein, "drug" or "prodrug" or "parent compound" refers to a compound having a natural isotope abundance at the amide site of interest. The present invention provides "heavy isotope enriched" forms of such compounds, compositions, preparation methods, and uses, thereby modulating or improving the pharmaceutical properties of the parent compound and enhancing or modulating the effect of disease treatment. In some embodiments, "drug" or "prodrug" or "parent compound" refers to a compound having a natural oxygen, carbon, and / or nitrogen abundance at each amide oxygen, carbon, and / or nitrogen position of interest; the present invention provides "heavy oxygen", "heavy carbon", and / or "heavy nitrogen" enriched forms of such compounds, compositions, preparation methods, and their applications, thereby modulating or improving the pharmaceutical properties of the parent compound and enhancing or modulating the effect of disease treatment.

[0096] As used herein, "organic moiety" or "organic fragment" refers to a group of atoms that forms part of the entire molecule or structure of a compound. This moiety, amide bond or functional group, protecting group, or substituent (if present) is covalently linked together to form the molecule or structure of the compound.

[0097] As used herein, the term "protecting group" has the meaning well known in the art, and in the present application, especially an amino protecting group, for example, tert-butoxycarbonyl, acetyl, (tert-butyldimethylsilyl)oxy, benzyloxycarbonyl, p-toluenesulfonyl, etc.

[0098] 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 forms of the compounds are prodrugs; in these embodiments, the substituents may be cleaved or the compounds otherwise transformed so as to release the active ingredient or drug molecule from the prodrug form after administration to a subject.

[0099] The terms "administer" or "administration" refer to delivering a compound to a subject, including all dosing and drug delivery methods known in the art.

[0100] As used herein, the word "comprising" (and any form of comprising, such as "comprises" and "comprising"), "having" (and any form of having, "has", "comprises", and "includes") as used in this specification and the claims is inclusive and open-ended and does not exclude additional, unrecited elements or process steps.

[0101] The term "about" is used to indicate that the value includes the error resulting from the measuring instrument and method used in determining the value.

[0102] 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 aspects.

[0103] This specification refers to many chemical terms and abbreviations used by those skilled in the art. However, for clarity and consistency, definitions of selected terms are provided.

[0104] As used herein, the term "substituted" or "having a substituent" means that the parent compound or moiety has at least one substituent group. The term "unsubstituted" or "not having a substituent" means that the parent compound or moiety has no other substituents except that the undetermined valence is chemically saturated with hydrogen atoms.

[0105] As described herein, a "substituent" or "substituent group" refers to a group selected from halogen (F, Cl, Br, or I), hydroxyl, mercapto, 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.

[0106] As used in the present invention, the term "alkyl" refers to a saturated hydrocarbon having 1 to 12 carbon atoms, including straight-chain, branched-chain, and cyclic alkyls. Examples of alkyls 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 alkyls and substituted alkyls. The term "C1-C n"Alkyl" (wherein n is an integer from 2 to 12) represents an alkyl group having 1 to the indicated "n" carbon atoms. The alkyl residue can be substituted or unsubstituted. In some embodiments, for example, the alkyl can be substituted with groups such as hydroxyl, amino, carboxyl, carboxylic ester, amide, carbamate, or aminoalkyl.

[0107] Unless otherwise limited as to carbon number, the "lower" in "lower aliphatic", "lower alkyl", "lower alkenyl", and "lower alkynyl" as used herein means that the moiety has at least one (at least two for alkenyl and alkynyl) and up to and including 6 carbon atoms.

[0108] The terms "cycloalkyl", "alicyclic", "carbocyclic", and equivalent expressions refer to groups containing saturated or partially unsaturated carbocycles in a monocyclic, spiro (sharing one atom), or fused (sharing at least one bond) carbocyclic system, where the carbocyclic system has 3 to 15 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopent - 1 - enyl, cyclopent - 2 - enyl, cyclopent - 3 - enyl, cyclohexyl, cyclohex - 1 - enyl, cyclohex - 2 - enyl, cyclohex - 3 - enyl, cycloheptyl, bicyclo[4,3,0]nonyl, norbornyl, etc. The term cycloalkyl includes unsubstituted cycloalkyl and substituted cycloalkyl. The term "C3 - C n cycloalkyl" wherein n is an integer from 4 to 15 represents a cycloalkyl having 3 to the indicated "n" carbon atoms in the ring structure. Unless otherwise specified, the "lower cycloalkyl" group used in the present invention refers to having at least 3 and up to and including 8 carbon atoms in its ring structure.

[0109] A "cycloalkyl residue" can be saturated or a group containing one or more double bonds in the ring system. In particular, they can be saturated or contain one double bond within the ring system. In unsaturated cycloalkyl residues, the double bond can be present at 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 can also be substituted with C 1-4 alkyl. Examples of substituted cycloalkyl residues are 4 - methylcyclohexyl and 2,3 - dimethylcyclopentyl. Examples of the parent structures of bicyclic systems are norbornane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.1]octane.

[0110] As used herein, the term "heterocycloalkyl" and equivalent expressions refer to groups containing saturated or partially unsaturated carbocyclic rings in a monocyclic, spiro (sharing one atom), or fused (sharing at least one bond) carbocyclic ring system, having from 3 to 15 carbon atoms, including 1 to 6 heteroatoms (such as N, O, S, P) or groups containing heteroatoms (such as NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl, or cycloalkyl), PO2, SO, SO2, etc.). Heterocycloalkyl can be linked to C or to a heteroatom (such as 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-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3,1,0]hexyl, 3-azabicyclo[4,1,0]heptyl, 3H-indolyl, quinolizinyl, and sugars, etc. The term heterocycloalkyl includes unsubstituted heterocycloalkyl and substituted heterocycloalkyl. The term "C3-C n heterocycloalkyl", where n is an integer from 4 to 15, refers to a heterocycloalkyl having from 3 to the indicated "n" atoms in the ring structure, including at least one hetero group or atom as defined above. Unless otherwise specified, "lower heterocycloalkyl" as used herein refers to having at least 3 and equal to or less than 8 carbon atoms in its ring structure.

[0111] As used herein, the terms "aryl" and "aryl ring" refer to aromatic groups having "(4n + 2)" (π) electrons in a conjugated monocyclic or polycyclic system (fused or unfused) and having from 6 to 14 ring atoms, where n is an integer from 1 to 3. The polycyclic system includes at least one aromatic ring. Aryl can be directly linked or linked through a C1-C3 alkyl group (also known as arylalkyl or aralkyl). Examples of aryl include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulyl, acenaphthylenyl, fluorenyl, phenanthryl, anthracenyl, etc. The term aryl includes unsubstituted aryl and substituted aryl. The term "C6-C n aryl" (where n is an integer from 6 to 15) refers to an aryl having from 6 to the indicated "n" carbon atoms in the ring structure, including at least one heterocyclic group or atom as defined above.

[0112] As used herein, the terms "heteroaryl" and "heteroaryl ring" refer to aromatic groups having "(4n + 2)" (π) electrons in a conjugated monocyclic or polycyclic system (fused or unfused), where n is an integer from 1 to 3, and include from 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 heteroaryl ring. The heteroaryl may be directly attached or attached via a C1-C3 alkyl (also referred to as heteroarylalkyl or heteroarylalkylene). The heteroaryl may be attached to carbon or to a heteroatom (e.g., via a nitrogen atom). Examples of heteroaryl include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl; isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolidinyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, chromenyl, isochromenyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, pteridinyl, furyl, benzofuranyl, benzothiazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinolinyl, quinolinone, isoquinolinone, quinoxalinyl, naphthyridinyl, furanopyridyl, carbazolyl, phenanthridinyl, acridinyl, perylenyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, dibenzofuranyl, etc. The term heteroaryl includes unsubstituted heteroaryl and substituted heteroaryl. The term "C5-C n heteroaryl", where n is an integer from 6 to 15, denotes 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.

[0113] As used herein, the terms "heterocycle" or "heterocyclic" include heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, 4αH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, 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, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinone, 4-piperidinone, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridyl, pyridyl, pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, 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, thiophenyl, thienothiazolyl, thienoxazolyl, thienobenzimidazolyl, 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.

[0114] As used herein, the term "amine" or "amino" refers to an unsubstituted or substituted moiety of the formula -NR a R b wherein R a and R b are each independently hydrogen, alkyl, aryl, or heterocyclic group, or R a and R bTogether with the nitrogen atoms to which they are attached, they form a heterocycle. The term amino refers to at least one carbon or heteroatom in a compound or moiety covalently bonded to a nitrogen atom. Thus, as used herein, the terms "alkylamino" and "dialkylamino" refer to amino groups having one and at least two C1-C6 alkyl groups attached to the nitrogen atom, respectively. The terms "arylamino" and "diarylamino" include groups in which at least one or two aryl groups are attached to the nitrogen atom. The term "amide" or "aminocarbonyl" refers to a structure in which the carbon of the carbonyl or thiocarbonyl of a compound or moiety is linked to a nitrogen atom. The term "acylamino" refers to a structure in which an amino group is directly linked to an acyl group.

[0115] The term "alkylthio" refers to an alkyl group having a thiol group attached thereto. Suitable alkylthio 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 carboxy group attached thereto.

[0116] As used herein, the term "alkoxy" or "lower alkoxy" refers to a structure in which an alkyl group is linked 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.

[0117] As used herein, the term "carbonyl" or "carboxy" refers to a carbon in a compound and moiety that is linked to an oxygen atom by a double bond. Examples of moieties containing a carbonyl group include aldehydes, ketones, carboxylic acids, amides, esters, acid anhydrides, etc.

[0118] As used herein, the term "acyl" is a carbonyl structure in which the carbon atom of the carbonyl is linked 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 heterocycloalkyl and C5-C6 heteroaryl), an aryl group (C6 aryl, such as benzoyl). The acyl group can be an unsubstituted or substituted acyl group (e.g., salicyl).

[0119] The term "solvate" refers to the physical association of a compound with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, solvates can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice. "Solvate" includes solvates in the solution phase and isolable solvates. Examples of "solvate" include, but are not limited to, hydrates, ethanolates, methanolates, semi-ethanolates, etc. The term "hydrate" refers to the physical association of a compound with water molecules.

[0120] "Pharmaceutically acceptable salts" of a compound refer to salts of pharmaceutically acceptable compounds. Salts of the desired compounds (basic, acidic or charged functional groups) can retain or improve the biological activity and properties of the parent compound as defined in the present invention and are not biologically undesirable. Pharmaceutically acceptable salts can be those mentioned by Berge et al. in "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977). These include but are not limited to:

[0121] (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, sulfamic acid, nitric acid, phosphoric acid, carbonic acid, 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, benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, laurylsulfonic acid, laurylsulfuric 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.

[0122] (2) When an acidic proton is present in the parent compound or it is replaced by a metal ion, a base can be added to obtain a salt. The metal ions include alkali 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.

[0123] Pharmaceutically acceptable salts can be synthesized from parent compounds that contain basic or acidic moieties by conventional chemical methods. Generally, such salts are prepared by reacting the compound (free acid or base) with an equi - stoichiometric amount of a base or acid in water or an organic solvent or in a mixture of both. The salts can be prepared in - situ during the final isolation or purification of the pharmaceutical agent, or by separately reacting the purified compound of the invention in its free acid or base form with the desired corresponding base or acid and isolating the salt thus formed. The term "pharmaceutically acceptable salt" also includes zwitterionic compounds that contain a cationic group covalently bonded to an anionic group, which are referred to as "inner salts". All acid, salt, base, and other ionic and non - ionic forms of the compounds of the invention are included. 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 forms of the compound are also included.

[0124] As used herein, the term "effective amount" refers to the amount or dose of a therapeutic agent (e.g., a compound) that, when administered to a subject in a single dose or multiple doses, provides the desired therapeutic, prophylactic, diagnostic, or prognostic effect in the subject. The attending or diagnosing physician can readily determine the effective amount by known techniques and by observing results obtained in similar circumstances. In determining the effective amount or dose of a 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 extent or severity of the disease or disorder to be treated; the individual response of the subject; the specific compound being administered; the mode of administration; the bioavailability characteristics of the formulation being administered; the chosen dosage regimen; the use of concomitant medications; and other relevant considerations.

[0125] "Pharmaceutically acceptable" means that the drug, pharmaceutical, inert ingredient, etc., described by this term is suitable for contact with the cells or tissues of humans and animals without undue toxicity, incompatibility, instability, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. It generally refers to a compound or composition that is approved or approvable by a regulatory agency of the federal or state government or listed in the United States Pharmacopeia or other recognized pharmacopeias for use in animals, and more particularly in humans.

[0126] "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, vehicle, or carrier that is administered together with a compound. The terms "pharmaceutically acceptable vehicle" and "pharmaceutically acceptable carrier" are used interchangeably herein.

[0127] "Pharmaceutical composition" means a composition comprising a compound as described herein, and at least one component depending on the mode of administration and the requirements of the dosage form, said at least one component comprising a pharmaceutically acceptable carrier, diluent, adjuvant, excipient or vehicle, such as preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersing agents, etc. "Prevent" or "preventing" is used to mean at least reducing the likelihood of acquiring a disease or disorder (or susceptibility thereto) (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 shown symptoms of the disease).

[0128] In some embodiments, "treating" or "treatment" of any disease or disorder means alleviating at least one disease or disorder. In certain embodiments, "treating" or "treatment" means alleviating at least one physical parameter, which may or may not be distinguishable to the patient. In certain embodiments, "treating" or "treatment" means inhibiting a disease or disorder physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of a physical parameter) or both. In certain embodiments, "treating" or "treatment" means improving the quality of life or side effects of a disease in a subject in need thereof. "Therapeutically effective amount" means an amount of a compound administered to a subject for treating or preventing a disease that is sufficient to achieve a therapeutic or preventive effect against the disease. A "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, a "therapeutically effective amount" means an amount of a compound or composition sufficient to prevent, treat, inhibit, reduce, alleviate or eliminate one or more etiologies, symptoms or complications of a disease, such as cancer.

[0129] The term "subject" means an animal including mammals and humans, particularly a human.

[0130] The term "prodrug" or its equivalent refers to a reagent that is converted directly or indirectly into an active form in vitro or in vivo (see, e.g., R.B. 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, 1470 p. Springer). Prodrugs can be used to alter the biodistribution of a particular drug (e.g., to keep a medicament from generally entering protease reaction sites) or the pharmacokinetics. A variety of groups have been used to modify compounds to form prodrugs, such as esters, ethers, phosphate esters / salts, etc. When a prodrug is administered to a subject, the group is cleaved off enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, or otherwise releases the active compound. As used herein, "prodrug" includes pharmaceutically acceptable salts or esters, or pharmaceutically acceptable solvates or chelates, as well as any crystalline forms of the foregoing. Prodrugs are generally (although not necessarily) pharmaceutically inactive until they are converted to the active form.

[0131] The term "ester" refers to a compound that can be represented by the formula RCOOR (carboxylic acid ester) or the formula RSO3R' (sulfonic acid ester), and can generally be formed by the reaction (with elimination of one molecule of water) between a carboxylic acid or a sulfonic acid and an alcohol, respectively.

[0132] 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 "non-natural" amino acids. Additionally, the term amino acid includes O-alkylated amino acids or N-alkylated amino acids, as well as amino acids having side chains containing nitrogen, sulfur, or oxygen (e.g., Lys, Cys, or Ser), where the nitrogen, sulfur, or oxygen atom may or may not be acylated or alkylated. Amino acids can be pure L-isomers or D-isomers, or mixtures of L-isomers and D-isomers, including (but not limited to) racemic mixtures.

[0133] The term "natural amino acid" and equivalent expressions refer to L-amino acids that are typically 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).

[0134] The term "non-natural amino acid" refers to any derivative of a natural amino acid, including D-amino acids, as well as α- and β-amino acid derivatives. The terms "non-natural amino acid" and "not a natural amino acid" are used interchangeably herein. It should be noted that certain amino acids (such as hydroxyproline) that can be classified as non-natural amino acids in the present invention may also be present in certain biological tissues or specific proteins in nature. Amino acids with many different protecting groups and 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 can be used according to the present invention (common abbreviations are in parentheses): 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 acid, 5-aminovaleric 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 (statine, 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-Cl-Tyr), p-benzoyl-phenylalanine (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), allo-hydroxylysine (aHyl), 5-hydroxytryptophan (5-OH-Trp), 3- or 4-hydroxyproline (3- or 4-Hyp), p-iodophenylalanine-isotyrosine (3-I-Tyr), indoline-2-carboxylic acid (Idc), iduronic acid (Ide), isoleucine (α-Ile), isonipecotic acid (Inp), N-methylisoleucine (MeLys), 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).

[0135] 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 various possible salt forms (e.g., TFA salts, tetrazole salts, sodium salts, potassium salts, etc.), and suitable salts can 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, as well as organic acids and bases). For example, for a compound containing a basic nitrogen, its salt can be prepared from a pharmaceutically acceptable non-toxic acid (including inorganic acids and organic acids). Pharmaceutically acceptable acids applicable to the present invention include, but are not limited to, acetic acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic 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 applicable to the present invention include, but are not limited to, metal salts made of aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made of lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, glucosamine (N-methylglucosamine), and procaine.

[0136] Composition

[0137] In one embodiment, a pharmaceutical composition is provided, which comprises a compound of the present invention, such as the compounds shown in Formula I to Formula III and the compounds in Table 1 or their pharmaceutically acceptable salts, esters, chelates, hydrates or solvates, and a pharmaceutically acceptable carrier. In yet another embodiment, a pharmaceutical composition is provided that comprises the compounds shown in Formula I to Formula III and the compounds in Table 1 or their pharmaceutically acceptable salts or esters, and a pharmaceutically acceptable carrier.

[0138] Example

[0139] The present invention will be more readily understood by reference to the following examples, which are used to illustrate the present invention and should not be construed as limiting the scope of the present invention in any way.

[0140] 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 this 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.

[0141] Example 1: N-(4-Methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridyl)-2-thiazolyl)aminocarbonyl-L-proline- 18O-Amidate (Compound 1 or Alpelisib- 18 O1) Preparation

[0142] 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 in a sealed tube at 60 °C for 24 hours. 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), and finally N-Boc-L-proline- 18 O-Amidate (48 mg; oxygen-18 abundance, 97.3%) was obtained.

[0143] Dissolve N-Boc-L-proline- 18 O-Amidate (48 mg, 0.22 mmol) in dichloromethane (0.5 mL), then add hydrochloric acid / dioxane solution (4 M, 0.5 mL), stir the reaction at 25 °C for 1 hour, and then spin-dry the reaction solution under an oil pump to obtain L-proline- 18 O-Amidate hydrochloride (35 mg).

[0144] Add N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridyl)-2-thiazolyl)aminocarbonyl-[1H]-imidazole ester (79 mg, 0.2 mmol) to DMF (1 mL), then add L-proline- 18 O-Amidate hydrochloride (33 mg, 0.22 mmol), triethylamine (80 mg, 0.8 mmol), stir the reaction solution at 30 °C for 16 hours. Spin-dry the reaction solution under an oil pump, and purify the residue 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%).

[0145] 1 1H NMR (500 MHz, DMSO-d6): δ ppm 10.96 (s, 1H), 8.60 (d, J = 5.0 Hz, 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).

[0146] 13 13C NMR (125 MHz, DMSO-d6): δ ppm 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.

[0147] m / z (ESI + ): 443.7; m / z (ESI - ): 441.5.

[0148] Example 2: Preparation of N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridyl)-2-thiazolyl)aminocarbonyl-L-proline- 17 O-amide (Compound 2 or Alpelisib- 17 O1)

[0149] Compound 2 was obtained in the same manner as in Example 1, except that H2 17 O was replaced with H2 17 O. 18

[0150] Example 3: Preparation of N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridyl)-2-thiazolyl)aminocarbonyl-L-proline- 13 C1-amide (Compound 4 or Alpelisib- 13 C1)

[0151] Compound 4 was obtained in a manner similar to Example 1, except that proline- 13 C1-amide hydrochloride was used as the starting material.

[0152] Example 4: Preparation of N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridyl)-2-thiazolyl)aminocarbonyl-L-prolinamide- 15 N (Compound 5 or Alpelisib- 15 N)

[0153] ​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, and (Boc)₂O (9.5 g, 43.5 mmol, 1 eq.) was slowly added. 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 - butoxycarbonyl - L - proline (6 g, 64.2%).

[0154] N - tert - butoxycarbonyl - 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.), 15 ammonium N - sulfate (1.19 g, 8.87 mmol, 1.3 eq.), and (Boc)₂O (1.98 g, 8.87 mmol, 1.3 eq.) were added. The reaction mixture was stirred at 25 °C overnight. After concentrating the reaction solution, the residue was purified by column chromatography (eluent: MeOH / DCM = 100 / 0 - 50 / 1) to obtain N - tert - butoxycarbonyl - L - prolyl - 15 N - amide (0.29 g; 15 N abundance, 99.4%).

[0155] The obtained N - tert - butoxycarbonyl - L - prolyl - 15 N - amide (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. The mixture was stirred at room temperature for 0.5 h. White solid precipitated out, which was filtered and dried in vacuo to obtain L - prolyl - 15 N - amide hydrochloride (0.16 g; 15 N abundance, 99.4%).

[0156] 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), and CDI (0.4 g, 2.46 mmol, 1.5 eq.) was added. The mixture was stirred at 40 °C for 4 h. A large amount of white solid precipitated out, which was filtered and dried in vacuo to obtain N - (4 - methyl - 5 - (2 - (2,2,2 - trifluoro - 1,1 - dimethylethyl)-4 - pyridin)-2 - thiazol)aminocarbonyl - [1H]-imidazole ester (0.5 g, yield 76.9%).

[0157] L - prolyl - 15N-Amidine hydrochloride (0.16 g, 1.06 mmol, 1.05 eq.), N-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl)-2-thiazolyl)carbamoyl-[1H]-imidazolide (400 mg, 1.01 mmol, 1.0 eq.) were dissolved in pyridine (5 mL), then DMAP (3 mg, 0.016 mmol, 0.023 eq.) was added, and the mixture was stirred overnight at 25 °C. After concentrating the reaction solution, 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%).

[0158] 1 H NMR (500 MHz, DMSO-d6): δ ppm 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).

[0159] 13 C NMR (125 MHz, DMSO-d6): δ ppm 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.

[0160] m / z (ESI - ) 440.6; m / z (ESI + ) 442.8.

[0161] Example 5: Comparative Pharmacokinetic Study of Compound 1 and Alpelisib in SD Rats

[0162] A group of (6) SD rats were used for the experiment. Compound 1 (Alpelisib- 18O1) was mixed with Alpelisib at a molar ratio of 1:1 to obtain a dosing solution, wherein the concentrations of both in the dosing solution were 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 0.167, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after administration). Using a general method, the blood samples were converted into plasma samples, and the concentrations of Compound 1 and Alpelisib in the samples were analyzed by LC-MS / MS. The obtained data are shown in Table 2 and Figure 1 。 Figure 1 in which, the markers -○- and --Δ-- represent the drug concentration-time curves of Compound 1 and Alpelisib in plasma after oral administration at equal doses, respectively.

[0163] Table 2. PK parameters of Compound 1 and Alpelisib in Sprague-Dawley rats.

[0164] 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

[0165] Example 6: Comparative pharmacokinetic study of Compound 1 and Alpelisib in ICR mice

[0166] Forty-eight ICR mice were randomly divided into 6 groups (8 mice in each group). Compound 1 (Alpelisib - 18 O1) was mixed with Alpelisib at a molar ratio of 1:1 to obtain a dosing solution, wherein the concentrations of both in the dosing solution were 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 taken from one group of animals at each time point. Using a general method, the blood samples were converted into plasma samples, and the concentrations of Compound 1 and Alpelisib in the samples were analyzed by LC-MS / MS. The obtained data are shown in Table 3 and Figure 2 。 Figure 2 in which, the markers -○- and --Δ-- represent the drug concentration-time curves of Compound 1 and Alpelisib in plasma after oral administration at equal doses, respectively.

[0167] Table 3. PK parameters of Compound 1 and Alpelisib in ICR mice.

[0168] 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

[0169] Example 7: Generation of metabolite M4 and M4 - 18 O1 in liver S9 medium.

[0170] Dilute a stock solution (50 μL) containing equimolar amounts of Compound 1 and Alpelisib to a working solution with a compound concentration of 4.5 μM using 0.1 M Tris - acetate buffer pre - warmed in a 37 °C water bath. Add the above - mentioned working solution (50 μL) and liver S9 solution (50 μL) to each incubation well and mix evenly. After pre - incubating for 5 minutes, add β - NADPH solution (100 μL) to each incubation well. Then, place the incubation plate at 37 °C for incubation, and collect and analyze the incubation samples at time points of 0, 15, 30, 60, and 240 minutes.

[0171] Sample analysis method: Collect three samples at each time point. After adding the termination solution (800 μL) to the samples at each preset time point, mix evenly (Vertex), centrifuge at 12,000 rpm for 5 minutes, transfer the supernatant to an analysis sample tube, and analyze the concentrations of M4 and M4 - 18 O1 in the samples by LC - MS / MS.

[0172] Under the same experimental conditions, the following two experiments were carried out in parallel: (1) A series of dilutions were made on a mixture solution of equimolar concentrations of M4 and M4 - 18 O1, and M4 and M4 - 18 O1 in each solution were analyzed by LC - MS / MS to prove that M4 and M4 - 18 O1 had the same response value and were linear under these conditions; (2) When only Compound 1 was incubated, no M4 was produced, and only M4 - 18 O1 was generated.

[0173] The liver S9 used in the experiment was respectively (a) monkey liver S9, (b) pooled human liver S9, (c) mini - pig liver S9, and (d) male Wistar rat liver S9. Figure 3 ( Figures 3a to 3d ) is a summary of the experimental results.

[0174] Although the present invention has been described in detail with reference to the embodiments of the present invention, these embodiments are provided for illustration rather than limitation of the present invention. Other embodiments that can be obtained according to the principles of the present invention all fall within the scope defined by the claims of the present invention.

[0175] The content of all documents and literature listed herein is incorporated herein by reference in its entirety.

Claims

1. A compound of formula II or a pharmaceutically acceptable salt, ester, hydrate, chelate or solvate thereof: Wherein, n is equal to 1, and the organic moiety R is i.e., N-((4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridyl)-2-thiazolyl)aminocarbonyl)-pyrrolidin-2-yl, and wherein, R 1 and R 2 are independently hydrogen or a protecting group; Preferably, the isotope-enriched amide functional group is composed of 18 O, 17 O, 13 C, and 15 N, with at least one of them being isotope-enriched; Further preferably, the compound is selected from the group consisting of:

2. The compound according to claim 1, wherein, The level of heavy isotope enrichment in the compound is about 5% or more, about 10% or more, about 20% or more, about 50% or more, about 75% or more, about 90% or more, about 95% or more, or 100%.

3. A pharmaceutical composition comprising the compound according to any one of claims 1 to 2 and a pharmaceutically acceptable carrier.

4. A method for modulating the pharmacokinetic properties of a drug or prodrug in a subject, the method comprising administering the compound according to any one of claims 1 to 2 or the pharmaceutical composition according to claim 3 to the subject, thereby modulating the pharmacokinetic properties of the drug or prodrug, and thereby enhancing the therapeutic or prophylactic effect of the drug or prodrug in treating a disease condition or symptom of the subject.

5. A method for reducing the metabolism of a compound, 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 or increasing the therapeutic or prophylactic effect of a compound in a subject, the compound comprising one or more amide functional groups, the method comprising: (a) Enrich one or more amide functional groups in the compound with one or more stable heavy isotopes selected from 18 O, 17 O, 13 C, and 15 N to form an isotope-enriched compound; (b) administering the isotope-enriched compound to a subject, wherein, relative to administering the non-isotope-enriched compound, metabolism is reduced, treatment toxicity is reduced, side effects are reduced, tolerance is increased, biodistribution is improved, and / or the therapeutic or prophylactic effect is increased; Preferably, the compound is a drug or a prodrug.

6. The method according to claim 4 or 5, wherein, The compound is a PI3K inhibitor for treating a disease condition or symptom associated with the activity of phosphoinositide 3-kinase.

7. The method according to claim 6, wherein, The compound is the compound of claim 1; Preferably, the compound is selected from the compounds shown below or pharmaceutically acceptable salts, esters, hydrates, chelates or solvates thereof:

8. The method according to claim 6 or 7, wherein, The disease condition or symptom is a solid tumor or cancer; preferably, 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.

9. The method according to any one of claims 4 to 7, wherein, The subject is a mammal; Preferably, the mammal is a human.

10. A kit, the kit comprising the compound according to any one of claims 1 to 2 or the pharmaceutical composition according to claim 3, and instructions for use thereof.

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