Aldose reductase inhibitors for the treatment of phosphomannomutase 2 deficiency

Abstract

The present disclosure relates to methods for treating PMM2-CDG using an aldose reductase inhibitor. In other embodiments, the present disclosure relates to a method for treating PMM2-CDG in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an AR inhibitor, such as a compound of any one of Formulas (I)-(VI), and a pharmaceutically acceptable carrier. The present disclosure relates to a method for increasing PMM2 enzyme activity in a subject having PMM2-CDG, comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor, such as a compound of any one of Formulas (I)-(VI).

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 912,441, filed October 8, 2019, which is incorporated herein by reference. [Background technology]

[0002] background Phosphomannomutase 2 (PMM2) is an enzyme that converts mannose-6-phosphate (M6P) to mannose-1-phosphate (M1P), a precursor of GDP-mannose, which is required for the production of dolichol-P-oligosaccharides, which are important for protein glycosylation.

[0003] PMM2 forms obligate homodimers in the cytoplasm and converts mannose-6-phosphate to mannose-1-phosphate. Each PMM2 monomer dimerizes with itself as a prerequisite for catalytic activity, but only one functional active site is required per dimer (Andreotti, G., et al., 2015, PLoS ONE 10, e0139882. doi:10.1371 / journal.pone.013988). Glucose-1,6-bisphosphate and mannose-1,6-bisphosphate are endogenous coactivators of PMM2 function, binding to and stabilizing the PMM2 dimer (ibid.).

[0004] PMM2 deficiency is responsible for the most common congenital disorders of glycosylation (CDG) (Van, SE et al., FEBS Lett. 1995, 377, 318-320; Ferreira, CR et al., J. Inherit. Metab. Dis. 2018, 41, 541-553). PMM2-CDG is a multisystem, multiorgan disease. Because a minimum level of glycosylation is always required in all cells of the body, different cell types and organs are more or less susceptible to the complex consequences of underglycosylation. Elevated residual levels of PMM2 enzyme activity decrease the number and severity of affected organ systems. Mutations in the gene encoding PMM2 are responsible for PMM2-CDG (Jaeken, J. et al., J Inherit Metab Dis. 2008, 31, 669-72), and more than 115 mutations causing PMM2-CDG have been identified in the PMM2 gene. All disease-causing mutations appear to reduce the enzymatic activity of PMM2, resulting in insufficient amounts of activated mannose to form oligosaccharides for normal protein glycosylation. PMM2-CDG is also known as CDG-1A or Jaeken syndrome. PMM2-CDG exhibits variable clinical progression and presentation, with affected individuals typically developing signs and symptoms during infancy. Organs affected by PMM2-CDG include the brain, liver, gastrointestinal tract, heart, and kidneys. Approximately 20% of affected infants die before the age of one due to multiple organ failure. The most severe cases of PMM2-CDG are characterized by fetal hydrops, and in most cases, newborns with fetal hydrops are stillborn or die shortly after birth. Most PMM2-CDG patients who survive infancy have intellectual disability and developmental delay (Schiff, M. et al., J Med Genet., 2017, 54, 843-851). Currently, there are no effective therapeutic approaches for treating PMM2-CDG, and the disease is managed through efforts to reduce the incidence of the disease (e.g., occupational therapy, physical therapy, and speech therapy). Thus, there is a recognized but unmet need for methods for treating PMM2-CDG. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Andreotti,G.,et.al.,2015,PLoS ONE 10,e0139882.doi:10.1371 / journal.pone.013988 [Non-patent document 2] Van,SEet al.,FEBS Lett.1995,377,318-320 [Non-patent document 3] Ferreira,CRet al.,J.Inherit.Metab.Dis.2018,41,541-553 [Non-patent document 4] Jaeken,J.et al.,J Inherit Metab Dis.2008,31,669-72 [Non-patent document 5] Schiff,M.et al.,J Med Genet.,2017,54,843-851 Summary of the Invention [Means for solving the problem]

[0006] overview The present disclosure relates to a method for treating PMM2-CDG by administering a therapeutically effective amount of an aldose reductase (AR) inhibitor to a subject in need thereof. Without being bound by any particular theory, it is believed that inhibition of AR can enhance PMM2 enzyme activity.

[0007] In one example, a method for treating PMM2-CDG comprises administering a therapeutically effective amount of zopolrestat to a subject in need thereof. In one example, a method for treating PMM2-CDG comprises administering a therapeutically effective amount of a compound of any one of Formulas (I)-(VI) to a subject in need thereof. In some embodiments, the AR inhibitor administered is not ponalrestat, epalrestat, sorbinil or sorbinol, imirestat, AND-138, CT-112, zopolrestat, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alkonyl, statyl, berberine, or SPR-210. In one example, a method for treating or preventing PMM2-CDG excludes the administration of epalrestat. In another example, a method for treating or preventing PMM2-CDG excludes the administration of epalrestat and α-cyano-4-hydroxycinnamic acid.

[0008] Subjects to be treated according to the methods disclosed herein may have classic pediatric clinical presentations, such as growth retardation, severe encephalopathy with axial hypotonia, abnormal eye movements, psychomotor retardation, and / or cerebellar hypoplasia. Subjects to be treated according to the methods disclosed herein may have hypogonadism, coagulation abnormalities and thrombotic events, retinitis pigmentosa, and / or peripheral neuropathy.

[0009] In other embodiments, the present disclosure relates to a method of treating PMM2-CDG in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an AR inhibitor, such as a compound of any one of Formulas (I)-(VI), and a pharmaceutically acceptable carrier. The present disclosure relates to a method of increasing PMM2 enzyme activity in a subject having PMM2-CDG, comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor, such as a compound of any one of Formulas (I)-(VI).

[0010] In other embodiments, the present disclosure provides a method of treating PMM2-CDG in a subject in need thereof, comprising administering a therapeutically effective amount of (a) a compound of Formulas (I)-(VI) and a pharmaceutically acceptable carrier; and (b) one or more of alponalrestat, epalrestat, sorbinil or sorbinol, imirestat, AND-138, CT-112, zopolrestat, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alkonyl, statyl, berberine, or SPR-210 The present invention relates to a method comprising administering

[0011] In other embodiments, the present disclosure relates to the use of AR inhibitors to increase PMM2 enzyme activity for the treatment of PMM2-CDG.

[0012] In other embodiments, the present disclosure relates to the use of an AR inhibitor for the manufacture of a medicament for treating PMM2-CDG.

[0013] The present disclosure also relates to the use of an AR inhibitor (e.g., zopolrestat, epalrestat, or a compound of any one of formulas (I) to (VI)) for the treatment of PMM2-CDG.

[0014] The present disclosure also relates to an AR inhibitor (e.g., zopolrestat, epalrestat, any one of the compounds of formulae (I) to (VI)) for the manufacture of a medicament for the treatment of PMM2-CDG.

[0015] The present disclosure also relates to a pharmaceutical formulation for the treatment of PMM2-CDG, comprising an AR inhibitor (e.g., zopolrestat, epalrestat, or any one of the compounds of formulae (I) to (VI)) as an active ingredient. [Brief explanation of the drawings]

[0016] [Figure 1]FIG. 1 illustrates the in vitro inhibition of aldose reductase by Compound B.

[0017] [Figure 2] FIG. 2 illustrates the activation of PMM2 activity in fibroblasts from a PMM2-CDG patient treated with Compound B. DETAILED DESCRIPTION OF THE INVENTION

[0018] Detailed Description Various aspects are described in more detail below. However, such aspects may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete.

[0019] The present disclosure relates to the use of AR inhibitors for the treatment of PMM2-CDG.

[0020] When a range of values ​​is provided in this disclosure, each intervening value between the upper and lower limits of that range, and any other stated or intervening value within the stated range, is intended to be encompassed within the disclosure. For example, if a range of 1 μM to 8 μM is stated, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, and 7 μM, as well as ranges of values ​​greater than or equal to 1 μM and ranges of values ​​less than or equal to 8 μM, are also intended to be expressly disclosed.

[0021] Unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include plural referents. Thus, for example, reference to "a compound of Formula I" includes a single compound as well as two or more of the same or different compounds; reference to "an excipient" includes a single excipient as well as two or more of the same or different excipients, etc.

[0022] The term "about," unless otherwise indicated in the context of this disclosure or inconsistent with such interpretation, refers to a range of plus or minus 10% of the given value; e.g., "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, etc. For example, in a list of numerical values ​​such as "about 49, about 50, about 55," "about 50" refers to a range extending to less than half the interval between the preceding and following values, e.g., greater than 49.5 to less than 52.5. Furthermore, the phrases "less than about a value" or "greater than about a value" should be understood in light of the definition of the term "about" provided herein.

[0023] To provide a complete, concise, and clear description of various embodiments, this disclosure includes descriptions of various elements, groups of elements, ranges, and other elements of the broader disclosure. It is contemplated that such elements may be combined in various ways to provide further embodiments of the disclosure. It is also contemplated that any disclosed feature (e.g., substituent, analog, compound, structure, element), including individual members of any disclosed group, including any subrange or combination of subranges within a group, may be excluded from the disclosure or an embodiment of the disclosure for any reason.

[0024] Various embodiments of the present disclosure are described in further detail in the following numbered paragraphs. I. Method

[0025] Generally, the present disclosure relates to a method for treating PMM2-CDG, comprising administering to the subject in need thereof a therapeutically effective amount of the compound that inhibits aldose reductase activity.The compound can be any suitable compound that inhibits AR activity, such as small molecule compound (for example, has a size of 5kDa or less), biological agent (for example, the inhibitory RNA of aldose reductase) or their combination.Preferably, AR inhibitor is a small molecule compound.Suitable small molecule AR inhibitor is known in the art and disclosed herein. Small molecule AR inhibitors include ponalrestat, sorbinil, sorbinol, imirestat, AND-138, CT-112, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alkonyl, statyl, berberine, SPR-210, zopolrestat, epalrestat, the compounds disclosed in US Patent No. 8,916,563, US Patent No. 9,650,383, US Patent No. 10,150,779 and the compounds disclosed herein.α-cyano-4-hydroxycinnamic acid is also an AR inhibitor.Preferred AR inhibitors for use in the present invention include zopolrestat, epalrestat, the compounds disclosed in US Patent No. 8,916,563, US Patent No. 9,650,383, US Patent No. 10,150,779 and the compounds disclosed herein. The AR inhibitors may be administered in any suitable molecular form, including pharmaceutically acceptable salts, solvates, prodrugs, and compounds containing stable isotopic forms of one or more atoms, e.g., deuterium, in place of hydrogen.

[0026] In one example, a method for the treatment of PMM2-CDG comprises administering a therapeutically effective amount of zopolrestat to a subject in need thereof.

[0027] In one example, a method for treating PMM2-CDG comprises administering a therapeutically effective amount of epalrestat to a subject in need thereof.

[0028] In one example, a method for treating PMM2-CDG comprises administering a therapeutically effective amount of an aldose reductase inhibitor to a subject in need thereof, wherein the aldose reductase inhibitor is not ponalrestat, epalrestat, sorbinil or sorbinol, imirestat, AND-138, CT-112, zopolrestat, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alkonyl, statyl, berberine, or SPR-210. In certain embodiments, the method for treating PMM2-CDG disclosed herein does not comprise administering epalrestat. In certain embodiments, the method for treating PMM2-CDG disclosed herein does not comprise administering epalrestat or α-cyano-4-hydroxycinnamic acid.

[0029] In one example, a method for treating PMM2-CDG includes administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Formulas (I)-(VI). In a particular example, the administered compound is Compound A, or the administered compound is Compound B, or a physiologically acceptable salt, hydrate, solvate, or prodrug of Compound A or Compound B. [ka]

[0030] As used herein, the term "treating" refers to curative or palliative (e.g., controlling or alleviating a disease or disease symptom) treatment. This can include ameliorating, alleviating, arresting, or delaying the symptoms, clinical signs, and underlying pathology of PMM2-CDG in a manner that improves or stabilizes the subject's condition. Thus, the methods can be used to treat PMM2-CDG, treat complications (e.g., symptoms and clinical signs) of PMM2-CDG, and / or treat and prevent complications (e.g., symptoms and clinical signs) of PMM2-CDG.

[0031] As used herein, a "therapeutically effective amount" refers to an amount of compound sufficient to achieve a desired therapeutic effect under the conditions of administration, e.g., an amount that reduces or ameliorates the severity of PMM2-CDG, prevents the progression of symptoms or symptoms associated with PMM2-CDG, or enhances or otherwise improves the therapeutic effect of another therapy for the treatment or management of PMM2-CDG. A therapeutically effective amount can be an amount that increases PMM2 enzyme activity in the subject being treated. The actual amount to be administered can be determined by a clinician of ordinary skill based on, for example, the subject's age, weight, sex, general health and drug tolerance, disease severity, the selected dosage form, route of administration, and other factors. Typically, the amount of AR inhibitor administered is about 0.5 to about 60 mg / kg body weight / day, e.g., about 1.0 to 10 mg / kg.

[0032] In some examples of the implementation of the methods disclosed herein, a therapeutically effective amount is an amount sufficient to reduce intracellular aldose reductase activity by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more, for example, about 100% (e.g., compared to pre-treatment levels). A therapeutically effective amount can be an amount that increases PMM2 enzyme activity by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more, for example, about 100% (e.g., compared to pre-treatment levels). A therapeutically effective amount can be sufficient to restore PMM2 enzyme levels in a subject with PMM2-CDG.

[0033] A "subject" can be any animal, particularly a mammal, that has PMM2-CDG, including, but not limited to, a human, a domestic animal, such as a feline or canine subject, livestock, such as, but not limited to, a bovine, equine, caprine, ovine, avian, and porcine subject, wild animal (whether wild or zoo), research or experimental animal, such as a mouse, rat, rabbit, goat, sheep, pig, dog, cat, etc., bird, such as a chicken, turkey, songbird, etc. Typically, a human subject to be treated using the methods disclosed herein is diagnosed with PMM2-CDG at the newborn stage by enzymatic or genetic screening and has a deficiency in PMM2 activity.

[0034] The present disclosure also relates to the prevention or treatment of at least one clinical feature or complication of PMM2-CDG in a subject. Representative clinical features or complications that may be present in children, adolescents, or adults include, for example, alternating internal strabismus and other abnormal eye movements, axial hypotonia, intellectual disability, ataxia, and hyporeflexia. After infancy, symptoms include retinitis pigmentosa, frequent seizure-like episodes, and occasionally epilepsy. Other features include various dysmorphisms (large, hypoplastic / dysplastic ears), abnormal subcutaneous adipose tissue distribution (fat pads, inverted nipples), mild to moderate hepatomegaly, skeletal abnormalities (including atlantoaxial subluxation), and hypogonadism. Some infants develop pericardial effusion and / or cardiomyopathy. At the other end of the clinical spectrum are patients with a very mild phenotype (no dysmorphism, very mild intellectual disability, ataxia) (Jaeken, J. et al., “Glycosylation and its Disorders: General Overview,” Elsevier, Reference Module in Biomedical Sciences, 2016).

[0035] In certain aspects, the present disclosure relates to methods for treating clinical features or complications of PMM2-CDG, comprising administering to a subject in need thereof a therapeutically effective amount of zopolrestat.

[0036] In one example, the present disclosure relates to a method for treating a clinical feature or complication of PMM2-CDG, comprising administering a therapeutically effective amount of epalrestat to a subject in need thereof.

[0037] In one example, the disclosure relates to a method for treating a clinical feature or complication of PMM2-CDG, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Formulas (I)-(VI).

[0038] In some embodiments, the methods are carried out by administering a formulation comprising one or more AR inhibitors, which formulation may be adapted for administration by once-daily, twice-daily, three-times-daily, or four-times-daily administration over the desired treatment period. Typically, the formulation is adapted for chronic administration over a period of weeks, months, years, or decades. Typically, the method is carried out by administering a formulation adapted for administration over a period of months. In yet other embodiments, the method is carried out by administering a formulation adapted for administration over a period of years or decades. II. AR inhibitors

[0039] Suitable small molecule AR inhibitor is known in the art and disclosed herein.Small molecule AR inhibitor includes ponalrestat, sorbinil, sorbinol, imirestat, AND-138, CT-112, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alkonyl, statyl, berberine, SPR-210, zopolrestat, epalrestat, United States Patent (USP) 8,916,563, United States Patent (USP) 9,650,383, the compound disclosed in International Publication No. 2012 / 009553 and the compound disclosed herein. The preferred AR inhibitor for use in the present invention includes zopolrestat, epalrestat, the compounds disclosed in US Patent No. 8,916,563, US Patent No. 9,650,383, International Publication No. 2017 / 038505, US Patent No. 10,150,779 and the compounds disclosed herein.The disclosures of US Patent No. 8,916,563, US Patent No. 9,650,383, US Patent No. 10,150,779, International Publication No. 2012 / 009553 and International Publication No. 2017 / 038505 are incorporated herein by reference in their entirety, and disclose the compounds suitable for use in the methods described herein. Compounds of Formula I and II

[0040] In one example, the AR inhibitor is a compound of formula (I) [ka] or a pharmaceutically acceptable salt, prodrug, or solvate thereof;

[0041] During the ceremony,

[0042] R 1 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl or (C1-C6)-aminoalkyl;

[0043] X 1 is N or CR 3 and;

[0044] X 2 is N or CR 4 and;

[0045] X 3 is N or CR 5 and;

[0046] X 4 is N or CR 6 where X 1 , X 2 , X 3 or X 4 two or three of which are N;

[0047] Y is a bond, C=O, C=S, C=NH or C=N(C1-C4)-alkyl;

[0048] Z is [ka] and;

[0049] A 1 is NR 11 , O, S or CH2;

[0050] A 2 is N or CH;

[0051] A 3 is NR 11 , O or S;

[0052] R 3 ~R 10 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C-C)-alkyl, (C-C)-alkoxy, (C-C)-alkylthio, (C-C)-alkylsulfinyl or (C-C)-alkylsulfonyl; or R 3 ~R 6 Either of these or R 7 ~R 10are both (C1-C4)-alkylenedioxy; and

[0053] R 11 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0054] Z is [ka] or Z is [ka] The specification that

[0055] Z is [ka] If

[0056] The compound of formula (I) [ka] It encompasses

[0057] Z is [ka] If

[0058] The compound of formula (I) [ka] It will be appreciated by those skilled in the art that the present invention is intended to encompass the

[0059] In certain embodiments, R 1 is hydrogen or (C-C)-alkyl. In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is (C1-C6)-alkyl. In certain embodiments, R 1is tert-butyl.

[0060] In certain embodiments, R 3 ~R 10 is independently hydrogen, halogen, or haloalkyl. In certain embodiments, R 3 ~R 10 are independently hydrogen, halogen, or trihaloalkyl.

[0061] In certain embodiments, R 3 ~R 6 is hydrogen.

[0062] In certain embodiments, R 7 ~R 10 is independently hydrogen, halogen, or haloalkyl. In certain embodiments, R 7 ~R 10 are independently hydrogen, halogen, or trihaloalkyl.

[0063] In certain embodiments, R 7 and R 10 is hydrogen.

[0064] In certain embodiments, R 8 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is halogen. In certain embodiments, R 8 is haloalkyl.

[0065] In certain embodiments, R 9 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is halogen. In certain embodiments, R 9 is haloalkyl.

[0066] In certain embodiments, Y is C=O, C=S, C=NH, or C=N(C1-C4)-alkyl. In certain embodiments, Y is C=O or C=S. In certain embodiments, Y is C=O. In certain embodiments, Y is C=S. In certain embodiments, Y is C=NH or C=N(C1-C4)-alkyl.

[0067] In certain embodiments, A 1 is NR 11 , S or CH2. In certain embodiments, A 1 is NR 11 or O. In certain embodiments, A 1 is NR 11 or S. In certain embodiments, A 1 is NR 11 In certain embodiments, A 1 is O. In certain embodiments, A 1 is S.

[0068] In certain embodiments, A 2 is N or CH. In certain embodiments, A 1 is N. In certain embodiments, A 1 is CH.

[0069] In certain embodiments, A 3 is O or S. In certain embodiments, A 3 is O. In certain embodiments, A 3 is S.

[0070] In certain embodiments, X 1 and X 4 is nitrogen.

[0071] In certain embodiments, X 1 and X 2 is nitrogen.

[0072] In certain embodiments, X 1 and X 3 is nitrogen.

[0073] In certain embodiments, X 2 and X 3 is nitrogen.

[0074] In certain embodiments, X 2 and X 4 is nitrogen.

[0075] In certain embodiments, X 3 and X 4 is nitrogen.

[0076] In certain embodiments, Z is [ka] is.

[0077] In certain embodiments, Z is [ka] is.

[0078] In certain embodiments, R 1 is hydrogen or (C1-C6)-alkyl;

[0079] X 1 and X 4 is N;

[0080] X 2 is CR 4 and;

[0081] X 3 is CR 5 and;

[0082] Y is C=O;

[0083] Z is [ka] and;

[0084] A 1is NR 11 , O or S;

[0085] A 2 is N;

[0086] A 3 is O or S;

[0087] R 4 and R 5 is hydrogen;

[0088] R 7 ~R 10 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C-C)-alkyl, (C-C)-alkoxy, (C-C)-alkylthio, (C-C)-alkylsulfinyl or (C-C)-alkylsulfonyl; and

[0089] R 11 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0090] In certain embodiments, R 1 is hydrogen or tert-butyl;

[0091] X 1 and X 4 is N;

[0092] X 2 is CR 4 and;

[0093] X 3 is CR 5 and;

[0094] Y is C=O;

[0095] Z is [ka] and;

[0096] A 1 is NR 11 , O or S;

[0097] A 2 is N;

[0098] A 3 is O or S;

[0099] R 4 and R 5 is hydrogen;

[0100] R 7 ~R 10 is independently hydrogen, halogen, or haloalkyl; and

[0101] R 11 is hydrogen, (C1-C4)-alkyl or C(O)O-tert-butyl.

[0102] In certain embodiments, R 1 is hydrogen or tert-butyl;

[0103] X 1 and X 4 is N;

[0104] X 2 is CH;

[0105] X 3 is CH;

[0106] Y is C=O;

[0107] Z is [ka] and;

[0108] A 1 is NR 11 , O or S;

[0109] A 2 is N;

[0110] A 3 is O or S;

[0111] R 7 , R 8 and R 10 are independently hydrogen, halogen, or haloalkyl;

[0112] R 9 is halogen or haloalkyl; and

[0113] R 11 is hydrogen or methyl.

[0114] In certain embodiments, R 1 is hydrogen or tert-butyl;

[0115] X 1 and X 4 is N;

[0116] X 2 is CH;

[0117] X 3 is CH;

[0118] Y is C=O;

[0119] Z is [ka] and;

[0120] A 1 is NR 11 , O or S;

[0121] A 2 is N;

[0122] A 3 is O or S;

[0123] R 7 , R 8 and R 10 are independently hydrogen, halogen, or haloalkyl;

[0124] R 9 is chlorine or trifluoromethyl; and

[0125] R 11 is hydrogen or methyl.

[0126] In certain embodiments, the AR inhibitor is a compound of formula (II): [ka] or a pharmaceutically acceptable salt or solvate thereof;

[0127] In the formula, R 1 , R 7 -R 9 and Y are as described in formula (I), preferably R 1 is hydrogen or (C1-C6)-alkyl and Y is C=O. Exemplary compounds of formula (II) include the following and salts thereof: [ka] Compound of formula (III)

[0128] The AR inhibitor is a compound of formula (III)

[0129] [ka] or a pharmaceutically acceptable salt, prodrug, or solvate thereof,

[0130] During the ceremony,

[0131] R 1 is CO2R 2 or CO2 - X+ and;

[0132] R 2 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl or (C1-C6)-aminoalkyl;

[0133] X 1 is H or a halogen;

[0134] X 2 is H or a halogen;

[0135] Y is a bond, C=O, C=S, C=NH or C=N(C1-C4)-alkyl;

[0136] Z is [ka] and;

[0137] A 1 is NR 7 , O, S or CH2;

[0138] A 2 is N or CH;

[0139] A 3 is NR 7 , O or S;

[0140] R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C-C)-alkyl, (C-C)-alkoxy, (C-C)-alkylthio, (C-C)-alkylsulfinyl or (C-C)-alkylsulfonyl;

[0141] R 7 is hydrogen, C1-C4 alkyl or C(O)O—(C1-C4)-alkyl; and

[0142] X + is the counterion.

[0143] By those skilled in the art,

[0144]

[0145] Z is [ka] or Z is [ka] The specification that Z is

[0146] [ka] When the compound of formula (III) is [ka] Z is understood to encompass [ka] When the compound of formula (I) is [ka] It will be appreciated that the term "invention" indicates that the invention is understood to encompass the following:

[0147] In certain embodiments, R 1 is CO2R 2 or CO2 - X + In certain embodiments, R 1 is CO2R 2 In certain embodiments, R 1 is CO2 - X + is.

[0148] In certain embodiments, R 2is hydrogen or (C-C)-alkyl. In certain embodiments, R 2 is hydrogen or (C-C)-alkyl. In certain embodiments, R 2 is hydrogen or (C-C)-alkyl. In certain embodiments, R 2 is hydrogen, methyl, or ethyl. In certain embodiments, R 2 is hydrogen or methyl. In certain embodiments, R 2 is methyl or ethyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is (C1-C6)-alkyl. In certain embodiments, R 2 is (C1-C6)-n-alkyl. In certain embodiments, R 2 is (C1-C2)-alkyl. In certain embodiments, R 2 is (C1-C3)-alkyl. In certain embodiments, R 2 is (C1-C4)-alkyl. In certain embodiments, R 2 is tert-butyl.

[0149] In certain embodiments, R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C-C)-alkyl, (C-C)-alkoxy, (C-C)-alkylthio, (C-C)-alkylsulfinyl or (C-C)-alkylsulfonyl.

[0150] In certain embodiments, R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl. In certain embodiments, R 3 ~R 6 are independently hydrogen, halogen, or trihaloalkyl.

[0151] In certain embodiments, R 3 and R6 is hydrogen. In certain embodiments, R 3 , R 5 and R 6 is hydrogen.

[0152] In certain embodiments, R 4 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is haloalkyl. In certain embodiments, R 4 is CF3.

[0153] In certain embodiments, R 3 ~R 6 is hydrogen. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is halogen or haloalkyl. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is haloalkyl. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is CF. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is halogen. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is F. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is Cl.

[0154] In certain embodiments, Y is C=O, C=S, C=NH, or C=N(C1-C4)-alkyl. In certain embodiments, Y is C=O or C=S. In certain embodiments, Y is C=O. In certain embodiments, Y is C=S. In certain embodiments, Y is C=NH or C=N(C1-C4)-alkyl.

[0155] In certain embodiments, A 1 is NR 7 , O, S, or CH2. In certain embodiments, A 1 is NR 7 , O or S. In certain embodiments, A 1 is NR 7 , S or CH2. In certain embodiments, A 1 is NR 7 or O. In certain embodiments, A 1 is NR 7 or S. In certain embodiments, A 1 is NR 7 In certain embodiments, A 1 is O. In certain embodiments, A 1 is S.

[0156] In certain embodiments, A 2 is N or CH. In certain embodiments, A 2 is N. In certain embodiments, A 2 is CH.

[0157] In certain embodiments, A 3 is NR 7 , O or S. In certain embodiments, A 3 is O. In certain embodiments, A 3 is S. In certain embodiments, A 3 is NR 7 is.

[0158] In certain embodiments, X 1 and X 2 is hydrogen.

[0159] In certain embodiments, X 1 and X 2 is a halogen. In certain embodiments, X 1 and X 2 is Cl.

[0160] In certain embodiments, X 1 and X 2 is independently hydrogen or halogen. In certain embodiments, X 1 is hydrogen and X 2 is Cl. In certain embodiments, X 1 is Cl and X 2 is hydrogen.

[0161] In certain embodiments, Z is [ka] is.

[0162] In certain embodiments, Z is [ka] is.

[0163] In certain embodiments, R 7 is hydrogen, C-C alkyl, or C(O)O-(C-C)-alkyl. In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C1-C4 alkyl. In certain embodiments, R 7 is C1-C3 alkyl. In certain embodiments, R 7 is C1-C2 alkyl. In certain embodiments, R 7 is C1-C4n-alkyl. In certain embodiments, R 7 is C1-C3n-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C4)-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C3)-alkyl. In certain embodiments, R 7is C(O)O—(C1-C2)-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C4)-n-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C3)-n-alkyl.

[0164] In certain embodiments, R 1 is CO2R 2 and;

[0165] R 2 is H or (C1-C6)-alkyl;

[0166] X 1 is H;

[0167] X 2 is H;

[0168] Y is C=O;

[0169] Z is [ka] and;

[0170] A 1 is NR 7 , O or S;

[0171] A 2 is N;

[0172] A 3 is O or S;

[0173] R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C-C)-alkyl, (C-C)-alkoxy, (C-C)-alkylthio, (C-C)-alkylsulfinyl or (C-C)-alkylsulfonyl; and

[0174] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0175] In certain embodiments, R 1 is CO2R 2 and;

[0176] R 2 is H or tert-butyl;

[0177] X 1 is H;

[0178] X 2 is H;

[0179] Y is C=O;

[0180] Z is [ka] and;

[0181] A 1 is NR 7 , O or S;

[0182] A 2 is N;

[0183] A 3 is O or S;

[0184] R 6 ~R 6 are independently hydrogen, halogen, haloalkyl; and

[0185] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0186] In certain embodiments, R 1 is CO2R 2 and;

[0187] R 2 is H or tert-butyl;

[0188] X 1 is H;

[0189] X 2 is H;

[0190] Y is C=O;

[0191] Z is [ka] and;

[0192] A 1 is NR 7 , O or S;

[0193] A 2 is N;

[0194] A 3 is O or S;

[0195] R 3 , R 5 and R 6 is hydrogen;

[0196] R 4 is hydrogen, halogen, or haloalkyl; and

[0197] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0198] In certain embodiments, R 1 is CO2R 2 and;

[0199] R 2 is H or (C1-C6)-alkyl;

[0200] X 1is a halogen;

[0201] X 2 is a halogen;

[0202] Y is C=O;

[0203] Z is [ka] and;

[0204] A 1 is NR 7 , O or S;

[0205] A 2 is N;

[0206] A 3 is O or S;

[0207] R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C-C)-alkyl, (C-C)-alkoxy, (C-C)-alkylthio, (C-C)-alkylsulfinyl or (C-C)-alkylsulfonyl; and

[0208] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0209] In certain embodiments, R 1 is CO2R 2 and;

[0210] R 2 is H or tert-butyl;

[0211] X 1 is a halogen;

[0212] X2 is a halogen;

[0213] Y is C=O;

[0214] Z is [ka] and;

[0215] A 1 is NR 7 , O or S;

[0216] A 2 is N;

[0217] A 3 is O or S;

[0218] R 3 ~R 6 are independently hydrogen, halogen, haloalkyl; and

[0219] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0220] In certain embodiments, R 1 is CO2R 2 and;

[0221] R 2 is H or tert-butyl;

[0222] X 1 is Cl;

[0223] X 2 is Cl;

[0224] Y is C=O;

[0225] Z is [ka] and;

[0226] A 1 is NR 7 , O or S;

[0227] A 2 is N;

[0228] A 3 is O or S;

[0229] R 3 ~R 6 are independently hydrogen, halogen, haloalkyl; and

[0230] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0231] In certain embodiments, R 1 is CO2R 2 and;

[0232] R 2 is H or tert-butyl;

[0233] X 1 is Cl;

[0234] X 2 is Cl;

[0235] Y is C=O;

[0236] Z is [ka] and;

[0237] A 1 is NR 7 , O or S;

[0238] A 2 is N;

[0239] A 3 is O or S;

[0240] R 3 , R 5 and R 6 is hydrogen;

[0241] R 4 is hydrogen, halogen, or haloalkyl; and

[0242] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0243] In certain embodiments, the compound of formula (III) is [ka] is selected from the group consisting of:

[0244] In certain embodiments, the compound of formula (III) is [ka] or a pharmaceutically acceptable salt thereof.

[0245] In certain embodiments, the compound of formula (III) is [ka] or a pharmaceutically acceptable salt thereof. Compounds of formula (IV), (V) and (VI)

[0246] The AR inhibitor is a compound of formula (IV)

[0247] [ka] or pharmaceutically acceptable salts and solvates thereof,

[0248] During the ceremony,

[0249] X 1 is H or a halogen;

[0250] X 2 is H or a halogen;

[0251] Y is a bond, C=O, C=S, C=NH or C=N(C1-C4)-alkyl;

[0252] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, and aryloxy; or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0253] [ka] Forming

[0254] where:

[0255] X is a substituted or unsubstituted C2-C5 alkylene;

[0256] Z is [ka] and;

[0257] A 1 is NR 7 , O, S or CH2;

[0258] A 2 is N or CH;

[0259] A 3 is NR 7 , O or S;

[0260] R 3 ~R 6are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C-C)-alkyl, (C-C)-alkoxy, (C-C)-alkylthio, (C-C)-alkylsulfinyl or (C-C)-alkylsulfonyl; and

[0261] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0262] Suitable substituents on the C2-C5 alkylene include one or more alkyl, alkoxy, aryl, aryloxy, halo, haloalkyl, haloalkoxy, and haloalkylthio. A preferred substituted C2-C5 alkylene is substituted ethylene. A more preferred substituted C2-C5 alkylene is -C(CH3)2C(CH3)2-.

[0263] By those skilled in the art,

[0264] Z is [ka] or Z is [ka] The specification that Z is [ka] When the compound of formula (IV) is [ka] is understood to encompass;

[0265] Z is [ka] When the compound of formula (IV) is [ka] It is recognized that the term "invention" indicates that it is understood to encompass the following:

[0266] where:

[0267] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, and aryloxy; or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0268] [ka] Forming

[0269] where:

[0270] X is a substituted or unsubstituted C2-C5 alkylene.

[0271] In certain embodiments, R in formula (IV) 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C-C)-alkyl, (C-C)-alkoxy, (C-C)-alkylthio, (C-C)-alkylsulfinyl or (C-C)-alkylsulfonyl.

[0272] In certain embodiments, R in formula (IV) 3 ~R 6 is independently hydrogen, halogen, or haloalkyl. In certain embodiments, R 3 ~R 6 are independently hydrogen, halogen, or trihaloalkyl.

[0273] In certain embodiments, R in formula (IV) 3 and R 6 is hydrogen. In certain embodiments, R 3 , R5 and R 6 is hydrogen.

[0274] In certain embodiments, R in formula (IV) 4 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is haloalkyl. In certain embodiments, R 4 is CF3.

[0275] In certain embodiments, R in formula (IV) 3 ~R 6 is hydrogen. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is halogen or haloalkyl. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is haloalkyl. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is CF. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is halogen. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is F. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is Cl.

[0276] In certain embodiments, Y in formula (IV) is C=O, C=S, C=NH, or C=N(C1-C4)-alkyl. In certain embodiments, Y is C=O or C=S. In certain embodiments, Y is C=O. In certain embodiments, Y is C=S. In certain embodiments, Y is C=NH or C=N(C1-C4)-alkyl.

[0277] In certain embodiments, A in formula (IV) 1 is NR 7 , O, S, or CH2. In certain embodiments, A 1 is NR 7 , O or S. In certain embodiments, A 1 is NR 7 , S or CH2. In certain embodiments, A 1 is NR 7 or O. In certain embodiments, A 1 is NR 7 or S. In certain embodiments, A 1 is NR 7 In certain embodiments, A 1 is O. In certain embodiments, A 1 is S.

[0278] In certain embodiments, A in formula (IV) 2 is N or CH. In certain embodiments, A 2 is N. In certain embodiments, A 2 is CH.

[0279] In certain embodiments, A in formula (IV) 3 is NR 7 , O or S. In certain embodiments, A 3 is O. In certain embodiments, A in formula (IV) 3 is S. In certain embodiments, A 3 is NR 7 is.

[0280] In certain embodiments, X in formula (IV) 1 and X 2 is hydrogen.

[0281] In certain embodiments, X in formula (IV) 1 and X 2 is a halogen. In certain embodiments, X 1 and X 2 is Cl.

[0282] In certain embodiments, X in formula (IV) 1 and X 2 is independently hydrogen or halogen. In certain embodiments, X 1 is hydrogen and X 2 is Cl. In certain embodiments, X 1 is Cl and X 2 is hydrogen.

[0283] In certain embodiments, Z in formula (IV) is [ka] is.

[0284] In certain embodiments, Z in formula (IV) is [ka] is.

[0285] In certain embodiments, R in formula (IV) 7 is hydrogen, C-C alkyl, or C(O)O-(C-C)-alkyl. In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C1-C4 alkyl. In certain embodiments, R 7 is C1-C3 alkyl. In certain embodiments, R 7 is C1-C2 alkyl. In certain embodiments, R 7 is C1-C4n-alkyl. In certain embodiments, R 7 is C1-C3n-alkyl. In certain embodiments, R 7is C(O)O—(C1-C4)-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C3)-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C2)-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C4)-n-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C3)-n-alkyl.

[0286] In certain embodiments, the compound of formula (IV) is

[0287] [ka]

[0288] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0289] During the ceremony,

[0290] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, and aryloxy; or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0291] [ka] Forming

[0292] where:

[0293] X is a substituted or unsubstituted C2-C5 alkylene.

[0294] In certain embodiments, the compound of formula (IV) is

[0295] [ka]

[0296] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0297] During the ceremony,

[0298] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, and aryloxy; or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0299] [ka] Forming

[0300] where:

[0301] X is a substituted or unsubstituted C2-C5 alkylene.

[0302] In certain embodiments, the compound of formula (IV) is

[0303] [ka]

[0304] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0305] During the ceremony,

[0306] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, and aryloxy; or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0307] [ka] Forming

[0308] where:

[0309] X is a substituted or unsubstituted C2-C5 alkylene.

[0310] In certain embodiments, the compound of formula (IV) is

[0311] [ka]

[0312] [ka]

[0313] [ka]

[0314] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0315] During the ceremony,

[0316] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, and aryloxy; or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0317] [ka] Forming

[0318] where:

[0319] X is a substituted or unsubstituted C2-C5 alkylene.

[0320] In another embodiment, the aldose reductase inhibitor is a compound of formula (V)

[0321] [ka]

[0322] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0323] During the ceremony,

[0324] X 3 is N or CR 8 and;

[0325] X 4 is N or CR 9 and;

[0326] X 5 is N or CR 10 and;

[0327] X 6 is N or CR 11 where X 3 , X 4 , X 5 , or X 6 two or three of which are N;

[0328] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, and aryloxy; or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0329] [ka] Forming

[0330] where:

[0331] X is a substituted or unsubstituted C2-C5 alkylene;

[0332] Z 3 teeth, [ka] and;

[0333] A 4 is NR 16 , O, S or CH2;

[0334] A 5 is N or CH;

[0335] A 6 is NR 16 , O or S;

[0336] R 8 ~R 15 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C-C)-alkyl, (C-C)-alkoxy, (C-C)-alkylthio, (C-C)-alkylsulfinyl or (C-C)-alkylsulfonyl; or R 8 ~R 11 Either of these or R 12 ~R 15 are both (C1-C4)-alkylenedioxy; and

[0337] R 16 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0338] Suitable substituents on the C2-C5 alkylene include one or more alkyl, alkoxy, aryl, aryloxy, halo, haloalkyl, haloalkoxy, and haloalkylthio. A preferred substituted C2-C5 alkylene is substituted ethylene. A more preferred substituted C2-C5 alkylene is -C(CH3)2C(CH3)2-.

[0339] By those skilled in the art,

[0340] Z is [ka] or Z is [ka] The specification that Z is [ka] When the compound of formula (V) is [ka] Z is understood to encompass [ka] When the compound of formula (V) is [ka] It will be appreciated that the term "invention" indicates that the invention is understood to encompass the following:

[0341] In some compounds of formula (V), R 8 ~R 15 are independently hydrogen, halogen, or haloalkyl, e.g., R 8 ~R 15 are independently hydrogen, halogen, or trihaloalkyl (e.g., —CF 3 ).

[0342] In other compounds of formula (V), R 8 ~R 11 is hydrogen.

[0343] In certain embodiments of compounds of Formula (V), R 12 ~R 15 are independently hydrogen, halogen, or haloalkyl, e.g., R 12 ~R 15are independently hydrogen, halogen, or trihaloalkyl (e.g., —CF 3 ).

[0344] In certain embodiments, R in formula (V) 12 and R 15 is hydrogen.

[0345] In certain embodiments, R in formula (V) 13 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 13 is hydrogen. In certain embodiments, R 13 is halogen. In certain embodiments, R 13 is haloalkyl.

[0346] In certain embodiments, R in formula (V) 14 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 14 is hydrogen. In certain embodiments, R 14 is halogen. In certain embodiments, R 14 is haloalkyl.

[0347] In certain embodiments, Y in formula (V) is C=O, C=S, C=NH, or C=N(C1-C4)-alkyl. In certain embodiments, Y is C=O or C=S. In certain embodiments, Y is C=O. In certain embodiments, Y is C=S. In certain embodiments, Y is C=NH or C=N(C1-C4)-alkyl.

[0348] In certain embodiments, A in formula (V) 4 is NR 16 , S or CH2. In certain embodiments, A 4 is NR 16 or O. In certain embodiments, A 4 is NR 16 or S. In certain embodiments, A 4 is NR 16 In certain embodiments, A 4 is O. In certain embodiments, A 4 is S.

[0349] In certain embodiments, A in formula (V) 5 is N or CH. In certain embodiments, A 4 is N. In certain embodiments, A 4 is CH.

[0350] In certain embodiments, A in formula (V) 6 is O or S. In certain embodiments, A 6 is O. In certain embodiments, A 6 is S.

[0351] In certain embodiments, X in formula (V) 3 and X 6 is nitrogen.

[0352] In certain embodiments, X in formula (V) 3 and X 4 is nitrogen.

[0353] In certain embodiments, X in formula (V) 3 and X 5 is nitrogen.

[0354] In certain embodiments, X in formula (V) 4 and X 5 is nitrogen.

[0355] In certain embodiments, X in formula (V) 4 and X 6 is nitrogen.

[0356] In certain embodiments, X in formula (V) 5 and X 6 is nitrogen.

[0357] In certain embodiments, Z in formula (V) 3 teeth [ka] is.

[0358] In certain embodiments, Z in formula (V) 3 teeth [ka] is.

[0359] In some embodiments, the compound of formula (V) is

[0360] [ka]

[0361] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0362] During the ceremony,

[0363] R 14 is hydrogen, halogen, or trihaloalkyl (e.g., —CF3); and

[0364] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, and aryloxy; or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0365] [ka] Forming

[0366] where:

[0367] X is a substituted or unsubstituted C2-C5 alkylene.

[0368] In an embodiment, the compound of formula (V) is

[0369] [ka]

[0370] [ka]

[0371] [ka]

[0372] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0373] In one embodiment, the aldose reductase inhibitor is a compound of formula (VI)

[0374] [ka]

[0375] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0376] During the ceremony,

[0377] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, and aryloxy; or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0378]

[0379] [ka] Forming

[0380] where:

[0381] X is a substituted or unsubstituted C2-C5 alkylene.

[0382] In one embodiment, the aldose reductase inhibitor of formula (VI) is

[0383] [ka]

[0384] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0385] In one embodiment, the AH inhibitor of formula (VI) is

[0386] [ka]

[0387] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0388] As used herein, unless otherwise indicated, the term "alkyl" refers to a monovalent aliphatic hydrocarbon radical having straight-chain, branched-chain, monocyclic, or polycyclic moieties, or combinations thereof, optionally substituted on one or more carbons of the straight-chain, branched-chain, monocyclic, or polycyclic moiety, or combinations thereof, with one or more substituents on each carbon, wherein the one or more substituents are independently selected from the group consisting of C1-C 10 Examples of "alkyl" groups include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0389] As used herein, the term "halogen" or "halo-" means chlorine (Cl), fluorine (F), iodine (I) or bromine (Br).

[0390] As used herein, the term "acyl" is used broadly to designate a radical of the type RCO-, where R represents an organic radical which may be a substituted or unsubstituted, saturated or unsaturated alkyl, aralkyl, aryl, alicyclic or heterocyclic radical; or, according to a different definition, the term "acyl" is used broadly to designate the monovalent radical which remains when the OH group of a carboxyl radical is removed from a molecule of carboxylic acid.

[0391] The term "alkoxy" is used to designate a group of formula -OR, where R is an alkyl group optionally containing substituents such as halogens. Preferably, the term "alkoxy" is used to designate an alkoxy having an alkyl group of 1 to 6 carbon atoms. Most preferably, the term "alkoxy" is used to designate an alkoxy having an alkyl group of 1 to 3 carbon atoms, such as methoxy or ethoxy.

[0392] The term "cycloalkyl group" is used herein to identify a cycloalkyl group having from 3 to 6 carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0393] As used herein, the term "solvate" refers to a compound or a pharmaceutically acceptable salt thereof, wherein molecules of a suitable solvent are incorporated into the crystal lattice. The suitable solvent is physiologically acceptable at the administered dosage. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is referred to as a "hydrate."

[0394] A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some cases, they are easier to administer than the parent drug. They are, for example, bioavailable by oral administration, whereas the parent drug is less bioavailable or not bioavailable at all. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. For example, the compound may carry a protecting group that is hydrolyzed in body fluids, such as the bloodstream, to release the active compound, or may be oxidized or reduced in body fluids to release the compound. The term "prodrug" can apply to such functional groups, such as the acidic functional group of a compound of Formula (I). Prodrugs can be constructed from structures in which the acidic group is protected, for example, as an ester or amide. Further examples of prodrugs are discussed herein. See also Alexander et al. (J. Med. Chem. 1988, 31, 318), incorporated by reference. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds that contain a biohydrolyzable moiety, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, and biohydrolyzable phosphate analogs. Prodrugs are also described, for example, in The Practice of Medicinal Chemistry (Camille Wermuth, ed., 1999, Academic Press, which is incorporated herein by reference in its entirety). In certain embodiments, prodrugs of compounds with carboxyl functional groups are lower alkyl esters of carboxylic acids. Carboxylic acid esters are conveniently formed by esterifying any of the carboxylic acid moieties present in the molecule. Prodrugs are typically prepared by well-known methods, for example, as described in Burger's Medicinal Chemistry and Drug Discovery 6 thed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh (each of which is incorporated herein by reference in its entirety). The biohydrolyzable portion of the compound of Formula I (a) does not interfere with the biological activity of the compound but may confer advantageous properties to the compound in vivo, such as uptake, duration of action, or onset of action; or (b) may be biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkylacylaminoalkyl esters, and choline esters. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

[0395] The term "salt" includes salts derived from any suitable organic and inorganic counterions known in the art, such as hydrochloride or hydrobromide salts or alkali or acid salts of the aforementioned amino acids. This term is intended to include salts derived from inorganic or organic acids, including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2 ​​sulfonic acid, and other acids; and salts derived from inorganic or organic bases, including, for example, sodium, potassium, calcium, ammonium, or tetrafluoroborate. Exemplary pharmaceutically acceptable salts are found, for example, in Berge et al. (J. Pharm. Sci. 1977, 66(1), 1; and U.S. Pat. Nos. 6,570,013 and 4,939,140, ​​each of which is incorporated by reference in its entirety. Pharmaceutically acceptable salts are also intended to encompass hemisalts in which the ratio of compound to acid is 2:1, respectively. Exemplary hemisalts are salts derived from acids containing two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid. Other exemplary hemisalts are salts derived from diprotonic mineral acids, such as sulfuric acid. Exemplary preferred hemisalts include, but are not limited to, hemimaleates, hemifumarates, and hemisuccinates.

[0396] The term "acid" contemplates all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids, such as hydrohalic acids, e.g., hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic, and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids, and fatty acids. Preferred acids are linear or branched, saturated, or unsaturated C1-C2 acids optionally substituted with halogen or hydroxyl groups. 20 Aliphatic carboxylic acids, or C6-C 12Aromatic carboxylic acids. Examples of such acids are carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, alpha-hydroxy acids such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methanesulfonic acid, and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid, and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylsteric acid. Other acids include gluconic acid, glycoheptonic acid, and lactobionic acid. III. Composition

[0397] The compound may be administered in the form of an appropriate composition, such as a pharmaceutical composition. Pharmaceutical compositions are physiologically acceptable and typically contain an active compound and a carrier. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Non-limiting examples of such pharmaceutical carriers include liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Pharmaceutical carriers can also be saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants, and coloring agents can be used. Other examples of suitable pharmaceutical carriers can be found in Remington's Pharmaceutical Sciences (Alfonso Gennaro ed., Krieger Publishing Company (1997); Remington's: The Science and Practice of Pharmacy, 21 stEd. (Lippincot, Williams & Wilkins (2005); Modern Pharmaceutics, vol. 121 (Gilbert Banker and Christopher Rhodes, CRC Press (2002) (each of which is incorporated herein by reference in its entirety).

[0398] The composition can be physiologically and / or pharmaceutically acceptable desired form, for example, table, capsule, solution, emulsion, suspension, gel, sol or colloid.Optionally, the carrier can comprise, for example, buffer solution, for example, alkaline buffer solution, for example, ammonium buffer solution, acidic buffer solution, for example, ethanoic acid salt, citrate salt, lactate, acetate, etc., or zwitterionic buffer solution, for example, glycine, alanine, valine, leucine, isoleucine and phenylalanine, Krebs-Ringer buffer, TRIS, MES, ADA, ACES, PIPES, MOPSO, coramine chloride, MOPS, BES, TES, HEPES, DIPSO, MOBS, TAPSO, acetamidoglycine, TEA, POPSO, HEPPSO, EPS, HEPPS, Tricine, TRIZMA, glycinamide, glycyl-glycine, HEPBS, bicine, TAPS, AMPB, CHES, AMP, AMPSO, CAPSO, CAPS and CABS.

[0399] In embodiments where the composition is in a liquid form, the carrier can be a solvent or dispersion medium, including, but not limited to, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), lipid (e.g., triglyceride, vegetable oil, liposome), and combinations thereof. The appropriate fluidity can be maintained, for example, by using a coating such as lecithin; by maintaining the required particle size by dispersing in a carrier such as liquid polyol or lipid; by using a surfactant such as hydroxypropylcellulose; or by a combination of such methods. If desired, a tonicity adjuster can be included, for example, sugar, sodium chloride, or a combination thereof. In some embodiments, the composition is isotonic.

[0400] The compositions may also include additional ingredients, such as acceptable surfactants, cosolvents, emollients, agents to adjust pH and osmolality, and / or antioxidants to retard oxidation of one or more components.

[0401] The composition can be prepared for administration by any suitable route, such as ocular (including periocular and intravitreal), oral, parenteral, intranasal, anal, intravaginal, topical, subcutaneous, intravenous, intraarterial, intrathecal, and intraperitoneal.Thus, intrathecal administration is optional and can be selected by the clinician (for example, if the aldose reductase inhibitor is not a central nervous system penetrant), but it is generally preferred not to administer the aldose reductase inhibitor intrathecally.Oral compositions can be directly incorporated into dietary food.Preferred carriers for oral administration include inert diluents, edible carriers, or combinations thereof.Examples of pharmaceutically acceptable carriers include, for example, water or saline, polymers such as polyethylene glycol, carbohydrates and their derivatives, oils, fatty acids, or alcohols.Surfactants, such as detergents, are also suitable for use in the formulation.Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, polyoxyethylenated esters of sorbitol or sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates; anionic surfactants, such as alkaline stearates, in particular sodium stearate, potassium stearate or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctyl sulfosuccinate; or fatty acids, in particular those derived from coconut oil; cationic surfactants, such as water-soluble quaternary ammonium salts of the formula NR'R"R'"R""Y", where the R radicals are optionally and Y" is an anion of a strong acid, such as a halide, sulfate, or sulfonate anion; cetyltrimethylammonium bromide, which is one of the cationic surfactants that can be used, and the amine salts of NR'R'R" (where the R radicals are the same or different hydrocarbon radicals, optionally hydroxylated); octadecylamine hydrochloride, which is one of the cationic surfactants that can be used; nonionic surfactants, such as optionally polyoxyethylated esters of sorbitan, in particular polysorbate 80 or polyoxyethylated alkyl ethers; polyethylene glycol stearate, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids, or copolymers of ethylene oxide and propylene oxide; and amphoteric surfactants, such as substituted lauryl compounds of betaine.

[0402] If desired, oral compositions can comprise one or more binders, excipients, disintegrants, lubricants, flavorings and their combinations.In certain embodiments, compositions can comprise one or more of the following: binders, such as gum tragacanth, acacia, corn starch, gelatin or their combinations; excipients, such as dicalcium phosphate, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate or their combinations; disintegrants, such as corn starch, potato starch, alginic acid or their combinations; lubricants, such as magnesium stearate; sweeteners, such as sucrose, lactose, saccharin or their combinations; flavorings, such as peppermint, wintergreen oil, cherry flavor, orange flavor or their combinations containing two or more of the above.

[0403] Additional formulations suitable for other modes of administration include suppositories. Sterile injectable solutions can also be prepared using appropriate solvents. Generally, dispersions are prepared by incorporating the various sterilized amino acid components into a sterile vehicle containing the basic dispersion medium and / or the other ingredients. Appropriate formulation methods for any desired mode of administration are well known in the art (generally, see Remington's Pharmaceutical Sciences, 18 th (See Ed. Mack Printing Company, 1990).

[0404] A typical pharmaceutically acceptable composition may contain the AR inhibitor and / or its pharmaceutically acceptable salt at a concentration ranging from about 0.01 to about 2 wt%, e.g., 0.01 to about 1 wt%, or about 0.05 to about 0.5 wt%. The composition may be formulated as a solution, suspension, ointment, capsule, or the like. The pharmaceutical composition may be prepared as an aqueous solution and may contain additional ingredients, such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity-adjusting ingredients, and the like. Other equivalent modes of administration may be found in U.S. Pat. No. 4,939,140.

[0405] When administered to a subject, AR inhibitor and pharmaceutically acceptable carrier can be sterile.Suitable pharmaceutical carrier can also contain excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, propylene glycol 300, water, ethanol, polysorbate 20 etc.The present composition can optionally contain a small amount of wetting agent or emulsifying agent or pH buffering agent.

[0406] The pharmaceutical preparations of the present disclosure are prepared by methods well known in the art of pharmacy. If necessary, one or more auxiliary ingredients (e.g., buffers, flavoring agents, surfactants, etc.) may also be added. The choice of carrier is determined by the solubility and chemical properties of the compound, the selected route of administration, and standard pharmaceutical practice.

[0407] In some embodiments, the composition is in unit dosage form, such as a tablet, capsule, or single-dose vial. The appropriate unit dose, i.e., the therapeutically effective amount, can be determined during appropriately designed clinical trials for each condition for which administration of the selected compound is indicated, and will, of course, vary depending on the desired clinical endpoint.

[0408] Any of the compounds and / or compositions of the present disclosure may be provided in a kit comprising the compound and / or composition. Thus, in one embodiment, the compounds and / or compositions of the present disclosure are provided in a kit comprising, in the same package or in separate packages, a carrier and, optionally, instructions for using the kit for therapeutic or prophylactic use. IV. Combination Therapy

[0409] The method described herein comprises administering AR inhibitor and one or more additional therapeutic agents.The additional therapeutic agent can be administered before, simultaneously with, or after the AR inhibitor, but can be administered in a manner that provides the overlap of the pharmacological activity of the AR inhibitor and the additional therapeutic agent.The additional therapeutic agent can be, for example, a second aldose reductase inhibitor, an antioxidant, or both.

[0410] For example, second aldose reductases can be synthesized using the methods described, for example, in U.S. Pat. No. 5,677,342; U.S. Pat. No. 5,155,259; U.S. Pat. No. 4,939,140; U.S. Patent Application Publication No. 2006 / 0293265; and Roy et al. (Diabetes Research and Clinical Practice, 10, Issue 1). 1,91-97,1990; and the references cited therein (each of which is incorporated herein by reference in its entirety).Aldose reductase inhibitors include, for example, zopolrestat, epalrestat, ranirestat, berberine and sorbinil, as described in U.S. Patent No. 4,939,140; U.S. Patent No. 6,159,976; and U.S. Patent No. 6,570,013.Preferably, the second aldose reductase inhibitor is selected from ponalrestat, epalrestat, sorbinil or sorbinol, imirestat, AND-138, CT-112, zopolrestat, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alkonyl, statyl, berberine or SPR-210.

[0411] Other therapeutic agents that may be administered include, for example, corticosteroids such as prednisone, methylprednisolone, dexamethasone, or triamcinalone acetinide, or noncorticosteroid anti-inflammatory compounds such as ibuprofen or flurbiproben. Similarly, vitamins and minerals, such as zinc and micronutrients, may be co-administered. Additionally, inhibitors of the protein tyrosine kinase pathway, including natural protein tyrosine kinase inhibitors such as quercetin, lavendustin A, erbstatin, and herbimycin A, and synthetic protein tyrosine kinase inhibitors such as tyrphostins (e.g., AG490, AG17, AG213 (RG50864), AG18, AG82, AG494, AG825, AG879, AG1112, AG1296, AG1478, AG126, RG13022, RG14620, and AG555), dihydroxy- and dimethoxybenzylidenemalononitriles, analogs of lavendustin A (e.g., AG814 and AG957), quinazolines (e.g., AG1478), 4,5-dianilinophthalimides, and thiazolidinediones, may be co-administered with genistein or an analog, prodrug, or pharmaceutically acceptable salt thereof (Levitzki et al., Science 267:1782-1788 (1995); and Cunningham et al., Anti-Cancer Drug Design 7:365-384 (1992). In this regard, potentially useful derivatives of genistein include those described in U.S. Patent No. 5,637,703 to Mazurek et al. Selenoindoles (2-thioindoles) and related disulfide selenides, such as those described in U.S. Patent No. 5,464,961 to Dobrusin et al., are useful protein tyrosine kinase inhibitors. Neutralizing proteins against growth factors, such as monoclonal antibodies specific for a given growth factor, e.g., VEGF (see, e.g., Aiello et al., PNAS USA 92:10457-10461 (1995)) or phosphotyrosine (Dhar et al., Mol. Pharmacol. 37:519-525 (1990)), can be co-administered.Various other compounds that may be co-administered include inhibitors of protein kinase C (see, e.g., U.S. Pat. Nos. 5,719,175 and 5,710,145), cytokine modulators, endothelial cell-specific inhibitors of proliferation such as thrombospondin, endothelial cell-specific inhibitory growth factors such as TNFα, antiproliferative peptides such as SPARC and proferrin-like peptides, glutamate receptor antagonists, aminoguanidine, angiotensin-converting enzyme inhibitors such as angiotensin II, calcium channel blockers, γ-tectorigenin, ST638, somatostatin analogs such as SMS 201-995, monosialoganglioside GM1, ticlopidine, neurotrophic growth factors, methyl-2,5-dihydroxycinnamate, angiogenesis inhibitors such as recombinant EPO, sulfonylurea oral hypoglycemic agents such as gliclazide (non-insulin dependent diabetes mellitus), ST638 (Asahi et al., FEBS Letters, 2004). 309:10-14 (1992)), thalidomide, nicardipine hydrochloride, aspirin, piceatannol, staurosporine, adriamycin, epidelstatin, (+)-aeroprisinin-1, phenazocine, halomethyl ketones, antilipidemic agents such as etofibrate, chlorpromazine, spingosine, and retinoic acid and their analogs (Burke et al., Drugs of the Future 17(2):119-131 (1992); and Tomlinson et al., Pharmac. Ther. 54:151-194 (1992)).

[0412] The present disclosure further provides the use of a compound of Formula (I)-(VI) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof in a method for treating a disease state and / or symptom caused by or associated with PMM2-CDG. In another embodiment, the present disclosure relates to the use of a compound of Formula (I)-(VI) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof in a method for treating a disease state and / or symptom caused by or associated with PMM2-CDG, the method comprising the steps of: (a) identifying a subject in need of such treatment; (b) providing a compound of Formula (I)-(VI) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof; and (c) administering a therapeutically effective amount of said compound of Formula (I)-(VI) to treat, inhibit, and / or prevent the disease state or symptom in the subject in need of such treatment.

[0413] In another embodiment, the present disclosure relates to the use of a compound of Formula (I)-(VI) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof in a method of treating a disease state and / or symptom caused by or associated with PMM2-CDG, the method comprising the steps of: (a) identifying a subject in need of such treatment; (ii) providing a composition comprising a compound of Formula (I)-(VI) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or tautomer thereof; and (iii) administering the composition in a therapeutically effective amount to treat, inhibit, and / or prevent the disease state or symptom in the subject in need of such treatment.

[0414] In the foregoing embodiments, the compound or composition is preferably administered orally. [Example]

[0415] V. Example - In Vitro Activation of PMM2 by Compound B In vitro activation of PMM2 by Compound B was studied in fibroblasts derived from PMM2-CDG patients. Compound B is a potent and selective inhibitor of aldose reductase. The AR inhibitory activity of Compound B was determined in a microplate assay in the presence of Compound B concentrations ranging from 0.1 nM to 10 μM, using D-glyceraldehyde and NADPH as substrates for aldose reductase. The results, presented as percentage inhibition of maximal activity, are summarized in Figure 1. The reported mean AR inhibitory concentration [IC] of 72 nM was 7.2 nM. 50 ] compared to epalrestat with Compound B (IC 50 =0.10 nM) is noted to be a significantly more potent inhibitor of aldose reductase enzyme activity.

[0416] Because of the deleterious effects on the central nervous system of PMM2-CDG patients, Compound B, a CNS-penetrating aldose reductase inhibitor, was tested in fibroblast cell lines derived from four unique individual PMM2-CDG patients to determine whether PMM2 enzyme activation could be detected.

[0417] Cells were seeded into 96-well plates, homogenization buffer (20 mM HEPES, 25 mM KCl, 1 mM DTT, 10 μg / ml leupeptin, 10 μg / ml antipain) was added, and the plates were freeze-thawed twice at −80° C. To lyse the cells, reaction buffer (50 mM HEPES, 5 mM MgCl, 0.5 mM NADP, 10 μg / ml yeast glucose-6-phosphate dehydratase, 10 μM glucose-1,6-bisphosphate, 10 μg / ml phosphoglucoisomerase, 5.25 μg / ml phosphomannose isomerase) containing 200 μM mannose-1-phosphate as a substrate was then added to each well. The plate was incubated at 37°C for 270 minutes, and absorbance was read at 340 nm at 30, 60, 90, 120, 150, 180, 210, 240, and 270 minutes by removing the plate from the incubation at each time point. All incubations were performed with or without substrate (mannose-1-phosphate), and the difference between these two values ​​was calculated as enzyme activity. Enzyme activity was normalized to total soluble protein levels. The enzyme activity of fibroblasts in the absence of AR inhibitors was determined. To evaluate the effect of Compound B on enzyme activity, Compound B was incubated with the cell line at a concentration of 50 nM for 24 hours. After this, enzyme activity was evaluated as described above. At least two biological replicates were performed, and enzyme activity in the presence of Compound B was compared with that of the DMSO-treated mutant cell line used as a control. To facilitate analysis, the enzyme activity (represented by NADPH concentration) of each treatment condition was compared to the activity of the baseline untreated mutant cell line at the last time point.

[0418] The results of these studies are shown in Figure 2. The heterozygous amino acid substitutions for each individual patient are indicated below each bar in the graph in Figure 2. Compound B increased PMM2 enzyme activity in each of the four patient-derived cell lines tested. Compound B was shown to be a potent activator of PMM2 activity in fibroblasts derived from PMM2-CDG patients.

[0419] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0420] Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, suitable methods and materials are described in the preceding paragraphs.In addition, the materials and methods are merely exemplary and are not intended to be limiting.All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated by reference.All published foreign patents and patent applications cited herein are incorporated by reference.All published references, documents, manuscripts, and scientific literature cited herein are incorporated by reference.All identifiers and accession numbers for scientific databases (e.g., PUBMED, NCBI, GENBANK, EBI) referenced herein are incorporated by reference. In one embodiment, for example, the following items are provided: (Item 1) A method for treating PMM2-CDG, comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor. (Item 2) A method for increasing PMM2 enzyme activity in a subject having PMM2-CDG, comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor. (Item 3) 3. The method according to any one of items 1 to 2, wherein the aldose reductase inhibitor is a compound of formula (III) or a salt thereof: (Item 4) The aldose reductase inhibitor is [ka] or a salt thereof. (Item 5) 5. The method according to any one of items 1 to 4, wherein the aldose reductase inhibitor is compound B or a salt thereof. (Item 6) 3. The method according to any one of items 1 to 2, wherein the aldose reductase inhibitor is a compound of formula (II) or a salt thereof: (Item 7) The aldose reductase inhibitor is

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Claims

1. 1. A composition for treating PMM2-CDG in a subject in need thereof, comprising an aldose reductase inhibitor, wherein the aldose reductase inhibitor is a compound of formula (III): [Chemistry 18] or a salt thereof, During the ceremony, R １ CO ２ R ２ and R ２ is H, (C １ -C ６ )-alkyl, (C １ -C ６ )-hydroxyalkyl or (C １ -C ６ )-aminoalkyl; X １ is H or halogen; X ２ is H or halogen; Y is a bond, C═O, C═S, C═NH or C═N(C １ -C ４ )-alkyl; Z is 【Chemistry 19】 and A １ NR ７ , O, S or CH ２ and A ２ is N or CH; A ３ NR ７ , O or S; R ３ ~R ６ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C １ -C ４ )-alkyl, (C １ -C ４ )-alkoxy, (C １ -C ４ )-alkylthio, (C １ -C ４ )-alkylsulfinyl or (C １ -C ４ )-alkylsulfonyl; and R ７ is hydrogen, (C １ -C ４ )-alkyl or C(O)O—(C １ -C ４ )-alkyl; composition.

2. 1. A composition for increasing PMM2 enzyme activity in a subject having PMM2-CDG, comprising an aldose reductase inhibitor, wherein the aldose reductase inhibitor is a compound of formula (III): [Chemistry 18] or a salt thereof, During the ceremony, R １ CO ２ R ２ and R ２ is H, (C １ -C ６ )-alkyl, (C １ -C ６ )-hydroxyalkyl or (C １ -C ６ )-aminoalkyl; X １ is H or halogen; X ２ is H or halogen; Y is a bond, C═O, C═S, C═NH or C═N(C １ -C ４ )-alkyl; Z is 【Chemistry 19】 and A １ NR ７ , O, S or CH ２ and A ２ is N or CH; A ３ NR ７ , O or S; R ３ ~R ６ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C １ -C ４ )-alkyl, (C １ -C ４ )-alkoxy, (C １ -C ４ )-alkylthio, (C １ -C ４ )-alkylsulfinyl or (C １ -C ４ )-alkylsulfonyl; and R ７ is hydrogen, (C １ -C ４ )-alkyl or C(O)O—(C １ -C ４ )-alkyl; composition.

3. R ２ is H or (C １ -C ６ )-alkyl; Y is C=O; A １ NR ７ , O or S; A ２ is N; A ３ is O or S; and R ３ ~R ６ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C １ -C ４ )-alkyl, (C １ -C ４ )-alkoxy, (C １ -C ４ )-alkylthio, (C １ -C ４ )-alkylsulfinyl or (C １ -C ４ )-alkylsulfonyl; and R ７ is hydrogen, (C １ -C ４ )-alkyl or C(O)O—(C １ -C ４ 3. The composition of claim 1, wherein the aryl group is aryl.

4. Z is 【Chemical 84】 The composition according to any one of claims 1 to 3, which is a compound selected from the group consisting of hydroxybenzoates, ...

5. R ２ is H or (C １ -C ６ )-alkyl; X １ is H; X ２ is H; Y is C=O; A １ is S; A ２ is N; and R ３ ~R ６ The composition of any one of claims 1 to 4, wherein is independently hydrogen, halogen, or haloalkyl.

6. The aldose reductase inhibitor is a compound of formula (III-1): 【Chemistry 93】 or a salt thereof, During the ceremony, R １ CO ２ R ２ and R ２ is H; X １ is H; X ２ is H; Y is C=O; A １ is S; A ２ is N; and R ３ ~R ６ are independently hydrogen, halogen, or (C １ -C ４ )-haloalkyl; The composition according to any one of claims 1 to 5.

7. Z is 【Chemical 85】 The composition according to any one of claims 1 to 3, which is a pharmaceutically acceptable salt or solvate thereof.

8. R ２ is hydrogen or (C １ -C ６ )-alkyl; Y is C=O; R ３ ~R ６ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C １ -C ４ )-alkyl, (C １ -C ４ )-alkoxy, (C １ -C ４ )-alkylthio, (C １ -C ４ )-alkylsulfinyl or (C １ -C ４ )-alkylsulfonyl; and R ７ is hydrogen, (C １ -C ４ )-alkyl or C(O)O—(C １ -C ４ 8. The composition of claim 7, wherein the aryl group is aryl.

9. R ４ is CF ３ The composition according to any one of claims 1 to 8, wherein

10. R ３ , R ５ , and R ６ is hydrogen and R ４ is CF ３ The composition according to any one of claims 1 to 9, wherein

11. The aldose reductase inhibitor is 【Chemical 86】 The composition according to any one of claims 1 to 6, wherein the compound is selected from the group consisting of: and salts thereof.

12. The aldose reductase inhibitor is compound B: 【Chemistry 87】 The composition according to any one of claims 1 to 6, which is a compound selected from the group consisting of hydroxybenzoates, ...

13. The aldose reductase inhibitor is 【Chemical 94】 The composition according to any one of claims 1 to 6, which is a compound selected from the group consisting of hydroxybenzoates, ...

14. The aldose reductase inhibitor is 【Chemical 95】 The composition according to any one of claims 1 to 6, which is a compound selected from the group consisting of hydroxybenzoates, ...

15. The aldose reductase inhibitor is 【Chemistry 96】 The composition according to any one of claims 1 to 6, which is a compound selected from the group consisting of hydroxybenzoates, ...

16. The composition of any one of claims 1 to 15, wherein the subject is a human.

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