Cystine diamide analogues for cystinuria

Abstract

This document discloses novel cystine analogs; methods for making the cystine analogs, compositions containing the cystine analogs; and methods for using these analogs to inhibit cystine stone formation and treat cystinuria.

Description

[Technical field]

[0001] Federally funded research This invention was made with Government support under Grant no. 1R01DK112782-01 awarded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. The United States Government has certain rights in this invention.

[0002] This patent document relates to novel cystine analogs; methods for making the cystine analogs, compositions containing the cystine analogs; and methods of using these analogs for inhibiting cystine stone formation and treating cystinuria. [Background technology]

[0003] Cystinuria is a rare, chronic, lifelong condition that affects approximately 20,000 Americans. It is the result of an autosomal recessive genetic disorder caused by a single mutation in either of two genes, SLC3A1 or SLC7A9, that results in abnormal transport of dibasic amino acids from the luminal fluid of the renal proximal tubules and small intestine. Approximately 5% of American women and 12% of American men will develop kidney stones at some point in their lives, and the prevalence is increasing in both sexes.

[0004] Recurrence of kidney stones is also common. It is estimated that nearly 50% of stone formers will have a recurrence within 10 years. Approximately 59% of kidney stones are calcium oxalate stones (pure stones) or with small amounts of calcium phosphate; 10% are primarily calcium phosphate stones; 17% are uric acid stones; 12% are struvite or infection stones; and the remaining 2% are cystine and other stones. The proportion of cystine stones is much lower than that of calcium oxalate stones, but cystine stones are larger, recur more frequently, and are more likely to cause chronic kidney disease. Medically, disease with cystine stones in the kidneys, ureters, and bladder is called cystinuria, which is a genetic abnormality that results in the abnormal transport of dibasic amino acids from the luminal fluid of the proximal renal tubules and small intestine.

[0005] Cystinuria is a chronic, lifelong condition that is most common in young adults under the age of 40. It is the result of an autosomal recessive genetic disorder caused by mutations in one of two genes, SLC3A1 (type A) on chromosome 2 or SLC7A9 (type B) on chromosome 19, which code for components of the major proximal tubule cystine and dibasic amino acid transporters. Current clinical treatment of cystinuria aims to reduce the concentration of free cystine in urine and increase its solubility. High fluid intake of about 4-5 liters per day and alkalinization of urinary pH with citrate or bicarbonate may inhibit, but not completely prevent, stone formation. In severe conditions, chelation therapy is required, utilizing the reaction of D-penicillamine or α-mercaptopropionylglycine with L-cystine to generate more soluble asymmetric disulfides. These drugs have side effects such as taste loss, fever, proteinuria, serum sickness-type reactions, and even frank nephritic syndrome.

[0006] Recently, a group of researchers reported an alternative approach to prevent cystinuria based on crystal growth inhibition, which is achieved through the binding of tailored growth inhibitors - L-cystine dimethyl ester (CDME) and L-cystine methyl ester (CME) - to specific crystal surfaces. CDME almost completely inhibits L-cystine crystallization in water at concentrations above 2 mg / L. In cell culture experiments, CDME causes loss of cell viability at about 1 mM and in rat studies shows adverse effects at doses of about 500 mg / kg / day.

[0007] Although CDME inhibits cystine stone formation in in vitro studies, the methyl esters in CDME are cleavable by a variety of esterases that are widely present in almost all organs and tissues, most abundantly in the digestive system, blood and liver. Furthermore, ester-mediated hydrolysis of cystine esters produces cystine, which increases already elevated levels of cystine in the kidneys and bladder, potentially increasing the likelihood of cystine crystal formation, thus further exacerbating the problem. Thus, new and improved methods for treating cystinuria are needed. Summary of the Invention

[0008] One aspect of this patent document provides a compound, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof, wherein the compound is represented by formula I:

[0009] [ka]

[0010] Here, R 1 and R 2 The pairs are independently defined as follows: a)R 1 is H and R 2 (CH2) m NR a R b and m is 2, 3, or 4, where R a and R b are each independently C 1-8 alkyl or R a and R b are joined together with the N to which they are attached to form a 4-8 membered heterocycle, wherein the carbons within said 4-8 membered heterocycle are selected from the group consisting of O, S, NH, and NC 1-8 optionally substituted with a heteroatom selected from the group consisting of alkyl, or b)R 1 and R 2is linked together with the amide nitrogen to form a ring of formula X-1:

[0011] [ka]

[0012] Where: R 3 is C 1-8 alkyl, r is 0, 1, or 2; n, p, and A are defined as follows: i) n and p are independently 2 or 3; A is NR C where R C is H, C 2-8 Alkyl or C 3-8 is cycloalkyl; ii) n is 0, 1, or 2; p is 2 or 3 or 4; A is a structure of formula Y-1:

[0013] [ka]

[0014] Here, R d is H or C 1-8 is alkyl; s is 0, 1, or 2; t is 2, 3, or 4; provided that when n is 0, s is 1 or 2; or iii) n and p are independently 1, 2, 3, or 4; A is CH(CH2) q NR e R f where R e and R f is independently C 1-8 alkyl; q is 0 to 3; Or, R e and R f are linked together with the N to which they are attached to form a 4- to 8-membered heterocycle.

[0015] In some embodiments, R 1 is H and R 2 (CH2) m NR a R b m is 2 or 3; R a and R b are each independently C 1-2 In some embodiments, R 1 is H and R 2 (CH2) m NR a R b where m is 2 or 3, and R a and R b are linked to form a 5-8 membered heterocycle, wherein a carbon within the ring may be substituted with O.

[0016] In some embodiments, R 1 and R 2 are linked together with the amide nitrogen to form a ring of formula X-1, where r is 0, n and p are independently 2 or 3 or 4, and A is NR c where R c is hydrogen, C 2-8 Alkyl or C 3-8 In some embodiments, n and p are independently 2; R c is selected from the group consisting of tert-butyl, cyclopropyl, cyclobutyl, and cyclopentyl.

[0017] [ka]

[0018] In some embodiments, R 1 and R 2 are linked together with the amide nitrogen to form a ring of formula X-1, where r is 0 and A is of formula Y-1. In some embodiments, n is 0, s is 1 or 2, n is 1 or 2, and s is 0, 1, or 2.

[0019] [ka]

[0020] In some embodiments, R 1 and R 2 are linked together with the amide nitrogen to form a ring of formula X-1, where r is 0; n and p are independently 1, 2, 3, or 4; A is CH(CH2) q NR e R f where R e and R f is independently C 1-8 alkyl; and q is 1, 2 or 3.

[0021] [ka]

[0022] In some embodiments, R 1 and R 2 is linked together with the amide nitrogen to form a ring of formula X-1, where r is 0 and A is CH(CH2) q NR e R f where q is 0 and R e and R f are linked together with the N to which they are attached to form a 4- to 8-membered heterocycle.

[0023] [ka]

[0024] In some embodiments, the compound is

[0025] [ka]

[0026] is selected from the group consisting of:

[0027] In some embodiments, the compound is

[0028] [ka]

[0029] is selected from the group consisting of:

[0030] In some embodiments, the compound is

[0031] [ka]

[0032] is selected from the group consisting of:

[0033] Another aspect discloses a compound, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof, wherein the compound is represented by formula II:

[0034] [ka]

[0035] Here, R 1 and R 2 The pairs are independently defined as follows: a)R 1 and R 2 are each independently H or (CH2) m NR a R b and m is 2, 3, or 4; a and R b are each independently C 1-8 alkyl or R a and R b are linked together with the N to which they are attached to form a 4-8 membered heterocycle, the carbons within said 4-8 membered heterocycle being O, S, NH and NC 1-8alkyl, with the proviso that R 1 and R 2 At least one of them is (CH2) m NR a R b is; or b)R 1 and R 2 is linked with the amide nitrogen to form a ring of formula P-1:

[0036] [ka]

[0037] Where: R 3 is C 1-8 alkyl; r is 0, 1, or 2; n, p, and A are defined as follows: i) n and p are independently 2 or 3; A is NR c where R c is H, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; ii) n is 0, 1, or 2; p is 2 or 3 or 4; A is a structure of formula Q-1,

[0038] [ka]

[0039] Here, R d is H or C 1-8 is alkyl; s is 0, 1, or 2; t is 2, 3, or 4; provided that when n is 0, s is 1 or 2; or iii) n and p are independently 1, 2, 3, or 4; A is CH(CH2) q NR e R f where R e and R f are independently H or C 1-8 alkyl; q is 0 to 3; Or, R e and R f join together with the N to which they are attached to form a 4- to 8-membered heterocycle; E is H or C 1-8 It is an alkyl.

[0040] Another aspect of the present disclosure provides pharmaceutical compositions comprising a compound described herein, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof, and one or more pharma- ceutically acceptable carriers.

[0041] Another aspect of the present disclosure provides a method of treating a disease associated with a mutation in the SLC3A1 gene and / or the SLC7A9 gene, comprising administering to a subject in need thereof a pharma- ceutically effective amount of a compound disclosed herein, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof. In some embodiments, the disease is cystinuria.

[0042] Another aspect of the present disclosure provides a method of treating, inhibiting or slowing the growth of L-cystine kidney stone formation in a subject in need thereof, comprising administering to a subject in need thereof a pharma- ceutical effective amount of a compound disclosed herein, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

[0043] In some embodiments of the treatment method disclosed herein, the method further comprises administering a second agent.Non-limiting examples of the second agent include citrate supplementation, acetazolamide, and a chelating agent.In some embodiments, the chelating agent is penicillamine or tiopronin. [Brief description of the drawings]

[0044] [Figure 1] The synthesis of compound LH1727 is shown. [Diagram 2] 1 shows the synthesis of compound LH1727 by thiol-sulfide exchange followed by air oxidation. [Diagram 3] The synthesis of meso-CDME (LH1728) is shown. [Figure 4] 1 shows dose response curves for LH708 and LH1727 compared to CDME and dl-CDME. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] Detailed Description This patent discloses novel cystine analogues for the treatment of diseases such as cystinuria, which exhibit enhanced ability to inhibit cystine crystal formation.

[0046] The following text may refer to or exemplify specific embodiments of compounds or methods for treating a disease or condition, but is not intended to limit the scope of the compounds or methods to such specific references or examples. Various modifications may be made by those skilled in the art in view of practical and economic considerations, such as substitutions of compounds and amounts or administration of compounds for treating or preventing a disease or condition.

[0047] As used herein, the articles "a" and "an" refer to "one or more" or "at least one," unless otherwise indicated. That is, reference to any element or component of an embodiment by the indefinite article "a" or "an" does not exclude the possibility that multiple elements or components are present.

[0048] The term "pharmaceutical composition" refers to a mixture of the compounds disclosed herein with other chemical components, such as diluents or additional carriers. Pharmaceutical compositions facilitate the administration of compounds to living organisms. Multiple techniques of administering pharmaceutical compositions exist in the art, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. In some embodiments, pharmaceutically acceptable salts of the compounds disclosed herein are provided. The pharmaceutically acceptable salt forms of the compounds disclosed herein can include, but are not limited to, acid addition salts of inorganic or organic acids. Examples of addition salts of inorganic acids include salts formed with hydrochloric, hydrobromic, sulfuric, disulfuric, nitric, phosphoric, perchloric, or bromic acid; examples of addition salts of organic acids include formic, acetic, propionic, oxalic, succinic, benzoic, citric, maleic, malonic, malic, tartaric, gluconic, lactic, mandelic, glycolic, pyruvic, glutaric, ascorbic, palmitic, hydroxymaleic, hydroxybenzoic, phenylacetic, cinnamic, methanesulfonic, benzenesulfonic, toluenesulfonic, ethanedisulfonic, gestinic, fumaric, lactobionic, salicylic, phthalic, embonic, aspartic, glutamic, camsylic, besylic, or acetylsalicylic acid.

[0049] The term "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues.

[0050] The term "diluent" refers to a compound diluted in water that will dissolve the composition of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffer solutions are utilized as diluents in the art. One commonly used buffer solution is phosphate buffered saline, as it mimics the salt conditions of human blood. Buffer diluents rarely alter the biological activity of a compound, since buffer salts can control the pH of the solution at low concentrations. As used herein, "excipient" refers to an inert substance added to a composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubricity, disintegration ability, and the like. "Diluent" is a type of excipient.

[0051] The term "physiologically acceptable" or "pharmaceutical acceptable" refers to a carrier or diluent that does not abolish the biological activity and properties of the compound.

[0052] The term "therapeutically effective amount" refers to an amount of a compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art without undue experimentation.

[0053] The term "alkyl" refers to a monovalent or divalent saturated alkane radical group having up to about 18 carbon atoms, more specifically as lower alkyl, 1 to 8 carbon atoms, and even more specifically 1 to 6 carbon atoms. In some embodiments, a divalent saturated alkane radical is also called an alkylene. The hydrocarbon chain may be straight or branched. "C1-C10 alkyl" or "C 1-10 The term "alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Similarly, "C1-C6 alkyl" or "C 1-6 The term "alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Non-limiting examples include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-octyl, tert-octyl, and the like.2-8 Non-limiting examples of "alkyl" include ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, n-octyl, tert-octyl, and the like.

[0054] The term "cycloalkyl" refers to cyclic hydrocarbyl groups having from 3 to about 10 carbon atoms, a single ring or multiple condensed rings (including fused and bridged ring systems), optionally substituted with one to three alkyl groups. Such cycloalkyl groups include, for example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ring structures such as adamantanyl.

[0055] The term "heterocyclyl" or "heterocyclic" group refers to a ring structure having about 3 to about 12 atoms, e.g., 4 to 8 atoms, where one or more atoms is selected from the group consisting of N, O, and S, and the remainder of the ring atoms are carbon. The heterocycle may be a monocyclic, bicyclic, spirocyclic or bridged ring system. Examples of heterocyclic groups of any embodiment disclosed herein include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, oxazepanyl, azabicycloheptane, azabicycloheptane, and oxazabicycloheptane. Examples of 4-8 or 5-8 membered heterocycles of any embodiment disclosed herein include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl, and azocanyl.

[0056] The term "hetero" when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group are replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above hydrocarbyl groups such as alkyl, e.g., heteroalkyl, cycloheteroalkyl.

[0057] The term "halogen" refers to F, Cl, Br, or I.

[0058] The term "carboxamide" refers to a group in which each R is independently C1-C 10 Refers to the group CONRR, which is alkyl or aryl.

[0059] The term "aromatic ring" or "aryl" refers to a monovalent or divalent aromatic structure, including carbocyclic rings in which all ring atoms are carbon. Aromatic structures also include heteroaromatic or heteroaryl rings in which one or more ring atoms are heteroatoms (e.g., oxygen, sulfur, nitrogen) or amino groups. Exemplary aryl groups having all carbon ring atoms include, but are not limited to, groups derived from aceanthrylene, acephenanthrylene, anthracene, azulene, benzene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, and the like. In some embodiments, the aryl group contains 6 to 14 carbon atoms.

[0060] Typical heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.

[0061] The term "subject" or "patient" refers to a mammal, including humans and animals, such as sheep, horses, cows, pigs, dogs, cats, rats, mice, birds, and reptiles.

[0062] The term "prodrug" refers to compounds including derivatives of the compounds of this patent document, each having a cleavable group that cleaves under physiological conditions to form a pharma- ceutically active form of the compound in vivo. Such examples include, but are not limited to, low and long chain alkyl ester derivatives, such as choline and N-alkylmorpholine esters. Prodrugs include acid derivatives well known to practitioners in the art, such as, for example, esters prepared by reacting the parent acid with an appropriate alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or an acid anhydride, or mixed anhydride. In some cases, it is desirable to prepare double ester type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. In some exemplary embodiments, the amino group (NHC) in the compound is cleaved from the carboxyl group of the carboxyl group. 1-6 Alkyl or NH2) is the N in the prodrug 1-6The alkyl group may be of the form X' or NHX', where X' is alkoxycarbonyl (ROCO) and (acyloxy)alkoxycarbonyl (RCOOCH(R')OCO, where R' is H or alkyl and R is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 4- to 8-membered heterocycle, and substituted or unsubstituted 5- to 10-membered heteroaryl.

[0063] The term "solvate" refers to a form of a compound associated with a solvent. Common solvents include water, ethanol, acetic acid, etc. The compounds of the present invention can be prepared, for example, in crystalline form, and can be solvated or hydrated. Suitable solvates include pharma- ceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates.

[0064] The term "treating" or "treatment" of any disease or condition, in some embodiments, refers to improving the disease or disorder (i.e., halting or reducing the onset of at least one of the disease or its clinical symptoms). In some embodiments, "treating" or "treatment" refers to improving at least one physical parameter that may not be discernible by the subject. In some embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In some embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder, or even preventing it. "Prophylactic treatment" is understood to mean any method of treatment used to prevent the progression of a disease or for prophylactic purposes in those at risk of developing the disease.

[0065] The compounds disclosed herein may possess one or more asymmetric centers; thus, such compounds may be produced as individual stereoisomers (e.g., R,R; R,S; or S,S about the two NH2-bonded stereocenters shown in Formula A below) or as mixtures thereof.

[0066] One aspect of this patent document provides a compound, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof, wherein the compound is represented by formula A:

[0067] [ka]

[0068] Here, R 1 and R 2 Each pair of is independently defined as follows: a)R 1 is H and R 2 (CH2) m NR a R b and m is 2, 3 or 4, where R a and R b are each independently C 1-8 alkyl or R a and R b are linked together with the N to which they are attached to form a 4-8 membered heterocycle, wherein the carbons within said 4-8 membered heterocycle are selected from the group consisting of O, S, NH, and NC 1-8 may be substituted with a heteroatom selected from the group consisting of alkyl; or b)R 1 and R 2 is linked together with the amide nitrogen to form a ring of formula X-1:

[0069] [ka]

[0070] Here, R 3 is C1-8 alkyl, r is 0, 1, or 2; n, p, and A are defined as follows: i) n and p are independently 2 or 3; A is NR c where R c is H, C 2-8 Alkyl or C 3-8 is cycloalkyl; ii) n is 0, 1, or 2; p is 2, 3, or 4; A is a structure of formula X-2

[0071] [ka]

[0072] Here, R d is H or C 1-8 is alkyl; s is 0, 1, or 2; t is 2, 3, or 4; provided that when n is 0, s is 1 or 2; or iii) n and p are independently 1, 2 or 3; A is CH(CH2) q NR e R f where R e and R f is independently C 1-8 alkyl; q is 0 to 3; Or, R e and R f are linked together with the N to which they are attached to form a 4- to 8-membered heterocycle.

[0073] Each of the chiral centers at the NH2-bonded carbon can have an R or S configuration. For example, the compound of formula A can have the RR, RS, or SS configurations at the two chiral centers.

[0074] When a substituent occurs more than once in a formula, its definition may be the same or different at each occurrence, regardless of the position of the multiple occurrences. For example, R 3 may be the same or different. In some embodiments, R 1 is the same in each case, and R 2 is the same in each case.

[0075] In some embodiments, Formula A is represented by Formula I:

[0076] [ka]

[0077] Here, R 1 is H and R 2 is as defined above.

[0078] In some embodiments of Formula I, R 1 is H and R 2 (CH2) m NR a R b m is 2 or 3; R a and R b are each independently C 1-2 In some embodiments, R a and R b Both are methyl.

[0079] In some embodiments of Formula I, R 1 is H and R 2 (CH2) m NR a R b and m is 2 or 3; where R a and R b are linked to form a 5-8 membered heterocycle, where a carbon within said ring may be substituted with O. Examples of 5-8 membered heterocycles include pyrrolidinyl, piperidinyl, morpholinyl, azepanyl, and azocanyl.

[0080] In some embodiments of Formula I, R 1 and R 2 is linked together with the amide nitrogen to form a ring of formula X-1:

[0081] [ka]

[0082] where r is 0, n and p are independently 2 or 3 or 4, and A is NR c where R c , H, C 2-8 Alkyl or C 3-8 In some embodiments of formula X-1, n and p are each 2 and R c is C 2-8 Alkyl or C 3-8 In some embodiments, R c is tert-butyl, tert-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, n and p are each 2 and R c is tert-butyl, tert-pentyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0083] In some embodiments of Formula I, R 1 and R 2 are linked together with the amide nitrogen to form a ring of formula X-1, where r is 0, A is of formula Y-1, n is 0, 1 or 2, p is 2 or 3 or 4, and A is a structure of formula X-2:

[0084] [ka]

[0085] Here, R d is H or C 1-8alkyl, s is 0, 1 or 2, and t is 2, 3 or 4, with the proviso that when n is 0, s is 1 or 2. In some embodiments, n is 0 and s is 1 or 2. In some embodiments, n is 1 or 2, s is 0, 1 or 2, and R d is H. In some embodiments, n is 1 or 2, s is 0, 1 or 2, and R d is H. In some embodiments, n is 2, s is 0, 1 or 2, and R d is H.

[0086] In some embodiments of Formula I, R 1 and R 2 are linked together with the amide nitrogen to form a ring of formula X-1, where r is 0; n and p are independently 1, 2, 3, or 4; and A is CH(CH2). q NR e R f where R e and R f is independently C 1-8 alkyl; and q is 0 to 3. In some embodiments, n and p are independently 1 or 2, and q is 0. In some embodiments, n and p are independently 1 or 2, q is 0, and R e and R f is independently C 1-3 In some embodiments, n and p are each 2, q is 0, and R e and R f is independently methyl or ethyl.

[0087] In some embodiments of Formula I, R 1 and R 2 are linked together with the amide nitrogen to form a ring of formula X-1, where r is 0; n and p are independently 1, 2, 3, or 4; and A is CH(CH2). q NR e R f where q is 0 and R e and R fare linked together with the N to which they are attached to form a 4-8 membered heterocycle. In some embodiments, n and p are independently 1 or 2, and q is 0. In some embodiments, n and p are independently 1 or 2, q is 0, and R e and R f are linked together with the N to which they are attached to form a 4-6 membered heterocycle. Examples of 4-6 membered heterocycles include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl, azocanyl, pyrrolidinyl, and piperidinyl.

[0088] In some embodiments, the compound of formula I is

[0089] [ka]

[0090] The compound is selected from the group consisting of:

[0091] In some embodiments, the compound of formula I is

[0092] [ka]

[0093] The compound is selected from the group consisting of:

[0094] In some embodiments, the compound of formula I is

[0095] [ka]

[0096] The compound is selected from the group consisting of:

[0097] In any embodiment disclosed herein, the compound may also be in its salt-free form, for example, the compound may be in the salt-free form of the exemplary HCl salt above.

[0098] The compounds disclosed herein can be prepared via a variety of suitable approaches. The reaction conditions for each step in the synthesis can be determined by considering the embodiments illustrated herein and the literature available in the art, such as U.S. Pat. No. 9,428,453. The synthesis can also include selective protection of functional groups for intermediates. Protective groups for different functional groups are well known in the art, as reported in Greene's Protective Groups in Organic Synthesis, Wiley-Interscience; 4th edition, by Peter Wuts et al. The entire disclosure of this patent and references is incorporated herein by reference.

[0099] An exemplary synthesis scheme for the compounds of this patent is shown below:

[0100] [ka]

[0101] A related embodiment provides a compound represented by formula A', a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0102] [ka]

[0103] Here, R 1 and R 2 Each pair of is independently defined as follows: a)R 1 is H and R 2 (CH2) m NR a R band m is 2, 3 or 4, where R a and R b are each independently C 1-8 alkyl or R a and R b is linked together with the N to which it is attached to form a 4-8 membered heterocycle, wherein the carbons within said 4-8 membered heterocycle are selected from the group consisting of O, S, NH, and NC 1-8 may be substituted with a heteroatom selected from the group consisting of alkyl; or b)R 1 and R 2 is linked together with the amide nitrogen to form a ring of formula X-1:

[0104] [ka]

[0105] Here, R 3 is C 1-8 alkyl, r is 0, 1, or 2; n and p are independently 2 or 3; A is NR c where R c is C 6-10 aryl (e.g., phenyl or naphthyl) or 5-10 membered heteroaryl. 6-10 Aryl and 5-10 membered heteroaryl are C 1-8 Alkyl, halogen, CN, NO2, OH, SH, and OC 1-6 It may be substituted with one or more substituents selected from alkyl.

[0106] Substituent subembodiments are as described above for formula I. Each of the chiral centers at the NH2-bonded carbon may have an R or S configuration. For example, the compound of formula A' may have RR, RS, or SS configuration at the two chiral centers. In some embodiments, the compound of formula A' has RR configuration at the two chiral centers.

[0107] Another aspect of this patent document provides a compound represented by formula B, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof:

[0108] [ka]

[0109] Here, R 1 and R 2 Each pair of is independently defined as follows: a)R 1 and R 2 are each independently H or (CH2) m NR a R b and m is 2, 3, or 4; a and R b are each independently C 1-8 alkyl or R a and R b are joined together with the N to which they are attached to form a 4-8 membered heterocycle, wherein the carbons within said 4-8 membered heterocycle are selected from the group consisting of O, S, NH, and NC 1-8 alkyl, but R 1 and R 2 At least one of (CH2) m NR a R b is; or b)R 1 and R 2 is linked with the amide nitrogen to form a ring of formula P-1:

[0110] [ka]

[0111] Here, R 3 is C 1-8 alkyl, and r is 0, 1, or 2; n, p, and A are defined as follows: i) n and p are independently 2 or 3; A is NR c where R c is H, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl; ii) n is 0, 1, or 2 and p is 2, 3, or 4; A is a structure of formula Q-1:

[0112] [ka]

[0113] Here, R d is H or C 1-8 is alkyl; s is 0, 1, or 2; t is 2, 3, or 4; provided that when n is 0, s is 1 or 2; or iii) n and p are independently 1, 2, 3 or 4; A is CH(CH2) q NR e R f and Here, R e and R f is independently C 1-8 alkyl; q is 0 to 3; Or, R e and R f join together with the N to which they are attached to form a 4- to 8-membered heterocycle; E is H or C 1-8 It is an alkyl.

[0114] Each of the chiral centers at the NH2-bonded carbon of formula B can have an R or S configuration. For example, the compound of formula B can have the RR, RS, or SS configuration at the two chiral centers.

[0115] In some embodiments, Formula B is in the form of Formula II.

[0116] [ka]

[0117] In some embodiments, R 1 is H and R 2 (CH2) m NR a R b m is 2 or 3; R a and R b are each independently C 1-2 In some embodiments, R 1 is H and R 2 (CH2) m NR a R b and m is 2 or 3, where R a and R b are linked to form a 4-, 5-, 6-, 7-, or 8-membered heterocycle, where a carbon within the ring may be optionally substituted with O.

[0118] In some embodiments, R 1 and R 2 are linked together with the amide nitrogen to form a ring of formula P-1, where r is 0, n and p are independently 2 or 3 or 4, and A is NR c and R c is hydrogen or methyl.

[0119] [ka]

[0120] In some embodiments, R 1 and R 2 is linked together with the amide nitrogen to form a ring of formula P-1, where r is 0, n and p are independently 2 or 3 or 4; A is NR c where R c is C 2-8 Alkyl or C 3-8In some embodiments, n and p are 2 and R c is selected from the group consisting of tert-butyl, cyclopropyl, cyclobutyl, and cyclopentyl. c is tert-butyl or cyclopentyl.

[0121] In some embodiments, R 1 and R 2 are linked together with the amide nitrogen to form a ring of formula P-1, where r is 0, n and p are independently 2 or 3 or 4; A is NR c where R c is C 6-10 aryl (e.g., phenyl or naphthyl) or 5-10 membered heteroaryl. 6-10 Aryl and 5-10 membered heteroaryl are C 1-8 Alkyl, halogen, CN, NO2, OH, SH, and OC 1-6 It may be substituted with one or more substituents selected from alkyl.

[0122] In some embodiments, R 1 and R 2 are linked together with the amide nitrogen to form a ring of formula P-1, where r is 0 and A is of formula Q-1. In some embodiments, n is 0 and s is 1 or 2. In some embodiments, n is 1 or 2 and s is 0, 1 or 2. In some embodiments, n is 0, p is 3 and n is 1 or 2. In some embodiments, n and p are each 2, s is 0 and t is 2 or 3.

[0123] [ka]

[0124] In some embodiments, R 1 and R 2are linked together with the amide nitrogen to form a ring of formula P-1, where r is 0; n and p are independently 1, 2, 3, or 4; A is CH(CH2) q NR e R f where R e and R f is independent, C 1-8 and q is 0, 1, 2, or 3. In some embodiments, q is 0.

[0125] [ka]

[0126] In some embodiments, R 1 and R 2 is linked together with the amide nitrogen to form a ring of formula P-1, where r is 0 and A is CH(CH2) q NR e R f where q is 0 and R e and R f are linked together with the N to which they are attached to form a 4-8 membered heterocycle. In some embodiments, R e and R f are linked together with the N to which they are attached to form a 4- or 5-membered ring.

[0127] [ka]

[0128] In some embodiments, E is H. In some embodiments, E is C 1-8 It is an alkyl.

[0129] In some embodiments, the compound of formula II is selected from:

[0130] [ka]

[0131] Another embodiment provides a prodrug compound represented by formula C, a pharma- ceutically acceptable salt thereof, or a solvate thereof:

[0132] [ka]

[0133] where: R 1 and R 2 Each pair of is independently defined as follows: a)R 1 is H or X', and R 2 (CH2) m NR a R b and m is 2, 3, or 4; a and R b are each independently C 1-8 alkyl or R a and R b are joined together with the N to which they are attached to form a 4-8 membered heterocycle, wherein the carbons within said 4-8 membered heterocycle are selected from the group consisting of O, S, NH, and NC 1-8 may be substituted with a heteroatom selected from the group consisting of alkyl; or b)R 1 and R 2 is linked together with the amide nitrogen to form a ring of formula X-1:

[0134] [ka]

[0135] where R 3 is C 1-8 where r is 0, 1, or 2; n, p, and A are defined as follows: i) n and p are independently 2 or 3; A is NR cwhere R c , H, C 2-8 Alkyl, C 3-8 cycloalkyl or X'; ii) n is 0, 1, or 2 and p is 2, 3, or 4; A is a structure of formula Y-1:

[0136] [ka]

[0137] Here, R d , H, C 1-8 is alkyl or X'; s is 0, 1, or 2; t is 2, 3, or 4; provided that when n is 0, s is 1 or 2; or iii) n and p are independently 1, 2, 3 or 4; A is CH(CH2) q NR e R f and Here, R e and R f is independently C 1-8 alkyl or R e and R f One of them is C 1-8 alkyl and the other is X'; q is 0 to 3; or R e and R f join together with the N to which they are attached to form a 4- to 8-membered heterocycle; R X is H or C 1-6 is alkyl; X' is H, alkoxycarbonyl (R'OCO) or (acyloxy)alkoxycarbonyl (R'COOCH(R")OCO, where R' is H or C 1-6 alkyl, R" is H or C 1-6 alkyl, with the proviso that at least one X' is not hydrogen.

[0138] The prodrug compounds of formula III can be derived from compounds of formula I or any of the exemplified compounds under formula A. The compounds can contain chiral centers having RR, RS, or SS configurations. In some embodiments, formula C has the stereochemistry as in formula III. All groups of formula III are R X , X′, including items (a) and (b), are all as defined in Formula C.

[0139] [ka]

[0140] When a substituent occurs multiple times in a formula, its definition may be the same or different, regardless of the position of the multiple occurrences. For example, X' and R' at each occurrence may be the same or different. In some embodiments, R 1 is the same in each case, and R 2 is the same in each case.

[0141] In some embodiments of Formula III, R 1 , R 2 or any of these subembodiments does not contain X', and X' is only present at one or both of the amino groups alpha to the carbonyl moiety.

[0142] In some embodiments, the compound is defined as formula III-a.

[0143] [ka]

[0144] In some embodiments of Formula III-a, R 1 is X', which is an alkoxycarbonyl (R'OCO) or (acyloxy)alkoxycarbonyl (R'COOCH(R")OCO), and R 2 (CH2) m NR aR b where m is 2 or 3; R a and R b are each independently C 1-2 In some embodiments of Formula III-a, R 1 is (R'OCO) or (acyloxy)alkoxycarbonyl (R'COOCH(R")OCO), and R 2 (CH2) m NR a R b and m is 2 or 3, where R a and R b are linked to form a 5- to 8-membered heterocycle, and a carbon in the ring may be substituted with O.

[0145] In some embodiments of Formula III-a, R 1 and R 2 is linked to the amide nitrogen to form a ring of formula X-1:

[0146] [ka]

[0147] where r is 0, and n and p are independently 2 or 3 or 4; A is NX', where X' is alkoxycarbonyl (R'OCO) or (acyloxy)alkoxycarbonyl (R'COOCH(R")OCO). In some embodiments, n and p are independently 2, and R c is selected from the group consisting of tert-butyl, cyclopropyl, cyclobutyl, and cyclopentyl.

[0148] In some embodiments of Formula III-a, R 1 and R 2 is linked to the amide nitrogen to form a ring of formula X-1:

[0149] [ka]

[0150] where r is 0 and A is of formula Y-1:

[0151] [ka]

[0152] In the formula, R d is X', where X' is alkoxycarbonyl (R'OCO) or (acyloxy)alkoxycarbonyl (R'COOCH(R")OCO). In some embodiments, n is 0 and s is 1 or 2. In some embodiments, n is 1 or 2 and s is 0, 1 or 2.

[0153] In some embodiments of Formula III-a, R 1 and R 2 is linked to the amide nitrogen to form a ring of formula X-1:

[0154] [ka]

[0155] wherein r is 0, and n and p are independently 1, 2, 3, or 4; A is CH(CH2) q NR e R f and R e and R f One is C 1-8 X' is an alkyl group and the other is an alkoxycarbonyl group (R'OCO) or an (acyloxy)alkoxycarbonyl group (R'COOCH(R"))OCO; and q is 0-3.

[0156] Another aspect of the present disclosure provides a pharmaceutical composition containing a therapeutically effective amount of the above-mentioned compound, its pharma- ceutically acceptable salt, its solvate, or its prodrug, and a pharma- ceutically acceptable carrier. The pharmaceutical composition can also contain one or more physiologically acceptable surfactants, additional carriers, diluents, excipients, lubricants, suspending agents, film-forming substances, and coating aids, or combinations thereof; and the compositions disclosed herein. Additional acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical arts, and are described, for example, 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, aromas, flavorings, and the like can be provided in the pharmaceutical composition. For example, sodium benzoate, esters of ascorbic acid and p-hydroxybenzoic acid can be added as preservatives. In addition, antioxidants and suspending agents can be used. In various embodiments, alcohols, esters, sulfated fatty alcohols, etc. can be used as surfactants, sucrose, glucose, lactose, starch, microcrystalline cellulose, crystallized cellulose, mannitol, light anhydrous silicic acid, magnesium aluminate, magnesium metasilicate, synthetic aluminum silicate, calcium carbonate, sodium carbonate, calcium hydrogen phosphate, calcium carboxymethylcellulose, etc. can be used as excipients, magnesium stearate, talc, hydrogenated oils, etc. can be used as lubricants, coconut oil, olive oil, sesame oil, peanut oil, soybean can be used as suspending agents or lubricants, cellulose acetate phthalate can be used as a derivative of carbohydrates such as cellulose or sugar, or methyl acetate-methacrylate copolymer as a derivative of polyvinyl can be used as a suspending agent, and plasticizers such as ester phthalates can be used as suspending agents.

[0157] The pharmaceutical compounds described herein can be administered to human patients by themselves or in pharmaceutical compositions in which they are mixed with other active ingredient(s), as in combination therapy, or in suitable carriers or excipient(s). In some embodiments, the dosage form includes a form in which the compound is administered by itself. Additionally, the dosage form may include a pharmaceutical composition. In either case, the dosage form may include a sufficient amount of the compound to treat a disease as part of a particular administration protocol, as will be understood by those skilled in the art. Techniques for formulation and administration of the compounds of the present application may be found in "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0158] Suitable routes of administration may include, for example, oral, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracerebroventricular, intraperitoneal, intranasal, or intraocular injection. Compounds may also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and / or timed pulse administration at a predetermined rate.

[0159] The pharmaceutical compositions may be manufactured in a manner that is itself known, for example by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.

[0160] Pharmaceutical compositions can be formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents that facilitate the processing of active compound into preparations that can be used medicaments.Appropriate formulation depends on the route of administration selected.Any of the well-known techniques, diluents, carriers and excipients can be used as appropriate and understood in the art, for example, in Remington's Pharmaceutical Sciences, above.

[0161] Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine ​​hydrochloride, and the like. In addition, if desired, the injectable pharmaceutical composition can contain small amounts of non-toxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. Physiologically compatible buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer. Absorption enhancing preparations can be utilized if desired.

[0162] For transmucosal administration, penetrants appropriate to the barrier to be permeated can be used in the formulation.

[0163] Pharmaceutical preparations for parenteral administration, for example by bolus injection or continuous infusion, include aqueous solutions of the active compound in water-soluble form. Additionally, suspensions of the active compound may be prepared as appropriate oily injection suspensions. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions. Injectable preparations may be presented in unit dosage form, for example in ampoules or multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0164] For oral administration, the composition can be easily formulated by combining the composition of interest with pharma- ceutically acceptable carriers well known in the art. Such carriers, which can be used in addition to cationic polymeric carriers, allow the composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use are prepared by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules to obtain tablets or dragee cores, after adding suitable auxiliaries if desired. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP), for example, povidone. If desired, disintegrating agents such as cross-linked polyvinylpyrrolidone (e.g., crospovidone), agar, or alginic acid or its salts such as sodium alginate may be added. Dragee cores are provided with suitable coatings. For this purpose, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and concentrated sugar solutions that may optionally contain suitable organic solvents or solvent mixtures may be used. Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0165] Orally usable pharmaceutical preparations include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain active ingredients mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycol, and the like. Additionally, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[0166] For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner. Buccal and sublingual administration are contemplated.

[0167] For administration by inhalation, the composition can be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer by using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount.Capsules and cartridges, for example of gelatin, for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base, for example, lactose or starch.

[0168] The compositions may also be formulated in rectal compositions such as suppositories or enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0169] A related aspect provides a kit comprising the compound disclosed herein or its pharma- ceutically acceptable salt, or its pharmaceutical composition, and instructions for treating or preventing a disease associated with mutations in SLC3A1 and / or SLC7A9 genes in a subject.In some embodiments, the kit further comprises an additional agent for treating such a disease.Non-limiting examples of the second agent include citrate supplementation, acetazolamide, and a chelating agent.

[0170] Another aspect of the present disclosure provides a method for treating a disease associated with a mutation in the SLC3A1 gene and / or the SLC7A9 gene in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, its pharma- ceutically acceptable salt, its solvate, or its prodrug, or its pharmaceutical composition. Particular embodiments of the compound of formula I, its salt, or its pharmaceutical composition are as described above.

[0171] In some embodiments, the disease is cystinuria. By reducing the concentration of L-cystine in urine and / or increasing the solubility of L-cystine in urine, the compounds disclosed herein effectively inhibit cystine stone formation.

[0172] Another aspect of this patent document provides a method for treating, inhibiting or slowing the development of L-cystine kidney stone formation in a subject in need thereof, the method comprising administering to a subject in need thereof a pharma- ceutical effective amount of a compound of formula I, a pharmaceutical salt thereof, or a pharmaceutical composition thereof.

[0173] The methods disclosed herein can be applied to humans and animals. In some embodiments, the subject or patient is a human. In some embodiments, the subject or patient is an animal, including, for example, sheep, horses, cows, pigs, dogs, cats, rats, mice, birds, and reptiles. In some embodiments, the subject or patient is a livestock animal.

[0174] In any of the methods disclosed herein, the compounds may also be used in combination with other agents used for the treatment of cystinuria or other agents that enhance such treatment regimens for subjects in need of such treatment. The individual components of such combinations may be administered separately at different times during the course of treatment, or in divided or single combined form, simultaneously to the patient or to the area of ​​such patient in need of such treatment. Thus, the present invention should be understood to embrace all such regimes of simultaneous or alternating treatment, and the term "administer" should be interpreted accordingly. The scope of combinations of the compounds of the present invention with other agents useful for treating the target condition is understood to include, in principle, any combination with any pharmaceutical composition useful for treating disorders related to kidney stones or related chronic kidney disease. In some embodiments, the second agent is selected from citrate supplementation, acetazolamide, and a chelating agent.

[0175] It should be noted that the attending physician would know how and when to discontinue, interrupt, or adjust dosing due to toxicity or organ dysfunction. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response was not adequate (excluding toxicity). The magnitude of the administered dose in the management of the disorder of interest will vary with the severity of the condition being treated and the route of administration. The severity of the condition may, for example, be assessed, in part, by standard prognostic evaluation methods. Furthermore, the dosage and perhaps frequency of administration will also vary according to the age, weight, and response of the individual patient. A program comparable to that discussed above can be used in veterinary medicine.

[0176] The exact dosage will be determined for each agent, but in most cases some generalizations regarding dosage are possible. A daily dosage regimen for an adult human patient may be, for example, an oral dose of about 0.1 mg to 2000 mg, preferably about 1 mg to about 500 mg, e.g., 5 to 200 mg, of active ingredient. In other embodiments, an intravenous, subcutaneous, or intramuscular dose of about 0.01 mg to about 100 mg, preferably about 0.1 mg to about 60 mg, e.g., about 1 to about 40 mg, of active ingredient is used. In the case of administration of a pharma-ceutically acceptable salt, the dosage may be calculated as the free acid. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively, the composition may be administered by continuous intravenous infusion, preferably at a dose of up to about 1000 mg per day. As will be appreciated by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed or far exceed the preferred dosage ranges set forth above in order to effectively and aggressively treat a particularly aggressive disease or condition. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0177] The amount of composition administered will be dependent on the subject being treated, on the subject's weight, the severity of the condition, the manner of administration, and the judgment of the prescribing physician.

[0178] The composition may be provided in a pack or dispenser device, if desired, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise a metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the agency of the form of pharmaceutical for human or veterinary administration. Such notice may, for example, be a label approved for prescription drugs by the U.S. Food and Drug Administration, or an approved product insert. A composition comprising a compound formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for the treatment of an indicated condition. EXAMPLES

[0179] synthesis [Example 1] L-cystine bispiperazide tetrahydrochloride (LH1726)

[0180] [ka]

[0181] Boc-L-cystine-OH (70 mg, 0.16 mmol) was suspended in 2 mL of dry DCM. DIEA (168 μL, 0.96 mmol) was added to give a clear solution. Then, tert-butyl piperazine-1-carboxylate (90 mg, 0.48 mmol) and PyAOP (174 mg, 0.33 mmol) were added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (20 mL) and extracted with DCM (3×40 mL). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the yellow residue was purified by ISCO (5% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 42%. The solvent was evaporated under reduced pressure to give a pale yellow solid (74 mg, 60% yield). 1H NMR (400 MHz, CDCl3)δ 1.43(s, 18H), 1.47(s, 18H), 3.01(b, 4H), 3.40-3.67(m, 16H), 4.93(t, 2H, J= 8 Hz), 5.44(d, 2H, J= 8 Hz). 13 C NMR (100 MHz, CDCl3)δ 169.16, 154.99, 154.44, 80.39, 49.13, 45.75, 42.23, 41.52, 28.33.LC-MS (ESI + ) m / z 777.1 [M + H] + .

[0182] The above compound (12 mg, 0.015 mmol) was dissolved in 60 μL of MeOH and cooled to 0° C. Four portions of 4M HCl / dioxane (70 μL, 0.28 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. Some mono-deprotected product was still present, so additional 4M HCl / dioxane (70 μL, 0.28 mmol) was added in two portions to the solution at 0° C., and the solution was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated with N2, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated three times. The residue was dried to give a pale yellow solid (6 mg, 85% yield). 1 H NMR (400 MHz, D2O)δ 3.34-3.44(m, 12H), 3.71-3.77(m, 2H), 3.94-4.10(m, 8H). 13 C NMR (100MHz, D2O) δ166.60, 49.70, 42.71, 39.36, 37.88. LC-MS(ESI+)m / z 377.2[M+H]+. HRMS (ESI+)M / z calculated for C 14 H 29 N6O2S2+[M+H]+377.1788, found 377.1799.

[0183] [Example 2] L-cystine bis(N'-tert-butylpiperazide) tetrahydrochloride (LH1729)

[0184] [ka]

[0185] Boc-L-Cystine-OH (70 mg, 0.16 mmol) was suspended in 2 mL of dry DCM. DIEA (168 μL, 0.96 mmol) was added to give a clear solution. 1-tert-butylpiperazine (77 μL, 0.48 mmol) and PyAOP (174 mg, 0.33 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (20 mL) and extracted with DCM (3×40 mL). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by ISCO (20% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 25%. The solvent was evaporated under reduced pressure to give a pale yellow solid (80 mg, 73% yield). 1 H NMR (400 MHz, CDCl3)δ 1.06(s, 18H), 1.42(s, 18H), 2.56(b, 8H), 2.94-3.02(m, 4H), 3.64(b, 8H), 4.93(b, 2H), 5.46(d, 2H, J= 8 Hz). 13 C NMR (100 MHz, CDCl3)δ 168.62, 155.04, 80.03, 49.05, 46.35, 45.51, 42.89, 41.84, 28.35, 25.84. + )M / z 689.22[M+H] + .

[0186] The above compound (27 mg, 0.04 mmol) was dissolved in 120 μL of MeOH and cooled to 0° C. Four portions of 4M HCl / dioxane (116 μL, 0.46 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. Some mono-deprotected product was still present, so additional 4M HCl / dioxane (58 μL, 0.23 mmol) was added to the solution at 0° C., and the solution was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated with N2, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated three times. The residue was dried to give a pale yellow solid (21 mg, 84% yield). 1 H NMR (400 MHz, D2O)δ 1.46(s, 18H), 3.21-3.44(m, 12H), 3.76(b, 8H), 4.29(b, 2H). 13 C NMR (100 MHz, D2O)δ 166.33, 64.82, 49.74, 45.66, 42.94, 39.88, 37.55, 23.62. LC-MS (ESI + ) m / z 489.23 [M + H] + . HRMS(ESI+)m / z calculated for C 22 H 45 N6O2S2 + [M + H] + 489.3040, found 489.3075.

[0187] [Example 3] L-cystine bis(N'-cyclopropylpiperazide) tetrahydrochloride

[0188] [ka]

[0189] Boc-L-Cystine-OH (70 mg, 0.16 mmol) was suspended in 2 mL of dry DCM. DIEA (168 μL, 0.96 mmol) was added to give a clear solution. 1-Cyclopropylpiperazine (58 μL, 0.48 mmol) and PyAOP (174 mg, 0.33 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (20 mL) and extracted with DCM (3×40 mL). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the dark yellow residue was purified by ISCO (5% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 25%. The solvent was evaporated under reduced pressure to give a yellow solid (70 mg, 67%). 1 H NMR (400 MHz, CDCl3)δ 0.40-0.46(m, 8H), 1.41(s, 18H), 1.60(b, 2H), 2.57-2.62(m, 8H), 2.96-3.03(m, 4H), 3.56(b, 8H), 4.93(t, 2H, J= 8 Hz), 5.47(d, 2H, J= 8 Hz). 13 C NMR (100 MHz, CDCl3)δ 168.76, 155.02, 80.06, 53.10, 49.11, 45.84, 41.81, 38.20, 28.35, 5.93.LC-MS (ESI + ) m / z 657.09[M + H] + .

[0190] The above compound (28 mg, 0.04 mmol) was dissolved in 120 μL of MeOH and cooled to 0° C. Four portions of 4M HCl / dioxane (192 μL, 0.77 mmol) were added to the cooled solution every 30 min, and after each addition, the solution was allowed to warm to room temperature. The solvent was evaporated with N2, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated three times. The residue was dried to give a pale yellow solid (19 mg, 80%). 1H NMR (400 MHz, D2O)δ 1.03(s, 8H), 2.91(b, 2H), 3.30-3.86(m, 20H), 4.69(b, 2H). 13 C NMR (100MHz, D2O) δ166.51, 51.88, 49.81, 42.57, 39.47, 37.86, 3.64. LC-MS(ESI+)m / z 457.3[M+H]+. HRMS (ESI+)m / z calculated for C20H 37 N6O2S2+[M+H]+457.2414, found 457.2444.

[0191] [Example 4] L-cystine bis(N'-cyclopentylpiperazide) tetrahydrochloride (LH1731)

[0192] [ka]

[0193] Boc-L-Cystine-OH (70 mg, 0.16 mmol) was suspended in 2 mL of dry DCM. DIEA (168 μL, 0.96 mmol) was added to give a clear solution. 1-Cyclopentylpiperazine (75 μL, 0.48 mmol) and PyAOP (174 mg, 0.33 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (20 mL) and extracted with DCM (3×40 mL). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by ISCO (20% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 25%. The solvent was evaporated under reduced pressure to give a pale yellow solid (85 mg, 75% yield). 1H NMR (400 MHz, CDCl3)δ 1.41(s, 18H), 1.48-1.58(m, 8H), 1.74(b, 4H), 1.89(b, 4H), 2.68(b, 8H), 2.98(b, 4H), 3.01-3.15(m, 2H), 3.75(b, 8H), 4.91(b, 2H), 5.44(d, 2H, J= 8 Hz). 13 LC-MS (ESI + ) m / z 713.19[M + H] + .

[0194] The above compound (36 mg, 0.05 mmol) was dissolved in 150 μL of MeOH and cooled to 0° C. Four portions of 4M HCl / dioxane (150 μL, 0.6 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. Some mono-deprotected product was still present, so additional 4M HCl / dioxane (75 μL, 0.3 mmol) was added to the solution at 0° C., and the solution was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated with N2, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated three times. The residue was dried to give a pale yellow solid (25 mg, 76% yield). 1 H NMR (400 MHz, D2O)δ 1.64-1.83(m, 14H), 2.18(b, 4H), 3.16-3.43(m, 10H), 3.60-3.82(m, 10H), 4.24(b, 2H). 13 C NMR (100MHz, D2O) δ166.23, 68.22, 50.17, 49.74, 42.77, 39.72, 27.84, 23.34. LC-MS(ESI+)m / z 513.32[M+H]+. HRMS (ESI+)m / z calculated for C 24 H 45N6O2S2+[M+H]+513.3040,found 513.3069.

[0195] [Example 5] L-cystine bis(2',2'-dimethylpiperazide) tetrahydrochloride (LH1733)

[0196] [ka]

[0197] Boc-L-Cystine-OH (70 mg, 0.16 mmol) was suspended in 2 mL of dry DCM. DIEA (168 μL, 0.96 mmol) was added to give a clear solution. Then tert-butyl 2,2-dimethylpiperazine-1-carboxylate (103 mg, 0.48 mmol) and PyAOP (174 mg, 0.33 mmol) were added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (20 mL) and extracted with DCM (3×40 mL). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the yellow residue was purified by ISCO (5% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 45%. The solvent was evaporated under reduced pressure to give a colorless oil (80 mg, 60% yield). 1 H NMR (400 MHz, CDCl3)δ 1.36(s, 12H), 1.41(s, 18H), 1.46(s, 18H), 2.99(b, 4H), 3.48-3.88(m, 12H), 4.88(b, 2H), 5.32(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 170.93, 155.11, 154.80, 80.31, 56.11, 54.05, 50.56, 49.34, 45.32, 43.96, 39.81, 28.35, 25.03. LC-MS(ESI+)m / z 832.98[M+H]+.

[0198] The above compound (7 mg, 0.009 mmol) was dissolved in 50 μL of MeOH and cooled to 0° C. Four portions of 4M HCl / dioxane (50 μL, 0.2 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. Some mono-deprotected product was still present, so additional 4M HCl / dioxane (25 μL, 0.1 mmol) was added to the solution at 0° C., and the solution was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated with N2, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated three times. The residue was dried to give a white solid (4 mg, 80% yield). 1 H NMR (400 MHz, D2O)δ 1.41-1.50(m, 12H), 3.34-3.50(m, 10H), 3.65-4.02(m, 6H), 4.28(b, 2H). 13 C NMR (100MHz, D2O) δ167.11, 55.09, 52.51, 49.72, 42.30, 39.06, 38.03, 22.45, 20.65. LC-MS(ESI+)m / z 433.3[M+H]+. HRMS (ESI+)m / z calculated for C 18 H 37 N6O2S2+[M + H]+433.2414,found 433.2444.

[0199] [Example 6] L-cystine bis(N',N'-dimethylethyleneamide) tetrahydrochloride (LH1734)

[0200] [ka]

[0201] Boc-L-Cystine-OH (200 mg, 0.45 mmol) was suspended in 6 mL of dry DCM. DIEA (488 μL, 2.8 mmol) was added to give a clear solution. N,N-Dimethylethylenediamine (151 μL, 1.38 mmol) and PyAOP (522 mg, 1 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (40 mL) and extracted with DCM (3×80 mL). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by ISCO (20% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 70%. The solvent was evaporated under reduced pressure to give a yellow-white solid (250 mg, 95% yield). 1 H NMR (400 MHz, DMSO)δ 1.36(s, 18H), 2.40(s, 12H), 2.64(t, 4H, J= 4 Hz), 2.83(dd, 2H, J= 8, 12 Hz), 3.08(dd, 2H, J= 4, 12 Hz), 3.24(b, 4H), 4.14(b, 2H), 7.05(d, 2H, J= 8 Hz), 8.01(b, 2H). 13 C NMR (100 MHz, DMSO)δ 170.44, 155.24, 78.36, 56.77, 53.64, 43.83, 40.54, 35.63, 28.12. LC-MS(ESI+)m / z 581.2[M + H]+.

[0202] The above compound (241 mg, 0.42 mmol) was dissolved in 1 mL of MeOH and cooled to 0° C. Two portions of 4M HCl / dioxane (1.3 mL, 5.1 mmol) were added to the cooled solution every 30 min, allowing the solution to warm to room temperature after each addition. Some mono-deprotected product was still present, so additional 4M HCl / dioxane (1.3 mL, 5.1 mmol) was added to the solution at 0° C., and the solution was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then filtered with an additional wash of diethyl ether. The residue was collected and dried to give a pale yellow solid (160 mg, 73% yield). 1 H NMR (400 MHz, D2O)δ 2.99(s, 12H), 3.23-3.29(m, 2H), 3.39(t, 4H, J= 4 Hz), 3.45-3.50(m, 2H), 3.58-3.68(m, 2H), 3.77-3.83(m, 2H), 4.44(dd, 2H, J= 8, 12 Hz). 13 C NMR (100MHz, D2O) δ168.79, 56.14, 52.03, 43.25, 37.14, 35.00. LC-MS(ESI+)m / z 381.21[M+H]+. HRMS (ESI+)m / z calculated for C 14 H 33 N6O2S2+[M+H]+381.2101,found 381.2125.

[0203] [Example 7] L-cystine bis(N'-pyrrolidinoethyleneamide) tetrahydrochloride (LH1735)

[0204] [ka]

[0205] Boc-L-Cystine-OH (70 mg, 0.16 mmol) was suspended in 2 mL of dry DCM. DIEA (168 μL, 0.96 mmol) was added to give a clear solution. N-(2-aminoethyl)pyrrolidine (61 μL, 0.48 mmol) and PyAOP (174 mg, 0.33 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (20 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the yellow residue was purified by ISCO (10% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 60%. The solvent was evaporated under reduced pressure to give a white solid (82 mg, 81%). 1 H NMR (400 MHz, CDCl3)δ 1.26(s, 18H), 1.68(b, 8H), 2.60(b, 12H), 2.86-3.10(m, 4H), 3.30(b, 4H), 4.47(b, 2H), 5.65(b, 2H), 7.64(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 170.50, 155.54, 79.86, 54.70, 54.24, 53.96, 44.24, 37.89, 28.28, 23.31. LC-MS(ESI+)m / z 633.26[M + H]+.

[0206] The above compound (31 mg, 0.05 mmol) was dissolved in 150 μL of MeOH and cooled to 0° C. Two portions of 4M HCl / dioxane (330 μL, 1.3 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. Some mono-deprotected product was still present, so additional 4M HCl / dioxane (330 μL, 1.3 mmol) was added to the solution in two portions at 0° C., and the solution was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure, and the residue was pumped dry. The yellow residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated six times. The residue was dried to give a yellow solid (25 mg, 86%).1 H NMR (400 MHz, D2O)δ 2.01(b, 4H), 2.16(b, 4H), 3.15-3.25(m, 6H), 3.45(b, 6H), 3.57(b, 2H), 3.73(b, 6H), 4.41(b, 2H). 13 C NMR (100MHz, D2O) δ168.70, 54.66, 53.34, 51.99, 37.07, 36.08, 22.68. LC-MS(ESI+)M / z 433.3[M+H]+. HRMS (ESI+)m / z calculated for C 18 H 37 N6O2S2+[M+H]+433.2414, found 433.2439.

[0207] [Example 8] L-cystine bis(N'-pyrrolidin-2-one ethyleneamide) dihydrochloride (LH1736)

[0208] [ka]

[0209] Boc-L-Cystine-OH (70 mg, 0.16 mmol) was suspended in 2 mL of dry DCM. DIEA (168 μL, 0.96 mmol) was added to give a clear solution. N-(2-aminoethyl)pyrrolidine (61 μL, 0.48 mmol) and PyAOP (174 mg, 0.33 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (20 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the yellow residue was purified by ISCO (10% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 60%. The solvent was evaporated under reduced pressure to give a white solid (82 mg, 81%). 1H NMR (400 MHz, CDCl3)δ 1.43(s, 18H), 1.95-2.01(m, 4H), 2.34(t, 4H, J= 8 Hz), 2.98(b, 4H), 3.34-3.52(m, 12H), 4.60(b, 2H), 5.58(b, 2H), 7.94(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 175.86, 170.69, 155.61, 80.24, 54.52, 47.34, 44.77, 42.13, 37.08, 31.02, 28.38, 18.03. LC-MS(ESI+)m / z 661.41[M+H]+.

[0210] The above compound (90 mg, 0.13 mmol) was dissolved in 350 μL of MeOH and cooled to 0° C. Four portions of 4M HCl / dioxane (920 μL, 3.68 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. The solvent was evaporated under reduced pressure and the residue was pumped dry. The yellow residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated three times. The residue was dried to give a pale yellow solid (67 mg, 99%). 1 H NMR (400 MHz, D2O)δ 2.04(b, 4H), 2.44(b, 4H), 3.12-3.19(m, 2H), 3.28-3.61(m, 14H), 4.32(b, 2H). 13 C NMR (100MHz, D2O) δ178.87, 167.90, 51.93, 47.91, 41.84, 37.22, 36.93, 31.13, 17.39. LC-MS(ESI+)m / z 461.43[M+H]+. HRMS (ESI+)m / z calculated for C 18 H 33 N6O2S2+[M+H]+461.2000, found 461.2028.

[0211] [Example 9] L-cystine bis(N'-piperidinoethyleneamide) tetrahydrochloride (LH1737)

[0212] [ka]

[0213] Boc-L-Cystine-OH (70 mg, 0.16 mmol) was suspended in 2 mL of dry DCM. DIEA (168 μL, 0.96 mmol) was added to give a clear solution. 1-(2-aminoethyl)piperidine (69 μL, 0.48 mmol) and PyAOP (174 mg, 0.33 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (20 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the yellow residue was purified by ISCO (5% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 80%. The solvent was evaporated under reduced pressure to give a yellow-white solid (95 mg, 90%). 1 H NMR (400 MHz, CDCl3)δ 1.37(s, 22H), 1.59(b, 8H), 2.54(b, 12H), 2.96-3.10(m, 4H), 3.38(b, 4H), 4.53(b, 2H), 5.65(d, 2H, J= 8 Hz), 7.65(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 170.42, 155.53, 79.99, 57.22, 55.24, 54.22, 43.89, 36.11, 28.34, 25.06, 23.62. LC-MS(ESI+)m / z 661.33[M + H]+.

[0214] The above compound (38 mg, 0.06 mmol) was dissolved in 150 μL of MeOH and cooled to 0° C. Two portions of 4M HCl / dioxane (404 μL, 1.62 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. Some mono-deprotected product was still present, so additional 4M HCl / dioxane (404 μL, 1.62 mmol) was added to the solution in two portions at 0° C., and the solution was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated six times. The residue was dried to give a yellow solid (31 mg, 86%). 1 H NMR (400 MHz, D2O)δ 1.15-1.19(m, 2H), 1.46-1.53(m, 6H), 1.96(b, 4H), 3.00(b, 4H), 3.19-3.25(m, 2H), 3.32(b, 4H), 3.41-3.47(m, 2H), 3.55-3.64(m, 6H), 3.71-3.77(m, 2H), 4.41(b, 2H). 13 C NMR (100MHz, D2O) δ168.62, 55.06, 53.64, 51.98, 37.08, 34.47, 22.76, 21.00. LC-MS(ESI+)m / z 461.4[M+H]+. HRMS(ESI+)m / z calculated for C 20 H 41 N6O2S2+[M+H]+461.2727, found 461.2755.

[0215] [Example 10] L-cystine bis(N'-morpholinoethyleneamide) tetrahydrochloride (LH1738)

[0216] [ka]

[0217] Boc-L-Cystine-OH (70 mg, 0.16 mmol) was suspended in 2 mL of dry DCM. DIEA (168 μL, 0.96 mmol) was added to give a clear solution. 4-(2-aminoethyl)morpholine (63 μL, 0.48 mmol) and PyAOP (174 mg, 0.33 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (20 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by ISCO (20% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 35%. The solvent was evaporated under reduced pressure to give a white solid (85 mg, 80%). 1 H NMR (400 MHz, CDCl3)δ 1.44(s, 18H), 2.44-2.50(m, 12H), 2.97-3.01(m, 4H), 3.29-3.45(m, 4H), 3.67(t, 8H, J= 4 Hz), 4.66(b, 2H), 5.63(d, 2H, J= 12 Hz), 7.51(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 170.18, 155.73, 80.16, 66.91, 57.45, 54.49, 53.53, 45.29, 36.43, 28.42. LC-MS(ESI+)m / z 665.3[M + H]+.

[0218] The above compound (55 mg, 0.08 mmol) was dissolved in 300 μL of MeOH and cooled to 0° C. Four portions of 4M HCl / dioxane (376 μL, 1.5 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. Some mono-deprotected product was still present, so additional 4M HCl / dioxane (188 μL, 0.74 mmol) was added to the solution at 0° C., warmed to room temperature, and stirred for 30 min. The solvent was evaporated under reduced pressure, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated four times. The residue was dried to give a yellow solid (49 mg, 100%). 1 H NMR (400 MHz, D2O)δ 3.20-3.28(m, 6H), 3.43-3.50(m, 6H), 3.60-3.68(m, 6H), 3.77-3.89(m, 6H), 4.13(b, 4H), 4.42-4.45(m, 2H). 13 C NMR (100MHz, D2O) δ168.70, 63.71, 55.57, 52.06, 51.95, 37.01, 34.11. LC-MS(ESI+)m / z 465.37[M+H]+. HRMS (ESI+)m / z calculated for C 18 H 37 N6O4S2+[M+H]+465.2313, found 465.2340.

[0219] [Example 11] L-cystine bis(N',N'-dimethyl-1',3'-diaminopropanamide) tetrahydrochloride (LH1739)

[0220] [ka]

[0221] Boc-L-Cystine-OH (70 mg, 0.16 mmol) was suspended in 2 mL of dry DCM. DIEA (168 μL, 0.96 mmol) was added to give a clear solution. Then 3-(dimethylamino)-1-propylamine (61 μL, 0.48 mmol) and PyAOP (174 mg, 0.33 mmol) were added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (20 mL) and extracted with DCM (3×40 mL). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by ISCO (20% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 75%. The solvent was evaporated under reduced pressure to give a pale yellow solid (55 mg, 58% yield). 1 H NMR (400 MHz, CDCl3)δ 1.45(s, 18H), 1.64-1.72(m, 4H), 2.20(s, 12H), 2.31(t, 4H, J= 8 Hz), 2.94-3.02(m, 4H), 3.25-3.33(m, 4H), 4.69(b, 2H), 5.61(d, 2H, J= 8 Hz), 7.90(b, 2H). 13 C NMR (100 MHz, DMSO)δ 170.07, 155.76, 80.08, 57.68, 54.51, 45.88, 45.41, 38.53, 28.41, 27.23. LC-MS(ESI+)m / z 609.23[M + H]+.

[0222] The above compound (18 mg, 0.03 mmol) was dissolved in 100 μL of MeOH and cooled to 0° C. Four portions of 4M HCl / dioxane (90 μL, 0.35 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. Some mono-deprotected product was still present, so additional 4M HCl / dioxane (90 μL, 0.35 mmol) was added in two portions to the solution at 0° C., and the solution was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated with N2, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated three times. The residue was dried to give a pale yellow solid (11 mg, 68% yield). 1 H NMR (400 MHz, D2O)δ 1.99-2.03(m, 4H), 2.91(s, 12H), 3.19-3.28(m, 6H), 3.35-3.43(m, 6H), 4.36(t, 2H, J= 8 Hz). 13 C NMR (100MHz, D2O) δ168.11, 55.34, 52.07, 42.87, 37.39, 36.68, 23.91. LC-MS(ESI+)m / z 409.26[M+H]+. HRMS (ESI+)m / z calculated for C 16 H 37 N6O2S2+[M+H]+409.2414, found 409.2438.

[0223] [Example 12] L-cystine bis(1'-pyrrolidine-3'-aminopropanamide) tetrahydrochloride (LH1740)

[0224] [ka]

[0225] Boc-L-Cystine-OH (70 mg, 0.16 mmol) was suspended in 2 mL of dry DCM. DIEA (168 μL, 0.96 mmol) was added to give a clear solution. Then 3-pyrrolidinopropylamine (66 μL, 0.48 mmol) and PyAOP (174 mg, 0.33 mmol) were added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (20 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the yellow residue was purified by ISCO (20% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 80%. The solvent was evaporated under reduced pressure to give a yellow solid (85 mg, 81%). 1 H NMR (400 MHz, CDCl3)δ 1.31(s, 18H), 2.02(b, 12H), 2.93(b, 4H), 3.18(b, 4H), 3.30(b, 4H), 3.60(b, 4H), 4.40(b, 2H), 5.78(b, 2H), 8.35(b, 2H). 13 C NMR (100 MHz, DMSO)δ 171.23, 155.33, 79.70, 54.14, 53.58, 52.94, 42.70, 36.55, 28.29, 25.59, 23.23. LC-MS(ESI+)m / z 661.33[M + H]+.

[0226] The above compound (39 mg, 0.06 mmol) was dissolved in 150 μL of MeOH and cooled to 0° C. Four portions of 4M HCl / dioxane (400 μL, 1.6 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. The solvent was evaporated under reduced pressure and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated six times. The residue was dried to give a yellow solid (16 mg, 45%). 1H NMR (400 MHz, D2O)δ 2.02-2.09(m, 8H), 2.16-2.24(m, 4H), 3.11-3.17(m, 4H), 3.27-3.33(m, 6H), 3.36-3.46(m, 6H), 3.70-3.76(m, 4H), 4.40(t, 2H, J= 8 Hz). 13 C NMR (100MHz, D2O) δ168.10, 54.34, 52.59, 52.16, 37.52, 36.89, 25.27, 22.73. LC-MS(ESI+)m / z 461.46[M+H]+. HRMS(ESI+)m / z calculated for C 20 H 41 N6O2S2+[M+H]+461.2727, found 461.2757.

[0227] [Example 13] L-cystine bis(1'-morpholine-3'-aminopropanamide) tetrahydrochloride (LH1741)

[0228] [ka]

[0229] Boc-L-Cystine-OH (70 mg, 0.16 mmol) was suspended in 2 mL of dry DCM. DIEA (168 μL, 0.96 mmol) was added to give a clear solution. 4-(2-aminoethyl)morpholine (63 μL, 0.48 mmol) and PyAOP (174 mg, 0.33 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (20 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (15 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by ISCO (20% MeOH: DCM + 0.1% TEA / DCM) and the product was eluted at 35%. The solvent was evaporated under reduced pressure to give a white solid (85 mg, 80%). 1H NMR (400 MHz, CDCl3)δ 1.30(s, 18H), 1.60-1.68(m, 4H), 2.40(b, 12H), 2.88(b, 4H), 3.15-3.20(m, 4H), 3.61(b, 8H), 4.49(b, 2H), 5.60(b, 2H), 7.76(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 170.27, 155.61, 79.99, 66.30, 56.48, 54.45, 53.46, 45.02, 38.09, 28.30, 25.56. LC-MS(ESI+)m / z 693.32[M + H]+.

[0230] The above compound (60 mg, 0.09 mmol) was dissolved in 250 μL of MeOH and cooled to 0° C. Four portions of 4M HCl / dioxane (584 μL, 1.5 mmol) were added to the cooled solution every 30 min, allowing the solution to warm to room temperature after each addition. The solvent was evaporated under reduced pressure and the residue was pumped dry. The yellow residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated six times. The residue was dried to give a yellow solid (40 mg, 85%). 1 H NMR (400 MHz, D2O)δ 2.06-2.12(m, 4H), 3.27-3.33(m, 10H), 3.41-3.48(m, 6H), 3.62(b, 4H), 3.89(t, 4H, J= 12 Hz), 4.20(b, 4H), 4.42(b, 2H). 13 C NMR (100MHz, D2O) δ168.16, 63.88, 54.89, 52.14, 51.91, 37.50, 36.82, 23.09. LC-MS(ESI+)m / z 493.47[M+H]+. HRMS(ESI+)m / z calculated for C 20 H 41 N6O4S2+[M+H]+493.2625, found 493.2662.

[0231] [Example 14] L-cystine bis(4'-(dimethylamino)-piperidinamide) tetrahydrochloride (LH1751)

[0232] [ka]

[0233] Boc-L-Cystine-OH (50 mg, 0.11 mmol) was suspended in 1 mL of dry DCM. DIEA (119 μL, 0.68 mmol) was added to give a clear solution. 4-(Dimethylamino)piperidine (40 μL, 0.28 mmol) and PyAOP (125 mg, 0.24 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (15 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by ISCO (20% MeOH: DCM + 0.3N NH3 / DCM) and the product was eluted at 35%. The solvent was evaporated under reduced pressure to give a colorless oil (68 mg, 94% yield). 1 H NMR (400 MHz, CDCl3)δ 1.40(s, 22H), 1.85(b, 4H), 2.24(s, 12H), 2.34(b, 2H), 2.58-2.67(m, 2H), 2.92-3.09(m, 6H), 4.07(b, 2H), 4.54(b, 2H), 4.93(b, 2H), 5.46(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 168.61, 155.00, 80.02, 74.76, 61.83, 53.42, 49.10, 44.83, 41.60, 29.01, 28.33. LC-MS(ESI+)m / z 633.1[M + H]+.

[0234] The above compound (24 mg, 0.036 mmol) was dissolved in 500 μL MeOH and cooled to 0° C. Two portions of 4M HCl / dioxane (270 μL, 1.08 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. Since there was still mono-deprotected product present, additional 4M HCl / dioxane (270 μL, 1.08 mmol) was added to the solution at 0° C., and the solution was allowed to warm to room temperature and stirred for 3 h. The solvent was evaporated under reduced pressure, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol, recrystallized with excess diethyl ether, and filtered. The residue was dried to give a white solid (22 mg, quantitative yield). 1 H NMR (400 MHz, D2O)δ 1.71-1.88(m, 4H), 2.25-2.36(m, 4H), 2.92(d, 12H, J= 4 Hz), 3.24-3.41(m, 6H), 3.62(b, 2H), 4.18(b, 2H), 4.64(b, 2H), 4.89-4.99(m, 2H). 13 C NMR (100MHz, D2O) δ166.16, 62.56, 49.91, 44.13, 41.34, 39.77, 26.25, 25.46. LC-MS(ESI+)M / z 461.3[M+H]+. HRMS(ESI+)M / z calculated for C 20 H 41 N6O2S2+[M+H]+461.2727, found 461.2757.

[0235] [Example 15] L-cystine bis(4'-(1"-pyrrolidinyl)piperidine) tetrahydrochloride (LH1752)

[0236] [ka]

[0237] Boc-L-Cystine-OH (50 mg, 0.11 mmol) was suspended in 1 mL of dry DCM. DIEA (119 μL, 0.68 mmol) was added to give a clear solution. 4-(1-pyrrolidinyl)-piperidine (44 mg, 0.28 mmol) and PyAOP (125 mg, 0.24 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (15 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the yellow residue was purified by ISCO (20% MeOH: DCM + 0.3N NH3 / DCM) and the product was eluted at 30%. The solvent was evaporated under reduced pressure to give a colorless oil (70 mg, 90% yield). 1 H NMR (400 MHz, CDCl3)δ 1.40(s, 20H), 1.76(b, 8H), 1.92(b, 4H), 2.25(b, 4H), 2.55(b, 8H), 2.76-3.15(m, 8H), 4.01(b, 2H), 4.40(b, 2H), 4.94(b, 2H), 5.50(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 168.59, 155.11, 80.03, 74.76, 61.36, 51.39, 49.10, 44.24, 41.14, 31.93, 30.97, 28.34, 23.24. LC-MS(ESI+)m / z 633.1[M+H]+.

[0238] The above compound (22 mg, 0.03 mmol) was dissolved in 500 μL MeOH and cooled to 0° C. Two portions of 4M HCl / dioxane (232 μL, 0.93 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. Since there was still mono-deprotected product present, additional 4M HCl / dioxane (232 μL, 0.93 mmol) was added to the solution at 0° C., and the solution was allowed to warm to room temperature and stirred for 3 h. The solvent was evaporated under reduced pressure, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol, recrystallized with excess diethyl ether, and filtered. The residue was dried to give a white solid (20 mg, quantitative yield).1 H NMR (400 MHz, D2O)δ 1.69-1.87(m, 4H), 2.02(b, 4H), 2.19(b, 4H), 2.35-2.43(m, 4H), 2.85-2.96(m, 2H), 3.20-3.46(m, 10H), 3.55(b, 2H), 3.71(b, 4H), 4.13(b, 2H), 4.59(b, 2H), 4.91-4.99(m, 2H). 13 C NMR (100MHz, D2O) δ165.86, 60.88, 51.76, 49.87, 43.90, 41.18, 28.52, 27.72, 22.48. LC-MS(ESI+)m / z 513.3[M+H]+. HRMS (ESI+)m / z calculated for C 24 H 45 N6O2S2+[M+H]+513.3040, found 513.3070.

[0239] [Example 16] L-cystine bis(1,8-diazaspiro[4.5]decan-8-yl) tetrahydrochloride (LH1753)

[0240] [ka]

[0241] Sodium carbonate (331 mg, 3.12 mmol) in 3 mL of water was added to a mixture of 1,8-diazapyro[4.5]decane-8-carboxylic acid tert-butyl ester (375 mg, 1.56 mmol) in 9 mL of dioxane and cooled to 0 °C. Fmoc-Cl (605 mg, 2.34 mmol) was added to the cooled mixture, then the reaction mixture was brought to room temperature and stirred for 2 h, then the mixture was kept in the refrigerator overnight. The mixture was concentrated as much as possible, diluted with water (30 mL) and extracted with DCM (3 x 60 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure and the yellow oil was purified via ISCO (50% EtOAc:Hexane / Hexane) and the product was eluted at 30%. The solvent was evaporated under reduced pressure to give a colorless oil (676 mg, 94%). 1H NMR (400 MHz, CDCl3)δ 0.81(b, 2H), 1.22(b, 2H), 1.39(s, 9H), 1.82(b, 4H), 2.63(b, 2H), 3.32-3.45(m, 4H), 4.20(b, 2H), 4.61(b, 1H), 7.25(t, 2H, J= 8 Hz), 7.34(t, 2H, J= 8 Hz), 7.54(d, 2H, J= 8 Hz), 7.71(d, 2H, J= 8 Hz). 13 C NMR (100 MHz, CDCl3)δ 154.58, 153.57, 144.24, 141.35, 127.61, 126.99, 125.08, 119.94, 79.40, 66.34, 62.84, 47.48, 42.09, 34.91, 32.91, 31.59, 28.47, 22.19. LC-MS(ESI+)m / z 633.1[M + H]+.

[0242] The above compound (324 mg, 0.7 mmol) was dissolved in 3 mL of dioxane and cooled to 0° C. To the cooled solution was added 4M HCl / dioxane (4.7 mL, 18.92 mmol) and the solution was warmed to room temperature and stirred for 1.5 h. The solvent was evaporated under reduced pressure and the white residue was pumped dry. The residue was then dissolved in a minimum amount of methanol, recrystallized with excess diethyl ether, and filtered. The residue was collected and dried to give a white solid (280 mg, quantitative yield). 1 H NMR (400 MHz, MeOD)δ 1.53(d, 2H, J= 12 Hz), 1.76(t, 2H, J= 8 Hz), 1.99(t, 2H, J= 8 Hz), 2.79(t, 2H, J= 12 Hz), 3.02(t, 2H, J= 12 Hz), 3.62-3.77(m, 3H), 4.20(dd, 2H, J= 4, 8 Hz), 4.41(d, 2H, J= 8 Hz), 7.30(t, 2H, J= 8 Hz), 7.38(t, 2H, J= 8 Hz), 7.58(d, 2H, J= 8 Hz), 7.78(d, 2H, J= 8 Hz). 13C NMR (100 MHz, MeOD)δ 145.39, 142.75, 128.82, 128.16, 126.01, 120.94, 67.62, 61.92, 47.40, 43.66, 36.22, 30.85, 23.00. Boc-L-Cystine-OH (97 mg, 0.22 mmol) was suspended in 3 mL of dry DCM. DIEA (460 μL, 2.64 mmol) was added to give a clear solution. The compound prepared above (263 mg, 0.66 mmol) and PyAOP (286 mg, 0.55 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 3 h. The mixture was quenched with water and concentrated under reduced pressure as much as possible, the residue was dissolved in (50 mL) of EtOAc, washed with (2×25 mL) of water, (3×25 mL) of 0.5N KHSO4, (25 mL) of water, (5 mL) of brine and dried over Na2SO4. The solvent was evaporated under reduced pressure and the yellow residue was purified via ISCO (EtOAc / Hexanes) and the product was eluted at 70%. The solvent was evaporated under reduced pressure to give a white solid (248 mg, quantitative yield). 1 H NMR (400 MHz, DMSO)δ 1.33(d, 22H, J= 12 Hz), 1.73(b, 4H), 1.92(b, 4H), 2.34(b, 4H), 2.50-3.08(m, 8H), 3.20(b, 4H), 3.99(b, 2H), 4.24(b, 2H), 7.25(b, 2H), 7.32(t, 4H, J= 8 Hz), 7.40(t, 4H, J= 8 Hz), 7.60(b, 4H), 7.88(d, 4H, J= 8 Hz). 13 C NMR (100 MHz, DMSO)δ 168.12, 154.73, 152.55, 143.97, 140.75, 127.58, 127.06, 125.02, 120.05, 78.30, 65.58, 62.26, 49.50, 47.20, 46.76, 42.68, 34.40, 32.93, 32.07, 28.09, 21.59. The above compound (177 mg, 0.15 mmol) was dissolved in 9 mL of anhydrous DCM and cooled to 0° C. Piperidine (155 μL, 1.57 mmol) was added to the cooled solution and the reaction mixture was stirred at room temperature for 7 h. The reaction mixture was cooled to 0° C. and additional piperidine (155 μL, 1.57 mmol) was added to the cooled solution and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the yellow residue was purified via ISCO (10% MeOH / DCM) and the product eluted at 90%. The solvent was evaporated under reduced pressure to give a colorless oil (70 mg, 70%). 1 H NMR (400 MHz, CDCl3)δ 1.41(s, 18H), 1.73(b, 2H), 1.89(m, 2H), 2.17(m, 12H), 2.81(m, 2H), 3.00(dd, 2H, J= 4, 12 Hz), 3.17(m, 2H), 3.27(m, 2H), 3.45(m, 2H), 3.50(m, 2H), 4.02(b, 2H), 4.46(b, 2H), 5.05(b, 2H), 5.38(b, 2H), 9.98(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 169.54, 154.77, 80.18, 65.56, 47.78, 43.76, 43.30, 39.04, 38.74, 35.30, 33.82, 32.70, 28.32, 22.55. The above compound (7 mg, 0.01 mmol) was dissolved in 50 μL of MeOH and cooled to 0° C. Two portions of 4M HCl / dioxane (76 μL, 0.3 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. The solvent was evaporated with N2, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol, recrystallized with excess diethyl ether, and filtered. The residue was dried to give a white solid (5 mg, quantitative yield). 1H NMR (400 MHz, D2O)δ 1.95-2.20(m, 12H), 3.19(t, 2H, J= 12 Hz), 3.25-3.47(m, 10H), 3.51-3.62(m, 2H), 3.90-3.98(m, 2H), 4.08(b, 2H), 4.29(b, 2H), 4.91(b,2H). 13 C NMR (100MHz, D2O) δ165.99, 65.81, 49.80, 44.40, 42.99, 39.98, 37.61, 33.46, 32.55, 22.30. LC-MS(ESI+)m / z 485.3[M+H]+. HRMS (ESI+)m / z calculated for C22H41N6O2S2+[M + H]+485.2727, found 485.2761.

[0243] [Example 17] L-cystine bis(1,8-diazaspiro[4.5]decan-1-yl) tetrahydrochloride (LH1754)

[0244] [ka]

[0245] Boc-L-Cystine-OH (120 mg, 0.272 mmol) was suspended in 4 mL of dry DCM. DIEA (285 μL, 1.63 mmol) was added to give a clear solution. 1,8-diazapyro[4.5]decane-8-carboxylic acid tert-butyl ester (327 mg, 1.36 mmol) and PyAOP (355 mg, 0.68 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water (10 mL), extracted with DCM (3×25 mL) and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure and the yellow residue was purified by ISCO (20% MeOH: DCM + 0.3N NH3 / DCM) and the product was eluted at 25%. The solvent was evaporated under reduced pressure to give a colorless oil (80 mg, 33%). 1H NMR (400 MHz, CDCl3)δ 1.21-1.25(m, 4H), 1.41(d, 36H, J= 8 Hz), 1.86-2.05(m, 8H), 2.70-2.98(m, 12H), 3.61(b, 2H), 3.70(b, 2H), 4.01(b, 2H), 4.10(b, 2H), 4.65(b, 2H), 5.34(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 168.87, 155.21, 154.52, 79.96, 79.42, 65.18, 52.42, 48.72, 41.83, 40.98, 34.96, 32.43, 28.45, 28.33, 22.70. The above compound (8 mg, 0.009 mmol) was dissolved in 50 μL of MeOH and cooled to 0° C. Two portions of 4M HCl / dioxane (76 μL, 0.3 mmol) were added to the cooled solution every 30 min, and the solution was allowed to warm to room temperature after each addition. The solvent was evaporated with N2, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated three times. The residue was dried to give a white solid (6 mg, quantitative yield). 1 H NMR (400 MHz, D2O)δ 1.75(b, 4H), 1.97-2.10(m, 6H), 2.15-2.22(m, 2H), 2.90-2.96(m, 4H), 3.07-3.18(m, 6H), 3.38-3.47(m, 6H), 3.66-3.72(m, 2H), 3.77-3.82(m, 2H), 4.57-4.60(m,2H). 13 C NMR (100MHz, D2O) δ165.92, 64.06, 51.94, 49.04, 42.18, 36.78, 34.57, 28.72, 28.08, 22.32. LC-MS(ESI+)m / z 485.3[M+H]+. HRMS (ESI+)m / z calculated for C 22 H 41 N6O2S2+[M+H]+485.2727, found 485.2761.

[0246] [Example 18] S-(((R)-2-amino-3-(4-methylpiperazin-1-yl)-3-oxopropyl)thio)-Z-cysteine ​​trihydrochloride (LH1727) Boc-L-cystine-OH (1 g, 2.27 mmol) was suspended in 10 mL of anhydrous DCM. Tert-butyl-2,2,2-trichloroacetimidate (1.2 mL, 6.81 mmol) was added to the mixture and the reaction mixture was stirred at room temperature for 4 h. Additional tert-butyl-2,2,2-trichloroacetimidate (0.6 mL, 3.4 mmol) was added to the mixture and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and washed with DCM and 3% EtOAc / Hexanes. The filtrate was evaporated under reduced pressure and the residue was purified by ISCO (50% EtOAc:Hexanes / Hexanes) and the product was eluted at 20%. The solvent was evaporated under reduced pressure to give diBoc-L-cystine di(t-butyl)ester as a colorless oil (760 mg, 61%). 1 H NMR (400 MHz, CDCl3)δ 1.45(d, 36H, J= 12 Hz), 3.09-3.22(m, 4H), 4.45(b, 2H), 5.33(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 169.63, 155.06, 82.70, 79.96, 53.81, 42.12, 28.33, 27.99. The above compound (693 mg, 1.25 mmol), triphenylphosphine (428 mg, 1.63 mmol), sodium acetate (41 mg, 0.7 mmol) were suspended in a mixture of 6 mL MeOH, 3 mL water, and 30 μL glacial acetic acid and heated to 60° C. for 75 min. The mixture was concentrated as much as possible, diluted with (200 mL) DCM, washed with (2×100 mL) water, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the yellow residue was purified via ISCO (50% EtOAc:hexane / hexane) and the product was eluted at 10%. The solvent was evaporated under reduced pressure to give Boc-L-cystine t-butyl ester as a white solid (600 mg, 87%). 1H NMR (400 MHz, CDCl3)δ 1.45(d, 19H, J= 12 Hz), 2.90-2.95(m, 2H), 4.45(b, 1H), 5.40(b, 1H). 13 C NMR (100 MHz, CDCl3)δ 169.29, 155.14, 82.67, 79.97, 55.09, 28.30, 28.01, 27.53. Boc-L-Cystine-OH (1 g, 2.27 mmol) was suspended in 25 mL of anhydrous DCM. DIEA (2.4 mL, 13.62 mmol) was added to obtain a clear solution. 1-Methylpiperazine (756 μL, 6.81 mmol) and PyAOP (2.9 g, 5.6 mmol) were then added to the solution and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water (100 mL) and extracted with DCM (2×200 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure and the yellow residue was purified by ISCO (20% MeOH: DCM + 0.3N NH3 / DCM) and the product was eluted at 90%. The solvent was evaporated under reduced pressure to give di-tert-butyl ((2R,2'R)-disulfanediylbis(3-(4-methylpiperazin-1-yl)-3-oxopropane-1,2-diyl)) dicarbamate (diBoc-LH708) as a pale yellow oil (1250 mg, 91%). 1 H NMR (400 MHz, CDCl3)δ 1.40(s, 18H), 2.27(s, 6H), 2.35-2.41(m, 8H), 2.92-3.04(m, 4H), 3.61(b, 8H), 4.92(b, 2H), 5.53(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 168.80, 155.02, 80.05, 54.53, 49.05, 45.74, 42.22, 41.67, 28.34. The di-Boc protected L-cystine diamide obtained above (1071 mg, 1.77 mmol), triphenylphosphine (604 mg, 2.3 mmol), sodium acetate (58 mg, 0.7 mmol) were suspended in a mixture of 10 mL MeOH, 5 mL water, and 42 μL glacial acetic acid and heated to 60° C. for 75 min. The mixture was concentrated as much as possible, diluted with (300 mL) DCM, washed with (2×100 mL) water, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the pale yellow oil was purified by ISCO (20% MeOH: DCM + 0.3N NH3 / DCM) and the product eluted at 35%. The solvent was evaporated under reduced pressure to give Boc-L-cysteine ​​amide as a colorless oil (900 mg, 84%). 1 H NMR (400 MHz, CDCl3)δ 1.39(s, 9H), 1.50(t, 1H, J= 8 Hz), 2.25(s, 3H), 2.33-2.38(m, 4H), 2.62-2.86(m, 2H), 3.54-3.61(m, 4H), 4.70(b, 2H), 5.59(d, 2H, J= 12 Hz). 13 C NMR (100 MHz, CDCl3)δ 168.58, 155.10, 80.02, 54.61, 51.63, 45.70, 42.18, 28.30, 27.39. To a stirred solution of 1-chlorobenzotriazole (74 mg, 0.48 mmol) and benzotriazole (29 mg, 0.24 mmol) in 8 mL of anhydrous DCM under argon at -78°C, a solution of the above Boc-L-cysteine ​​amide (73 mg, 0.24 mmol) in 2 mL of anhydrous DCM was added dropwise over 10 min. After 30 min, a solution of thiourea (54 mg, 0.72 mmol) in 6 mL of anhydrous THF was added and the reaction mixture was stirred at -78°C for an additional 15 min. The above obtained Boc-L-cystine t-butyl ester (100 mg, 0.36 mmol) in 2 mL of anhydrous DCM was added slowly at -78°C and the reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was filtered with additional DCM washings and the filtrate was evaporated under reduced pressure. The residue was purified by ISCO (20% MeOH:DCM + 0.3N NH3 / DCM) and the product eluted at 25%. The solvent was evaporated under reduced pressure to give diBoc L-cystine monoamide mono(t-butyl) ester as a colorless oil (80 mg, 58%). 1 H NMR (400 MHz, CDCl3)δ 1.40(d, 27H, J= 12 Hz), 2.26(s, 3H), 2.34-2.41(m, 4H), 2.83-3.16(m, 4H), 3.60(b, 4H), 4.39(b, 1H), 4.87-4.93(m, 1H), 5.43(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 169.55, 168.91, 155.05, 82.70, 80.13, 55.02, 54.45, 53.93, 48.98, 45.80, 42.08, 28.35, 27.98. The above compound (15 mg, 0.025 mmol) was dissolved in 100 μL of dioxane and cooled to 0° C. Two portions of 4M HCl / dioxane (324 μL, 1.3 mmol) were added to the cooled solution every 30 min, and after each addition, the solution was allowed to warm to room temperature. The reaction mixture was shaken overnight at room temperature. The solvent was evaporated with N2, and the residue was pumped dry. The residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated three times. The residue was dried to give the target compound (LH1727) as a white solid (11 mg, quantitative yield). 1 H NMR (400 MHz, D2O)δ 2.83(d, 3H, J= 8 Hz), 3.18-3.48(m, 8H), 3.67-3.80(m, 4H), 4.23(b, 1H), 4.37(b, 1H). 13 C NMR (100 MHz, D2O)δ 171.56, 166.67, 52.49, 49.52, 43.00, 42.47, 39.59, 37.09, 36.55. LC-MS (ESI + ) m / z 323.2 [M + H] + . HRMS(ESI+)m / z calculated for C 11 H 23 N4O3S2 + [M + H] + 323.1206, found 323.1233.

[0247] [Example 19] Meso-cystine dimethyl ester dihydrochloride (LH1728) D-Cystine-OH (500 mg, 2.1 mmol) was dissolved in 10 mL of methanol and cooled to 0° C. Thionyl chloride (1 mL, 12.5 mmol) was slowly added to the solution, then the reaction mixture was allowed to come to room temperature and stirred overnight. The solvent was evaporated under reduced pressure, then redissolved in chloroform and evaporated again under reduced pressure, which was repeated twice to aid in the removal of thionyl chloride. The white foamy residue was then pumped dry overnight to give D-cystine dimethyl ester dihydrochloride as a white solid (701 mg, 98%). 1H NMR (400 MHz, D2O)δ 3.34-3.45(m, 4H), 3.88(s, 6H), 4.61(b, 2H). 13 C NMR (100 MHz, D2O)δ 169.13, 53.97, 51.56, 35.70. D-Cystine dimethyl ester (670 mg, 1.96 mmol) was dissolved in dioxane / water (2:1, 6 mL). A solution of sodium carbonate (445 mg, 4.2 mmol) in 2 mL of water was added to the solution, then the mixture was cooled to 0° C. Di-tert-butylpyrocarbonate (1075 mg, 4.93 mmol) was added in one portion to the cooled mixture, then the reaction mixture was allowed to come to room temperature and stirred for 5 h. The reaction mixture was concentrated as much as possible under reduced pressure, then diluted with EtOAc (15 mL). The organic phase was washed with (2×5 mL) water, (2×5 mL) 0.5 N KHSO4, (3×5 mL) saturated NaHCO3 and (3 mL) brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure to give diBoc D-cystine dimethyl ester as a white solid (850 mg, 92%). 1 H NMR (400 MHz, CDCl3)δ 1.35(s, 18H), 3.07(b, 4H), 3.67(s, 6H), 4.51(b, 2H), 5.42(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 170.94, 155.02, 80.08, 66.96, 52.49, 41.13, 28.21. The diBoc D-cystine dimethyl ester (800 mg, 1.7 mmol), triphenylphosphine (493 mg, 1.88 mmol), and sodium acetate (56 mg, 0.68 mmol) obtained above were suspended in a mixture of 8 mL MeOH, 3.5 mL water, and 58 μL glacial acetic acid and heated to 50° C. for 3 h. The mixture was concentrated as much as possible, diluted with (60 mL) EtOAc, washed with (2×20 mL) water, (10 mL) brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified via ISCO (EtOAc / Hexanes) and the product was eluted at 30%. The solvent was evaporated under reduced pressure to give Boc-D-cysteine ​​methyl ester as a colorless oil (447 mg, 56%). 1 H NMR (400 MHz, CDCl3)δ 1.41(t, 1H, J= 8 Hz), 1.44(s, 9H), 2.94-2.99(m, 2H), 3.77(s, 3H), 4.61(b, 1H), 5.42(b, 1H). 13 C NMR (100 MHz, CDCl3)δ 170.82, 155.10, 80.27, 54.84, 52.68, 28.28, 27.32. To a stirred solution of 1-chlorobenzotriazole (262 mg, 1.7 mmol) and benzotriazole (102 mg, 0.85 mmol) in 22 mL of dry DCM under argon at -78 °C, a solution of compound Boc-D-cysteine ​​methyl ester (200 mg, 0.85 mmol) in 4 mL of dry DCM was added dropwise over 10 min. After 15 min, a solution of thiourea (195 mg, 2.6 mmol) in 30 mL of anhydrous THF was added and the reaction mixture was stirred at -78 °C for another 15 min. Boc-L-cysteine ​​methyl ester (200 mg, 0.85 mmol) in 4 mL of dry DCM was added slowly at -78 °C and the reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in EtOAc (200 mL), washed with water (4 x 50 mL), brine (20 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the pale white residue was purified via ISCO (50% EtOAc / Hexanes) and the product eluted at 40%. The solvent was evaporated under reduced pressure to give diBoc mesocystine dimethyl ester as a colorless oil (250 mg, 63%). 1 H NMR (400 MHz, CDCl3)δ 1.44(s, 18H), 3.10-3.26(m, 4H), 3.76(s, 6H), 4.61(b, 2H), 5.38(b, 2H). 13 C NMR (100 MHz, CDCl3)δ 171.20, 155.07, 80.35, 52.66, 41.25, 28.30. LC-MS (ESI + ) m / z 469.45 [M + H] + .

[0248] DiBoc mesocystine dimethyl ester (7 mg, 0.015 mmol) was dissolved in 50 μL of MeOH and cooled to 0° C. Four portions of 4M HCl / dioxane (68 μL, 0.27 mmol) were added to the cooled solution every 30 min, and after each addition, the solution was allowed to warm to room temperature. Additional 4M HCl / dioxane (17 μL, 0.07 mmol) was added to the cooled solution, and the mixture was allowed to warm to room temperature and shaken for 30 min. The solvent was evaporated with N2, and the residue was pumped dry. The yellow residue was then dissolved in a minimum amount of methanol and recrystallized with excess diethyl ether, then the vial was centrifuged and the solvent was decanted; this purification step was repeated three times. The residue was dried to give mesocystine dimethyl ester dihydrochloride (LH1728) as a pale yellow solid (4 mg, 80%). 1 H NMR (400 MHz, D2O)δ 3.39(b, 4H), 3.86(s, 6H), 4.58(b, 2H). 13 C NMR (100 MHz, D2O)δ 169.12, 53.88, 51.43, 35.59. LC-MS (ESI + ) m / z 269.1 [M + H] + . HRMS(ESI+)m / z calculated for C8H 17 N2O4S2 + [M + H] + 269.0624, found 269.0643.

[0249] [Example 20] Synthesis of L-cystine monoamide by thiol-sulfide exchange followed by air oxidation, exemplified by the synthesis of LH1727 L-cystine diamide (e.g., LH708, 1.0 mg, 2.47 nmol) and L-cysteine ​​(6 mg, 49.4 nmol, 20 eq.) were dissolved in 2.5 mL of ammonium hydroxide (pH 10), and the reaction mixture was stirred under argon at room temperature for 4 hours or until L-cystine diamide disappeared as monitored by LCMS. Air was then introduced into the reaction mixture, and vigorous stirring was continued overnight. The reaction mixture was then lyophilized to obtain a given mixture of L-cystine monoamide (e.g., LH1727, 1.94 eq.) with L-cystine (9.03 eq.) and a small amount of L-cystine diamide (e.g., LH708, 0.03 eq.). If necessary, further purification such as cation exchange chromatography can be used to further separate the components.

[0250] [Example 21] Preparation of metastable supersaturated solutions of L-cystine and crystallization inhibition assay For the preparation of L-cystine supersaturated solution, 70 mg of L-cystine was dissolved in 100 mL of Millipore water (~3 mM) under reflux at 120 °C for 30 min until L-cystine was completely dissolved. The supersaturated solution was then allowed to cool slowly with stirring until the oil bath temperature reached 40 °C, which took about 70 min depending on the laboratory atmosphere. To determine the L-cystine concentration, all test compounds were dissolved in water to form a 10 mM stock solution. 5 μL of each solution was added to 495 μL of L-cystine supersaturated solution. The mixture was left at 25 °C for 72 h. At the end of the incubation, the mixture was centrifuged at 13,000 rpm for 5 min, and the supernatant was diluted 10-fold for concentration measurement. To construct a standard curve, L-cystine (2.1 mg) was dissolved in 0.1 M Na2CO3 solution (9 mL) to form a 1 mM solution as a stock solution. 50 μL of the L-cystine stock solution was then diluted to 0.6 mM with 0.1 M Na2CO3 (33.3 μL) solution and diluted to 0.4, 0.2, 0.1, 0.05 mM solutions using 75, 200, 450 and 950 μL of Millipore water, respectively.

[0251] Fluorescence assay for determining L-cystine concentration 10 μL of each L-cystine solution or diluted mixture of test compounds, 100 μL of DTT solution (12.5 mM) in 0.1 M disodium phosphate solution (1:9) were mixed for 10 minutes at room temperature, after which 10 μL of iodoacetic acid (100 mM) was added and incubation continued for another 15 minutes at room temperature. This was then followed by the addition of 20 μL of OPA (100 mM in methanol) / NBC (100 mM in methanol) (1:1). Derivatization was allowed to proceed for 3 minutes, after which 3×40 μL of the mixture was placed into a 384-well plate and read at Ex 355 nm / Em 460 nm. A standard curve was repeated for each set of experiments and used to calculate the concentration of L-cystine in each sample.

[0252] Cyanide-nitroprusside colorimetric method for determining L-cystine concentration 3 x 40 μL of each L-cystine solution or diluted mixture of test compounds were placed in a 96-well plate (black, clear bottom). 80 μL of an aqueous solution (1:7) of potassium cyanide (30% w / v) in PBS (pH = 7.4) was added to each well, then the plate was left shaking at 550 rpm for 25 min. 10 μL of an aqueous solution of sodium nitroprusside (20% w / v) was added to each well using an automated dispenser, then the plate was immediately centrifuged at 1500 rpm for 20 s. UV absorbance was then measured at 530 nm using a Victor 3V plate reader. A standard curve was repeated for each plate and used to calculate the concentration of L-cystine in each sample.

[0253] [Table 1-1]

[0254] [Table 1-2]

[0255] It will be understood by those skilled in the art that the fibers described herein are not limited to those specifically shown and described. Rather, the scope of the fibers is defined by the following claims. Furthermore, it should be understood that the above description is merely representative of illustrative examples of embodiments. The description is not exhaustive of all possible variations. Alternative embodiments may not be presented for the specific portions of the fiber, may result from different combinations of the described portions, or other undescribed alternative embodiments may be available for the portions, and should not be considered as a disclaimer of these alternative embodiments. It will be understood that many of these undescribed embodiments are within the literal scope of the following claims, and others are equivalent.

Claims

1. A compound represented by the following formula I, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof: The prodrug thereof is represented by the following formula C: A compound represented by the following formula I, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof: 【Chemistry 1】 Here, R １ and R ２ The pairs are independently defined as follows: a) R １ is H, and R ２ (CH ２ ) ｍ N.R. ａ R ｂ and m is 2, 3, or 4, where R a and R ｂ are joined together with the N to which they are attached to form a 4-8 membered heterocycle, wherein the carbons within said 4-8 membered heterocycle are selected from the group consisting of O, S, NH, and NC. １－８ optionally substituted with a heteroatom selected from the group consisting of alkyl, or b) R １ and R ２ is linked together with the amide nitrogen to form a ring of formula X-1: 【Chemistry 2】 Where: R ３ is C １－８ alkyl, r is 0, 1, or 2; n, p, and A are defined as follows: i) n and p are independently 2; r is 0; A is NR Ｃ where R Ｃ is selected from the group consisting of tert-butyl, cyclopropyl, cyclobutyl, and cyclopentyl; ii) n is 0, 1, or 2; p is 2 or 3 or 4; A is a structure of formula Y-1: 【Chemistry 3】 Here, R ｄ is H or C １－８ is alkyl; s is 0, 1, or 2; t is 2, 3, or 4; provided that when n is 0, then s is 1 or 2; or iii) n and p are independently 1, 2, 3 or 4; A is CH (CH ２ ) ｑ N.R. ｅ R ｆ where R ｅ and R ｆ is independent and C １－８ alkyl; q is 0 to 3; Or, R ｅ and R ｆ are linked together with the N to which they are attached to form a 4- to 8-membered heterocycle; R x is H or C 1-6 alkyl; X' is H, alkoxycarbonyl (R'OCO) or (acyloxy)alkoxycarbonyl (R'COOCH(R'')OCO, where R' is H or C 1-6 alkyl and R'' is H or C 1-6 alkyl), and at least one X' is not hydrogen.

2. R １ is H, and R ２ (CH ２ ) ｍ N.R. ａ R ｂ m is 2 or 3, where R ａ and R ｂ are linked to form a 5-8 membered heterocycle, wherein a carbon within said cycle is optionally substituted with O, or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof, of the compound of claim 1 .

3. R １ and R ２ is linked together with the amide nitrogen to form a ring of formula X-1: 【Chemistry 4】 Here, A is NR ｃ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein:

4. R １ and R ２ is linked together with the amide nitrogen to form a ring of formula X-1: 【Chemistry 5】 where r is 0 and A is of formula Y-1: 【Chemistry 6】 2. The compound of claim 1, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

5. 5. The compound of claim 4, wherein n is 0 and s is 1 or 2, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

6. 5. The compound of claim 4, wherein n is 1 or 2 and s is 0, 1 or 2, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

7. R １ and R ２ is linked together with the amide nitrogen to form a ring of formula X-1: 【Chemistry 7】 wherein r is 0; n and p are independently 1, 2, 3, or 4; A is CH (CH ２ ) ｑ N.R. ｅ R ｆ where R ｅ and R ｆ is independent and C １－８ alkyl; q is 0 to 3; 2. The compound of claim 1, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

8. R １ and R ２ is linked together with the amide nitrogen to form a ring of formula X-1: 【Chemistry 8】 where r is 0; A is CH (CH ２ ) ｑ N.R. ｅ R ｆ where q is 0; R ｅ and R ｆ are linked together with the N to which they are attached to form a 4- to 8-membered heterocycle; 2. The compound of claim 1, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

9. The compound is selected from the group consisting of: 【Chemistry 9】 2. The compound of claim 1, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

10. The compound is selected from the group consisting of: 【Chemistry 10】 2. The compound of claim 1, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

11. The compound is selected from the group consisting of: 【Chemistry 11】 2. The compound of claim 1, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

12. R １ and R ２ is linked together with the amide nitrogen to form a ring of formula P-1, a pharma- ceutically acceptable salt, solvate, or prodrug thereof: 【Chemistry 12】 wherein r is 0, and n and p are independently 1, 2, 3, or 4; A is CH (CH ２ ) ｑ N.R. ｅ R ｆ where R ｅ and R ｆ is independent and C １－８ alkyl and q is 0-3.

13. R １ and R ２ is linked together with the amide nitrogen to form a ring of formula P-1, a pharma- ceutically acceptable salt, solvate, or prodrug thereof: 【Chemistry 13】 where r is 0; A is CH (CH ２ ) ｑ N.R. ｅ R ｆ where q is 0; R ｅ and R ｆ are linked together with the N to which they are attached to form a 4- to 8-membered heterocycle.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, a pharma- ceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof, and at least a pharma- ceutically acceptable carrier.

15. 15. The pharmaceutical composition of claim 14, wherein the pharma- ceutically acceptable salt is a hydrochloride salt.

16. A compound selected from the group consisting of the following, a pharma- ceutically acceptable salt thereof, or a solvate thereof: 【Chemistry 14】

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