Methods of treating diabetic cardiomyopathy

Abstract

Disclosed herein are methods of treating diabetic cardiomyopathy (DbCM) using an aldose reductase inhibitor, and methods of inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with DbCM using an aldose reductase inhibitor. Also disclosed are aldose reductase inhibitors and compositions thereof for use in treating diabetic cardiomyopathy (DbCM), or inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with DbCM. Subjects treated by the methods and uses are not administered a sodium-glucose cotransporter-2 (SGLT2) inhibitor and / or have an HbA1C value greater than 8.5%.

Description

METHODS OF TREATING DIABETIC CARDIOMYOPATHYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application number 63 / 708,948 filed on October 18, 2024, the disclosure of which is incorporated by reference herein in its entirety.FIELD

[0002] The present application pertains to the field of diabetic cardiomyopathy therapy. More particularly, the present application pertains to uses of aldose reductase inhibitors in methods for treatment of diabetic cardiomyopathy or inhibiting progress of diabetic cardiomyopathy.BACKGROUND

[0003] Diabetic cardiomyopathy (DbCM) is a form of heart failure characterized by abnormal myocardial structure and performance in subjects with diabetes mellitus (see Jia, G. et al. Circulation Research (2018) 122:624-638). It is estimated that over 38 million people in the United States have diabetes mellitus, which is over eleven percent of the U.S. population, and DbCM is believed to affect one in five people with type-2 diabetes mellitus (see Centers for Disease Control and Prevention (CDC): National Diabetes Statistics Report, May 15, 2024). Subjects with DbCM are at high risk of progression to overt heart failure and increased morbidity and mortality (see Swiatkiewicz et al. BMC Medicine (2024) 22: 195). Approximately twenty-five percent of subjects with DbCM progress to overt heart failure or death within 18 months of diagnosis, and there is currently no approved treatment for DbCM.

[0004] Accordingly, there is a recognized but unmet need for a DbCM treatment, particularly a treatment that can stabilize cardiac functional capacity and avoid worsening of the condition and progression to overt heart failure.SUMMARY

[0005] The present disclosure relates to methods of treating diabetic cardiomyopathy (DbCM) with an aldose reductase inhibitor. In particular, the present disclosure relates to a method of treating DbCM in a subject that is not administered a sodium-glucose cotransporter-2 (SGLT2) inhibitor and / or has an HbAlc value of greater than 8.5%.

[0006] Without wishing to be bound by theory, it is believed that aldose reductase inhibitors, particularly an aldose reductase inhibitor of the present disclosure (e.g., a compound ofFormula (I), (la), (lb), (Ic), (II), or Compound A), provide a greater therapeutic benefit to a subject with DbCM who is a non-user of an SGLT2 inhibitor, relative to the benefit received by a subject with DbCM that is administered an SGLT2 inhibitor. It is also believed that aldose reductase inhibitors, particularly an aldose reductase inhibitor of the present disclosure (e.g., a compound of Formula (I), (la), (lb), (Ic), (II), or Compound A), provide a greater therapeutic benefit to a subject with DbCM that has an HbAlc value of greater than 8.5%, relative to the benefit received by a subject with DbCM that has an HbAlc value of 8.5% or less.

[0007] As such, in some aspects the present disclosure relates to a method of treating DbCM, comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor, wherein: the subject has DbCM; the subject is not administered a SGLT2 inhibitor; the aldose reductase inhibitor is orally administered in an amount of about 2000 mg / day to about 3000 mg / day; and the aldose reductase inhibitor is a compound ofpharmaceutically acceptable salt thereof, wherein R1is H, (Ci-Ce)-alkyl, (Ci-Ce)-hydroxyalkyl, or (Ci-Cej-aminoalkyl; X1is N or CR3, X2is N or CR4, X3is N or CR5, and X4is N or CR6, with the proviso that two or three of X1, X2, X3, and X4are N; Y is a bond, C=O, C=S, C=NH, or C=N(Ci-C4)-alkyl; Z isis NR11, O, or S; R3through R10are independently hydrogen, halogen, cyano, acyl, (C1-C4)- haloalkyl, (Ci-C4)-haloalkoxy, (Ci-C4)-haloalkylthio, trifluoroacetyl, (Ci-C4)-alkyl, (C1-C4)- alkoxy, (Ci-C4)-alkylthio, (Ci-C4)-alkylsulfinyl, or (Ci-C4)-alkylsulfonyl; or two of R3 through Re or two of R7 through Rio taken together are (Ci-C4)-alkylenedioxy; and R11 is hydrogen, (Ci-Cij-alkyl, or C(O)O-(Ci-C4)-alkyl.

[0008] The present disclosure also relates to a method of inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with DbCM, comprising administering to the subject a therapeutically effective amount of an aldosereductase inhibitor, wherein: the subject is not administered a SGLT2 inhibitor; the aldose reductase inhibitor is orally administered in an amount of about 2000mg / day to about 3000 mg / day; and the aldose reductase inhibitor is a compound of Formula (I), as defined herein.

[0009] Additionally, the present disclosure relates to a method of treating DbCM, comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor, wherein: the subject has DbCM and an HbAlC value of greater than 8.5%; the aldose reductase inhibitor is orally administered in an amount of about 2000 mg / day to about 3000 mg / day; and the aldose reductase inhibitor is a compound of Formula (I), as defined herein.

[0010] The present disclosure further relates to a method of inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with DbCM, comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor, wherein: the subject has an HbAlc value greater than 8.5%; the aldose reductase inhibitor is orally administered in an amount of about 2000mg / day to about 3000 mg / day; and the aldose reductase inhibitor is a compound of Formula (I), as defined herein.

[0011] In a method of the present disclosure, the subject with DbCM that is not administered an SGLT2 inhibitor can have any HbAlc value. Preferably, the subject with DbCM that is not administered an SGLT2 inhibitor has an HbAlc value greater than or equal to about 5.5%, e.g., greater than or equal to about 6.0%, greater than or equal to about 6.5%, greater than or equal to about 7.0%, greater than or equal to about 7.5%, greater than or equal to about 8.0%, greater than or equal to about 8.5%, greater than or equal to about9.0%, greater than or equal to about 9.5%, or greater than or equal to about 10.0%. In some embodiments, the subject has an HbAlc value greater than 8.5%.

[0012] In a method of the present disclosure, the subject with an HbAlc value of greater than 8.5% can also be administered an SGLT2 inhibitor. In some embodiments, the subject has an HbAlc value greater than 8.5% and is administered an SGLT inhibitor. In some embodiments, the subject has an HbAlc value greater than 8.5% and is not administered an SGLT inhibitor.

[0013] In other aspects, the present disclosure relates to a use of an aldose reductase inhibitor, or a pharmaceutical composition comprising the aldose reductase inhibitor compound, in a method for treating DbCM in a subject in need thereof, wherein: the subject is not receiving or being administered a SGLT2 inhibitor; the aldose reductase inhibitor is for oral administration in an amount of about 2000 mg / day to about 3000 mg / day; and the aldose reductase inhibitor is a compound of Formula (I), as defined herein.

[0014] The present disclosure also relates to a use of an aldose reductase inhibitor compound, or a pharmaceutical composition comprising the aldose reductase inhibitor compound, in a method for inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with DbCM, wherein: the subject is not being administered a SGLT2 inhibitor; the aldose reductase inhibitor is for oral administration in an amount of about 2000 mg / day to about 3000 mg / day; and the aldose reductase inhibitor is a compound of Formula (I), as defined herein.

[0015] Additionally, the present disclosure relates to a use of an aldose reductase inhibitor compound, or a pharmaceutical composition comprising the aldose reductase inhibitor compound, in a method for treating DbCM in a subject in need thereof, wherein: the subject has DbCM and an HbAlC value of greater than 8.5%; the aldose reductase inhibitor is for oral administration in an amount of about 2000 mg / day to about 3000 mg / day; and the aldose reductase inhibitor is a compound of Formula (I), as defined herein.

[0016] The present disclosure further relates to use of an aldose reductase inhibitor compound, or a pharmaceutical composition comprising the aldose reductase inhibitor compound, in a method of inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with DbCM, wherein: the subject has an HbAlc value greater than 8.5%; the aldose reductase inhibitor is for oral administration in an amount of about 2000 mg / day to about 3000 mg / day; and the aldose reductase inhibitor is a compound of Formula (I), as defined herein.

[0017] In a use of the present disclosure, the subject with DbCM that is not receiving or being administered an SGLT2 inhibitor can have any HbAlc value. Preferably, the subject with DbCM that is not receiving or being administered an SGLT2 inhibitor has an HbAlc value greater than or equal to about 5.5%, e.g., greater than or equal to about 6.0%, greater than or equal to about 6.5%, greater than or equal to about 7.0%, greater than or equal to about 7.5%, greater than or equal to about 8.0%, greater than or equal to about 8.5%, greater than or equal to about 9.0%, greater than or equal to about 9.5%, or greater than or equal to about 10.0%. In some embodiments, the subject has an HbAlc value greater than 8.5%.

[0018] In a use of the present disclosure, the subject with an HbAlc value of greater than 8.5% can also be receiving an SGLT2 inhibitor. In some embodiments, the subject has an HbAlc value greater than 8.5% and is receiving an SGLT inhibitor. In some embodiments, the subject has an HbAlc value greater than 8.5% and is not receiving or being administered an SGLT inhibitor.

[0019] In a method or use disclosed herein, cardiac functional capacity is stabilized in the subject, as determined by: (i) a decrease of peak VO2 from baseline of no more than 0.5; or (ii) no substantial change in peak VO2 from baseline; after a period of time, e.g., after about 1 month, about 2 months, about 3 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or more, of treatment. Also, for example, in a method of the present disclosure cardiac functional capacity is improved in the subject, as determined by an increase of peak VO2 from baseline after a period of time, e.g., after about 1 month, about 2 months, about 3 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or more, of treatment.

[0020] A method of the present disclosure can comprise administering (e.g., orally administering) a therapeutically effective amount of an aldose reductase inhibitor, e.g., an aldose reductase inhibitor disclosed herein (e.g., a compound of Formula (I), (la), (lb), (Ic), (II), or Compound A). The therapeutically effective amount can comprise a dose of between about 1000 mg / day and about 5000 mg / day, e.g., in an amount of about 2000 mg / day to about 3000 mg / day, e.g., about 3000 mg / day. It will be understood that the daily amount can be administered at one or more times during the day. For example, in a method disclosed herein, the aldose reductase inhibitor can be administered (e.g., orally administered) twice daily, such as a dose of about 1500 mg twice a day. For example, the aldose reductase inhibitor can be administered (e.g., orally administered) once in the morning and once again in the evening. Alternatively, the aldose reductase inhibitor can be administered once daily, such as an oral dose of about 3000 mg once a day. Preferably, the aldose reductase inhibitor is administered (e.g., orally administered) in an amount of about 3000 mg / day. For example, in an embodiment the aldose reductase inhibitor is administered in an amount of 1500 mg twice daily, preferably by oral administration.

[0021] An aldose reductase inhibitor compound for use as disclosed herein can be in a pharmaceutical composition additionally comprising at least one pharmaceutically acceptable excipient. The pharmaceutical composition can be formulated for administering (e.g., orally administering) a therapeutically effective amount of an aldose reductase inhibitor, e.g., an aldose reductase inhibitor disclosed herein (e.g., a compound of Formula (I), (la), (lb), (Ic), (II), or Compound A). The therapeutically effective amount can comprise a dose of between about 1000 mg / day and about 5000 mg / day, e.g., in an amount of about 2000 mg / day to about 3000 mg / day, e.g., about 3000 mg / day. It will be understood that the daily amount can be administered at one or more times during the day. For example, in a pharmaceutical composition for use as disclosed herein, the composition can be formulated for administration(e.g., oral administration) of the aldose reductase inhibitor twice daily, such as a dose of about 1500 mg twice a day. For example, the administration can be once in the morning and once again in the evening. Alternatively, the pharmaceutical composition can be formulated for administration of the aldose reductase inhibitor once daily, such as at an oral dose of about 3000 mg once a day. Preferably, the pharmaceutical composition is formulated for administration (e.g., oral administration) of the aldose reductase inhibitor in an amount of about 3000 mg / day. For example, in an embodiment the pharmaceutical composition is formulated for administration of the aldose reductase inhibitor in an amount of 1500 mg twice daily, preferably by oral administration.

[0022] In a method or use of the present disclosure the subject can be administered an additional therapeutic agent. In some embodiments, the additional therapeutic agent is not an SGLT2 inhibitor. For example, the additional therapeutic agent can be a glucagon-like peptide 1 (GLP-1) agonist or a dual GLP-l / gastric inhibitory peptide (GIP) receptor agonist, such as dulaglutide (e.g., TRULICITY®), exenatide (e.g., BYETTA® or BYDUREON®), liraglutide (e.g., VICTOZA® or SAXENDA®), lixisenatide (e.g., ADLYXIN®), semaglutide (e.g., OZEMPIC®, WEGOVY®, or RYBELSUS®), or tirzepatide (e.g., MOUNJARO® or ZEPBOUND®).

[0023] In some embodiments, the aldose reductase inhibitor is a compound with the structure(Compound A), or a pharmaceutically acceptable salt thereof.

[0024] A subject treated by a method of the present disclosure can have type-1 diabetes mellitus (T1DM). A subject treated by a method of the present disclosure can have type-2 diabetes mellitus (T2DM).

[0025] In some embodiments, the subject has Stage B Heart Failure (Stage B HF).BRIEF DESCRIPTION OF DRAWINGS

[0026] FIG. 1A is a graph depicting adjusted peak V02mean change (mL / kg / min) from baseline to month 15, comparing all subjects that were treated with Compound A (1500 mg, bid) vs. all subjects that received placebo.

[0027] FIG. IB is a graph depicting adjusted peak VO2 mean change (mL / kg / min) from baseline to month 15, comparing subjects that were non-users of SGLT2 or GLP-1 therapies and were treated with Compound A (1500 mg, bid) vs. subjects that were non-users of SGLT2 or GLP-1 therapies that received placebo.

[0028] FIG. 1C is a graph depicting adjusted peak VO2 mean change (mL / kg / min) from baseline to month 15, comparing subjects that were non-users of SGLT2 therapies and were treated with Compound A (1500 mg, bid) vs. subjects that were non-users of SGLT2 therapies only that received placebo. Subjects that were users of a GLP-1 agonist are included in this data.

[0029] FIG. 2 is a graph depicting the peak VO2 mean change (mL / kg / min) to 15 months in subjects treated with Compound A (1500 mg, bid) vs. subjects that received placebo, contrasting all tested subjects with sub-groups defined by HbAlc levels of >7.5% (121 subjects), >8% (52 subjects), and >8.5% (13 subjects).DETAILED DESCRIPTION

[0030] This disclosure relates to methods of treating diabetic cardiomyopathy (DbCM), and to methods of inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with DbCM, using an aldose reductase inhibitor. In particular, subjects treated according to the methods disclosed herein are not also treated with (are not administered) a sodium-glucose cotransporter-2 (SGLT2) inhibitor, and / or have an HbAlC value greater than 8.5%.Methods of Treatment

[0031] This disclosure relates to methods of treating DbCM, comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor. The subject to be treated has DbCM, and the subject is not administered a SGLT2 inhibitor (e.g., the method does not include administration of a SGLT2 inhibitor). The aldose reductase inhibitor can be orally administered, such as in an amount of about 2000 mg / day to about 3000 mg / day. The aldose reductase inhibitor can be a compound of Formula (I), for example, Compound A.

[0032] This disclosure also relates to methods of inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with DbCM, comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor. The subject is not administered a SGLT2 inhibitor (e.g., the method does notinclude administration of a SGLT2 inhibitor). The aldose reductase inhibitor can be orally administered, such as in an amount of about 2000 mg / day to about 3000 mg / day. The aldose reductase inhibitor can be a compound of Formula (I), for example, Compound A.

[0033] This disclosure also relates to methods of treating DbCM, comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor, wherein the subject has DbCM and an HbAlC value greater than 8.5%. The aldose reductase inhibitor can be orally administered, such as in an amount of about 2000 mg / day to about 3000 mg / day. The aldose reductase inhibitor can be a compound of Formula (I), for example, Compound A.

[0034] This disclosure also relates to methods of inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with DbCM, comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor, wherein the subject has DbCM and an HbAlC value greater than 8.5%. The aldose reductase inhibitor can be orally administered, such as in an amount of about 2000 mg / day to about 3000 mg / day. The aldose reductase inhibitor can be a compound of Formula (I), for example, Compound A. In some embodiments, the subject that has DbCM and an HbAlC value greater than 8.5% is administered an SGLT2 inhibitor.

[0035] Subjects treated in accordance with the methods disclosed herein have diabetes mellitus and DbCM. A subject treated by a method disclosed herein can have type-1 diabetes mellitus (T1DM). A subject treated by a method disclosed herein can have type-2 diabetes mellitus (T2DM). A subject treated by a method of the present disclosure can have DbCM and / or Stage B Heart Failure, for example as determined by echocardiogram or other suitable diagnostic procedure.

[0036] In a method of the present disclosure, the subject can be a non-user of SGLT2 inhibitors. In other words, the subject is not administered, treated with, or concomitantly receiving an SGLT2 inhibitor. Accordingly, there is no overlap of pharmacological activity of SGLT2 inhibitor and aldose reductase inhibitor in a subject treated in accordance with the methods disclosed herein. In some embodiments, the subject treated by a method of the present disclosure has not been administered an SGLT2 inhibitor for at least about 12 hours, 24 hours, 2 days, 4 days, one week or longer, prior to administration of aldose reductase inhibitor.

[0037] Preferably, the methods disclosed herein exclude administration of a SGLT2 inhibitor. SGLT2 inhibitors are a well-known class of therapeutics used to lower blood sugar in adults with type 2 diabetes. There are several SGLT2 inhibitors currently available on the U.S.market, including empagliflozin (e.g., JARDIANCE®), bexagliflozin (e.g., BRENZAVVY™), canagliflozin (e.g., INVOKANA®), dapagliflozin (e.g., FARXIGA®), ertugliflozin (e.g., STEGLATRO®), and sotagliflozin (e.g., INPEFA®).

[0038] In some embodiments, the subject is not receiving an SGLT2 inhibitor. The subject treated by a method of the present disclosure can have any HbAlc greater than about 5.5%, e.g., greater than about 6.0%, greater than about 6.5%, e.g., an HbAlc value of between about 6.5% and about 20%, e.g., between about 7.0% and about 20%, between about 7.5% and about 20%, between about 7.5% and about 15%, between about 7.5% and about 12.5%, between about 7.5% and about 10%, between about 7.5% and about 9.5%, between about 7.5% and about 9.0%, between about 8.0% and about 20%, between about 8.0% and about 15%, between about 8.0% and about 12.5%, between about 8.0% and about 10%, between about 8.0% and about 9.5%, between about 8.0% and about 9.0%, between about 8.5% and about 20%, between about 8.5% and about 15%, between about 8.5% and about 12.5%, between about 8.5% and about 10%, between about 8.5% and about 9.5%, or between about 8.5% and about 9.0%. For example, the subject who is not receiving an SGLT2 inhibitor can have an HbAlc value of about 7.0%, about 7.1%, about 7.2%, about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8.0%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9.0%, about 9.1%, about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9%, about 10.0%, about 10.1%, about 10.2%, about 10.3%, about 10.4%, or about 10.5%.

[0039] Also disclosed herein are methods of treating a subject with DbCM who is undergoing treatment with an SGLT2 inhibitor (e.g., using an SGLT2 inhibitor) and has an HbAlc greater than 8.5%. For example, the subject with DbCM who is under treatment with an SGLT2 inhibitor can have an HbAlc between 8.51% and about 20%, between 8.51% and about 15%, between 8.51% and about 12.5%, between 8.51% and about 10%, between 8.51% and about 9.5%, or between 8.51% and about 9.0%. For example, the subject who is receiving an SGLT2 inhibitor can have an HbAlc of about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9.0%, about 9.1%, about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9%, about 10.0%, about 10.1%, about 10.2%, about 10.3%, about 10.4%, or about 10.5%, or greater. In some embodiments, the subject that has an HbAlc greater than 8.5% is administered empagliflozin (e.g., JARDIANCE®). In some embodiments, the subject that has an HbAlc greater than 8.5% is administered bexagliflozin (e.g., BRENZAVVY™). In some embodiments, the subject that has an HbAlc greater than8.5% is administered canagliflozin (e.g., INVOKANA®). In some embodiments, the subject that has an HbAlc greater than 8.5% is administered dapagliflozin (e.g., FARXIGA®). In some embodiments, the subject that has an HbAlc greater than 8.5% is administered ertugliflozin (e.g., STEGLATRO®). In some embodiments, the subject that has an HbAlc greater than 8.5% is administered sotagliflozin (e.g., INPEFA®).

[0040] Certain methods of the present disclosure in which a subject with an HbAlc greater than 8.5% is administered an aldose reductase inhibitor as described herein, can exclude the administration of a sodium-glucose cotransporter-2 (SGLT2) inhibitor. In other words, a subject with an HbAlc value greater than 8.5% treated by a method disclosed herein may also be a non-user of a SGLT2 inhibitor.

[0041] The methods disclosed herein can exclude treating a subject with an HbAlc of 8.5% or lower. In some embodiments, the method excludes treating a subject with an HbAlc that is 8.25% or lower. In some embodiments, the method excludes treating a subject with an HbAlc that is 8.0% or lower. In some embodiments, the method excludes treating a subject with an HbAlc that is 7.75% or lower. In some embodiments, the method excludes treating a subject with an HbAlc that is 7.5% or lower. In some embodiments, the method excludes treating a subject with an HbAlc that is 7.0% or lower. In some embodiments, the method excludes treating a subject with an HbAlc that is 6.5% or lower.

[0042] Methods of the present disclosure can comprise stabilizing or improving cardiac functional capacity in a subject. Suitable techniques for determining cardiac functional capacity, including improvements or stabilization of cardiac functional capacity, are well- known in the art. For example, the cardiac functional capacity of a subject can be determined by measuring peak oxygen consumption (peak VO2) at one or more timepoints. Peak VO2 is a clinically accepted measurement for the evaluation of cardiac function, that is often used to assess patients with heart failure, and is obtained in conjunction with cardiopulmonary exercise testing. See, e.g., Arena, R. et al. Circ. Heart Fail. 2.2 (2009): 113-120. Comparing the peak VO2 measured at baseline (e.g., at the start of treatment or immediately before the start of treatment) with peak VO2 measured at a later timepoint (e.g., during treatment or after treatment) can determine if the treatment provides an improvement or stabilization of cardiac functional capacity.

[0043] Treatment according to the methods disclosed herein can stabilize cardiac functional capacity in the subject, e.g., as determined by a decrease of peak VO2 from baseline of no more than 1.0 mL / kg / min, e.g., a decrease of no more than 0.9 mL / kg / min, a decrease of no more than 0.8 mL / kg / min, a decrease of no more than 0.7 mL / kg / min, a decrease of no morethan 0.6 mL / kg / min, a decrease of no more than 0.5 mL / kg / min, a decrease of no more than 0.4 mL / kg / min, a decrease of no more than 0.3 mL / kg / min, a decrease of no more than 0.2 mL / kg / min, a decrease of no more than 0.1 mL / kg / min, a decrease of no more than 0.075 mL / kg / min, a decrease of no more than 0.05 mL / kg / min, a decrease of no more than 0.025 mL / kg / min, or a decrease of no more than 0.01 mL / kg / min, after a period of treatment. Methods disclosed herein can stabilize cardiac functional capacity in the subject, e.g., as determined by no substantial decrease of peak VO2 from baseline, after the period of treatment. The period of treatment can be, e.g., about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or longer.

[0044] The methods disclosed herein can improve cardiac functional capacity in the subject, e.g., as determined by an increase of peak VO2 from baseline, after a period of treatment. For example, a method disclosed herein can lead to an increase of peak VO2 from baseline of about 0.01 mL / kg / min, e.g., an increase of about 0.02 mL / kg / min, an increase of about 0.03 mL / kg / min, an increase of about 0.04 mL / kg / min, an increase of about 0.06 mL / kg / min, an increase of about 0.08 mL / kg / min, an increase of about 0. 1 mL / kg / min, an increase of about 0.2 mL / kg / min, an increase of about 0.4 mL / kg / min, an increase of about 0.6 mL / kg / min, an increase of about 0.8 mL / kg / min, an increase of about 1.0 mL / kg / min, or greater. The period of treatment can be, for example, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or longer.

[0045] Elevated N-terminal pro-B type natriuretic peptide (NT-proBNP) concentrations can be associated with worse health status, lower activity levels, and reduced functional capacity, in subjects with heart failure. (See, e.g., Gouda et al. Cardiovascular Diabetology (2024) 23:281). Treatment according to the methods disclosed herein can lead to a decrease in NT- proBNP concentration in plasma. For example, plasma concentrations of NT-proBNP can decrease by about 1%, by about 2%, by about 4%, by about 8%, by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 75%, or more, after the start of treatment, e.g., after a period of about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months, 15 months, or 24 months, or longer.

[0046] Treatment according to the methods disclosed herein can inhibit further increase in NT-proBNP concentration in plasma. For example, NT-proBNP can increase after the start of treatment by no more than about 20%, e.g., an increase of no more than about 19%, an increase of no more than about 18%, an increase of no more than about 17%, an increase of no more than about 16%, an increase of no more than about 15%, an increase of no more than about 14%, an increase of no more than about 13%, an increase of no more than about 12%, an increase of no more than about 11%, an increase of no more than about 10%, an increase of no more than about 9%, an increase of no more than about 8%, an increase of no more than about 7%, an increase of no more than about 6%, an increase of no more than about 5%, an increase of no more than about 4%, an increase of no more than about 3%, an increase of no more than about 2%, or an increase of no more than about 1%, after the start of treatment, e.g., after a period of about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or longer.

[0047] The Kansas City Cardiomyopathy Questionnaire (KCCQ) has been qualified by the U.S. Food and Drug Administration (FDA) as a Clinical Outcome Assessment and recommended as a performance measure for quantifying the quality of care in heart failure (see, e.g., Spertus, J.A. et al. Journal of the American College of Cardiology (2020) 76(20): 2379-2390). Treatment according to the methods disclosed herein can lead to an increase in KCCQ score after the start of treatment. For example, KCCQ score can increase by 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 10 points, 12 points, 14 points, 16 points, 18 points, 20 points, 25 points, or more, after the start of treatment, e.g., after a period of about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or longer. Treatment according to the methods disclosed herein can lead to an increase in KCCQ score from the range of from 0 to 24 to a score in the range from 25 to 49, or greater; or KCCQ score can increase from a score in the range of from 25 to 49 to a score in the range from 50 to 74, or greater; or KCCQ score can increase from a score in the range of from 50 to 74 to a score in the range from 75 to 100. Persons of ordinary skill in the art will be familiar with administering and interpreting the KCCQ which has been described in the literature (see, e.g., Spertus, J.A. supra).

[0048] Cardiac abnormalities can be detected by echocardiography (manifesting as echocardiographic abnormalities), and therefore echocardiography is useful to evaluate theheart condition in a subject with DbCM. Treatment according to the methods disclosed herein can decrease the number or magnitude of echocardiographic abnormalities in a subject after the start of treatment, e.g., after a period of about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or longer. Also, treatment according to the methods disclosed herein can inhibit an increase in the number or magnitude of echocardiographic abnormalities in a subject after the start of treatment, e.g., after a period of about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or longer.

[0049] Treatment according to the methods disclosed herein can delay progression to overt heart failure, or death, in a subject with DbCM.Aldose Reductase Inhibitors

[0050] Methods of the present disclosure comprise administering to a subject an aldose reductase inhibitor. The aldose reductase inhibitor can be a compound of Formula (I):pharmaceutically acceptable salt thereof, wherein: R1is H,(Ci-Ce)-alkyl, (Ci-Ce)-hydroxyalkyl, or (Ci-C6)-aminoalkyl; X1is N or CR3; X2is N or CR4; X3is N or CR5; X4is N or CR6; with the proviso that two or three of X1, X2, X3, and X4arethrough R10are independently hydrogen, halogen, cyano, acyl, (Ci-C4)-haloalkyl, (C1-C4)- haloalkoxy, (Ci-C4)-haloalkylthio, trifluoroacetyl, (Ci-C4)-alkyl, (Ci-C4)-alkoxy, (C1-C4)- alkylthio, (Ci-C4)-alkylsulfmyl, or (Ci-C4)-alkylsulfonyl; or two of R3 through Re or two of R7 through Rio taken together are (Ci-C4)-alkylenedioxy; and R11 is hydrogen, (Ci-C4)-alkyl, or C(O)O-(Ci-C4)-alkyl.

[0051] It will be understood that when, the compounds ofFormula (I) encompass a structure of Formula (la):

[0052] It will also be understood that whenFormula (I) encompass a structure of Formula (lb) or Formula (Ic):

[0053] In certain embodiments, R1is hydrogen or (Ci-Ce) -alkyl. In certain embodiments, R1is hydrogen. In certain embodiments, R1is (Ci-Ce)-alkyl. In certain embodiments, R1is tert-butyl.

[0054] In certain embodiments, R3through R10are each independently hydrogen, halogen, or (Ci-C4)-haloalkyl. In certain embodiments, R3through R10are each independently hydrogen, halogen, or trihaloalkyl, e.g., trifluoromethyl.

[0055] In certain embodiments, R3through R6are each hydrogen.

[0056] In certain embodiments, R7through R10are each independently hydrogen, halogen or (Ci-C4)-haloalkyl. In certain embodiments, R7through R10are each independently hydrogen, halogen or trihaloalkyl, e.g., trifluoromethyl.

[0057] In certain embodiments, R7and R10are each hydrogen.

[0058] In certain embodiments, R8is hydrogen, halogen or (Ci-C4)-haloalkyl. In certain embodiments, R8is hydrogen. In certain embodiments, R8is halogen. In certain embodiments, R8is (Ci-C4)-haloalkyl.

[0059] In certain embodiments, R9is hydrogen, halogen or (Ci-C4)-haloalkyl. In certain embodiments, R9is hydrogen. In certain embodiments, R9is halogen. In certain embodiments, R9is (Ci-C4)-haloalkyl.

[0060] In certain embodiments, Y is C=O, C=S, C=NH, or C=N(Ci-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(Ci-C4)-alkyl.

[0061] In certain embodiments, A1is NR11, S, or CH2. In certain embodiments, A3is NR11or O. In certain embodiments, A1is NR11or S. In certain embodiments, A1is NR11. In certain embodiments, A1is O. In certain embodiments, A1is S.

[0062] In certain embodiments, A2is N or CH. In certain embodiments, A1is N. In certain embodiments, A1is CH.

[0063] In certain embodiments, A3is O or S. In certain embodiments, A3is O. In certain embodiments, A3is S.

[0064] In certain embodiments, X1and X4are each nitrogen.

[0065] In certain embodiments, X1and X2are each nitrogen.

[0066] In certain embodiments, X1and X3are each nitrogen.

[0067] In certain embodiments, X2and X3are each nitrogen.

[0068] In certain embodiments, X2and X4are each nitrogen.

[0069] In certain embodiments, X3and X4are each nitrogen.

[0070] In certain embodiments, X1and X4are each nitrogen, and X2and X3are each CH.

[0071] In certain embodiments, X1and X2are each nitrogen, and X3and X4are each CH.

[0072] In certain embodiments, X1and X3are each nitrogen, and X2and X4are each CH.

[0073] In certain embodiments, X2and X3are each nitrogen, and X1and X4are each CH.

[0074] In certain embodiments, X2and X4are each nitrogen, and X1and X3are each CH.

[0075] In certain embodiments, X3and X4are each nitrogen, and X1and X2are each CH.

[0076] In certain embodiments,

[0077] In certain embodiments,

[0078] In certain embodiments,

[0079] In certain embodiments,

[0080] In certain embodiments, R1is hydrogen or (Ci-Ce)-alkyl; X1and X4are N; X2is CR4;S; A2is N; A3is O, or S; R4and R5are hydrogen; R7through R10are each independently hydrogen, halogen, cyano, acyl, (Ci-C4)-haloalkyl, (C1-C4) -haloalkoxy, (C1-C4)- haloalkylthio, (Ci-C4)-alkyl, (Ci-C4)-alkoxy, (Ci-C4)-alkylthio, (Ci-C4)-alkylsulfinyl, or (Ci- C4)-alkylsulfonyl; and R11is hydrogen, C1-C4 alkyl, or C(O)O-(Ci-C4)-alkyl.

[0081] In certain embodiments, R1is hydrogen or tert-butyl; X1and X4are N; X2is CR4; X3isA2is N; A3is O or S; R4and R5are hydrogen; R7through R10are independently hydrogen, halogen, or (Ci-C4)-haloalkyl; and R11is hydrogen, (Ci-C4)-alkyl, or C(O)O-tert-butyl.

[0082] In certain embodiments, R1is hydrogen or tert-butyl; X1and X4are N; X2is CH; X3isA2is N; A3is O or S; R7, R8and R10are independently hydrogen, halogen, or (C1-C4)- haloalkyl; R9is halogen, or (Ci-C4)-haloalkyl; and R11is hydrogen or methyl.

[0083] In certain embodiments, R1is hydrogen or tert-butyl; X1and X4are N; X2is CH; X3isA2is N; A3is O or S; R7, R8and R10are independently hydrogen, halogen, or (C1-C4)- haloalkyl; R9is chloro, or trifluoromethyl; and R11is hydrogen or methyl.

[0084] Preferably, the aldose reductase inhibitor is a compound of Formula (II):acceptable salt thereof, wherein R1, R7, R8, R9, R10, and Y are as described in Formula (I), and preferably wherein R1is hydrogen or (Ci-Ce)-alkyl, and Y is C=O.

[0085] Exemplary compounds of Formula (I) and Formula (II) include the following, and pharmaceutically acceptable salts thereof:

[0086] Even more preferably, the aldose reductase inhibitor is Compound A, which has the structure:(Compound A).Pharmaceutical Compositions and Dose Forms

[0087] Compounds of the present disclosure can be administered in the form of a suitable composition, such as a pharmaceutical composition. Pharmaceutical compositions are physiologically acceptable and typically include the active compound (e.g., a Compound of Formula (I), (la), (lb), (Ic), (II), or Compound A) and a pharmaceutically acceptable excipient, such as a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Non-limiting examples of pharmaceutically acceptable excipients are provided herein, and can 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. The pharmaceutically acceptable excipient can also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used. Other examples of pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences (Alfonso Gennaro ed., Krieger Publishing Company (1997); Remington's: The Science and Practice ofPharmacy, 21stEd. (Lippincot, Williams & Wilkins (2005); Modem Pharmaceutics, vol. 121 (Gilbert Banker and Christopher Rhodes, CRC Press (2002); each of which hereby incorporated by reference in its entirety).

[0088] The composition can be in a desired dose form, such as a tablet, capsule, solution, emulsion, suspension, gel, sol, or colloid, that is physiologically and / or pharmaceutically acceptable.

[0089] If desired, the pharmaceutically acceptable excipient can include a buffer, for example an alkaline buffer, e.g., ammonium buffer or acidic buffers, e.g., ethanoates, citrates, citric acid, lactates, acetates, etc., or zwitterionic buffers, such as, glycine, alanine, valine, leucine, isoleucine and phenylalanine, Kreb's-Ringer buffer, TRIS, MES, ADA, ACES, PIPES, MOPSO, cholamine 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.

[0090] A pharmaceutically acceptable excipient can be a solvent or dispersion medium comprising, but not limited to, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), lipids (e.g., triglycerides, vegetable oils, liposomes) and combinations thereof. The desired fluidity can be maintained, for example, by the use of a coating, such as lecithin; by the maintenance of the required particle size by dispersion in excipients such as, for example liquid polyol or lipids; by the use of surfactants such as, for example hydroxypropylcellulose; or combinations thereof. If desired, tonicity adjusting agents can be included, such as, for example, sugars, sodium chloride or combinations thereof. In some embodiments, the composition is isotonic.

[0091] The compositions can also include additional ingredients, such as acceptable surfactants, co-solvents, emollients, agents to adjust the pH and osmolarity and / or antioxidants to retard oxidation of one or more component.

[0092] The compositions can be prepared for administration by any suitable route, such as ocular (including periocular and intravitreal administration), oral, parenteral, intranasal, anal, vaginal, topical, subcutaneous, intravenous, intra-arterial, intrathecal and intraperitoneal administration. A preferred route of administration is oral administration.

[0093] Oral compositions can be incorporated directly with the food of the diet. Preferred pharmaceutically acceptable excipients for oral administration comprise inert diluents, edible carriers, or combinations thereof. Examples of pharmaceutically acceptable excipient can include, for example, water or saline solution, polymers such as polyethylene glycol,carbohydrates and derivatives thereof, oils, fatty acids, or alcohols. Surfactants such as, for example, detergents, are also suitable for use in the formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates and others, anionic surfactants, such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fatty acids, in particular those derived from coconut oil, cationic surfactants, such as water-soluble quaternary ammonium salts (e.g., cetyltrimethylammonium bromide), amine salts (e.g., octadecylamine hydrochloride), non-ionic surfactants, such as optionally polyoxyethylenated esters of sorbitan, in particular polysorbate 80 (PS80), or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide, amphoteric surfactants, such as substituted lauryl compounds of betaine, and any other pharmaceutically acceptable excipient disclosed herein.

[0094] If desired, an oral composition can comprise one or more binders, excipients, disintegration agents, lubricants, flavoring agents, or combinations thereof. In certain embodiments, a composition can comprise one or more of the following: a binder, such as, for example, gum tragacanth, acacia, cornstarch, gelatin or combinations thereof; an excipient, such as, for example, dicalcium phosphate, mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate or combinations thereof; a disintegrating agent, such as, for example, com starch, potato starch, alginic acid or combinations thereof; a lubricant, such as, for example, magnesium stearate; a sweetening agent, such as, for example, sucrose, lactose, saccharin or combinations thereof; a flavoring agent, such as, for example peppermint, oil of wintergreen, cherry flavoring, orange flavoring, etc., or combinations thereof.

[0095] Additional formulations which are suitable for other modes of administration include suppositories. Sterile injectable solutions can be prepared using an appropriate solvent. Suitable formulation methods for any desired mode of administration are well known in the art (see, generally, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990).

[0096] When administered to a subject, the aldose reductase inhibitor and pharmaceutically acceptable excipient can be sterile. Suitable pharmaceutically acceptable excipients can also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, a polysorbate, and the like. The present compositions, if desired, can also contain a wetting or emulsifying agents, or pH buffering agent.

[0097] The pharmaceutical formulations of the present disclosure can be prepared by methods well-known in the art. The choice of pharmaceutically acceptable excipient can be determined, e.g., by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.

[0098] In some embodiments, the composition is in unit dose form such as a tablet, capsule, or single-dose vial. Suitable unit doses, i.e., therapeutically effective amounts, can be determined during clinical trials designed appropriately for each of the conditions for which administration of a chosen compound is indicated and will, of course, vary depending on the desired clinical endpoint. For example, a suitable unit dose can comprise about 1500 mg of an aldose reductase inhibitor.

[0099] Any of the compounds and / or compositions of the disclosure can be provided in a kit comprising the compounds and / or compositions. Thus, in one embodiment, the compound and / or composition of the disclosure is provided in a kit comprising in the same package or separate package, a pharmaceutically acceptable excipient and optionally instructions for using the kit for therapeutic or prophylactic end usage.Dosage

[0100] The amount of aldose reductase inhibitor to be administered to the subject in a method of the present disclosure can be determined by the attending skilled clinician, who can determine appropriate dosing based on a variety of considerations including the severity of the disease, the subject’s age, weight, general health, and other considerations.

[0101] In some embodiments, the subject will receive a dose (e.g., orally administered dose) from about 200 mg / day to about 6000 mg / day. For example, the subject can receive between about 1000 mg / day and about 5000 mg / day, e.g., between about 2000 mg / day and about 4000 mg / day, e.g., between about 2000 mg / day and about 3000 mg / day, e.g., about 3000 mg / day, e.g., by oral administration.

[0102] For example, the subject can receive a dose of about 2000 mg / day, about 2100 mg / day, about 2200 mg / day, about 2300 mg / day, about 2400 mg / day, about 2500 mg / day, about 2600 mg / day, about 2700 mg / day, about 2800 mg / day, about 2900 mg / day, about 3000 mg / day, about 3100 mg / day, about 3200 mg / day, about 3300 mg / day, about 3400 mg / day, about 3500 mg / day, about 3600 mg / day, about 3700 mg / day, about 3800 mg / day, about 3900 mg / day, about 4000 mg / day, e.g., by oral administration. In some embodiments, the subject receives a dose of about 3000 mg / day, by oral administration.

[0103] The aldose reductase inhibitor can be administered (e.g., orally administered) once daily, twice daily, three times daily, or four times daily for the desired treatment period, to achieve a desired daily dose. In some embodiments, the aldose reductase inhibitor is administered (e.g., orally administered) once daily. In some embodiments, the aldose reductase inhibitor is administered (e.g., orally administered) twice daily. For example, in some embodiments, the aldose reductase inhibitor is administered (e.g., orally administered) twice daily, each time at a dosage of 1500 mg, to provide a total dosage of 3000 mg / day. Also, for example, in some embodiments, the aldose reductase inhibitor is administered (e.g., orally administered) once daily at a dosage of 3000 mg, to provide a total dosage of 3000 mg / day.Combination Therapy

[0104] Diabetes mellitus is commonly treated or managed using a range of interventions, including pharmaceuticals, or sometimes a combination of pharmaceuticals. It will be understood that the subject treated by a method of the present disclosure can be receiving other interventions, such as an additional therapeutic agent, in addition to the aldose reductase inhibitor administered in a method of the present disclosure. The additional intervention can be for treating diabetes mellitus, a co-morbidity of diabetes mellitus, or a disease or disorder unrelated to diabetes mellitus.

[0105] For example, subjects treated by a method of the present disclosure can be administered an additional therapeutic agent. In some embodiments, the additional therapeutic agent is not an SGLT2 inhibitor.

[0106] The additional therapeutic agent can be, for example, a biguanide (e.g., metformin), a dipeptidyl peptidase 4 (DPP-4) inhibitor, a glucagon-like peptide 1 (GLP-1) agonist, a dual GLP-l / gastric inhibitory peptide (GIP) receptor agonist, a sulfonylurea, a thiazolidinedione, an alpha glucosidase inhibitor, a bile acid sequestrant, a dopamine-2 agonist, or a meglitinide. Also, the additional therapeutic agent can be an insulin or insulin analog.

[0107] Subjects with diabetes mellitus are also commonly treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors. However, subjects that are administered SGLT2 inhibitors can be excluded from a method of the present disclosure. Preferably, the methods disclosed herein exclude administration of a sodium-glucose cotransporter-2 (SGLT2) inhibitor. Examples of SGLT2 inhibitors include, but are not limited to, empagliflozin (e.g., JARDIANCE®), bexagliflozin (e.g., BRENZAVVY™). canagliflozin (e.g., INVOKANA®), dapagliflozin (e.g., FARXIGA®), ertugliflozin (e.g., STEGLATRO®), sotagliflozin (e.g., INPEFA®).

[0108] In some embodiments, the subject is administered an additional therapeutic agent that is a biguanide (e.g., metformin).

[0109] In some embodiments, the subject is administered an additional therapeutic agent that is a dipeptidyl peptidase-4 (DPP -4) inhibitor, such as alogliptin (e.g., NESINA®), linagliptin (e.g., TRADJENTA®), saxagliptin (e.g., ONGLYZA®), or sitagliptin (e.g., JANUVIA®).

[0110] In some embodiments, the subject is administered an additional therapeutic agent that is a glucagon-like peptide 1 (GLP-1) agonist, e.g., dulaglutide (e.g., TRULICITY®), exenatide (e.g., BYETTA® or BYDUREON®), liraglutide (e.g., VICTOZA® or SAXENDA®), lixisenatide (e.g., ADLYXIN®), or semaglutide (e.g., OZEMPIC®, WEGOVY®, or RYBELSUS®). In some embodiments, the subject is administered an additional therapeutic agent that is a dual GLP-l / gastric inhibitory peptide (GIP) receptor agonist such as tirzepatide (e.g., MOUNJARO® or ZEPBOUND®).[oni] In some embodiments, the subject is administered an additional therapeutic agent that is a sulfonylurea, e.g., glimepiride (e.g., AMARYL®), glipizide (e.g., GLUCOTROL®), or glyburide (e.g., MICRONASE®, GLYASE®, or DIABETA®).

[0112] In some embodiments, the subject is administered an additional therapeutic agent that is athiazolidinedione, e.g., rosiglitazone (e.g., AVANDIA®) or pioglitazone (e.g., ACTOS®).

[0113] In some embodiments, the subject is administered an additional therapeutic agent that is an alpha glucosidase inhibitor, e.g., acarbose (e.g., PRECOSE®), or migtilol (e.g., GLYSET®).

[0114] In some embodiments, the subject is administered an additional therapeutic agent that is a bile acid sequestrant, e.g., colesevelam (e.g., WELCHOL®).

[0115] In some embodiments, the subject is administered an additional therapeutic agent that is a dopamine-2 agonist, e.g., bromocriptine (e.g., CYCLOSET®).

[0116] In some embodiments, the subject is administered an additional therapeutic agent that is a meglitinide, e.g., nateglinide (e.g., STARLIX®) or repaglinide (e.g., PRANDIN®).

[0117] In some embodiments, the subject is administered an additional therapeutic agent that is an insulin or insulin analog, e.g., insulin aspart (e.g., NOVOLOG®), insulin glulisine (e.g., APIDRA®), insulin lispro (e.g., HUMALOG®), insulin detemir (e.g., LEVEMIR®), insulin degludec (e.g., TRESIBA®), insulin glargine (e.g., BASAGLAR®, LANTUS®, TOUJEO®), or human insulin (e.g., HUMULIN® N, HUMULIN® R, HUMULIN® 30 / 70, NOVOLIN® R, NOVOLIN® N, NO VOLIN® 30 / 70).Definitions

[0118] As used herein, the term “alkyl” refers to a radical of a saturated hydrocarbon group. An alkyl group can be a straight chain or a branched chain saturated hydrocarbon group. An alkyl disclosed herein can have 1 to 18 carbon atoms (Ci-is-alkyl), such as 1 to 6 carbon atoms (Ci-6-alkyl) or 1 to 4 carbon atoms (Ci-4-alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like. Throughout this disclosure, abbreviations that are well known in the art to describe various alkyl groups or their derivatives can be used, such as Me (methyl), Et (ethyl), Pr (propyl), Bu (butyl), and the like. Each instance of an alkyl group can be unsubstituted (an “unsubstituted alkyl”), or substituted (a “substituted alkyl”) with one or more substituents, e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0119] As used herein, the term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having one or more carbon-carbon double bonds, and no triple bonds. An alkenyl group can have from 2 to 18 carbon atoms, for example, an alkenyl group can have 2 to 8 carbon atoms (C2-8-alkenyl), 2 to 6 carbon atoms (C2-6-alkenyl), 2 to 5 carbon atoms (C2- 5-alkenyl), 2 to 4 carbon atoms (C2-4-alkenyl), or 2 to 3 carbon atoms (C2-3 -alkenyl). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of alkenyl groups include ethenyl, 1 -propenyl, 2-propenyl, 1- butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, heptenyl, octenyl, octatrienyl, and the like. Each instance of an alkenyl group can be independently optionally substituted, e.g., unsubstituted (an “unsubstituted alkenyl”), or substituted (a “substituted alkenyl”) with one or more substituents, e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0120] As used herein, the term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 18 carbon atoms, and one or more carbon-carbon triple bonds. The alkynyl group can have 2 to 8 carbon atoms (C2-8-alkynyl), 2 to 6 carbon atoms (C2-6-alkynyl), 2 to 5 carbon atoms (C2-5-alkynyl), 2 to 4 carbon atoms (C2-4-alkynyl), or 2 to 3 carbon atoms (C2-3 -alkynyl). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like. Each instance of an alkynyl group can be unsubstituted (an “unsubstituted alkynyl”), or substituted (a “substituted alkynyl”) with one or more substituents, e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0121] As used herein, the term “acyl” refers to a radical of the formula: RC(O)-, in which R represents an organic radical which can be an alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or the like, that can be substituted or unsubstituted, saturated or unsaturated. Examples of acyl groups include, but are not limited to, Me-C(O)-, Et-C(O)-,zBu-C(O)-, and the like.

[0122] As used herein, the term “alkoxy” refers to a group of the formula: -OR, in which R is an alkyl group, such as methoxy (-OMe), ethoxy (-OEt), tert-butoxy (-O'Bu). and the like.

[0123] As used herein, the term “alkylthio” refers to a group of the formula: -SR, in which R is an alkyl group, such as -SMe), -SEt, -S^Bu, and the like.

[0124] As used herein, the term “alkylsulfinyl” refers to a group of the formula: -S(O)R, in which R is an alkyl group, such as -S(O)Me), -S(O)Et, -S(O)zBu, and the like.

[0125] As used herein, the term “alkylsulfonyl” refers to a group of the formula: -S(O)2R, in which R is an alkyl group, such as -S(O)2Me), -S(0)2Et, -S(O)2zBu, and the like.

[0126] As used herein, the term “aminoalkyl” refers to an alkyl group comprising at least one amino (e.g., -NEE) group. An aminoalkyl can be defined in terms of the number of carbon atoms it contains, e.g., a (Ci-C6)-aminoalkyl is an aminoalkyl containing between 1 and 6 carbon atoms.

[0127] As used herein, the term “heteroalkyl” refers to a non-cyclic, stable, straight, or branched chain, that comprises at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen (N) and sulfur (S) atoms can optionally be oxidized, and the nitrogen heteroatom can optionally be quatemized. A heteroalkyl disclosed herein can have 1 to 18 carbon atoms (Ci-is-heteroalkyl), such as 1 to 12 carbon atoms (Ci-12-heteroalkyl), or 1 to 6 carbon atoms (Ci-6-heteroalkyl). The heteroatom(s) O, N, P, S, and Si can be placed at any position of the heteroalkyl group, including at the terminus. Where “heteroalkyl” is recited in this disclosure together with recitations of specific heteroalkyl groups, such as -(CH2)-C(O)-OH, -NH-CH3, or the like, it will be understood that the terms heteroalkyl and recitations of specific heteroalkyl groups are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding the specific heteroalkyl groups, such as -(CH2)-C(O)-OH, -NH-CH3, or the like. Each instanceof a heteroalkyl group can be unsubstituted (an “unsubstituted heteroalkyl”), or substituted (a “substituted heteroalkyl”) with one or more substituents, e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0128] As used herein, the term “haloalkyl” refers to a radical of a saturated or unsaturated hydrocarbon group, that can be straight or branched chain, and that includes at least one halogen atom (e.g., F, Cl, Br, or I). A haloalkyl disclosed herein can have 1 to 18 carbon atoms (Ci-is-haloalkyl), such as 1 to 6 carbon atoms (Ci-6-haloalkyl), or 1 to 4 carbon atoms (Ci-4-haloalkyl). The halogen atom(s) can be placed at any position of the haloalkyl group. Exemplary haloalkyl groups include, but are not limited to: -CF3 (trifluoromethyl), -CCh (trichloromethyl), -CH2-CF3, -CH2-CCI3, -CH2-CI, -CH2-I, -(CH2)-F, and the like. Each instance of a haloalkyl can be unsubstituted (an “unsubstituted haloalkyl”), or substituted (a “substituted haloalkyl”) with one or more substituents, e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0129] As used herein, the term “haloalkoxy” refers to a group -OR, in which R is haloalkyl, for example, -OCF3.

[0130] As used herein, the term “haloalkylthio” refers to a group of the formula: -SR, in which R is a haloalkyl group, such as -SCF3.

[0131] As used herein, the term “aryl,” refers to a stable aromatic ring system, that can be monocyclic or polycyclic, of which all the ring atoms are carbon. The aromatic ring system can have, for example, six, ten, or fourteen ring carbon atoms. Examples include phenyl (Ph), naphthyl, anthracyl, and the like, which can be referred to herein as benzene, naphthalene, or anthracene, respectively. Each instance of an aryl group can be unsubstituted (an “unsubstituted aryl”), or substituted (a “substituted aryl”) with one or more substituents. For example, a phenyl can be substituted with 1, 2, 3, 4, or 5 substituents.

[0132] As used herein, the term “heteroaryl” refers to an aryl group that includes one or more ring heteroatoms. For example, a heteroaryl can include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, or 9-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms, and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom can be substituted or unsubstituted. Examples of heteroaryl groups include pyrrole, furan, indole, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, phthalazine, 1,2,3- triazine, 1,2,4-triazine, 1,3, 5 -triazine, acridine, and the like.

[0133] As used herein, the term “cycloalkyl” refers to a radical of a cyclic hydrocarbon group having from three to ten carbon atoms and no heteroatoms in the cyclic structure. Cycloalkyl can include cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, norbomyl, and the like. The cycloalkyl group can be either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated. “Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group can be independently optionally substituted, e.g., unsubstituted (an “unsubstituted cycloalkyl”), or substituted (a “substituted cycloalkyl”) with one or more substituents.

[0134] As used herein, the term “heterocyclyl” refers to a radical of a 3- to 10-membered cyclic structure comprising one or more carbon atoms and one or more heteroatoms in the ring or rings (a radical of a heterocyclic ring). The heteroatom can be selected from nitrogen, oxygen, sulfur, boron, phosphorous, and silicon. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can be either monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Each instance of heterocyclyl can be independently optionally substituted, e.g., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. Additional reference is made to: Oxford Dictionary of Biochemistry and Molecular Biology, Oxford University Press, Oxford, 1997 as evidence that heterocyclic ring is a term well-established in field of organic chemistry.

[0135] The terms “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” or “haloalkylene,” alone or as part of another substituent, mean, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl, respectively. For instance, the term “alkylene,” by itself or as part of another substituent,means, unless otherwise stated, a divalent radical derived from an alkyl. In the case of heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). No orientation of the group is implied by the direction in which the formula is written. For example, the formula -C(O)OR’- can represent both -C(O)OR’- and -R’OC(O)-. Each instance of an alkylene, alkenylene, alkynylene, or heteroalkylene group can be unsubstituted or substituted with one or more substituents.

[0136] As used herein, the terms “cycloalkylene,” “heterocyclylene,” “arylene,” and “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl, heterocyclyl, aryl, and heteroaryl, respectively. Each instance of a cycloalkylene, heterocyclylene, arylene, or heteroarylene can be unsubstituted or substituted with one or more substituents.

[0137] As used herein, the term “cyano” or “-CN” refer to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C=N.

[0138] As used herein, the term “halo” or “halogen” refers to F, Cl, Br, or I.

[0139] As used herein, the term “hydroxy” refers to a group of formula -OH.

[0140] As used herein, the term “hydroxyalkyl” refers to an alkyl group comprising at least one hydroxy. A hydroxyalkyl group can be defined in terms of the number of carbon atoms it contains, e.g., a (Ci-Ce)-hydroxyalkyl is a hydroxyalkyl containing between 1 and 6 carbon atoms.

[0141] As used herein, the term “leaving group” refers to a molecular fragment of a compound (e.g., a precursor compound) which, upon reaction of the compound with an appropriate reactant, undergoes heterolytic bond cleavage. The leaving group can be an anionic leaving group (i.e., the molecular fragment generated upon the heterolytic bond cleavage is an anionic group). Exemplary anionic leaving groups include, but are not limited to, halo groups (e.g., chloride, bromide, or iodide), sulfonate esters (e.g., tosylate or mesylate, which can be referred to herein as tosyl (Ts) or mesyl (Ms), respectively). The leaving group can be a neutral leaving group (i.e., the molecular fragment generated upon the heterolytic bond cleavage is a neutral group). Exemplary neutral leaving groups include, but are not limited to, water and ammonia.

[0142] As used herein, the term “nitro” refers to a substituent having two oxygen atoms bound to a nitrogen atom, e.g., -NO2.

[0143] As used herein, the term “oxo” refers to an oxygen group which is double bonded to another atom, e.g., carbon. For example, “oxo” refers to the =0 in a carbonyl group (C=O) or the oxygen substituent in -CH2-C(O)-CH3.

[0144] As used herein, the phrase “optionally substituted” means unsubstituted or substituted, and the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A “substitutable atom” means any atom bound to one or more hydrogen atoms, such as the nitrogen in -NH-, or the carbon in -CH- or -CH2-, that can be substituted by replacing the one or more hydrogen atoms with a substituent. It is to be understood that substitution at a given atom is limited by valency. For example, the term “substituted” can be in reference to a substituted alkyl, substituted alkylene, substituted alkenyl, substituted alkenylene, substituted alkynyl, substituted alkynylene, substituted heteroalkyl, substituted heteroalkylene, substituted heteroalkenyl, substituted heteroalkenylene, substituted heteroalkynyl, substituted heteroalkynylene, substituted haloalkyl, substituted haloalkenyl, substituted cycloalkyl, substituted cycloalkylene, substituted heterocyclyl, substituted heterocyclylene, substituted aryl, substituted arylene, substituted heteroaryl, substituted heteroarylene, and the like, i.e., an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heteroalkyl, heteroalkylene, heteroalkenyl, heteroalkenylene, heteroalkynyl, heteroalkynylene, haloalkyl, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, arylene, heteroaryl, heteroarylene moieties, and the like, having substituents replacing one or more hydrogen atoms on one or more carbon atoms or heteroatoms of the moiety. In general, the term substituted means that at least one hydrogen present on a group (e.g., a hydrogen bonded to carbon or nitrogen atom of said group) is replaced with a suitable substituent, such as a substituent described herein. Substituents can be any suitable substituent including, for example, alkyl (e.g., Ci-Ce alkyl), alkenyl (e.g., C2-C6 alkenyl), alkynyl (e.g., C2-C6 alkynyl), heteroalkyl (e.g., Ci-Ce heteroalkyl), haloalkyl (e.g., Ci-Ce haloalkyl, e.g., -CF3, cycloalkyl (e.g., C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), heterocyclyl (e.g., C3-C8 heterocyclyl), alkylaryl (e.g., benzyl), aryl (e.g., phenyl), heteroaryl (e.g., pyrrolyl, imidazolyl, quinolinyl, or indolyl), halo (e.g., -F, -Cl, -Br, or -I), hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy (e.g., -OMe, -OEt, or -OBn), alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino,sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfinyl, sulfonyl, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, oxo, nitro, trifluoromethyl, cyano, azido, alkyl-cycloalkyl, alkyl-heterocyclyl, alkylheteroaryl,-C(O)OH, -C(O)O-alkyl (e.g., -C(O)O-tBu or -C(O)OMe), -C(O)O-heteroalkyl, -C(O)O- alkylaryl, -OC(O)O-alkyl, -OC(O)O-heteroalkyl, -OC(O)O-alkylaryl, -C(O)NH2, - C(O)NH-alkyl, -C(O)NH-heteroalkyl, -C(O)NH-alkylaryl, -NHC(O)O-alkyl (e.g., - NHC(O)OtBu), -NHC(O)O-heteroalkyl, -NHC(O)O-alkylaryl (e.g., -NH-Cbz), - C(O)N(alkyl)2, -C(O)N(alkyl)(heteroalkyl), -C(O)N(heteroalkyl)2, -N(alkyl)C(O)O-alkyl (e.g., N(Me)C(O)OtBu), -N(alkyl)C(O)O-heteroalkyl, -N(alkyl)C(O)O-alkylaryl, - N(alkyl)C(O)N(alkyl)2, -N(alkyl)C(O)N(alkyl)(heteroalkyl), -N(alkyl)C(O)N(heteroalkyl)2, -N(alkyl)C(O)NH-alkylaryl, =NH, or =N-alkyl. Cyclic groups (e.g., cycloalkyl, heterocyclyl, aryl, and heteroaryl) can be substituted at one or more ring positions with any suitable substituent, such as one of the substituents listed above.

[0145] As used herein, the term “protecting group” refers to a group that acts to temporarily block a particular functional moiety, e.g., -OH, -SH, or -NH2, so that a reaction can be carried out selectively at another reactive site in a multifunctional compound. It will be appreciated by one of ordinary skill in the art that the synthetic methods and compounds described herein can utilize a variety of protecting groups. Protecting groups can be introduced and removed at appropriate stages during the synthesis of a compound using methods that are known to one of ordinary skill in the art. The protecting groups are applied according to standard methods of organic synthesis as described in the literature (Theodora W. Greene and Peter G. M. Wuts (2007) Protecting Groups in Organic Synthesis, 4lhedition, John Wiley and Sons, incorporated by reference in its entirety). Exemplary protecting groups include, but are not limited to, oxygen, sulfur, nitrogen and carbon protecting groups. For example, oxygen protecting groups include, but are not limited to, methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMB (p-methoxybenzyl), optionally substituted ethyl ethers, optionally substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether), esters (e.g., formate, acetate, benzoate (Bz), trifluoroacetate, dichloroacetate), carbonates, cyclic acetals and ketals. In addition, nitrogen or amino protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g., Boc or Troc), amides, cyclic imide derivatives, N-alkyl and N-aryl amines, imine derivatives, and enamine derivatives,fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), acetamide, trifluoroacetamide, etc. It will be appreciated that the present disclosure is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be utilized according to methods known to one skilled in the art.

[0146] The compounds provided herein can exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to: cis- and trans- forms; E- and Z-forms; endo- and exo- forms; R-, S-, and meso-forms; D- and L-forms; d- and 1- forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and P-forms; axial and equatorial forms; boat-, chair-, twist-, envelope- and half chair-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”).

[0147] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. In an embodiment, the stereochemistry depicted in a compound is relative rather than absolute. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high- pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. This disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0148] Compounds disclosed herein can also comprise one or more isotopic substitutions. For example, H can be in any isotopic form, including1H,2H (D or deuterium), or3H (T or tritium); C can be in any isotopic form, including12C,13C, or14C; O can be in any isotopic form, including16O or18O; N can be in any isotopic form, including14N or15N.

[0149] The term “pharmaceutically acceptable salt” as used herein refers to a salt of the compound prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the respective compound. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable solvent (e.g., an inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basicfunctionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable solvent (e.g., an inert solvent). Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic (acetate), propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, pamoic (pamoate), phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methane sulfonic (mesylate), and the like. For example, a pharmaceutically acceptable salt disclosed herein can be a hydrochloride salt. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like. Certain compounds of the present disclosure can contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable salts known to those of skill in the art are suitable for pharmaceutical compositions the present disclosure relates to.

[0150] The term “solvate” as used herein refers to forms of a compound that are associated with a solvent, usually by a solvolysis reaction. This physical association can include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, and the like. Compounds of the present disclosure can be prepared, e.g., in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0151] The term “hydrate” as used herein refers to a compound which is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R’xFEO, wherein R is the compound and wherein x is a number greater than 0. A given compound can form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R’O.SFEO)),and polyhydrates (x is a number greater than 1, e.g., dihydrates (R«2H2O) and hexahydrates (R«6H2O)).

[0152] The term “tautomer” as used herein refers to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the movement of 7i electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0153] Throughout this disclosure, the terms “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. Likewise, the term “include” and its grammatical variants are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.

[0154] The articles “a” and “an” are used herein to refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0155] The term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or less, or in some instances ±15% or less, or in some instances ±10% or less, or in some instances ±5% or less, or in some instances ±1% or less, or in some instances ±0.1% or less, from the specified value, as such variations are appropriate.

[0156] The phrase “and / or” as used herein should be understood to mean “either or both” of the elements so conjoined, e.g., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, e.g., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B,” when used in conjunction with open- ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0157] The term “effective amount” or a “therapeutically effective amount” as used herein refers to an amount of a compound, or a pharmaceutical composition, described herein which is sufficient to achieve the desired therapeutic effect under the conditions of administration. The actual amount can be based upon, for example, the subjects age, weight, sex, general heath and tolerance to drugs, severity of disease, dosage form selected, route of administration and other factors. Typically, the amount of an aldose reductase inhibitor that is administered is from about 1000 mg / day to about 5000 mg / day, e.g., about 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, or 4000 mg / day. Preferably, about 3000 mg / day are administered preferable in two doses of 1500 mg each.

[0158] In some examples of the practice of the methods disclosed herein, the therapeutically effective amount is an amount sufficient to reduce intracellular aldose reductase activity at least by about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more (e.g., compared to pre-treatment level). The therapeutically effective amount can be an amount that reduces intracellular sorbitol levels at least by about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more (e.g. , compared to pre-treatment level). The therapeutically effective amount can be an amount that reduces plasma sorbitol concentration to less than 800 pM, e.g., less than 700 pM, less than 600 pM, less than 500 pM, or less than 400 pM, in a human subject with diabetes mellitus. Plasma sorbitol levels are typically elevated in untreated diabetics compared to non-diabetics.

[0159] The term “pharmaceutically acceptable excipient” as used herein refers to a non-toxic material that can be formulated with a compound disclosed herein to provide a pharmaceutical composition. Preferably, the pharmaceutically acceptable excipient is inert and does not interfere with the pharmacological activity of a compound which it is formulated with. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions disclosed herein are any of those well known in the art, and include without limitation, diluents, dispersing agents, granulating agents, surface active agents, emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, ion exchangers, salts, electrolytes, waxes, and / or oils. For example, a pharmaceutically acceptable excipient can be alumina, aluminum stearate, lecithin, a serum protein (e.g., human serum albumin), a phosphate, glycine, sorbic acid, potassium sorbate, a glyceride mixture (e.g., saturated vegetable fatty acids), water (e.g., purified water), protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, dibasic sodium phosphate, sodium chloride, a zinc salt, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose or a derivative thereof (e.g., microcrystalline cellulose), xanthan gum, carrageenan, simethicone, a paraben (e.g., methylparaben), polyethylene glycol or a derivative thereof (e.g., PEG-300), sodium carboxymethylcellulose (e.g., high viscosity carboxymethylcellulose sodium), citric acid, a polyacrylate, a polyethylenepoly oxypropylene -block polymer, wool fat, a cyclodextrin (e.g., CAPTISOL®), dimethylacetamide (DMA), a polysorbate (e.g., a TWEEN®, e.g., TWEEN-20®), ethylenediaminetetraacetic acid (EDTA) or a salt thereof, and any combination thereof.

[0160] The term “subject” as used herein refers to any animal, such as any mammal, including but not limited to, humans, non-human primates, rodents, dogs, and the like. Nonhuman primates include chimpanzees, cynomolgus monkeys, spider monkeys, baboons, and macaques (e.g., Rhesus). Rodents include mice, rats, woodchucks, ferrets, rabbits, and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species (e.g., domestic cat), canine species (e.g., dog, fox, wolf), avian species, and fish. In some embodiments, the subject is a mammal (e.g., a human, a rat, or a mouse). The subject can be male or female. The subject can be of any age, including an elderly human subject (e.g., 65 years or older), a human subject that is not elderly (e.g., less than 65 years old), or a human pediatric subject (e.g., 18 years old or less). In preferred aspects, the subject is a human. A subject to be treated using the methods disclosed herein has diabetes mellitus (e.g., T1DM or T2DM). Particularly preferred subjects for treatment as described herein have DbCM, and are not administered an SGLT2 inhibitor and / or have an HbAlc value of greater than 8.5%.

[0161] As used herein, the terms “treat,” “treatment,” “treating,” or grammatically related terms, refer to a method of reducing the effects and / or inhibiting progression of a disease or disorder, including stabilizing function of an organ damaged by the disease or disorder, or improving function of an organ damaged by the disease or disorder. For example, treating can involve stabilizing cardiac functional capacity in a subject with DbCM, and / or improving cardiac functional capacity in a subject with DbCM. As is readily appreciated in the art, full eradication of the disease, disorder, or symptoms thereof is preferred but not a requirement for treatment. Desirable effects of treatment include, but are not limited to, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease or disorder, or other improvement of any sign, symptom, or consequence of the disease or disorder, such as prolonged survival, less morbidity, and / or a lessening of side effects.

[0162] Throughout this disclosure, various embodiments can be presented in a range format (e.g., from X - Y). It should be understood that the description in range format is merely forconvenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 5, from 1 to 4, from 1 to 3, from 2 to 6, from 2 to 4, from 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 2.8, 3, 3.6, 4, 5, 5.4, and 6. As another example, a range such as 95-99% includes 95%, 96%, 97%, 98%, or 99% and all subranges such as 96-99%, 96-98%, 96-97%, 97-99%, 97-98%, etc. This applies regardless of the breadth of the range.EXEMPLIFICATION

[0163] Compounds of Formulae (I), (la), (lb), (Ic), (II), and Compound A, can be prepared from readily available precursors according to known methods. For example, the preparation of Compound A and other compounds of Formula (I) has been described, e.g., in U.S. Patent No. 8,916,563, which is incorporated herein by reference in its entirety. The aldose reductase inhibition activity of compounds of Formulae (I), (la), (lb), (Ic), (II), and Compound A and its analogs, is well established, and has been described, e.g., in U.S. Patent No. 8,916,563.

[0164] Compound A has the structure:(Compound A), and is also known as caficrestat, AT-001, and 2-(8-oxo-7-((5- (trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-7,8-dihydropyrazino[2,3-d]pyridazin-5- yl)acetic acid.

[0165] Example 1. Clinical study using Compound A in subjects with DbCM

[0166] A multicenter, randomized, quadruple-blinded, placebo-controlled phase 3 clinical trial was carried out to establish the efficacy and safety of Compound A in adult subjects with DbCM. These subjects were considered at high risk of progression to overt heart failure.

[0167] Peak VO2 is the greatest amount of oxygen a person can use while performing dynamic exercise involving a large part of total muscle mass. Oxygen uptake is expressed in metabolic equivalent (MET) as units of sitting, resting oxygen uptake (3.5 mL O2 per kilogram body weight per minute [mL • kg-1• min-1]). Peak VO2 is significantly related to age and gender, as illustrated by the data in Table 1 (see Fletcher, et al. “Exercise standards. A statement for healthcare professionals from the American Heart Association. Writing Group,” Circulation (1995) 91(2):580-615).Table 1. Normal values of maximal oxygen uptake at different ages.VIET indicates metabolic equivalent; 1 MET = 3.5 mL • kg1• min1oxygen uptake. Values are expressed as milliliters per kilogram per minute.

[0168] As the criteria of inclusion in this randomized double-blind study, Peak VO2 was evaluated for each patient and eligibility to enter the study included having a peak VO2 lower than 75% of the predicted Peak VO2 based on age and gender, as described in Table 1.

[0169] Subjects were separated into three groups: Group 1 received Compound A orally, 1500 mg twice daily (bid), for a total dose of 3000 mg / day; Group 2 received Compound A orally, 1000 mg twice daily (bid), for a total dose of 2000 mg / day; and Group 3 received placebo. Approximately 225 subjects were in each of the three groups, and 691 subjects were enrolled in total.

[0170] The primary endpoint of the study was stabilization or improvement in cardiac functional capacity as measured by peak VO2, comparing Group 1 treated subjects with Group 3 placebo subject. In Group 3 peak VO2 declined by a mean of -0.31 mL / kg / min over15 months of treatment, while in Group 1 peak VO2 remained primarily stable, with a mean change in peak VO2 of -0.01 mL / kg / min over 15 months. While atrend favored active treatment, the difference between active and placebo treated groups (0.30 mL / kg / min) was not statistically significant (p=0.210) (see FIG. 1A).

[0171] The study evaluated the treatment effect of Compound A as an add-on to diabetes mellitus standard of care therapies. Approximately 38% of study subjects were on SGLT2 or GLP-1 therapies for treatment of diabetes mellitus, while 62% were not. In a pre-specified subgroup analysis of the primary endpoint in subjects not concomitantly treated with SGLT2 or GLP-1 therapies, the peak VO2 in the placebo group declined by a mean of -0.54 mL / kg / min, while peak VO2 in Group 1 treated subjects improved by a mean of 0.08 mL / kg / min over 15 months of treatment, with a difference between groups of 0.62 mL / kg / min (p=0.040) (see FIG. IB). Further analysis surprisingly revealed a similar difference (0.53 mL / kg / min, p = 0.06) between treated group and placebo when excluding only subjects that were concomitantly treated with an SGLT2 inhibitor therapy (see FIG. 1C). In other words, the effect is primarily maintained in subjects being treated with GLP1 therapies, and the results indicate that Compound A provided a more significant therapeutic effect in subjects who are not receiving SGLT2 inhibitor therapy. As shown in FIG. 1C, cardiac functional capacity improved in the study subjects that were not administered a SGLT2 inhibitor.

[0172] Further post-hoc subgroup analysis was carried out, based on HbAlc levels of subjects at baseline, and this analysis surprisingly revealed that the therapeutic effect of Compound A was much greater in subjects with HbAlc over 8.5% at baseline, as determined by cardiac functional capacity (peak VO2) change from baseline to month 15, compared with placebo. See FIG. 2.

[0173] The number of subjects that experienced a clinically significant worsening in cardiac functional capacity of 6% or more was substantially higher in the placebo group (46%) as compared to the Group 1 treated subjects (32.7%), odds ratio 0.56 (p=0.035). A worsening in cardiac functional capacity of 6% or more is predictive of poor long-term survival and hospitalization for heart failure. The effect of Compound A was dose dependent, with the low dose Group 2 subjects demonstrating an intermediate effect between the high dose and placebo.

[0174] A comparison was made between the number of subjects that progressed to overt heart failure in Group 1 (subjects treated with Compound A, 1500 mg bid) and placebo(Group 3). A total of 26 subjects in the placebo group progressed to overt heart failure, compared to only 13 subjects in Group 1, with statistical significance (p = 0.03).

[0175] Compound A was generally safe and well tolerated, with no substantial differences in serious adverse events between the Compound A-treated groups (Groups 1 and 2) as compared to placebo Group 3 (14.3% placebo, Group 3; 12.3% Group 2; and 17.3% Group 3), no substantial differences in treatment emergent adverse events (79. 1% Group 3; 81.6% Group 2; 81% Group 1) and low incidence of treatment-related discontinuations (3.9% Group 3; 9.6% Group 2; and 9.5% Group 1).

[0176] In conclusion, Compound A stabilized or improved cardiac functional capacity as compared to placebo, and prevented clinically significant worsening of disease. Surprisingly, the therapeutic effect of Compound A was enhanced in subjects not on concomitant treatment with an SGLT2 inhibitor and / or in subjects with an HbAlc value of greater than 8.5%.

Claims

What is claimed is:

1. A method of treating diabetic cardiomyopathy (DbCM), comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor, wherein: the subject has DbCM; the subject is not administered a sodium-glucose cotransporter-2 (SGLT2) inhibitor; the aldose reductase inhibitor is orally administered in an amount of about 2000 mg / day to about 3000 mg / day; and the aldose reductase inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinR1is H, (Ci-Ce)-alkyl, (Ci-Ce)-hydroxyalkyl, or (Ci-Cej-aminoalkyl;X1is N or CR3;X2is N or CR4;X3is N or CR5;X4is N or CR6; with the proviso that two or three of X1, X2, X3, and X4are N;Y is a bond, C=O, C=S, C=NH, or C=N(Ci-C4)-alkyl;A1is NR11, O, S, or CH2;A2is N or CH;A3is NR11, O, or S;R3through R10are independently hydrogen, halogen, cyano, acyl, (Ci-C4)-haloalkyl, (Ci-C4)-haloalkoxy, (Ci-C4)-haloalkylthio, trifluoroacetyl, (Ci-C4)-alkyl, (Ci-C4)-alkoxy,(Ci-C4)-alkylthio, (Ci-C4)-alkylsulfmyl, or (C1-C4) -alkylsulfonyl; or two of R3 through Re or two of R7 through Rio taken together are (Ci-C4)-alkylenedioxy; andR11 is hydrogen, (Ci-C4)-alkyl, or C(O)O-(Ci-C4)-alkyl.

2. A method of inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with diabetic cardiomyopathy (DbCM), comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor, wherein the subject is not administered a sodium-glucose cotransporter-2 (SGLT2) inhibitor; the aldose reductase inhibitor is orally administered in an amount of about 2000mg / day to about 3000 mg / day; and the aldose reductase inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinR1is H, (Ci-Ce)-alkyl, (Ci-Ce)-hydroxyalkyl, or (Ci-C6)-aminoalkyl;X1is N or CR3;X2is N or CR4;X3is N or CR5;X4is N or CR6; with the proviso that two or three of X1, X2, X3, and X4are N;Y is a bond, C=O, C=S, C=NH, or C=N(Ci-C4)-alkyl;R3through R10are independently hydrogen, halogen, cyano, acyl, (Ci-C4)-haloalkyl, (Ci-C4)-haloalkoxy, (Ci-C4)-haloalkylthio, trifluoroacetyl, (Ci-C4)-alkyl, (Ci-C4)-alkoxy, (Ci-C4)-alkylthio, (Ci-C4)-alkylsulfinyl, or (C1-C4) -alkylsulfonyl; or two of R3 through Re or two of R7 through Rio taken together are (Ci-C4)-alkylenedioxy; andR11 is hydrogen, (Ci-C4)-alkyl, or C(O)O-(Ci-C4)-alkyl.

3. The method of claim 1 or 2, wherein the subject has an HbAlc value of greater than or equal to 6.5% (e.g., greater than or equal to 7.0%, greater than or equal to 7.5%, greater than or equal to 8.0%, greater than or equal to 8.5%, greater than or equal to 9.0%, greater than or equal to 9.5%, or greater than or equal to 10.0%).

4. The method of any one of the preceding claims, wherein the subject has an HbAlc value > 8.5%.

5. The method of any one of the preceding claims, wherein cardiac functional capacity is stabilized the subject.

6. The method of claim 5, wherein stabilized cardiac functional capacity in the subject is determined by: (i) a decrease of peak oxygen consumption (peak VO2) from baseline of no more than 0.5; or (ii) no substantial change in peak VO2 from baseline; after a period of time, e.g., after about 1 month, about 2 months, about 3 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or more, of treatment.

7. The method of any one of the preceding claims, wherein cardiac functional capacity is improved in the subject.

8. The method of claim 7, wherein improved cardiac functional capacity in the subject is determined by an increase of peak VO2 from baseline after a period of time, e.g., after about1 month, about 2 months, about 3 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or more, of treatment.

9. The method of any one of the preceding claims, wherein the aldose reductase inhibitor is administered in an amount of about 3000 mg / day.

10. The method of any one of the preceding claims, wherein the aldose reductase inhibitor is administered in an amount of 1500 mg twice daily.

11. The method of any one of the preceding claims, wherein the subject is administered an additional therapeutic agent that is not an SGLT2 inhibitor, optionally, wherein the additional therapeutic agent is a glucagon-like peptide 1 (GLP-1) agonist or a dual GLP- 1 / gastric inhibitory peptide (GIP) receptor agonist, such as dulaglutide (e.g., TRULICITY®), exenatide (e.g., BYETTA® or BYDUREON®), liraglutide (e.g., VICTOZA® or SAXENDA®), lixisenatide (e.g., ADLYXIN®), semaglutide (e.g., OZEMPIC®, WEGOVY®, or RYBELSUS®), or tirzepatide (e g., MOUNJARO® or ZEPBOUND®) .

12. The method of any one of the preceding claims, wherein the aldose reductase inhibitor is a compound with the structurepharmaceutically acceptable salt thereof.

13. A method of treating diabetic cardiomyopathy (DbCM), comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor, wherein: the subject has DbCM and an HbAlC value greater than 8.5%; the aldose reductase inhibitor is orally administered in an amount of about 2000 mg / day to about 3000 mg / day; and the aldose reductase inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinR1is H, (Ci-Ce)-alkyl, (Ci-Ce)-hydroxyalkyl, or (Ci-Cej-aminoalkyl;X1is N or CR3;X2is N or CR4;X3is N or CR5;X4is N or CR6; with the proviso that two or three of X1, X2, X3, and X4are N;Y is a bond, C=O, C=S, C=NH, or C=N(Ci-C4)-alkyl;A1is NR11, O, S, or CH2;A2is N or CH;A3is NR11, O, or S;R3through R10are independently hydrogen, halogen, cyano, acyl, (Ci-C4)-haloalkyl,(Ci-C4)-haloalkoxy, (Ci-C4)-haloalkylthio, trifluoroacetyl, (Ci-C4)-alkyl, (Ci-C4)-alkoxy, (Ci-C4)-alkylthio, (Ci-C4)-alkylsulfmyl, or (C1-C4) -alkylsulfonyl; or two of R3 through Re or two of R7 through Rio taken together are (Ci-C4)-alkylenedioxy; andR11 is hydrogen, (Ci-C4)-alkyl, or C(O)O-(Ci-C4)-alkyl.

14. A method of inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with diabetic cardiomyopathy (DbCM), comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor, wherein the subject has an HbAlc value greater than 8.5%; the aldose reductase inhibitor is orally administered in an amount of about 2000mg / day to about 3000 mg / day; and the aldose reductase inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinR1is H, (Ci-Ce)-alkyl, (Ci-Ce)-hydroxyalkyl, or (Ci-C6)-aminoalkyl;X1is N or CR3;X2is N or CR4;X3is N or CR5;X4is N or CR6; with the proviso that two or three of X1, X2, X3, and X4are N;Y is a bond, C=O, C=S, C=NH, or C=N(Ci-C4)-alkyl;A1is NR11, O, S, or CTh:A2is N or CH;A3is NR11, O, or S;R3through R10are independently hydrogen, halogen, cyano, acyl, (Ci-C4)-haloalkyl, (Ci-C4)-haloalkoxy, (Ci-C4)-haloalkylthio, trifluoroacetyl, (Ci-C4)-alkyl, (Ci-C4)-alkoxy, (Ci-C4)-alkylthio, (Ci-C4)-alkylsulfmyl, or (C1-C4) -alkylsulfonyl; or two of R3 through Re or two of R7 through Rio taken together are (Ci-C4)-alkylenedioxy; andR11 is hydrogen, (Ci-C4)-alkyl, or C(O)O-(Ci-C4)-alkyl.

15. The method of claim 13 or 14, wherein the subject is not administered a sodiumglucose cotransporter-2 (SGLT2) inhibitor.

16. The method of any one of claims 13-15, wherein cardiac functional capacity is stabilized the subject.

17. The method of claim 16, wherein stabilized cardiac functional capacity in the subject is determined by: (i) a decrease of peak VO2 from baseline of no more than 0.5; or (ii) no substantial change in peak VO2 from baseline; after a period of time, e.g., after about 1 month, about 2 months, about 3 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or more, of treatment.

18. The method of any one of claims 13-17, wherein cardiac functional capacity is improved in the subject.

19. The method of claim 18, wherein improved cardiac functional capacity in the subject is determined by an increase of peak VO2 from baseline after a period of time, e.g., after about 1 month, about 2 months, about 3 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or more, of treatment.

20. The method of any one of claims 13-19, wherein the aldose reductase inhibitor is administered in an amount of about 3000 mg / day.

21. The method of any one of claims 13-20, wherein the aldose reductase inhibitor is administered in an amount of 1500 mg twice daily.

22. The method of any one of claims 13-21, wherein the subject is administered an additional therapeutic agent that is not an SGLT2 inhibitor, optionally, wherein the additional therapeutic agent is a glucagon-like peptide 1 (GLP-1) agonist or a dual GLP-l / gastric inhibitory peptide (GIP) receptor agonist, such as dulaglutide (e.g., TRULICITY®), exenatide (e.g., BYETTA® or BYDUREON®), liraglutide (e.g., VICTOZA® or SAXENDA®), lixisenatide (e.g., ADLYXIN®), semaglutide (e.g., OZEMPIC®, WEGOVY®, or RYBELSUS®), ortirzepatide (e.g., MOUNJARO® or ZEPBOUND®).

23. The method of any one of the claims 13-22, wherein the aldose reductase inhibitor is a compound with the structurepharmaceutically acceptable salt thereof.

24. The method of any one of the preceding claims wherein the subject has Type 1 diabetes mellitus.

25. The method of any one of claims 1-23, wherein the subject has Type 2 diabetes mellitus.

26. The method of any one of the preceding claims, wherein the subject has Stage B Heart Failure (Stage B HF).

27. An aldose reductase inhibitor that is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinR1is H, (Ci-Ce)-alkyl, (Ci-Ce)-hydroxyalkyl, or (Ci-Ce)-aminoalkyl;X1is N or CR3;X2is N or CR4;X3is N or CR5;X4is N or CR6; with the proviso that two or three of X1, X2, X3, and X4are N;Y is a bond, C=O, C=S, C=NH, or C=N(Ci-C4)-alkyl;A1is NR11, O, S, or CH2;A2is N or CH;A3is NR11, O, or S;R3through R10are independently hydrogen, halogen, cyano, acyl, (Ci-C4)-haloalkyl, (Ci-C4)-haloalkoxy, (Ci-C4)-haloalkylthio, trifluoroacetyl, (Ci-C4)-alkyl, (Ci-C4)-alkoxy, (Ci-C4)-alkylthio, (Ci-C4)-alkylsulfmyl, or (C1-C4) -alkylsulfonyl; or two of R3 through Re or two of R7 through Rio taken together are (Ci-C4)-alkylenedioxy; andR11 is hydrogen, (Ci-C4)-alkyl, or C(O)O-(Ci-C4)-alkyl, wherein said aldose reductase inhibitor is for use in a method for treatment of diabetic cardiomyopathy (DbCM) in a subject with DbCM, and wherein: the subject is not being administered a sodium-glucose cotransporter-2(SGLT2) inhibitor; andthe aldose reductase inhibitor is for oral administration in an amount of about2000 mg / day to about 3000 mg / day.

28. An aldose reductase inhibitor that is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinR1is H, (Ci-Ce)-alkyl, (Ci-Ce)-hydroxyalkyl, or (Ci-C6)-aminoalkyl;X1is N or CR3;X2is N or CR4;X3is N or CR5;X4is N or CR6; with the proviso that two or three of X1, X2, X3, and X4are N;Y is a bond, C=O, C=S, C=NH, or C=N(Ci-C4)-alkyl;A1is NR11, O, S, or CH2;A2is N or CH;A3is NR11, O, or S;R3through R10are independently hydrogen, halogen, cyano, acyl, (Ci-C4)-haloalkyl,(Ci-C4)-haloalkoxy, (Ci-C4)-haloalkylthio, trifluoroacetyl, (Ci-C4)-alkyl, (Ci-C4)-alkoxy, (Ci-C4)-alkylthio, (Ci-C -alkylsulfmyl, or (C1-C4) -alkylsulfonyl; or two of R3 through Re or two of R7 through Rio taken together are (Ci-C4)-alkylenedioxy; andR11 is hydrogen, (Ci-C4)-alkyl, or C(O)O-(Ci-C4)-alkyl, wherein the aldose reductase inhibitor is for use in a method for inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with diabetic cardiomyopathy (DbCM), and wherein:the subject is not being administered a sodium-glucose cotransporter-2 (SGLT2) inhibitor; and the aldose reductase inhibitor is for oral administration in an amount of about 2000 mg / day to about 3000 mg / day.

29. The aldose reductase inhibitor for use according to claims 27 or 28, wherein the subject has an HbAlc value of greater than or equal to 6.5% (e.g., greater than or equal to 7.0%, greater than or equal to 7.5%, greater than or equal to 8.0%, greater than or equal to 8.5%, greater than or equal to 9.0%, greater than or equal to 9.5%, or greater than or equal to 10.0%).

30. The aldose reductase inhibitor for use according to any one of claims 27 to 29, wherein the subject has an HbAlc value > 8.5%.

31. The aldose reductase inhibitor for use according to any one of claims 27 to 30, wherein the cardiac functional capacity in the subject is stabilized by the aldose reductase inhibitor.

32. The aldose reductase inhibitor for use according to claim 31, wherein stabilized cardiac functional capacity in the subject is determined by: (i) a decrease of peak oxygen consumption (peak VO2) from baseline of no more than 0.5; or (ii) no substantial change in peak VO2 from baseline; after a period of time, e.g., after about 1 month, about 2 months, about 3 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or more, of treatment.

33. The aldose reductase inhibitor for use according to claims 27 to 32, wherein cardiac functional capacity in the subject is improved by the aldose reductase inhibitor.

34. The aldose reductase inhibitor for use according to claim 33, wherein improved cardiac functional capacity in the subject is determined by an increase of peak VO2 from baseline after a period of time, e.g., after about 1 month, about 2 months, about 3 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or more, of treatment.

35. The aldose reductase inhibitor for use according to any one of claims 27 to 34, wherein the aldose reductase inhibitor is for administration in an amount of about 3000 mg / day.

36. The aldose reductase inhibitor for use according to any one of claims 27 to 35, wherein the aldose reductase inhibitor is for administration in an amount of 1500 mg twice daily.

37. The aldose reductase inhibitor for use according to any one of claims 27 to 35, wherein the subject is being administered an additional therapeutic agent that is not an SGLT2 inhibitor, optionally, wherein the additional therapeutic agent is a glucagon-like peptide 1 (GLP-1) agonist or a dual GLP-l / gastric inhibitory peptide (GIP) receptor agonist, such as dulaglutide (e.g., TRULICITY®), exenatide (e.g., BYETTA® or BYDUREON®), liraglutide (e.g., VICTOZA® or SAXENDA®), lixisenatide (e.g., ADLYXIN®), semaglutide (e.g., OZEMPIC®, WEGOVY®, or RYBELSUS®), or tirzepatide (e.g., MOUNJARO® or ZEPBOUND®) .

38. The aldose reductase inhibitor for use according to any one of the claims 27 to 37, wherein the aldose reductase inhibitor is a compound with the structurepharmaceutically acceptable salt thereof.

39. An aldose reductase inhibitor that is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinR1is H, (Ci-Ce)-alkyl, (Ci-Ce)-hydroxyalkyl, or (Ci-Cej-aminoalkyl:X1is N or CR3;X2is N or CR4;X3is N or CR5;X4is N or CR6; with the proviso that two or three of X1, X2, X3, and X4are N;Y is a bond, C=O, C=S, C=NH, or C=N(Ci-C4)-alkyl;A1is NR11, O, S, or CH2;A2is N or CH;A3is NR11, O, or S;R3through R10are independently hydrogen, halogen, cyano, acyl, (Ci-C4)-haloalkyl, (Ci-C4)-haloalkoxy, (Ci-C4)-haloalkylthio, trifluoroacetyl, (Ci-C4)-alkyl, (Ci-C4)-alkoxy, (Ci-C4)-alkylthio, (Ci-C -alkylsulfmyl, or (C1-C4) -alkylsulfonyl; or two of R3 through Re or two of R7 through Rio taken together are (Ci-C4)-alkylenedioxy; andR11 is hydrogen, (Ci-C4)-alkyl, or C(O)O-(Ci-C4)-alkyl, wherein said aldose reductase inhibitor is for use in a method for treatment of diabetic cardiomyopathy (DbCM) in a subject with DbCM, and wherein: the subject has an HbAlC value greater than 8.5%; and the aldose reductase inhibitor is for oral administration in an amount of about2000 mg / day to about 3000 mg / day.

40. An aldose reductase inhibitor that is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinR1is H, (Ci-Ce)-alkyl, (Ci-Ce)-hydroxyalkyl, or (Ci-C6)-aminoalkyl;X1is N or CR3;X2is N or CR4;X3is N or CR5;X4is N or CR6; with the proviso that two or three of X1, X2, X3, and X4are N;Y is a bond, C=O, C=S, C=NH, or C=N(Ci-C4)-alkyl;A1is NR11, O, S, or CH2;A2is N or CH;A3is NR11, O, or S;R3through R10are independently hydrogen, halogen, cyano, acyl, (Ci-C4)-haloalkyl, (Ci-C4)-haloalkoxy, (Ci-C4)-haloalkylthio, trifluoroacetyl, (Ci-C4)-alkyl, (Ci-C4)-alkoxy, (Ci-C4)-alkylthio, (Ci-C -alkylsulfmyl, or (C1-C4) -alkylsulfonyl; or two of R3 through Re or two of R7 through Rio taken together are (Ci-C4)-alkylenedioxy; andR11 is hydrogen, (Ci-C4)-alkyl, or C(O)O-(Ci-C4)-alkyl, wherein the aldose reductase inhibitor is for use in a method for inhibiting decline in cardiac functional capacity and / or progression to overt heart failure in a subject with diabetic cardiomyopathy (DbCM), and wherein: the subject has an HbAlC value greater than 8.5%; and the aldose reductase inhibitor is for oral administration in an amount of about2000 mg / day to about 3000 mg / day.

41. The aldose reductase inhibitor for use according to claim 39 or 40, wherein the subject is not being administered a sodium-glucose cotransporter-2 (SGLT2) inhibitor.

42. The aldose reductase inhibitor for use according to any one of claims 39 to 41, wherein the cardiac functional capacity in the subject is stabilized by the aldose reductase inhibitor.

43. The aldose reductase inhibitor for use according to claim 42, wherein stabilized cardiac functional capacity in the subject is determined by: (i) a decrease of peak VO2 from baseline of no more than 0.5; or (ii) no substantial change in peak VO2 from baseline; after aperiod of time, e.g., after about 1 month, about 2 months, about 3 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or more, of treatment.

44. The aldose reductase inhibitor for use according to any one of claims 39 to 43, wherein cardiac functional capacity in the subject is improved by the aldose reductase inhibitor.

45. The aldose reductase inhibitor for use according to claim 44, wherein improved cardiac functional capacity in the subject is determined by an increase of peak VO2 from baseline after a period of time, e.g., after about 1 month, about 2 months, about 3 months, about 6 months, about 8 months, about 10 months, about 12 months, about 15 months, about 24 months, or more, of treatment.

46. The aldose reductase inhibitor for use according to any one of claims 39 to 45, wherein the aldose reductase inhibitor is for administration in an amount of about 3000 mg / day.

47. The aldose reductase inhibitor for use according to any one of claims 39 to 46, wherein the aldose reductase inhibitor is for administration in an amount of 1500 mg twice daily.

48. The aldose reductase inhibitor for use according to any one of claims 39 to 47, wherein the subject is being administered an additional therapeutic agent that is not an SGLT2 inhibitor, optionally, wherein the additional therapeutic agent is a glucagon-like peptide 1 (GLP-1) agonist or a dual GLP-l / gastric inhibitory peptide (GIP) receptor agonist, such as dulaglutide (e.g., TRULICITY®), exenatide (e.g., BYETTA® or BYDUREON®), liraglutide (e.g., VICTOZA® or SAXENDA®), lixisenatide (e.g., ADLYXIN®), semaglutide (e.g., OZEMPIC®, WEGOVY®, or RYBELSUS®), or tirzepatide (e.g., MOUNJARO® or ZEPBOUND®).

49. The aldose reductase inhibitor for use according to any one of the claims 39 to 48, wherein the aldose reductase inhibitor is a compound with the structurepharmaceutically acceptable salt thereof.

50. The aldose reductase inhibitor for use according to any one of claims 27 to 49, wherein the subject has Type 1 diabetes mellitus.

51. The aldose reductase inhibitor for use according to any one of claims 27 to 49, wherein the subject has Type 2 diabetes mellitus.

52. The aldose reductase inhibitor for use according to any one of claims 27 to 51, wherein the subject has Stage B Heart Failure (Stage B HF).

53. The aldose reductase inhibitor for use according to any one of claims 27 to 52, wherein the aldose reductase inhibitor is in a pharmaceutical composition additionally comprising at least one pharmaceutically acceptable excipient.

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