Oxalate derivatives and prodrugs for the prevention of CaOx stone formation

Abstract

This patent document discloses a novel oxamic acid that can act as a potent inhibitor of calcium oxalate (CaOx) crystallization, and a novel macrocyclic prodrug that will provide improved lipophilicity, small size, lower polar surface area, and significantly reduced solvent-accessible surface area, all of which are known to confer better oral bioavailability. This document also discloses methods for treating diseases associated with abnormal levels of calcium oxalate and its crystallization.

Description

[0001] Cross-reference with related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 610,507, filed December 15, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention relates to novel compounds that combine molecular mimicry and multi-site binding, and possess the ability to inhibit calcium oxalate (CaOx) crystallization in patients with hyperoxaluria. Prodrugs designed to improve their oral bioavailability are also disclosed, as well as methods for preventing kidney stone formation in patients with all types of hyperoxaluria. Background Technology

[0004] Urolithiasis is a common disease worldwide. It occurs when urine is supersaturated with high levels of calcium, oxalate, phosphate, uric acid, or cystine, leading to the formation of calculi or stones in the urinary system, including the kidneys, ureters, and bladder. The incidence of urolithiasis is influenced by a variety of factors, including sex, race, metabolic abnormalities, and geographic location. In developed countries, the lifetime risk of urolithiasis is higher, approximately 10% to 15%; in some geographic locations (such as the Middle East), this risk can be as high as 20% to 25%. In the United States, the incidence of urolithiasis has been steadily increasing over the past 30 years. The latest assessment of the prevalence of urolithiasis in the United States is 8.8%. The prevalence is higher in men than in women (10.6% vs. 7.1%). White people are at higher risk, approximately three times the risk of Black people. The recurrence rate is high, with an estimated 5-year recurrence rate of 40% and a 20-year recurrence rate of 75%. In the United States, the economic cost associated with kidney stones, due to hospitalization, surgery, and lost work time, is estimated at approximately $5 billion annually. Urolithiasis is associated with an increased incidence of other common diseases and conditions, including chronic kidney disease, hypertension, osteoporosis, and obesity.

[0005] Calcium oxalate (CaOx) represents the main chemical type in kidney stones, accounting for approximately 70%-80% of all stones. Since oxalate cannot be metabolized in mammals, it is freely filtered by the glomeruli and secreted by the renal tubules, primarily eliminated through urine as a metabolic end product. Normally, urine containing millimoles of calcium ions becomes supersaturated with calcium oxalate in hyperoxaluria, leading to crystal formation within the renal tubular lumen. These crystals further aggregate in the urinary tract to form stones, while some crystals are incorporated into renal tubular cells and can further migrate into the renal interstitium. This is a clinical characteristic of primary hyperoxaluria and can lead to renal failure. Once renal function declines to a certain extent, the ability of the kidneys to excrete oxalate is severely impaired, and plasma oxalate concentrations rise rapidly, exceeding the solubility threshold of calcium oxalate. This results in systemic deposition of calcium oxalate in tissues outside the kidneys. This oxalosis can occur in the retina, heart, blood vessel walls, and brain, and can lead to death if left untreated.

[0006] CaOx has been identified as having three distinct crystalline phases: the most common is calcium oxalate monohydrate (COM or Whewellite); calcium oxalate dihydrate (COD or Weddelite), the frequency of which depends on geographical location; and calcium oxalate trihydrate (COT, caoxite), a rare and unstable crystalline phase. Hyperoxaluria, caused by increased urinary oxalate excretion, can be classified as primary or secondary hyperoxaluria. Primary hyperoxaluria has two types: type I and type II. Both type I and type II primary hyperoxaluria are rare autosomal recessive genetic disorders. In type I, a deficiency of a specific enzyme involved in glyoxylate metabolism leads to excessive endogenous oxalate production primarily in the liver, while in type II, there is also a small degree of overproduction in other cells. Type I primary hyperoxaluria is caused by a deficiency of peroxisome alanine / glyoxylate aminotransferase (AGT) in the liver, while type II primary hyperoxaluria is caused by a deficiency of the cytoplasmic / mitochondrial enzyme glyoxylate / hydroxypyruvate reductase (GR / HPR). A small number of patients with a phenotype similar to types I and II but with normal AGT and GR / HPR enzyme activity are referred to as non-type I, non-type II primary hyperoxaluria. More common forms of secondary hyperoxaluria are caused by excessive dietary oxalate or oxalate precursors, or by increased intestinal absorption of dietary oxalate due to underlying conditions such as cystic fibrosis, inflammatory bowel disease, short bowel syndrome, and the post-barbiturate surgery state. Primary hyperoxaluria is the most severe form and, if left untreated, will eventually lead to end-stage renal failure and death.

[0007] Management and prevention of calcium oxalate stones are limited. Strategies include general preventative measures such as increasing fluid intake to increase urine output, increasing dietary calcium intake, limiting the intake of oxalate-rich foods, and using thiazide diuretics and alkalizing agents that may inhibit calcium oxalate growth and aggregation. Inhibition of calcium oxalate crystallization has been studied for many years, primarily using naturally occurring metal ions, small-molecule organic acids, and anionic macromolecules such as magnesium, pyruvate, citrate, α-ketoglutarate, phytate, and polymers of aspartic acid, glutamic acid, and acrylic acid. Different inhibitory mechanisms have been proposed. For example, magnesium is known to compete with calcium, while citrate, pyruvate, α-ketoglutarate, and phytate are known inhibitors of calcium oxalate nucleation and crystal growth. Citrate is perhaps the most studied inhibitor and is considered one of the most effective inhibitors of calcium oxalate crystallization. Clinicians have consistently advised patients to consume more citrus fruits and juices and prescribe potassium citrate to prevent CaOx stone formation.

[0008] There is an ongoing need in this field to develop effective solutions for reducing calcium oxalate crystallization and treating related diseases or conditions. Summary of the Invention

[0009] The compounds in this patent document address this need. Introducing one or more oxalamidic acids into a single molecule can provide interaction sites / attachment sites with the crystal surface, thereby providing a strong affinity for the crystal surface and preventing the binding of additional calcium oxalate to the crystal surface, thus inhibiting crystal growth.

[0010] One aspect of this patent document provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula I.

[0011] Formula I

[0012] in: R 1 For H or C 1-8 alkyl; R 2 C 1-8 Alkylene-NR a R b Peptides derived from one or more natural or non-natural amino acids, or L-[NR] 2' C(O)COOR 1' ] m ; L is a linker derived from one or more parts selected from the group consisting of: amino acids, C 1-8 Alkylene, SS, NH-C 1-8 Alkylene, NH-C 1-8Alkylene NH, optionally substituted phenyl, optionally substituted 5-10-membered heteroaryl, 5-10-membered carbocyclic, 5-10-membered heterocyclic, wherein L is optionally partially substituted by one or more of the following groups: COOH, COOC 1-6 Alkyl, CN, halogen, halogenated -C 1-6 Alkyl, C 1-4 Alkylene-OH and CN; m is 1, 2 or 3 R 1’ H or C independently in each case. 1-8 alkyl; R 2’ H or C independently in each case. 1-4 alkyl; R 3 For H or C 1-8 alkyl, Or R 2 and R 3 The links form 5-8 quintic heterocycles, which are optionally C 1-8 Alkyl, COOH, COOC 1-8 Alkyl, C(O)NR a R b or C(O)COOR 1’ Replace, and R a and R b Independently H or C 1-8 alkyl.

[0013] On the other hand, it provides compounds of formula II or their pharmaceutically acceptable salts.

[0014] Formula II

[0015] in: T is a bifunctional or trifunctional linker; When T is a bifunctional linker, A is empty; When T is a trifunctional linker, A is ; R 1 For H or C 1-8 alkyl; R 2 For H or C 1-8 alkyl; L 1 and L 2 Each is a linker base; It is an optional oxo group. L 3 It is a linker.

[0016] Another aspect of this patent document discloses a compound of formula III or a pharmaceutically acceptable salt thereof.

[0017] Formula III

[0018] in: L 1 and L 2 Each is a linker base and can be arbitrarily connected to each other; L 3 and L 4 Each is a linker; and It is an optional oxo group.

[0019] Another aspect of this patent document discloses a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt, isomer, or prodrug thereof.

[0020] Another aspect of this disclosure provides a method for treating a subject's disease, comprising administering to a subject in need a therapeutically effective amount of a compound of formula I, a pharmaceutically acceptable salt or isomer thereof, or a pharmaceutical composition thereof.

[0021] On the other hand, a method for inhibiting calcium oxalate formation is provided, comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject in need. Attached Figure Description

[0022] Figure 1 The assay used to measure the inhibition of calcium oxalate crystallization is shown.

[0023] Figure 2 The synthesis of compound I is shown.

[0024] Figure 3 The synthesis of compound III is shown. Invention Details

[0026] Various embodiments of this patent document disclose compounds for inhibiting calcium oxalate crystallization, the most common form of kidney stones in all types of hyperoxaluria. Pharmaceutical compositions of the compounds disclosed herein are also provided.

[0027] While the following text may cite or illustrate specific embodiments of compounds or methods for treating diseases or conditions, it is not intended to limit the scope of the compounds or methods to such specific citations or examples. Various modifications may be made by those skilled in the art, such as substitution of the compound and the amount or administration of the compound for treating or preventing diseases or conditions, based on practical and economic considerations.

[0028] Unless otherwise stated, the article “a or an” as used herein means “one or more” or “at least one”. That is, a reference to any element or component of an embodiment by the indefinite article “a or an” does not preclude the possibility that there may be more than one element or component.

[0029] The term "pharmaceutical composition" refers to a mixture of the disclosed compounds with other chemical components, such as diluents or additional carriers. Pharmaceutical compositions facilitate the administration of the compounds to a living organism. Various techniques for administering pharmaceutical compositions exist in the art, including but not limited to oral, injectable, aerosol, parenteral, and topical administration. In some embodiments, pharmaceutically acceptable salts of the disclosed compounds are provided.

[0030] The term "subject" covers any animal, but preferably a mammal, such as a human, a non-human primate, a dog, a cat, a horse, a cow, or a rodent. More preferably, the subject is a human.

[0031] The term "carrier" refers to a chemical compound that facilitates the entry of a compound into cells or tissues.

[0032] The terms "physiologically acceptable" or "pharmaceutically acceptable" refer to a carrier or diluent that does not negate the biological activity and properties of a compound.

[0033] The term "therapeuticly effective amount" refers to the amount of a compound that effectively prevents, reduces, or improves disease symptoms or prolongs the survival of a treated subject. The determination of a therapeutically effective amount is entirely within the competence of those skilled in the art, particularly based on the detailed disclosure provided herein.

[0034] The term "alkyl" refers to a monovalent group in a saturated alkane, particularly having up to about 18 carbon atoms, more particularly as a lower alkyl group having 1 to 8 carbon atoms, and even more particularly having 1 to 6 carbon atoms. The hydrocarbon chain can be straight or branched. The term "C" refers to a monovalent group in a saturated alkane. 1-10 Alkyl" or "C1-C" 10 "Alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Similarly, the term "C"... 1-4 "Alkyl" refers to an alkyl group having 1, 2, 3, or 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-octyl, tert-octyl, etc.

[0035] The term "alkylene" refers to a divalent hydrocarbon, which can be straight-chain or branched. Unlike alkyl groups, which have only one bond site with other groups or atoms, alkylene groups have two bond sites. Non-limiting examples include groups such as CH2, (CH2)2, and CH2CH(CH3). 1-8 Alkyl groups have 1, 2, 3, 4, 5, 6, 7, or 8 carbons. (C) 1-4 Alkyl groups have 1, 2, 3 or 4 carbons.

[0036] The term "alkenyl" refers to a divalent hydrocarbon containing a double bond, which can be straight-chain or branched. Non-limiting examples include groups such as CH2, (CH2)2, CHCH, CH2CHCHCH2, and CH2CH2CHCHCH2CH2. 2-8 The alkenyl group has 2, 3, 4, 5, 6, 7, or 8 carbons. C 2-4 Alkyl groups have 2, 3, or 4 carbons.

[0037] The term "carbocyclic" or "cycloalkyl" refers to a 3- to 10-membered cyclic hydrocarbon group having only carbon atoms as ring atoms and possessing a single ring or multiple fused rings, including fused and bridged ring systems, which may optionally be substituted with 1 to 3 alkyl groups. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc.; and polycyclic structures such as adamantyl.

[0038] The term "heterocyclic" refers to a non-aromatic cyclic group with 3 to 10 substituted or unsubstituted members, wherein one or more carbocyclic atoms are replaced by heteroatoms or heteroatom-containing groups (e.g., NH, NCl-C4 alkyl, O, and S). Non-limiting examples include pyrrolidine, piperidine, N-methylpiperazine, and morpholine. Optional substituents include C... 1-6 Alkyl, C 1-4 Alkoxy, halogen, haloalkyl, sulfonamide, and amide groups.

[0039] The term "aryl" is intended to denote any stable monocyclic or bicyclic carbon ring, each ring having up to seven members, at least one of which is aromatic, and all ring atoms of the aromatic ring are carbon atoms. Typical aryl groups include, but are not limited to, groups derived from the following compounds: aceanthrylene, acephenanthrylene, anthracene, azulene, benzene, fluoranthene, fluorene, hexylene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, oleophane, penta-2,4-diene, pentane, cyclopentadiene, pentaphene, perylene, phenanthracene, fentanyl, etc. In particular, aryl groups contain 6 to 10 or 6 to 14 carbon atoms.

[0040] The term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9 or 10 ring atoms, and sharing 6, 10 or 14 π electrons in a ring array, wherein at least one ring atom contributing to the sharing of π electrons in the ring array is a heteroatom. Typical heteroaryl groups include, but are not limited to, groups derived from the following compounds: acridine, carbazole, cyclophosphine, furan, imidazole, indazole, indole, dihydroindole, indazine, isobenzofuran, isochromene, isoindole, isodihydroindole, isoquinoline, isothiazole, isoxazole, naphthidine, oxadiazole, oxazole, phenanthridine, phenanthroline, phenazine, phthalazine, benzodicarboximide, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrolizine, pyrrolizine, quinazoline, quinoline, quinazine, quinoxaline, tetrazolium, thiadiazole, thiazolium, thiophene, triazole, xanthanil, etc. Preferably, the heteroaryl group is a 5-15 membered heteroaryl group, and particularly preferably a 5-10 membered heteroaryl group.

[0041] The term "oxo" refers to the =O group as a substituent. Non-limiting examples of compounds having an oxo group include pyrrolidone (oxolated on pyrrolidine) and cyclopentanone.

[0042] In some implementations, “treating” or “treatment” for any disease or condition means improving the disease or disorder (i.e., stopping or reducing the development of the disease or at least one of its clinical symptoms). In some implementations, “treating” or “treatment” means improving at least one bodily parameter, which may not be perceptible to the subject. In some implementations, “treating” or “treatment” means regulating a disease or disorder from a physical (e.g., stability of perceptible symptoms), a physiological (e.g., stability of bodily parameters), or both. In some implementations, “treating” or “treatment” means delaying the onset of a disease or disorder, or even preventing the disease or disorder. “Preventive treatment” should be interpreted as any treatment modality used to prevent disease progression or for preventative purposes for individuals at risk of developing the condition.

[0043] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is pharmaceutically acceptable as defined above and has the desired pharmacological activity. Non-limiting examples of such salts include acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or salts formed with organic acids, such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-en-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-en-1-carboxylic acid, acetic acid, aliphatic monocarboxylic and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, and camphor. Sulfonic acids, carbonic acids, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthenic acid, lactic acid, lauryl sulfate, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, and trimethylacetic acid. Pharmaceutically acceptable salts also include base addition salts that may form when the present acidic protons can react with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Non-limiting examples of acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, aminobutanetriol, and N-methylglucosamine. It should be recognized that the specific anion or cation forming part of any salt of the present invention is not critical, as long as the salt as a whole is pharmacologically acceptable. Other examples of pharmaceutically acceptable salts and their preparation and use methods are described in [the literature / document / etc.]. Handbook of Pharmaceutical Salts: Properties, and UseAvailable in (PH Stahl & CG Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0044] Most small molecule drugs bind to enzymes or receptors in tight, well-defined pockets. On the other hand, Design score The methods used to inhibit crystal growth are very different. Enzymes or receptors typically have only a limited number, and usually only one, well-defined, binding site. However, at the crystal growth front (whether a step or a surface), there are arrays of identically stacked growth molecules (e.g., oxalate molecules on COM). Each such stacked growth molecule on a crystal step or surface can be replaced by a mimic and can serve as a binding site for the mimic. Many such repeating units form an array of active / binding sites, allowing the design of crystallization inhibitors that leverage multi-site binding to enhance binding affinity. Multiple binding units linked together in an optimized inhibitor can utilize the additive enthalpy of interactions between multiple binding sites and the favorable entropy change of multi-site binding events (i.e., enhanced affinity due to multivalency).

[0045] One aspect of this patent document provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula I.

[0046] Formula I

[0047] in: R 1 For H or C 1-8 alkyl; R 2 C 1-8 Alkylene-NR a R b amides or peptides derived from one or more natural or non-natural amines or amino acids (the N-terminus of the peptide forms an amide with an oxalate), or L-[NR] 2' C(O)COOR 1' ] m ; L is a linking base, where L is linked to one, two, or three NHC(O)COOR groups depending on the value of m. 1' Partial connection, m is 1, 2 or 3 R 1’ H or C independently in each case. 1-8 alkyl; R 2’ H or C independently in each case. 1-8 alkyl; R 3 For H or C1-8 alkyl, Or R 2 and R 3 The links form 5-8 quintic heterocycles, which are optionally C 1-8 Alkyl or C(O)COOR 1’ Replace, and R a and R b Independently H or C 1-8 alkyl.

[0048] The linker L can be linear, branched, cyclic, or any combination thereof, and can contain or derive from structural components selected from, for example, the following: C 1-8 Alkylene, C 2-8 imidene group, NH-C 1-8 Alkylene, NH-C 1-8 Alkylene -NH, O, C(O), NHNH, C(O)NH-C 1-8 Alkylene-NHC(O), 5-8 membered heterocycles, -(CH2) a C(O)NR a (CH2) b -、-(CH2) a O(CH2CH2O) c -、-(CH2) a Heterocyclic groups -, -(CH2) a C(O)-、-(CH2) a NR a -、-CR a =N-NR a -、-CR a =NO-、-CR a =N-NR b -CO-, -N=N-CO-, -SS-, amino acids, where a, b, and c are each integers selected from 0 to 25, including all subunits; and R in each case a and R b Independently representing hydrogen or a C1-C10 alkyl group. The two adjacent components of L can be bonded to each other by amide, ester, ether, C / C bond, or any chemically feasible linkage. It should be noted that L is related to [NR]. 2’ C(O)COOR 1’ ] m The lines between [NR] do not necessarily represent single bonds, because when L is branched, it can be bonded to two or three [NR]. 2’ C(O)COOR 1’ Partial connection. When m is 2 or 3, L can have multiple arms, each arm connected to a [NR] 2’ C(O)COOR 1’Partial connection. This line only indicates L as a whole with one or more [NR] connections. 2’ C(O)COOR 1’ Partial connection. L (e.g., C) 1-8 Alkylene, NH-C 1-8 Alkylene, NH-C 1-8 Alkylene (NH, 3-8 membered carbocyclic ring, 3-8 membered heterocyclic ring, phenyl, 5-10 membered heteroaryl) is optionally partially substituted by one or more of the following groups: COOH, COOC 1-6 Alkyl, CN, halogen, halogenated -C 1-6 Alkyl groups (e.g., CF2, CF3), C 1-4 Alkylene-OH and CN.

[0049] In some embodiments, L comprises a moiety derived from an amino acid, wherein the carboxylic acid moiety is reduced to a hydroxyl group. L may also be derived from two or more amino acids, wherein at least one carboxylic acid of one of the amino acids is reduced to OH. When the amino acid (e.g., aspartic acid or glutamic acid) has two carboxylic acids, R... 2 One of the carboxylic acid groups can be reduced to OH. Non-limiting examples of L-components derived from amino acids include lysinol and cystinol.

[0050] In some embodiments, L forms a heterocycle together with the nitrogen to which it is attached. For example, L may be a piperazine moiety, wherein the two nitrogen atoms are part of an amide (e.g., a terminal oxyamide).

[0051] In some implementations, the linker L is or contains a subset selected from NHNH, C 2-6 Alkylene, C 2-6 alkenyl group, C(O)NH-C 0-6 The components of alkylene-NHC(O) and C(O)-piperazinyl-C(O).

[0052] In some implementation schemes, R 2 For L-NR 2’ C(O)COOR 1’ In some implementations, L is C. 2-6 Alkylene and R 3 For H. In some implementations, R 3 C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl). In some embodiments, any R 2’ Independently H or C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl). In some embodiments, all R groups in Formula I... 2’ All are C 1-4Alkyl (e.g., methyl, ethyl, propyl). In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R 1 C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl). In some embodiments, any carboxylic acid ester group of Formula I may be an ester C group. 1-4 In the form of alkyl groups (e.g., methyl, ethyl, propyl). In some embodiments, all carboxylic acid ester groups in Formula I are in the form of ester C. 1-4 Alkyl form.

[0053] In some implementation schemes, R 2 and R 3 The linkage forms an optionally substituted heterocycle. In some embodiments, the heterocycle is morpholine or piperazine, wherein the ring is optionally substituted with H, C 1-8 Alkyl or C(O)COOR 1’ Replace. R 1’ H or C independently in each case. 1-8 alkyl.

[0054] In some implementation schemes, R 2 C 1-8 Alkylene-NR a R b In some implementations, R 2 C 2-6 Alkylene-NH2.

[0055] In some implementation schemes, R 2 It is a peptide derived from one or more amino acids. For example, R 2 It can be derived from amino acids, where the carboxylic acid moiety is reduced to a hydroxyl group. R 2 It can also be derived from two or more amino acids, in which at least one carboxylic acid of one amino acid is reduced to OH. When an amino acid (e.g., aspartic acid or glutamic acid) has two carboxylic acids, R 2 One of the carboxylic acid groups can be reduced to OH. The N-terminus of the peptide forms an amide group with the oxalate. When R 2 When the peptide is derived from one or more amino acids, the C-terminus of the peptide can be an amide (e.g., C(O)NR). a R b R a and R b Independently H or C 1-8 Alkyl groups or esters (e.g., C(O)C) 1-8The amino acid can be in the form of an alkyl group. In each case, the amino acid can be natural or non-natural. In some embodiments, the amino acid is selected from one or more of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, serine, arginine, cysteine, cystine, glutamine, glycine, proline, tyrosine, β-aminopropionic acid, and γ-aminobutyric acid. Two adjacent amino acids can be linked in any chemically feasible manner, including, for example, an amide or disulfide bond.

[0056] In some implementation schemes, R 2 L-NHC(O)COOR 1’ It also includes portions derived from one or more amino acids, the range of which is as described above. Non-limiting examples include lysine, cystine, and other amino acids in which carboxylic acids are reduced to hydroxyl groups.

[0057] In some implementation schemes, R 1 and R 3 Each independently is C 1-4 Alkyl group. In some embodiments, R 2 For L-[NR 2’ C(O)COOR 1’ ] m , where R 1’ and R 2’ Each independently is C 1-4 Alkyl group. When R 1 R 3 R 1’ and R 2’ C 1-4 When alkyl groups are used, they can be the same or different. In some embodiments, R... 1 R 3 R 1’ and R 2’ Independently methyl or ethyl. In some embodiments, all amide nitrogen is independently C 1-4 Alkylation.

[0058] In any of the embodiments disclosed herein, when the compound contains one or more stereocenters, each stereocenter may be configured independently as R or S.

[0059] In some implementations, L is branched and coupled with two NHC(O)COOR 1’ Linkage. L can therefore contain a trifunctional or polyfunctional linker derived from, for example, lysine, 1,3-diamino-2-propanol, spermidine, spermine, or thermal spermine. In some embodiments, L contains one or two lysine residues to extend the linker and connect to one, two, or more NHC(O)COOR.1’ Of course, the linker can contain one or more additional components, such as C as described above. 1-8 Alkylene, NH-C 1-8 Alkylene and NH-C 1-8 Alkylene-NH.

[0060] R 2 Non-restrictive examples include the following:

[0061] NR 2 R 3 Non-restrictive examples include the following:

[0062] Unrestricted examples of L include the following:

[0063] In some implementations, L is branched, m is 3, and L is associated with three NHC(O)COOR chains. 1’ Connections. For example, as shown in the following formula, L includes interconnected Ls. 1 and L 2 In addition to the original first oxamate moiety (shown in the box), they are further connected to three additional oxamate moieties. 1 and L 2 Each may contain one or more components as described above for the linker. In some embodiments, L 1 and L 2 One or two of them contain a moiety derived from lysine.

[0064]

[0065] In some implementations, L 1 and L 2 Connected by linear components, such as C 1-8 Alkylene, NH-C 1-8 Alkylene and NH-C 1-8 Alkylene-NH. In some embodiments, L 1 and L 2 Linked by components containing rings, such as 5-6 membered carbon rings or 5-6 membered heterocycles. In some embodiments, L 1 and L 2 The connection between them is or contains elements selected from NHNH, C 2-6 Alkylene, C 2-6 alkenyl group, C(O)NH-C 0-6The components of alkylene-NHC(O) and C(O)-piperazinyl-C(O).

[0066] Related parties have provided cyclized forms of compounds of formula I. In some embodiments, the cyclized compounds are represented by formula II.

[0067]

[0068] Formula II

[0069] in: T is a bifunctional or trifunctional linker; When T is a bifunctional linker, A is empty; When T is a trifunctional linker, A is ; R 1 For H or C 1-8 alkyl; R 2 For H or C 1-8 alkyl; It is an optional oxo group. In the cyclic structure where the carbonyl group of the oxamic acid moiety is in the form of an ester, the ester bond can be enzymatically cleaved under in vivo conditions. Furthermore, as shown below, when enzymatic cleavage produces the glycine moiety, the α-carbon of the glycine can be further oxidized to a carbonyl group under in vivo conditions, thereby generating a newly formed oxamic acid moiety.

[0070]

[0071] L 1 L 2 and L 3 It can be linear, branched, cyclic, or any combination thereof, and can contain or derive from one or more structural components selected from, for example, the following: C 1-8 Alkylene, C 2-8 imidene group, NH-C 1-8 Alkylene, NH-C 1-8 Alkylenes -NH, O, NHNH, C(O)NH-C 1-8 Alkylene-NHC(O), 5-8 membered heterocycles, -(CH2) a C(O)NR a (CH2) b -、-(CH2) a O(CH2CH2O) c -、-(CH2) a Heterocyclic groups -, -(CH2) a C(O)-、-(CH2) a NRa -、-CR a =N-NR a -、-CR a =NO-、-CR a =N-NR b -CO-, -N=N-CO-, -SS-, amino acids, where a, b, and c are each integers selected from 0 to 25, including all subunits; and R a and R b In each case, hydrogen or C1-C is represented independently. 10 alkyl.

[0072] In some embodiments, the compound is in the form of formula II-a. T is L 1 or L 2 Part of it.

[0073] Formula II-a

[0074] In some embodiments of Formula II, oxygenation It does not exist, and L 3 For O or NR a R b , where R a and R b Independently H or C 1-8 alkyl.

[0075] In some embodiments, the compound is in the form of formula II-b, where T is a trifunctional linker. Formula II-b

[0076] In some embodiments of Formula II, an oxo group is present, L 3 For OC 1-8 Alkylene-O. T itself or with L 1 and L 2 One or two of the components together can be derived from any suitable branched structure, including, for example, lysine, 1,3-diamino-2-propanol, spermine, and spermine.

[0077] Another relevant aspect provides information on the cyclic structures associated with the aforementioned compounds. The cyclic structures are represented by Formula III.

[0078]

[0079] Formula III

[0080] in: L 1 and L 2 Each is a linker base and can be arbitrarily connected to each other; L 3and L 4 Each is a linker; and It is an optional oxo group.

[0081] L 1 L 2 L 3 and L 4 Each is a linker, which can be linear, branched, cyclic, or any combination thereof, and can contain or derive from one or more structural components selected from, for example, the following: C 1-8 Alkylene, C 2-8 imidene group, NH-C 1-8 Alkylene, NH-C 1-8 Alkylenes -NH, O, NHNH, C(O)NH-C 1-8 Alkylene-NHC(O), 5-8 membered heterocycles, -(CH2) a C(O)NR a (CH2) b -、-(CH2) a O(CH2CH2O) c -、-(CH2) a Heterocyclic groups -, -(CH2) a C(O)-、-(CH2) a NR a -、-CR a =N-NR a -、-CR a =NO-、-CR a =N-NR b -CO-, -N=N-CO-, -SS-, amino acids, where a, b, and c are each integers selected from 0 to 25, including all subunits; and R a and R b In each case, hydrogen or C1-C10 alkyl is represented independently.

[0082] Preferably, L 3 and / or L 4 It is linked to the carbonyl group of oxalamidate via an ester bond. L 3 and / or L 4 It can also be linked to a carbon with optional oxygenation so that, as described above, it can be enzymatically cleaved or oxidized to a carbonyl group.

[0083] In some implementations, two oxo groups are present, L 3 and L 4 Each independently contains OC 1-8 Alkylene-O. In some embodiments, L 1 and L 2Derived independently from or containing one or more parts selected from the group consisting of: amino acids, C 1-8 Alkylene, NH-C 1-8 Alkylene, NH-C 1-8 Alkylene NH, optionally substituted phenyl, optionally substituted 5-10-membered heteroaryl, 5-10-membered carbon ring, 5-10-membered heterocycle.

[0084] In some implementations, L 1 and L 2 Interconnected. In some implementations, L 1 and L 2 The connection between them is or includes one or more selected from NHNH, C 2-12 Alkylene, C 2-12 alkenyl group, C(O)NH-C 0-12 The components of alkylene-NHC(O) and C(O)-piperazinyl-C(O).

[0085] In some embodiments of Formula III, the oxo group is absent, and L 3 and L 4 Each is O. L 1 and L 2 Interconnected. L 1 and L 2 The possible bond range between them is the same as that described in compounds containing two oxo groups.

[0086] On the other hand, a compound or a pharmaceutically acceptable salt thereof is provided, wherein the compound is represented by formula IV.

[0087] Formula IV

[0088] in: R 1 and R 2 Each independently is H or C 1-8 alkyl; B is a ring that can be substituted by any means, and Dashed lines indicate optional keys.

[0089] Ring B can be a 3-8 membered carbon ring, a 3-8 membered heterocyclic ring, a 6-10 membered aryl ring, or a 5-10 membered heteroaryl ring. In some embodiments, B is a 5-membered heteroaryl ring. In some embodiments, B is an optionally substituted imidazole. In some embodiments, the ring is a 3-8 membered carbon ring or a 3-8 membered heterocyclic ring. In some embodiments, the dashed line is present as part of an aromatic aryl or heteroaryl group.

[0090] Non-restrictive substituents of the ring include C 1-6 Alkyl, OC 1-4 Alkyl, NRa R b Halogenated C 1-4 Alkyl groups, halogens (F, Cl, Br, or I), OH, and CN. In some embodiments, B is a substituted C. 1-4 alkyl.

[0091] Non-limiting examples of Formula IV include the following, which may be in the form of an acid, ester or other salt.

[0092] On the other hand, a pharmaceutical composition is provided comprising a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0093] The following structures illustrate the anionic form of compounds of formula I. Of course, these compounds can also be in other forms, including, for example, acids, zwitterions, and esters (e.g., C14, C24, C34, C44, C54, C6 ... 1-6 Alkyl esters, salts, or neutral forms.

[0094]

[0095] The following structures illustrate the cyclic forms of the compounds disclosed herein.

[0096]

[0097] Non-limiting examples of compounds of formula I, II, or III include the following. 2 The nitrogen atom of one or more amides in the formula may be alkylated (e.g., methylated or ethylated). The subscripts m and n are each independently 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0098] Table 1 (1-20 – Equation I; 21-26 – Equation II; 27-28 – Equation III)

[0099] Non-limiting examples of N-methyl analogues include the following:

[0100] Another aspect of this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described compound and a pharmaceutically acceptable carrier.

[0101] The pharmaceutical composition may also comprise one or more physiologically acceptable surfactants, other carriers, diluents, excipients, smoothers, suspending agents, film-forming substances, and coating agents, or combinations thereof; as well as the compositions disclosed herein. Other acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical industry, for example described in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, flavorings, and the like may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid, and parabens may be added as preservatives. Additionally, antioxidants and suspending agents may be used. In various implementation schemes, alcohols, esters, sulfated aliphatic alcohols, etc., can be used as surfactants; sucrose, glucose, lactose, starch, microcrystalline cellulose, crystalline cellulose, mannitol, light anhydrous silicates, magnesium aluminate, magnesium aluminum metasilicate, synthetic aluminum silicate, calcium carbonate, sodium carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, etc., can be used as excipients; magnesium stearate, talc, hardened oil, etc., can be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, soybean oil, etc., can be used as suspending agents or lubricants; cellulose acetate phthalate, as a carbohydrate (such as cellulose or sugar) derivative, or methyl acetate-methacrylate copolymer, as a polyethylene derivative, can be used as a suspending agent; plasticizers such as phthalates can be used as suspending agents.

[0102] The pharmaceutical compounds described herein may be administered to human patients either directly or in combination with other active ingredients (as in combination therapy) or suitable carriers or excipients in a pharmaceutical composition. In some embodiments, dosage forms include those for administration of the compound directly. Furthermore, dosage forms may include pharmaceutical compositions. In any case, a dosage form may contain sufficient amounts of the compound to treat a disease as part of a specific administration regimen, as understood by those skilled in the art. Formulation and administration techniques of the compounds of this application can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0103] Pharmaceutical compositions can be manufactured in ways known per se, such as by conventional mixing, dissolving, granulating, coating, levigating, emulsifying, encapsulating, embedding, or tableting processes.

[0104] Pharmaceutical compositions can be formulated in any conventional manner using one or more physiologically acceptable carriers, said carriers containing excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. Appropriate formulations depend on the chosen route of administration. Any well-known techniques, diluents, carriers, and excipients may be used, as is deemed appropriate and understood in the art; for example, in Remington's Pharmaceutical Sciences mentioned above.

[0105] Another aspect of this disclosure provides a method for inhibiting calcium oxalate formation, comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject in need. The compound or a pharmaceutically acceptable salt thereof may be administered after diagnosis of a related disease or condition. Alternatively, the compound may be administered prophylactically, particularly to subjects at risk of having higher than normal levels of calcium oxalate, or to individuals at risk of developing a disease or condition associated with higher than normal levels of calcium oxalate. A related aspect provides a method for treating a disease selected from urolithiasis, kidney disease, hypertension, osteoporosis, and obesity. This method comprises administering a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, the method involves inhibiting calcium oxalate formation in the retina, heart, blood vessel walls, and / or brain of a subject.

[0106] The compounds or pharmaceutical compositions thereof disclosed herein may also be used in combination with or contain one or more other therapeutic agents, such as those selected from citrate, pyruvate, α-ketoglutarate, and phytate.

[0107] Suitable pharmaceutical compositions include those in which the amount of active ingredient contained herein is effective in achieving its intended purpose. In some embodiments, a therapeutically effective amount of the compound is an amount that is effective in treating, for example, a viral infection in a mammalian subject (e.g., a human). The therapeutically effective amount of the compounds disclosed herein as a dosage will depend on the route of administration, the type of animal being treated (including humans), and the physical characteristics of the particular animal under consideration. The dosage may be adjusted to achieve the desired effect, but will depend on factors such as weight, diet, concomitant medications, and other factors that a person skilled in the medical field will identify. More specifically, a therapeutically effective amount refers to an amount of compound that is effective in preventing, alleviating, or improving disease symptoms or prolonging the survival of a treated subject. The determination of a therapeutically effective amount is entirely within the competence of those skilled in the art, particularly based on the detailed disclosure provided herein.

[0108] As will be apparent to those skilled in the art, the useful in vivo dose and specific route of administration will vary depending on the age, weight, and species of the mammal being treated, the specific compound used, and the specific purpose for which the compound is applied. The determination of the effective dose level, i.e., the dose level required to achieve the desired result, can be accomplished by those skilled in the art using conventional pharmacological methods. Typically, human clinical application of a product begins at a lower dose level, increasing the dose level until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to determine the useful dose and route of administration of the composition identified by this method using established pharmacological methods.

[0109] In non-human animal studies, the application of a potential product begins at a higher dose level and is tapered until the desired effect is no longer achieved or adverse side effects disappear. The dose range can be wide, depending on the expected effect and therapeutic indication. Typically, the dose can be from about 10 micrograms / kg to about 100 mg / kg body weight, preferably from about 100 micrograms / kg to about 10 mg / kg body weight. Alternatively, the dose can be calculated and determined based on the patient's surface area, as understood by those skilled in the art.

[0110] The precise formulation, route of administration, and dosage of the pharmaceutical composition can be selected by an individual physician based on the patient's condition (see, for example, Fingle et al. 1975, "The Pharmacological Basis of Therapeutics," which is hereby incorporated in its entirety by reference, particularly Chapter 1, page 1). In some embodiments, the dosage range of the composition administered to the patient can be from about 0.5 to about 1000 mg / kg of patient body weight. The dosage can be a single administration or a series of two or more administrations over a day or several days as required by the patient. Where a human dose of the compound has been determined for at least certain conditions, the same dose can be used, or a dose of about 0.1% to about 500%, more preferably about 25% to about 250% of the determined human dose. Where a human dose has not been determined (as is the case with newly discovered pharmaceutical compositions), a suitable human dose can be inferred from the ED50 or ID50 value, or other appropriate values ​​derived from in vitro or in vivo studies, in conjunction with animal toxicity and efficacy studies.

[0111] It should be noted that the attending physician will know and when to discontinue, interrupt, or adjust medication due to toxicity or organ dysfunction. Conversely, if the clinical response is insufficient (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The range of dosages administered in the management of a condition will vary depending on the severity of the condition being treated and the route of administration. For example, the severity of the condition can be assessed in part by standard prognostic methods. Furthermore, the dosage and possible dosing frequency will also vary based on the individual patient's age, weight, and response. Procedures comparable to those discussed above can also be used in veterinary medicine.

[0112] While the precise dosage will be determined individually for each drug, some generalizations regarding dosage can be made in most cases. Daily dosing regimens for adult human patients may be, for example, oral doses of about 0.1 mg to 2000 mg of the active ingredient, preferably about 1 mg to about 500 mg, such as 5 to 200 mg. In other embodiments, intravenous, subcutaneous, or intramuscular doses of the active ingredient are used, such as about 0.01 mg to about 100 mg, preferably about 0.1 mg to about 60 mg, such as about 1 to about 40 mg. In the case of administering pharmaceutically acceptable salts, the dosage can be calculated using free acid. In some embodiments, the composition is administered 1 to 4 times daily. Alternatively, the composition may be administered by continuous intravenous infusion, preferably at a dose up to about 1000 mg daily. As those skilled in the art will understand, in some cases, it may be necessary to administer the compounds disclosed herein in amounts exceeding or even far exceeding the preferred dosage ranges described above to effectively and aggressively treat particularly invasive diseases or infections. In some embodiments, the compounds will be administered during continuous therapy, such as for a week or longer, or for months or years.

[0113] The dosage and intervals can be individually adjusted to provide plasma levels of the active component sufficient to maintain antibiotic action, or minimum effective concentration (MEC). MEC varies for each compound but can be estimated based on in vitro data. The dose required to achieve MEC will depend on individual characteristics and route of administration. However, plasma concentrations can be determined using HPLC or bioassays.

[0114] The MEC value can also be used to determine the dosing interval. The composition should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.

[0115] In cases of local application or selective absorption, the effective local concentration of a drug may be independent of its plasma concentration.

[0116] The amount of the composition applied may depend on the subject being treated, the subject's weight, the severity of the infection, the method of administration, and the prescribing physician's judgment.

[0117] The compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a compound can be established by determining its in vitro toxicity to cell lines, such as mammals, and preferably human cell lines. The results of such studies can often predict toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of a particular compound in animal models, such as mice, rats, rabbits, or monkeys, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for almost every type of condition. Similarly, acceptable animal models can be used to determine the efficacy of a chemical substance for treating such conditions. In selecting a model to determine efficacy, those skilled in the art can choose an appropriate model, dosage, route of administration, and regimen under the guidance of their technical expertise. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0118] If desired, the composition may be presented in a packaging or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The packaging may, for example, contain metal or plastic foil, such as blister packs. The packaging or dispenser device may be accompanied by instructions for use. The packaging or dispenser may also be accompanied by a notification related to the container, in the form prescribed by a government agency regulating the manufacture, use, or sale of the drug, reflecting that the agency has approved the form of the drug for human or veterinary use. Such notification may, for example, be a prescription drug label approved by the U.S. Food and Drug Administration (FDA) or an approved product information label. Compositions comprising a compound formulated in a compatible drug carrier may also be prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0119] In some embodiments, it is standard practice in the pharmaceutical industry to provide substantially pure substances when formulating pharmaceutical compositions. Therefore, in some embodiments, "substantially pure" refers to the purity required to formulate the pharmaceutical product, which may include, for example, small amounts of other substances that do not affect suitability for pharmaceutical use. In some embodiments, the substantially pure compound contains at least about 96% of the compound by weight, such as at least about 97%, 98%, 99%, or 100% of the compound.

[0120] Example

[0121] Example 1

[0122] Oxalamic acid is synthesized from amines. The following scheme illustrates the synthesis of ethyl oxamic acid.

[0123]

[0124] A suspension of the free base or hydrochloride of an organic amine (1 mmol) in DMF (1 mL) containing DIPEA (1.1 eq., with additional eq. if salts are used) was added dropwise to an ice-cold solution of ethyl oxalyl chloride (1.1 mmol, 1.1 eq., with additional eq. if multiple amines are present). The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete as monitored by TLC and / or LCMS, ice water was added to quench excess reagent, and the product was extracted three times with dichloromethane. The combined organic phases were washed twice with saturated NaHCO3, twice with 5% citric acid, and dried over anhydrous Na2SO4. The purified intermediate, ethyl oxalate, was obtained by ISCO rapid chromatography on a pre-packed silica column, eluted with a MeOH / DCM gradient.

[0125] The intermediate ethyl ester obtained above is hydrolyzed at room temperature with 1 N NaOH (1 eq for each ester present). The hydrolysis is usually completed within 2 h. The reaction mixture is lyophilized to give the desired oxalamidic acid in its sodium salt form.

[0126] Example 2

[0127] The following scheme illustrates L-lysine N , N - Synthesis of dioxalate.

[0128]

[0129] A suspension of L-lysine methyl ester hydrochloride (233 mg, 1 mmol) in DMF (1 mL) containing DIPEA (582 mg, 4.5 mmol, 4.5 eq.) was added dropwise to an ice-cold solution of oxaloyl chloride (600 mg, 4.4 mmol, 4.4 eq.). The reaction mixture was stirred at room temperature for 3 h. After LCMS showed that the reaction was complete, ice water (~10 mL) was added to quench excess reagent, and the product was extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed twice with saturated NaHCO3, twice with 5% citric acid, and dried over anhydrous Na2SO4. The product was purified by ISCO on a 12 g silica gel column, eluted with 0–10% MeOH in DCM solution, to give the desired product N. N -Bis(ethoxyoxaloyl)-L-lysine methyl ester (DW-I-006A) (230 mg, 64% yield). 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J= 8.4 Hz, 1H), 7.15 (s, 1H), 4.64 (td, J = 8.0, 5.1 Hz, 1H), 4.44 – 4.26 (m, 4H), 3.80 (s, 3H), 3.35 (q, J = 6.8 Hz, 2H), 1.97 (m, 1H), 1.80 (m, 1H), 1.71 – 1.54 (m, 2H), 1.41 (m, 8H). 13 C NMR (101 MHz, CDCl3) δ 171.5, 160.7, 160.0, 156.7, 156.3, 63.4, 63.2,52.7, 52.3, 39.4, 31.8, 28.5, 22.4, 14.0.

[0130] The intermediate ester obtained above (C-1, 60 mg, 0.167 mmol) was hydrolyzed with 1 N NaOH (0.5 mmol, 3 eq) at room temperature. The hydrolysis was completed within 2 h. The reaction mixture was lyophilized to give the desired L-lysine N. N - Dioxalate trisodium salt (60 mg, 100% yield, DW-I-007). 1 H NMR (400 MHz, D2O) δ 4.05 (dd, J =8.2, 4.9 Hz, 1H), 3.11 (t, J = 7.1 Hz, 2H), 1.74 (dt, J = 13.6, 6.7 Hz, 1H), 1.64 (dq, J = 14.7, 7.8 Hz, 1H), 1.45 (tt, J = 9.2, 5.0 Hz, 2H), 1.27 (p, J =7.7 Hz, 2H). 13 C NMR (100 MHz, DO) δ 178.1, 166.0, 165.7, 165.2, 164.1, 55.1, 31.8, 28.3, 22.7. HRMS (ESI - ) m / z Calculated as C 10 H 13 N₂O₈ 289.0677, measured at 289.0670 ([MH]) - ).

[0131] Example 3

[0132] 1,n-bis(L-lysamido)alkane) N ,N ´,N ,N ´ - Synthetic procedure for tetraoxalates. The following scheme illustrates the synthesis of compounds containing four oxalate moieties.

[0133]

[0134] N at 0 °C N - A suspension of bis(L-lysine) (2 mmol), HATU (2 mmol), and DIPEA (2 mmol) in DMF was added to an organic diamine (1 mmol). If an organic diamine salt was used, an additional equivalent or DIPEA was added. The reaction mixture was stirred at room temperature and monitored using TLC and / or LCMS. After the reaction was complete (~2 h), the reaction mixture was quenched with cold water. After decanting the liquid phase, the viscous residue was purified by ISCO rapid chromatography on a pre-packed silica column, eluting with a gradient of 0-40% ethyl acetate in DCM solution to give the desired Boc-protected 1,n-bis(L-lysamide) alkane intermediate.

[0135] The Boc-protected 1,n-bis(L-lysamido)alkane intermediate obtained above was deprotected using a 4 N HCl solution in dioxane or a concentrated HCl solution in acetone to give a 1,n-bis(L-lysamido)alkane intermediate containing four primary amine groups, in its HCl salt form. Following the general procedure for the synthesis of oxalamidic acid from amines, the 1,n-bis(L-lysamido)alkane intermediate was acylated with ethyl oxaloyl chloride. The resulting tetraethyl ester was hydrolyzed with four equivalents of NaOH, and lyophilized to give the desired 1,n-bis(L-lysamido)alkane. N ´,N N ´-Tetraoxalate, in sodium salt form.

[0136] Example 4

[0137] The following scheme describes N,N'-(1,5-pentadiyl)bis(L-lysine amide)N N ´,N N Synthesis of ´-tetraoxalate (C-2).

[0138]

[0139] N at 0 °C N HATU (955 mg, 2.5 mmol) was added to a suspension of diBoc-L-lysine (692 mg, 2 mmol), 1,5-pentanediamine hydrochloride (175 mg, 1 mmol), and DIPEA (646 mg, 5 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature and monitored using LCMS. After the reaction was complete (2 h), it was quenched with cold water (20 mL). After decanting the liquid phase, the viscous residue was purified by ISCO (40 g column) at a flow rate of 40 mL / min for 15 min using a gradient of 0–40% ethyl acetate / DCM to give a Boc-protected N,N'-(1,5-pentanediyl)bis(L-lysine amide) intermediate.

[0140] The tetra-Boc-protected N,N'-(1,5-pentadiyl)bis(L-lysine amide) intermediate (1 mmol) obtained above was dissolved in DCM (10 mL) and cooled to 0 °C. Then, a dioxane solution of 4 N HCl (5.4 mL, 5 eq) was added dropwise. After stirring at room temperature for 2 h, the reaction mixture was concentrated to remove reagents and solvents, yielding the N,N'-(1,5-pentadiyl)bis(L-lysine amide) HCl salt.

[0141] N,N'-(1,5-pentadiyl)bis(L-lysine amide) HCl salt (1 mmol) was dissolved in DMF (6 mL) containing 10 eq DIPEA. The solution was cooled to 0 °C, and then a solution of ethoxyoxalyl chloride (6 eq.) in THF (3 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h, and then at room temperature for 2 h. LCMS monitoring showed the presence of a triacylated intermediate, indicating incomplete reaction. An additional 3 eq. of oxalyl chloride ethyl ester and 5 eq. of DIPEA were added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then at room temperature for 1 h, until LCMS monitoring showed the reaction was complete. The reaction was quenched with cold water (20 mL) and then extracted with DMC (3 x 20 mL). The combined organic phases were washed with 5% citric acid, saturated NaHCO3, and water, and then dried over anhydrous Na2SO4. The crude product was obtained by removing the organic solvent and then purified by ISCO on a 40 g pre-packed silica column at a flow rate of 40 mL / min for 15 min using a gradient of 0-10% methanol / DCM. N ´,N N ´-tetra(ethoxyoxalyl)-N,N´-(1,5-pentadiyl)bis(L-lysine amide) intermediate, a pale yellow oil (630 mg, total yield of 83% for 3 steps).

[0142] 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.3 Hz, 2H), 7.45 (t, J = 6.2Hz, 2H), 7.05 (t, J = 5.7 Hz, 2H), 4.48 (q, J = 7.3 Hz, 2H), 4.34 (q, J = 7.1Hz, 8H), 3.39 – 3.33 (m, 4H), 3.33 – 3.15 (m, 4H), 1.94 (dq, J = 14.5, 7.3Hz, 2H), 1.85 – 1.71 (m, 4H), 1.63 (q, J = 7.3 Hz, 4H), 1.57 – 1.34 (m, 20H), 1.34 – 1.21 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 171.2, 170.6, 160.6, 156.8,63.3, 63.2, 60.4, 53.5, 53.4, 50.7, 39.5, 39.2, 31.9, 28.6, 28.5, 23.6, 22.6,14.2, 14.0, 14.0.

[0143] At 0 °C, to N N ´,N N 1 N NaOH (1.69 mL, 4 eq) was added to a methanol (4 mL) solution (320 mg) of N,N'-tetra(ethoxyoxalyl)-N,N'-(1,5-pentadiyl)bis(L-lysine amide) intermediate. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 2 h, or until the starting material disappeared as monitored by LCMS. The reaction mixture was concentrated, the residue was dissolved in water (5 mL), and then lyophilized to give the desired product N,N'-(1,5-pentadiyl)bis(L-lysine amide)N N ´,N N ´-Tetra-oxalate tetrasodium salt, a grayish-white solid (270 mg, 87% yield).

[0144] 1 H NMR (400 MHz, D2O) δ 4.12 (dd, J = 8.3, 5.9 Hz, 2H), 3.16 – 3.02(m, 8H), 1.83 – 1.64 (m, 4H), 1.46 (q, J = 7.2 Hz, 4H), 1.39 (q, J = 7.4 Hz,4H), 1.35 – 1.23 (m, 4H), 1.20 (d, J = 7.3 Hz, 2H).

[0145] Example 5

[0146] The following scheme describes N,N'-(1,6-hexadiyl)bis(L-lysine amide) N , N ´,N N Synthesis of tetraoxalate.

[0147]

[0148] N at 0 °C N HATU (955 mg, 2.5 mmol) was added to a suspension of bis(L-lysine) (692 mg, 2 mmol), 1,6-hexanediamine (116 mg, 1 mmol), and DIPEA (388 mg, 3 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature and monitored using LCMS. After 1 h, a second portion of HATU (300 mg) and DIPEA (200 mg) was added at room temperature. After the reaction was complete (2 h in total), the reaction was quenched with cold water (20 mL). After decanting the liquid phase, the viscous residue was purified by ISCO (40 g column) at a flow rate of 40 mL / min for 15 min using a gradient of 0–100% ethyl acetate / hexane to give a Boc-protected N,N'-(1,6-hexanediyl)bis(L-lysine amide) intermediate (671 mg, 43% yield).

[0149] The tetra-Boc-protected N,N'-(1,6-hexamethylenediyl)bis(L-lysine amide) intermediate obtained above (620 mg, 0.8 mmol) was dissolved in DCM (5 mL) and cooled to 0 °C. Then, a dioxane solution of 4 N HCl (4.8 mL, 6 eq) was added dropwise. After stirring at room temperature for 3 h, the reaction mixture was concentrated to remove reagents and solvents, giving N,N'-(1,6-hexamethylenediyl)bis(L-lysine amide) HCl salt (410 mg, 79% yield).

[0150] N,N'-(1,6-hexadiyl)bis(L-lysamide)HCl salt (410 mg, 0.79 mmol) was dissolved in DMF (5 mL), and 10 eq DIPEA was added. The solution was cooled to 0 °C, and then a solution of oxaloyl chloride ethyl ester (5 eq.) in THF (5 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min, and then stirred at room temperature for 2 h until the reaction was complete as indicated by LCMS. The reaction was quenched with cold water (20 mL), and then extracted with DMC (3 x 20 mL). The combined organic phases were washed with 5% citric acid, saturated NaHCO3, and water, respectively, and then dried over anhydrous Na2SO4. The crude product was obtained by removing the organic solvent and purified by ISCO on a 24 g pre-packed silica gel column with a 0-10% methanol / DCM gradient for 15 min to obtain N , N ´,N N ´-Tetra(ethoxyoxalyl)-N,N´-(1,6-hexadiyl)bis(L-lysine amide) intermediate, as a pale yellow oil (360 mg, 59% yield).

[0151] At 0 °C, to N , N ´,N N 1 N NaOH (1.5 mL, 4 eq) was added to a methanol (4 mL) solution of 290 mg (0.375 mmol) of the N,N'-tetra(ethoxyoxalyl)-N,N'-(1,6-hexadiyl)bis(L-lysine amide) intermediate. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 4 h, or until the starting material disappeared as monitored by LCMS. The reaction mixture was concentrated, the residue was dissolved in water (5 mL), and then lyophilized to give the desired product N,N'-(1,6-hexadiyl)bis(L-lysine amide). , N ´,N N ´-Tetra-oxalate tetrasodium salt, a grayish-white solid (168 mg, 60% yield).

[0152] Figure 2 The synthesis of compound I was also explained. Figure 3 The synthesis of the cyclic form of compound III is explained.

[0153] Example 6

[0154] The assay for calcium oxalate (CaOx) crystallization inhibition in HEPES buffer at pH 6.8 included assay A and assay B. Assay A: a fluorescence-based assay using Quin-2 to measure the concentration of free calcium in solution (Ex 340 nm / Em 495 nm). Figure 1 The following shows an exemplary measurement scheme.

[0155]

[0156] Determination B: Spectrophotometric determination using EnzyChrom from Bioassay Systems. TM The oxalate assay kit (EOXA-100) measures the concentration of free oxalate in solution at OD 595 nm.

[0157] For the CaOx crystallization inhibition assay, equal volumes of 2 mM CaCl2 and 500 mM Na2Ox were combined and dissolved in 10 mM HEPES buffer (pH 6.8) containing 150 mM NaCl to produce a 250 mM CaOx supersaturated solution. The higher CaOx concentration used in this assay... ++ The concentrations were designed to mimic typical calcium levels measured in human urine. After incubation at different concentrations of inhibitor for 72 h at room temperature and subsequent centrifugation, the results were analyzed using EnzyChromium. TM The oxalate assay kit (EOXA-100, BioAssay Systems) was used to spectrophotometrically measure the residual oxalate concentration (595 nm) in the solution. This assay determined the concentration of each inhibitor. EC 50 This assay was used to determine the activity of approximately 50 synthesized oxamic acid derivatives. Additionally, dose-response curves for calcium and inhibitor concentrations were obtained using a supersaturated solution: 10 mM HEPES containing 250 µM CaCl2 + 250 µM Na2C2O4, pH 6.8 + 150 mM NaCl; the calcium concentration in the supernatant after centrifugation was measured using a fluorescence assay with Quin2 (Ex 340 nm / Em 495 nm).

[0158] Table 1 lists the various oxalamidic acid derivatives obtained using this assay. EC 50 In addition, other structural features, such as the length of the connection base and the number of OMA cells used for SAR analysis.

[0159] Table 2. Activity of oxalamidic acid derivatives as CaOx crystallization inhibitors

[0160] All references cited herein are incorporated herein by reference in their entirety. Those skilled in the art will understand that the invention is not limited to what is specifically shown and described. Rather, the scope of the invention is defined by the following claims. It should also be understood that the above description represents only illustrative examples of embodiments. This description does not attempt to exhaustively list all possible variations. Alternative embodiments may not be proposed for a particular part of the invention and may arise from different combinations of said parts, or other undescribed alternative embodiments may be available for a particular part, which should not be construed as a waiver of such alternative embodiments. It should be understood that many undescribed embodiments are within the literal scope of the appended claims, while other embodiments are equivalent.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, Formula I in R 1 For H or C 1-8 alkyl; R 2 C 1-8 Alkylene-NR a R b Peptides derived from one or more natural or non-natural amino acids, or L-[NR] 2’ C(O)COOR 1’ ] m ; L is a linker derived from one or more parts selected from the group consisting of: amino acids, C 1-8 Alkylene, SS, NH-C 1-8 Alkylene, NH-C 1-8 Alkylene NH, optionally substituted phenyl, optionally substituted 5-10-membered heteroaryl, 5-10-membered carbocyclic, 5-10-membered heterocyclic, wherein L is optionally partially substituted by one or more of the following groups: COOH, COOC 1-6 Alkyl, CN, halogen, halogenated -C 1-6 Alkyl, C 1-4 Alkylene-OH and CN; m is 1, 2, or 3. R 1’ H or C independently in each case. 1-8 alkyl; R 2’ H or C independently in each case. 1-4 alkyl; R 3 For H or C 1-8 alkyl, Or R 2 and R 3 The links form 5-8 quintic heterocycles, which are optionally C 1-8 Alkyl, COOH, COOC 1-8 Alkyl, C(O)NR a R b or C(O)COOR 1’ Replace, and R a and R b Independently H or C 1-8 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 For L-NR 2’ C(O)COOR 1’ L is C 2-6 Alkylene and R 3 It is H or methyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 L-NHC(O)COOR 1’ , where L contains a portion derived from one or more amino acids.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 The links form 5- or 6-membered heterocycles, which are optionally C 1-8 Alkyl or C(O)COOR 1’ replace.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 C 2-6 Alkylene NH2.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 Derived from amino acids.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 Each independently is C 1-4 Alkyl, R 2 For L-[NR 2’ C(O)COOR 1’ ] m , where R 1’ and R 2’ Each independently is C 1-4 alkyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is with two or three NR 2’ C(O)COOR 1’ connect.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is branched and comprises one or two moieties derived from lysine.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is branched and comprises a heterocyclic moiety.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 。 12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 。 13. A compound of formula II or a pharmaceutically acceptable salt thereof, Formula II in: T is a bifunctional or trifunctional linker; When T is a bifunctional linker, A is empty; When T is a trifunctional linker, A is ; R 1 For H or C 1-8 alkyl; R 2 For H or C 1-8 alkyl; L 1 and L 2 Each is a linker base; It is an optional oxo group. L 3 It is a linker.

14. The compound of formula II according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula II-a. Formula II-a Where A is empty and T is a bifunctional linker.

15. The compound of formula II according to claim 14, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula II-b. Formula II-b Where T is a trifunctional linker.

16. A compound of formula III or a pharmaceutically acceptable salt thereof, Formula III in: L 1 and L 2 Each is a linker base and can be arbitrarily connected to each other; L 3 and L 4 Each is a linker; and It is an optional oxo group.

17. The compound of formula III according to claim 16, or a pharmaceutically acceptable salt thereof, wherein L 1 and L 2 Interconnected.

18. A compound or a pharmaceutically acceptable salt thereof, wherein said compound is represented by formula IV. Formula IV in: R 1 and R 2 Each independently is H or C 1-8 alkyl; B is a ring that can be substituted by any means, and Dashed lines indicate optional keys.

19. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1-18 or a pharmaceutically acceptable salt thereof.

20. A method for inhibiting the formation of calcium oxalate crystals, comprising administering to a subject in need a therapeutically effective amount of the compound of any one of claims 1-18 or a pharmaceutically acceptable salt of claim 19.

21. The method of claim 20, wherein the subject has been diagnosed with a disease selected from the group consisting of: urolithiasis, kidney disease, hypertension, osteoporosis, obesity, and oxalate storage disease.

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