Benzothiazole compound for treating or preventing diabetes

Abstract

Provided here are methods of treating or preventing diabetes mellitus using the compounds provided herein.

Description

BENZOTHIAZOLE COMPOUND FOR TREATING OR PREVENTING DIABETESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 687,243, filed August 26, 2024, the content of which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Diabetes mellitus encompasses a collection of metabolic disorders characterized by elevated blood sugar levels over a prolonged period. This condition is a significant public health issue, affecting a large number of individuals worldwide. Broadly, diabetes is classified into two primary types:

[0003] Type 1 diabetes is predominantly seen in individuals who are dependent on insulin due to the body's autoimmune destruction of insulin-producing beta cells, often with triggers linked to infectious diseases. This form of diabetes typically manifests in people under 30 years of age and constitutes approximately 5-10% of all diabetes cases.

[0004] Type 2 diabetes, on the other hand, is characterized by the body's ineffective use of insulin, leading to insulin resistance. It generally develops later in life, earning it the moniker "adult-onset" diabetes, and represents about 90-95% of diabetes instances. Various factors, including hypertension, high cholesterol levels, metabolic syndrome, and particularly overweight or obesity, can contribute to the development or exacerbation of type 2 diabetes. Notably, around 90% of individuals with type 2 diabetes are overweight or obese.

[0005] Other diabetes forms include gestational diabetes, which occurs during pregnancy, congenital diabetes, cystic fibrosis-related diabetes, steroid-induced diabetes, and several types of monogenic diabetes.

[0006] The management of diabetes involves insulin administration for individuals with type 1 diabetes and glucose-lowering medications or insulin sensitizers for those with type 2 diabetes. Insulin plays a crucial role in glucose homeostasis, facilitating the uptake of glucose by liver, muscle, and fat cells for energy use or storage, while also inhibiting fat breakdown. Conversely, low blood glucose levels lead to reduced insulin production and release, with glucagon helping to elevate blood glucose levels. In diabetes, either a deficiency in insulin production (type 1) or a reduced response to insulin (type 2) results in chronically high blood glucose levels. The exact mechanisms underlying these conditions are complex and not yet fully understood.

[0007] Novel strategies are needed to treat or prevent diabetes mellitus.SUMMARY

[0008] Provided herein is a method of treating or preventing diabetes mellitus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I or la:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscripts n and p are independently selected from 0, 1 or 2; each R1is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro;A is an arylene or heteroarylene, having 1 to 4 heteroatoms;W is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;X is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is as defined above, provided that when A is arylene, and Y is -S- or -NR2-, then X is not -S-;Y is selected from the group consisting of -O-, -S-, -SO-, S(O)2-, and -NR2-, wherein R2is as defined above; andZ is selected from the group consisting of -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R3)O)q-T, wherein subscript q is an integer from 1 to 100, R3is selected from the group consisting of hydrogen and methyl, and T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L-monosaccharide, and -L-oligosaccharide, wherein L is selected from the group consisting of a bond, phosphate, and sulfate.

[0009] Also provided herein is a method of treating or preventing diabetes mellitus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula II:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein:Y is -NR33- or -S-; each R31is independently halogen, -CX31, -CHX31, -CH2X31, -OCX313, -OCHX312, -OCH2X31, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, - C(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; each R32is independently halogen, -CX323, -CHX322, -CH2X32, -OCX323, -OCHX322, -OCH2X32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R33is H, alkyl, or substituted alkyl; each of X31and X32is independently halogen; each of zl and z2 is independently an integer from 0 to 4; and z3 is an integer from 1 to 12.

[0010] In certain embodiments, the diabetes mellitus is type I diabetes or type II diabetes, gestational diabetes mellitus, congenital diabetes, cystic fibrosis-related diabetes, steroid diabetes, or several forms of monogenic diabetes.

[0011] In certain embodiments, one or more symptoms of diabetes mellitus comprises impaired glucose tolerance, impaired fasting glucose, insulin resistance, metabolic syndrome, postprandial hyperglycemia and overweight or obesity.

[0012] In certain embodiments, the subject is middle aged or old subject.

[0013] In certain embodiments, the subject suffers from diabetes mellitus without symptom of retinopathy.

[0014] In certain embodiments, the administering comprises a dose of 10 mg / day-3000 mg / day.

[0015] In certain embodiments, the administering comprises a dose of at least 10 mg / day.

[0016] In certain embodiments, the administering comprises one dose per day, two doses per day, three doses per day, or one dose per two days.

[0017] In certain embodiments, Compound 1 is administered orally, rectally, transdermally, buccally, sublingually, or parenterally.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIGS. 1A-1B show body weight (FIG. 1A) and relative body weight (FIG. IB) measured during the treatment period with Compound 1. Data are presented as mean + SEM.

[0019] FIGS. 2A-2B show fasting blood glucose levels measured at baseline (FIG. 2A) and during the treatment period with Compound 1 (FIG. 2B). Data are presented as mean + SEM.

[0020] FIGS. 3A-3B show glucose tolerance test results in Db / + (FIG. 3A) and Db / Db (FIG. 3B) mice following treatment with Compound 1. Data are presented as mean + SEM.

[0021] FIGS. 4A-4B show insulin tolerance test results in Db / + (FIG. 4A) and Db / Db (FIG. 4B) following treatment with Compound 1. Data are presented as mean + SEM.

[0022] FIGS. 5A-5C show survival analysis of Compound 1 treated mice.

[0023] FIGS. 6A-6B show the effects of Compound 1 in enhancing survival of RGCs (FIG. 6A) and the corresponding bar chart (FIG. 6B).

[0024] FIG. 7 shows the effects of Compound 1 in mitigating both the loss of pERG responses and the delay in VEP. Statistical significance: *P < 0.05, **P < 0.01, ****P < 0.0001.

[0025] FIG. 8 shows the effects of Compound 1 in promoting synaptic markers in retina.

[0026] FIGS. 9A-9B show the effects of Compound 1 in mitigating the loss of PSD95 (FIG. 9A) and synaptophysin (FIG. 9B).

[0027] FIGS. 10A-10B show the effects of Compound 1 in reversing glial cell activation (reducing GFAP expression).

[0028] FIG. HA shows that Compound 1 suppresses the increase of Bax and pBad, and reverses the decrease of Bcl-XL. FIG. 11B demonstrates that the effect on Bax is supported by immunofluorescence imaging.DETAILED DESCRIPTIONDefinitions

[0029] Before describing the disclosure in detail, it is to be understood that this disclosure is not limited to particular compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodimentsonly, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a molecule” optionally includes a combination of two or more such molecules, and the like.

[0030] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In case of doubt, or should there be no art recognized common understanding regarding the error range for a certain value or parameter, “about” means + 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of this value or parameter.

[0031] It is understood that aspects and embodiments of the disclosure described herein include “comprising,” “consisting,” and “consisting essentially of aspects and embodiments.

[0032] As used herein, “at least” refers to an amount that is10% of the recited value and is preferably ^5% of the recited value, or more preferably %2% of the recited value.

[0033] The term “derivative” includes any functionally and structurally related compound, such as acid derivatives, amide derivatives, ester derivatives, ether derivatives, prodrugs and metabolites.

[0034] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0035] “Pharmaceutically acceptable salt” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds as disclosed herein 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 inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds as disclosed herein contain relatively basic functionalities, 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 inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from about inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, phosphoric, partially neutralized phosphoric acids, sulfuric, partially neutralized sulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from about relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the present disclosure may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton, Pa., (1985) and Journal of Pharmaceutical Science, 66:2 (1977), each of which is incorporated herein by reference in its entirety.

[0036] As used herein, the terms “treat” or “treatment” refer to therapeutic treatment, wherein the object is to slow down (lessen) an undesired physiological change or disorder, such as the progression of a condition or disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder.

[0037] The term “prevent” or “prevention” means any treatment of a disease or condition that causes the clinical symptoms of the disorder or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0038] A “disorder” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0039] The terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to an amount that may be effective to elicit the desired biological or medical response, including the amount of a compound or a polypeptide that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound or the polypeptide, the disease and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. A pharmaceutically effective amount includes amounts of an agent which are effective when combined with other agents.

[0040] By “subject” or “individual” or “animal” or “patient” or “mammal,” is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include humans, domestic animals, farm animals, and zoo, sport, or pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, and so on.

[0041] As used herein, phrases such as “to a patient in need of treatment” or “a subject in need of treatment” includes subjects, such as mammalian subjects, that would benefit from aboutadministration of an antibody or composition of the present disclosure used, e.g., for detection, for a diagnostic procedure and / or for treatment.

[0042] “Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CHs^CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CHs CHCkfc-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CHs^C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0043] “Substituted alkyl” refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy nitro, -SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.

[0044] “Alkenyl” refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and Ce- Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1 -pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl,1.4-pentadienyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1 ,4-hexadienyl, 1,5-hexadienyl,2.4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

[0045] “ Substituted alkenyl” refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy and thiol and with the proviso that any hydroxyl or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.

[0046] “Acyl” refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-. Acyl includes the “acetyl” group CH3C(O)-.

[0047] “Acylamino” refers to the groups -NR47C(O) alkyl, -NR47C(O)substituted alkyl, -NR47C(O)cycloalkyl, -NR47C(O) substituted cycloalkyl, -NR47C(O)cycloalkenyl, -NR47C(O) substituted cycloalkenyl, -NR47C(O)alkenyl, -NR47C(O)substituted alkenyl, -NR47C(O)aryl, -NR47C(O) substituted aryl, -NR47C(O)heteroaryl, -NR47C(O)substituted heteroaryl, -NR47C(O)heterocyclic, and -NR47C(O) substituted heterocyclic, wherein R47is hydrogen or alkyl.

[0048] “Acyloxy” refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic -C(O)O-.

[0049] “Alkynyl” refers to an unbranched or branched hydrocarbon group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2 s alkynyl), 2 to 6 carbon atoms (i.e., C26 alkynyl), or 2 to 4 carbon atoms (i.e., C24 alkynyl). The term “alkynyl” also includes those groups having at least one carbon-carbon triple bond and a carbon-carbon double bond.

[0050] “Alkoxy” refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy. “Substituted alkoxy” refers to the group -O-(substituted alkyl) wherein substituted alkyl is defined herein.

[0051] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.

[0052] “Alkylthio” refers to the group “alkyl-S-”.

[0053] ‘ ‘Amido” refers to both a “C-amido” group which refers to the group -C(O)NRyRzand an “N- amido” group which refers to the group -NRyC(O)Rz, wherein Ryand Rzare independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0054] ‘ ‘Amino” refers to the group -NH2. “Substituted amino” refers to the group -NR48R49wherein R48and R49are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SC -alkyl, -SCh-substitutcd alkyl, -SC -alkenyl, -SCh-substitutcd alkenyl, -SCh-cycloalkyl, -SCh-substitutcd cycloalkyl, -SC -cycloalkenyl, -SCh-substitutcd cycloalkenyl, -SC -aryl, -SC -substituted aryl, -SC -heteroaryl, -SC -substituted heteroaryl, -SC -heterocyclic, and -SCh-substitutcd heterocyclic, and wherein R48and R49are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R48and R49are both not hydrogen.

[0055] “Aminocarbonyl” refers to the group -C(O)NR50R51, wherein R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group. “Aminocarbonylamino” refers to the group -NR47C(O)NR50R51, wherein R47is hydrogen or alkyl; R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and, wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0056] “Aminocarbonyloxy” refers to the group -O-C(O)NR50R51, wherein R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0057] “Aminosulfonyl” refers to the group -SC>2NR50R51, wherein R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0058] “Aminosulfonyloxy” refers to the group -O-SC>2NR50R51wherein R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, andwherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0059] “Aminosulfonylamino” refers to the group -NR47SC>2NR50R51, wherein R47is hydrogen or alkyl; R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and, wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0060] “Amidino” refers to the group -C(=NR52)NR50R51, wherein R50, R51, and R52are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0061] “Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). The condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like), provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl. “Substituted aryl” refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.

[0062] “Arylene” refers to a divalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings. “Substituted arylene” refers to an arylene having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents as defined for aryl groups.

[0063] “Aryloxy” refers to the group -O-aryl, wherein aryl is as defined herein. Exemplary aryloxy groups include phenoxy and naphthoxy. “Substituted aryloxy” refers to the group -O-(substituted aryl).

[0064] “Carbonyl” refers to the divalent group -C(O)- (i.e., -C(=O)-).

[0065] “Aralkyl” refers to an aryl group pendant to an alkyl group. Examples of aralkyl groups include benzyl, phenethyl, and 3-naphthylpropyl.

[0066] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O- C(O)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ryand Rzare independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0067] “Carboxyl” or “carboxy” refers to -COOH, or salts thereof.

[0068] “Carboxyl ester” or “carboxy ester” refers to the group -C(O)(O)-alkyl,-C(O)(O)-substituted alkyl, -C(O)O-alkenyl, -C(O)(O)-substituted alkenyl, -C(O)(O)-aryl, -C(O)(O)-substituted aryl, -C(O)(O)-cycloalkyl, -C(O)(O)-substituted cycloalkyl, -C(O)(O)-cycloalkenyl, -C(O)(O)-substituted cycloalkenyl, -C(O)(O)-heteroaryl, -C(O)(O)-substituted heteroaryl, -C(O)(O)-heterocyclic, and -C(O)(O)-substituted heterocyclic. “(Carboxyl ester)amino” refers to the group -NR47C(O)(O)-alkyl,-NR47C(O)(O)-substituted alkyl, -NR47C(O)O-alkenyl, -NR47C(O)(O)-substituted alkenyl, -NR47C(O)(O)-aryl, -NR47C(O)(O)-substituted-aryl, -NR47C(O)(O)-cycloalkyl, -NR47C(O)(O)-substituted cycloalkyl, -NR47C(O)(O)-cycloalkenyl,-NR47C(O)(O)-substituted cycloalkenyl, -NR47C(O)(O)-heteroaryl,-NR47C(O)(O)-substituted heteroaryl, -NR47C(O)(O)-heterocyclic, and-NR47C(O)(O)-substituted heterocyclic. “(Carboxyl ester)oxy” refers to the group -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl,-O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic, and -O-C(O)O-substituted heterocyclic.

[0069] “Cyano” refers to the group -CN.

[0070] “Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, Ce-8, C3-9, C3-10, C3-11 , and C3-12. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. “Cycloalkenyl” refers to cycloalkyl groups which are partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. When cycloalkyl is a saturated monocyclic C3-8 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a saturated monocyclic C3-6 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl and cycloalkenyl groups can be substituted or unsubstituted. “Substituted cycloalkyl” and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.

[0071] “Cycloalkyloxy” refers to -O-cycloalkyl. “Substituted cycloalkyloxy” refers to -O-(substituted cycloalkyl). “Cycloalkenyloxy” refers to -O-cycloalkenyl. “Substituted cycloalkenyloxy” refers to -O-(substituted cycloalkenyl).

[0072] ‘ ‘Guanidino” refers to the group -NHC(=NH)NH2.

[0073] “Hydroxy” or “hydroxyl” refers to the group -OH.

[0074] “Imino” refers to a group -C(NR)R, wherein each R is independently alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0075] “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0076] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon andheteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include - OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0077] “Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heteroaryl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8,3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, which may or may not contain a heteroatom, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, benzofuran, indolizine or benzothiene. The heteroaryl groups can be fused to non-aromatic ring systems, which may or may not contain a heteroatom, provided that the point of attachment is through an atom of the aromatic heteroaryl group. For example, the nitrogen and / or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N— >0), sulfinyl, or sulfonyl moieties. Certain non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, thiazolyl, and furanyl. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted. “Substituted heteroaryl” refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.

[0078] “Heteroarylene” refers to a divalent heteroaryl. “Substituted heteroarylene” refers to a heteroarylene having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents as defined for heteroaryl groups.

[0079] “Heteroaryloxy” refers to -O-heteroaryl. “Substituted heteroaryloxy” refers to the group -O-(substituted heteroaryl).

[0080] “Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated, or partially saturated, ring system having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-.Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, or sulfonyl moieties. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with Ci-6 alkyl, oxo (=0), nitro (-NO2), or sulfonyl (-S(O)2-), among many others. “Substituted heterocyclic” or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.

[0081] “Heterocyclyloxy” refers to the group -O-heterocyclyl. “Substituted heterocyclyloxy” refers to the group -O-(substituted heterocyclyl).

[0082] “Oxo” refers to the group (=0) or (O).

[0083] “Spirocycloalkyl” and “spiro ring systems” refers to divalent cyclic groups from 3 to 10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro union (the union formed by a single atom which is the only common member of the rings) as exemplified by the following structure:

[0084] “Sulfonyl” refers to the group -S(O)2R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl. “Substituted sulfonyl” refers to the group -SC -alkyl, -SCE-substituted alkyl, -SC>2-alkenyl, -SCE-substituted alkenyl, -SCE-cycloalkyl, -SCE-substituted cycloalkyl, -SCE-cycloalkenyl, -SCE-substituted cycloalkenyl, -SCE-aryl, -SCE-substituted aryl, -SCE-heteroaryl, -SCE-substituted heteroaryl, -SCE-heterocyclic, -SCE-substituted heterocyclic. Substituted sulfonyl includes groups such as methyl-SCE-, phenyl-SCE-, and 4-methylphenyl-SO2-. “Substituted sulfonyloxy” refers to the group -OSCE-alkyl, -OSCE-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cycloalkenyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, and -OSO2-substituted heterocyclic.

[0085] “Alkylsulf onyl” refers to the group -S(O)2R, where R is alkyl.

[0086] “Alkylsulfinyl” refers to the group -S(O)R, where R is alkyl.

[0087] As used herein, the term “saccharide” refers to a sugar, such as a monosaccharide, a disaccharide, an oligosaccharide or a polysaccharide. Monosaccharides include, but are not limited to, glucose, ribose and fructose. Disaccharides include, but are not limited to, sucrose and lactose. Oligosaccharides refers to 2 to 10 sugars linked together preferably through an alpha linkage. Examples of oligosaccharides include maltose, lactose, sucrose, and the like. Polysaccharides include, but are not limited to, cellulose, hemicellulose and lignocellulose or starch. Saccharides or sugars useful in the present invention include any and all naturally occurring sugars, such as, but not limited to, glucose, glucuronic acid, iduronic acid, galactose, fucose, glucosamine, N- acetylglucosamine, fructose, sialic acid, including aldol and pyranose forms thereof, as well as D and L isomers thereof.

[0088] “Thiocyanate” refers to the group -SCN.

[0089] “Thioxo” or “thione” refer to the group (=S) or (S).

[0090] A substituted ring can be substituted with one or more fused and / or spiro cycles. Such fused cycles include a fused cycloalkyl, a fused heterocyclyl, a fused aryl, a fused heteroaryl ring, each of which rings can be unsubstituted or substituted. Such spiro cycles include a fused cycloalkyl and a fused heterocyclyl, each of which rings can be unsubstituted or substituted.

[0091] The groups defined above can optionally be substituted by any suitable number and type of substituents. Representative substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, haloalkyl, haloalkoxy, -OR’, =0, -OC(O)R’, -(O)R’, -O2R’, -ONR’R”, -0C(0)NR’R”, =NR’,=N-0R’, -NR’R”, -NR”C(0)R’, -NR’-(0)NR”R”’, -NR”C(0)0R’, -NH-(NH2)=NH, -NR’C(NH2)=N H, -NH-(NH2)=NR’, -SR’, -S(O)R’, -S(O)2R’, -S(O)2NR’R”, -NR’S(O)2R”, -N3and -NO2. R’, R” and R’” each independently refer to hydrogen, unsubstituted alkyl, such as unsubstituted Ci-6 alkyl. Alternatively, R’ and R”, or R” and R’”, when attached to the same nitrogen, are combined with the nitrogen to which they are attached to form a heterocycloalkyl or heteroaryl ring, as defined above.

[0092] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three. In other words, each of the above definitions is constrained by a limitation that, for example, substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0093] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0094] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen. The term “optionally substituted” with reference to a group is intended to be construed as describing the unsubstituted group and the group substituted by the indicated or defined substituent(s).

[0095] A protecting group may be any known in the art, for example, as described in Peter G. M. Wuts and Theodora W. Greene, Greene's protective groups in organic synthesis (Wiley-Interscience, 2007).

[0096] Some compounds exist as tautomers. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise all tautomers.

[0097] Any formula or structure given herein is also intended to represent isotopically labeled forms of the compounds as well as unlabeled forms. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an isotope having the indicated atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure, or counter-ions thereto, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to2H (deuterium, D),3H (tritium), ”C,13C,14C,15N,18F,31P,32P,35S,36C1 and125I. Various isotopically labeled compounds are possible under the present disclosure, for example those into which radioactive isotopes such as3H and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single -photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0098] The disclosure also includes “deuterated analogs” of compounds, and counter-ions thereto, in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and thus may be useful for increasing the half-life of a compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0099] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound.

[0100] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of thisdisclosure any atom specifically designated as a deuterium (D) is meant to represent enrichment of deuterium above a naturally occurring level at the indicated position.

[0101] Compounds described herein may be present as a salt, such as a pharmaceutically acceptable salt. Compounds are capable of forming salts such as acid and / or base salts. Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. Salts of compounds described herein can be prepared according to procedures described herein and as known in the art.

[0102] The term “pharmaceutically acceptable salt” of a given compound, refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, isobutyric acid, suberic acid, lactic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2( alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri( substituted alkyl) amines (i.e., N(substituted alkyds), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di( substituted alkenyl) amines (i.e., HN(substituted alkenyl^), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl^,mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)s), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Methods of preparing a salt also include mixing a compound by redox reaction with an active metal, or by exchange of ions, for example, due to differing solubility of salts.

[0103] The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. If not specified, the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, aryl, -Ns, carbamoyl, carboxyl, carboxyl ester, -CN, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, -OH, imino, oxo, -NO2, alkylsulfinyl, -SO3H, alkylsulfonyl, thiocyanate, -SH, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorine atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0104] A “solvate” is a solid form of a compound in which solvent molecules are incorporated. A solvate is formed by the interaction of a solvent and a compound. A hydrate is a solvate in which the solvent is water. Solvates of salts of compounds described herein are also provided.

[0105] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0106] “Treatment” or “treating” provides a beneficial or desired result, e.g., an improvement in one or more clinical indicia of a disorder. Beneficial or desired results may include one or more of the following: decreasing or ameliorating one or more symptoms of the disorder, and / or diminishing the extent of the disorder; (e.g., stabilizing the disorder, preventing or delaying the worsening or progression of the disorder); providing partial or total remission of the disorder; enhancing effect of another medication; increasing the quality of life; and / or prolonging survival in a population of patients.

[0107] ‘ ‘Prevention” or “preventing” means blocking development of a disorder, or symptoms thereof. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk of or has a family history of the disorder. Prevention may comprise delay in reaching predefined disease milestones or reduction in appearance or progression of a marker.

[0108] “Subject” refers to an animal, such as a mammal, e.g. a human that may benefit from administration of a compound described herein. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. When the subject is a human person, the subject may be referred to as a “patient.”

[0109] The term “therapeutically effective amount” or “effective amount” of a compound described herein means an amount sufficient to effect treatment when administered to a subject, to provide a benefit as described herein. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a mood disorder. The therapeutically effective amount may vary depending on the subject, the disorder being treated, the weight and age of the subject, the severity of the disorder, and the manner of administering, which can readily be determined by a medical practitioner.Compounds

[0110] It is contemplated that the compounds described herein are capable of regenerating retinal synapses. The compound may be a compound described in International Patent Publication No. WO 2019 / 028164, which is hereby incorporated by reference herein. In some embodiments, the compound is of formula I or formula la:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscripts n and p are independently selected from 0, 1 or 2; each R1is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro;A is an arylene or heteroarylene, having 1 to 4 heteroatoms;W is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;X is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is as defined above, provided that when A is arylene, and Y is -S- or -NR2-, then X is not -S-;Y is selected from the group consisting of -O-, -S-, -SO-, S(O)2-, and -NR2-, wherein R2is as defined above; andZ is selected from the group consisting of -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R3)O)q-T, wherein subscript q is an integer from 1 to 100, R3is selected from the group consisting of hydrogen and methyl, and T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L-monosaccharide, and -L-oligosaccharide, wherein L is selected from the group consisting of a bond, phosphate, and sulfate.

[0111] In some embodiments, A is phenylene or pyridylene. In some embodiments, X is S. In some embodiments, Y is -O-. In some embodiments, X is S, Y is -O-, and A is phenylene.

[0112] In some embodiments, provided is a compound according to Formula lb, Formula Ic, Formula Id, Formula le, and / or Formula Ig:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein:R1, R2, A, Y, Z, n and p are as defined above with respect to formula I and formula la; and subscript m is 0, 1 or 2.

[0113] In some embodiments, provided is a compound selected from:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0114] In some embodiments, the compound is a compound of formula Ik:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscripts n and p are each independently 0, 1 or 2; subscript q is an integer from 2 to 8; and each R41and each R42are independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro.

[0115] In some embodiments, each of subscripts n and p is 0.

[0116] In some embodiments, provided is a compound, or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, as described herein, selected from:

[0117] In some embodiments, provided is a compound according to Formula Ij:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscript q is an integer from 4 or 6;R3, R4, R5, and R6are independently selected from the group consisting of hydrogen halo, -CH3, and -OCH3; andR7, R8, R9, and R10are independently selected from the group consisting of hydrogen, halo, -CH3, -CF3, -OCH3, -OCF3, phenyl, and -NO2; wherein at least six of R3-R10 are hydrogen.

[0118] In some embodiments, provided is a compound, or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, selected from:

[0119] In some embodiments, the compound isor a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0120] In some embodiments, the compound is a compound described in International PublicationNo. WO 2017 / 120198. In some embodiments, the compound is a compound of formula II:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein:Y is -NR33-, or -S-;R31is independently halogen, -CX313, -CHX312, -CH2X31, -OCX313, -OCHX312, -OCH2X31, - CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,- C(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;; each R32is independently halogen, -CX323, -CHX322, -CH2X52. -OCX323, -OCHX322, -OCH2X52. -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R33is H, alkyl, or substituted alkyl; each of X31and X32is independently halogen; each of zl and z2 is independently an integer from 0 to 4; and z3 is an integer from 1 to 12.

[0121] In some embodiments, Y is S. In some embodiments, each of zl and z2 is 0.

[0122] In some embodiments, the compound is a compound of formula Ila:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein:each R1is independently halogen, -CX , -CHX*2, -CH2X1, -OCXS,-OCHXS, -OCH2X1, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H,-SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H,-NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; each R2is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCHX22, -OCH2X2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;; each of X1and X2is independently halogen; each of zl and z2 is independently an integer from 0 to 4; and n is an integer from 1 to 12.

[0123] In some embodiments, the compound isor a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0124] In some embodiments, the compound isor a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0125] In some embodiments, Y is NH or NMe. In some embodiments, zl is 1 , z2 is 0, and R31is alkyl.

[0126] In some embodiments, the compound isor a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0127] In some embodiments, the compound isor a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0128] In some embodiments, the compound is a compound described in US Patent No. 8,741,883.In some embodiments, the compound is a compound of formula III:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: each of R,-R8are independently selected from the group consisting of hydrogen, deuterium, tritium, fluoro, chloro, bromo, iodo, hydroxyl, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, and trifluoromethyl, wherein at least one of Rs-R8and one of R1-R4 is H; andP is selected from the group consisting ofwherein: m is an integer from 1 and 20; n is 0, 1, or 2; q is an integer from 1 and 20; each of R9-R16 is independently selected from the group consisting of hydrogen, deuterium, tritium, fluoro, chloro, bromo, iodo, hydroxyl, amino, methylamino, dimethylamino,trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, and trifluoromethyl, wherein at least one of R9-R12 and one of R13-R16 is H; andX is hydrogen, methyl, or ethyl.

[0129] In some embodiments, the compound of formula Illa:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: each of Ri-Rs is independently selected from the group consisting of hydrogen, deuterium, tritium, fluoro, chloro, bromo, iodo, hydroxyl, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, and trifluoromethyl, wherein at least one of R5-R8 and one of R1-R4 is H; andwherein m is an integer from 1 and 20; q is an integer from 1 and 20; each of R9-R16 are independently selected from the group consisting of hydrogen, deuterium, tritium, fluoro, chloro, bromo, iodo, hydroxyl, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, and trifluoromethyl, wherein at least one of R9-R12 and one of R13-R16 is H; andX is hydrogen, methyl, or ethyl.

[0130] In some embodiments, the compound is selected from:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0131] In some embodiments, the compound is a compound described in US Patent Publication No. 2015 / 0299191. In some embodiments, the compound is a compound described in US Patent Publication No. 2014 / 0080843.

[0132] In some embodiments, the compound is a compound described in International Patent Publication No. WO 2013 / 013240. In some embodiments, the compound is a compound described in US Patent Publication No. 2014 / 0024705.

[0133] In some embodiments, the compound is G2 (or G2-044), having the name N-(l-(4-(trifluoromethyl)benzyl)-lH-indazol-3-yl)furan-2-carboxamide:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0134] In some embodiments, the compound is imipramine or semapimod or a or a pharmaceutically acceptable salt of each thereof.

[0135] Provided herein is a derivative of 2-(2-(2-(2-(4-(benzo[d]thiazol-2- yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-l-ol having the following structure:

[0136] The compound of Formula I is described in International application number PCT / US2017 / 012139, which is hereby incorporated by refence in its entirety.

[0137] The derivatives of Formula I is useful in treating or preventing diseases related to diabetes mellitus. One derivative of Formula I, Compound 1 has the below structure:or a pharmaceutically acceptable salt thereof.Compositions

[0138] The present disclosure also provides pharmaceutical compositions. Such compositions include a pharmaceutically effective amount of a compound provided herein, and a pharmaceutically acceptable carrier.

[0139] The term “pharmaceutically acceptable” component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio. Further, a “pharmaceutically acceptable carrier” will generally be a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.

[0140] The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile 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. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients 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, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates or phosphates. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned.

[0141] A composition or compound provided herein that can be used in the methods described herein can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and / or mode of administration will vary depending upon the desired results. The route of administration can depend on a variety of factors, such as the environment and therapeutic goals. In particular, the composition or compound provided herein can be administration by any route known in the art, e.g., subcutaneous (e.g., by subcutaneous injection), intravenously, orally, nasally, intramuscularly, sublingually, intrathecally, or intradermally. In certain embodiments, the compounds or compositions provided herein is administered to a subject orally.

[0142] Depending on the intended mode of administration, the disclosed compounds or compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, gelcap, syrups, powders, gel, liquids, solution, suspensions, ointment, cream, nebulae, mist, atomized vapor, aerosol, phytosome, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

[0143] Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E. W. Martin, incorporated herein by reference. Such compositions will contain a therapeutically effective amount of the antigen-binding polypeptide, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0144] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes, and / or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 90, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0145] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0146] The disclosed compounds can be also formulated as a suppository that can be prepared from about fatty emulsions or suspensions; using poly alkylene glycols such as propylene glycol, as the carrier.

[0147] The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from about a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.

[0148] In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564, which is hereby incorporated by reference in its entirety.

[0149] Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, poly dihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a poly acrylate.

[0150] Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

[0151] Pharmaceutical dosage forms of a compound of this disclosure may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extruding, spray-drying, levigating, emulsifying, (nano- / micro-) encapsulating, entrapping, or lyophilization processes. As noted above, the compositions of this disclosure can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.

[0152] In certain embodiments, the compositions are comprised of a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are nontoxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0153] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semi-solid excipients may be selected from about glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0154] Compressed gases may be used to disperse a compound of this disclosure in an aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

[0155] The compositions of this disclosure may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of this disclosure that can be formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0156] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below.Methods of Treatment

[0157] The present disclosure provides a method of treating or preventing diabetes mellitus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof, or a composition as provided herein.

[0158] Provided herein are use of a therapeutically effective amount of Compound I or a composition in the manufacture for a medicament for treating or preventing diabetes mellitus in a subject in need thereof.

[0159] Also provided herein is a therapeutically effective amount of Compound I or a composition for use in the treatment or prevention of ophthalmic disease or diabetes mellitus in a subject in need thereof.

[0160] In certain embodiments, the subject of the present disclosure is middled aged or elderly patient. In the present disclosure, the term “middle-aged” typically applies to adults agedapproximately 45 to 65 years. And the term “old” or “elderly” is generally used to describe individuals aged 65 years and older.

[0161] In certain embodiments, the subject suffers from ophthalmic disease without the symptom of diabetes mellitus.

[0162] In certain embodiments, the subject suffers from both diabetes mellitus and ophthalmic disease.

[0163] In some embodiments of the present disclosure, the ophthalmic disease comprises glaucoma, macular ischemia, diabetic retinopathy, non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, diabetic maculopathy, diabetic macular edema, age-related macular degeneration, choroidal neovascularization, retinal neovascularization, disorder associated with neovascularization in the eye, or a combination thereof.Diabetes mellitus

[0164] The term “diabetes” refers herein to a group of metabolic diseases in which patients have high blood glucose levels, including Type 1 diabetes, Type 2 diabetes, gestational diabetes, congenital diabetes, cystic fibrosis-related diabetes, steroid diabetes, and several forms of monogenic diabetes.

[0165] Individuals diagnosed with type 1 diabetes, are considered insulin- dependent as they require injections or other medications to supply the insulin that the body is unable to produce on its own. Due to lack of insulin the blood sugar is unregulated and levels are too high. Individuals with type 2 diabetes are considered non-insulin- dependent or insulin-resistant. The individuals affected with this type of diabetes, produce enough insulin but the body is unable to make proper use of it. The body then compensates by producing even more insulin, which can cause an accompanying abnormal increase in blood sugar levels. All people with Type I diabetes (juvenile onset) and with Type II diabetes (adult onset) are at risk of developing diabetic retinopathy. However, people with Type 1 diabetes are more likely to cause retinopathy compared to type 2 diabetes.

[0166] In certain embodiments, administration of the compound of the present disclosure corrects, retardates, or reduces an impaired glucose homeostasis. The level of glucose in the blood fluctuates throughout the day. Glucose levels are usually lower in the morning, before the first meal of the day and rise after meals for some hours.

[0167] In certain embodiments, these drugs or compositions may be used to normalize blood glucose level by acting, e.g., on insulin release, glucagon release, glucose utilization and / or glucose production, and offer novel potent therapies for diabetes and related disorders.

[0168] In certain embodiments, administration of the compound of the present disclosure reduces blood glucose level in a subject having diabetes or a related disorder. The related disorder includes insulin release (e.g., by pancreatic P-cells), glucagon release (e.g., by pancreatic a-cells), glucose utilization and / or uptake (e.g., capture of glucose by muscle cells or adipocytes), and / or hepatic neoglucogenesis.

[0169] In certain embodiments, administration of the compound of the present disclosure improves insulin release (e.g., by pancreatic P-cells), glucagon release (e.g., by pancreatic a-cells), glucose utilization and / or uptake (e.g., capture of glucose by muscle cells or adipocytes), and / or hepatic neoglucogenesis.

[0170] One or more symptoms of the diabetes include hyperglycemia, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance, metabolic syndrome, postprandial hyperglycemia or overweight / obesity.

[0171] Impaired Glucose Tolerance (IGT) is a pre-diabetic state of dysglycemia that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT is characterized by higher than normal blood glucose levels after eating (postprandial) or during an oral glucose tolerance test (OGTT), but not high enough to be classified as diabetes. Specifically, in an OGTT, individuals with IGT have a 2-hour blood glucose level that falls between 140 mg / dL (7.8 mmol / L) and 199 mg / dL (11.0 mmol / L).

[0172] IGT is considered a significant risk factor for the development of type 2 diabetes and is often accompanied by other components of the metabolic syndrome, including high blood pressure, high levels of triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, and obesity, particularly abdominal obesity. However, not everyone with IGT will progress to type 2 diabetes; lifestyle modifications such as diet, exercise, and weight loss can help lower blood glucose levels and potentially return them to the normal range, thus reducing the risk of developing diabetes in the future.

[0173] Impaired Fasting Glucose (IFG) is a condition characterized by higher than normal blood glucose levels after a period of fasting (usually overnight) but below the threshold for a diagnosis of diabetes. Specifically, IFG is defined as a fasting plasma glucose level of 100 mg / dL (5.6 mmol / L) to 125 mg / dL (6.9 mmol / L). This condition is considered a form of pre-diabetes, indicating a risk of developing type 2 diabetes and cardiovascular disease.

[0174] Like Impaired Glucose Tolerance (IGT), IFG is associated with insulin resistance. Individuals with IFG have a compromised ability to regulate glucose levels, which results in elevated fasting blood sugar. However, their glucose levels might not reach the diabetic range during an Oral Glucose Tolerance Test (OGTT).

[0175] Insulin resistance is a metabolic condition where the body's cells become less responsive to the hormone insulin. Insulin, produced by the pancreas, plays a crucial role in regulating blood glucose levels by facilitating the uptake of glucose (sugar) from the bloodstream into the cells for energy or storage. When cells become insulin resistant, they fail to respond effectively to insulin, making it difficult for them to absorb glucose. As a result, higher levels of insulin are needed to help glucose enter cells, leading to increased insulin production by the pancreas.

[0176] Over time, insulin resistance can lead to an accumulation of glucose in the bloodstream, resulting in elevated blood sugar levels. This condition is a key feature of type 2 diabetes and is closely associated with other health issues, including obesity, hypertension, high levels of triglycerides, low levels of HDL (good) cholesterol, and metabolic syndrome — a cluster of conditions that increase the risk of heart disease, stroke, and type 2 diabetes.

[0177] Metabolic syndrome is a cluster of conditions that occur together, increasing an individual's risk of heart disease, stroke, and type 2 diabetes. These conditions include increased blood pressure, high blood sugar levels, excess body fat around the waist, and abnormal cholesterol or triglyceride levels. While each of these conditions poses health risks on its own, having a combination of them significantly amplifies the risk of serious health complications.

[0178] Diagnosis of metabolic syndrome typically requires the presence of three or more of the following criteria: Waist circumference greater than 40 inches (102 cm) in men and 35 inches (88 cm) in women, indicating abdominal obesity; Triglyceride levels of 150 milligrams per deciliter (mg / dL) or higher, or taking medication for elevated triglyceride levels; Reduced HDL ("good") cholesterol levels — less than 40 mg / dL in men or less than 50 mg / dL in women, or taking medication for low HDL levels; Elevated fasting blood glucose of 100 mg / dL or higher, or taking medication for elevated blood sugar; Blood pressure of 130 / 85 millimeters of mercury (mm Hg) or higher, or using medication to treat high blood pressure.

[0179] Postprandial hyperglycemia refers to abnormally high blood glucose levels that occur after eating. Typically, this condition is defined as a blood glucose level exceeding 140 mg / dL (7.8 mmol / L) within two hours following a meal. It is a common issue in individuals with diabetes, as their bodies struggle to adequately regulate blood sugar levels due to insufficient insulin production or insulin resistance.

[0180] In certain embodiments, administration of the compound of the present disclosure improves impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance, metabolic syndrome, postprandial hyperglycemia and overweight / obesity.

[0181] For most non-diabetic individuals, normal fasting blood glucose levels are between 70 and 99 mg / dE (3.9 to 5.5 mmol / E). Postprandial (after meals) levels should be less than 140 mg / dE (7.8 mmol / L). However, diabetes is typically diagnosed when fasting blood glucose levels are 126 mg / dL (7.0 mmol / L) or higher on two separate tests, or when random blood glucose levels are 200 mg / dL (11.1 mmol / L) or higher and accompanied by symptoms of hyperglycemia. Target ranges can vary based on the individual, their age, the type of diabetes, the duration of diabetes, pregnancy status, and the presence of diabetes complications or other health conditions. For example, the American Diabetes Association (ADA) suggests the following targets for most nonpregnant adults withdiabetes: preprandial (before meals): 80-130 mg / dL (4.4-7.2 mmol / L) and postprandial (1-2 hours after beginning of the meal): Less than 180 mg / dL (10.0 mmol / L).

[0182] The administration of Compound I of the present disclosure lower the levels of blood glucose in a patient suffering from the diabetes. In certain embodiments, the methods of the present disclosure result in a decrease of blood glucose from about 0.1-10 mmol / L (e.g. from about 0.1-6 mmol / L, from about 0.1-5 mmol / L, from about 0.1-4 mmol / L, from about 0.1-3 mmol / L, from about 0.1-2 mmol / L, from about 0.1-1 mmol / L, or from about 0.1 -0.5 mmol / L). In certain embodiments, the methods of the present disclosure result in a decrease of blood glucose of at least about 10% (e.g., at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) relative to the level prior to administration of the compounds or compositions provided herein.

[0183] The normal range of insulin levels in the body can vary depending on the laboratory and the specific assay used for measurement. However, a general guideline for fasting insulin levels in nondiabetic individuals is typically between 2 to 20 microU / mL (microunits per milliliter) or approximately 12 to 120 pmol / L (picomoles per liter), considering the conversion factor for insulin is roughly 6.945 (1 microU / mL equals approximately 6.945 pmol / L). It is important to note that these ranges can be influenced by several factors, including age, body mass, dietary habits, and the time of day. Fasting insulin levels are measured after an 8 to 12-hour fast and provide information about baseline insulin secretion. Elevated fasting insulin levels may indicate insulin resistance or a higher risk of developing type 2 diabetes.

[0184] The administration of Compound 1 of the present disclosure increase the levels of fasting insulin in a patient suffering from the diabetes. In certain embodiments, the methods of the present disclosure result in a increase of fasting insulin from about 0.1-20 pU / mL (e.g. from about 0.1-15 pU / mL , from about 0.1-10 pU / mL , from about 0.1-8 pU / mL , from about 0.1-5 pU / mL , from about 0.1-4 pU / mL , from about 0.1-3 pU / mL , from about 0.1-2 pU / mL , from about 0.1-1 pU / mL , or from about 0.1-0.5 pU / mL ). In certain embodiments, the methods of the present disclosure result in a increase of fasting insulin of at least about 10% (e.g., at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) relative to the level prior to administration of the compounds or compositions provided herein.Dosing Methods

[0185] In certain embodiments, the composition provided herein containing the compounds described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compounds are administered to a patient already suffering from about a disease or disorder, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of a healthcare practitioner. Therapeutically effective amounts areoptionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0186] In prophylactic applications, the compounds provided herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient’s state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of a healthcare professional. In one aspect, prophylactic treatments include administering to a patient, who previously experienced at least one symptom of the disease being treated and is currently in remission, an composition provided herein comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[0187] Dosages of compositions or compounds provided herein can be provided in either a single or multiple dosage regimens. Doses can be administered, e.g., hourly, bihourly, daily, bidaily, twice a week, three times a week, four times a week, five times a week, six times a week, weekly, biweekly, monthly, bimonthly, or yearly. Alternatively, doses can be administered, e.g., twice, three times, four times, five times, six times, seven times, eight times, nine times, 10 times, 11 times, or 12 times per day. In particular, the dosing regimen is once weekly. The duration of the dosing regimen can be, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 day(s), week(s), or month(s), or even for the remaining lifespan of the patient. The amount, frequency, and duration of dosage will be adapted by the clinician in accordance with conventional factors such as the extent of the disease and different parameters from about the patient.

[0188] In certain embodiments wherein the patient’s condition does not improve, upon the discretion of a healthcare professional the administration of the composition provided herein are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0189] In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (z.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0190] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0191] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0192] In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 2000 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 1000 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 500 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 200 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 150 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 100 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 25 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 10 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 5 mg / kg per body weight. In some of these embodiments, the dose relates to mg / kg per body weight of Compound I. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0193] The compounds of the present disclosure is administered to a subject at various dosing amounts per dose or per day. Daily dosage of Compound I may be between about 1 mg and 5,000mg, about 1 mg and 4,000 mg, about 1 mg and 3,000 mg, between about 2,000 to 4,000 mg / day, between about 1 to 2,000 mg / day, between about 1 to 1,000 mg / day, between about 10 to 500 mg / day, between about 20 to 500 mg / day, between about 50 to 300 mg / day, between about 75 to 200 mg / day, or between about 15 to 150 mg / day. For example, from about 0.1 mg / day to 5000 mg / day, from about 0.1 mg / day to 4500 mg / day, from about 0.1 mg / day to 4000 mg / day, from about 0.1 mg / day to 3500 mg / day, from about 0.1 mg / day to 3000 mg / day, from about 0.1 mg / day to 2500 mg / day, from about 0.1 mg / day to 2000 mg / day, from about 0.1 mg / day to 1500 mg / day, from about 0.1 mg / day to 1000 mg / day, from about 0.1 mg / day to 900 mg / day, from about 0.1 mg / day to 800 mg / day, from about 0.1 mg / day to 700 mg / day, from about 0.1 mg / day to 600 mg / day, from about 0.1 mg / day to 500 mg / day, from about 0.1 mg / day to 400 mg / day, from about 0.1 mg / day to 300 mg / day, from about 0.1 mg / day to 200 mg / day, from about 0.1 mg / day to 100 mg / day, from about 0.1 mg / day to 90 mg / day, from about 0.1 mg / day to 80 mg / day, from about 0.1 mg / day to 70 mg / day, from about 0.1 mg / day to 60 mg / day, from about 0.1 mg / day to 50 mg / day, from about 0.1 mg / day to 40 mg / day, from about 0.1 mg / day to 30 mg / day, from about 0.1 mg / day to 20 mg / day, from about 0.1 mg / day to 10 mg / day, from about 0.1 mg / day to 9 mg / day, from about 0.1 mg / day to 8 mg / day, from about 0.1 mg / day to 7 mg / day, from about 0.1 mg / day to 6 mg / day, from about 0.1 mg / day to 5 mg / day, from about 0.1 mg / day to 4 mg / day, from about 0.1 mg / day to 3 mg / day, from about 0.1 mg / day to 2 mg / day, from about 0.1 mg / day to 1 mg / day, from about 1 mg / day to 5000 mg / day, from about 1 mg / day to 4000 mg / day, from about 1 mg / day to 3000 mg / day, from about 5 mg / day to 2000 mg / day, from about 1 mg / day to 4000 mg / day, from about 5 mg / day to 4000 mg / day, from about 10 mg / day to 4000 mg / day, from about 20 mg / day to 4000 mg / day, from about 30 mg / day to 4000 mg / day, from about 40 mg / day to 4000 mg / day, from about 50 mg / day to 4000 mg / day, from about 60 mg / day to 4000 mg / day, from about 70 mg / day to 4000 mg / day, from about 80 mg / day to 4000 mg / day, from about 90 mg / day to 4000 mg / day, from about 100 mg / day to 4000 mg / day, from about 150 mg / day to 4000 mg / day, from about 200 mg / day to 4000 mg / day, from about 250 mg / day to 4000 mg / day, from about 300 mg / day to 4000 mg / day, from about 350 mg / day to 4000 mg / day, from about 400 mg / day to 4000 mg / day, from about 450 mg / day to 4000 mg / day, from about 500 mg / day to 4000 mg / day, from about 550 mg / day to 4000 mg / day, from about 600 mg / day to 4000 mg / day, from about 650 mg / day to 4000 mg / day, from about 700 mg / day to 4000 mg / day, from about 750 mg / day to 4000 mg / day, from about 800 mg / day to 4000 mg / day, from about 850 mg / day to 4000 mg / day, from about 900 mg / day to 4000 mg / day, from about 950 mg / day to 4000 mg / day, from about 1000 mg / day to 4000 mg / day, from about 1500 mg / day to 4000 mg / day, from about 5 mg / day to 1500 mg / day, from about 5 mg / day to 1000 mg / day, from about 5 mg / day to 900 mg / day, from about 10 mg / day to 1000 mg / day, from about 10 mg / day to 900 mg / day, from about 10 mg / day to 800 mg / day, from about 10 mg / day to 700 mg / day, from about 10 mg / day to 600 mg / day, from about 10 mg / day to 500 mg / day, from about 10 mg / day to 400 mg / day, from about 10 mg / day to 300 mg / day, from about 10 mg / day to 200 mg / day, from about 10 mg / day to 100 mg / day, from about 10 mg / day to 90 mg / day, from about 10 mg / day to80 mg / day, from about 10 mg / day to 70 mg / day, from about 10 mg / day to 60 mg / day, from about 10 mg / day to 50 mg / day, from about 10 mg / day to 40 mg / day, from about 10 mg / day to 30 mg / day, from about 10 mg / day to 20 mg / day, from about 50 mg / day to 1000 mg / day, from about 50 mg / day to 900 mg / day, from about 50 mg / day to 800 mg / day, from about 50 mg / day to 700 mg / day, from about 50 mg / day to 600 mg / day, from about 50 mg / day to 500 mg / day, from about 50 mg / day to 400 mg / day, from about 50 mg / day to 300 mg / day, from about 50 mg / day to 200 mg / day, from about 50 mg / day to 100 mg / day, from about 50 mg / day to 90 mg / day, from about 50 mg / day to 80 mg / day, from about 50 mg / day to 70 mg / day, from about 50 mg / day to 60 mg / day.

[0194] In certain embodiments, the dosing amount is equivalent or at least about 0.1 mg / day, about 0.5 mg / day, about 1 mg / day, about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 450 mg / day, about 500 mg / day, about 550 mg / day, about 600 mg / day, about 650 mg / day, about 700 mg / day, about 750 mg / day, about 800 mg / day, about 850 mg / day, about 900 mg / day, about 950 mg / day, about 1000 mg / day, about 1200 mg / day, about 1500 mg / day, about 2000 mg / day, about 2500 mg / day, about 3000 mg / day, about 3500 mg / day, about 4000 mg / day, about 4500 mg / day, about 5000 mg / day.

[0195] In certain embodiments, dosing amounts of the compounds of the present disclosure per dose or per day is from about 0.1 mg / kg to 200 mg / kg, from about 0.1 mg / kg to 100 mg / kg, from about 0.1 mg / kg to 90 mg / kg, from about 0.1 mg / kg to 80 mg / kg, from about 0.1 mg / kg to 70 mg / kg, from about 0.1 mg / kg to 60 mg / kg, from about 0.1 mg / kg to 50 mg / kg, from about 0.1 mg / kg to 40 mg / kg, from about 0.1 mg / kg to 30 mg / kg, from about 0.1 mg / kg to 20 mg / kg, from about 0.1 mg / kg to 10 mg / kg, from about 0.1 mg / kg to 9 mg / kg, from about 0.1 mg / kg to 8 mg / kg, from about 0.1 mg / kg to 7 mg / kg, from about 0.1 mg / kg to 6 mg / kg, from about 0.1 mg / kg to 5 mg / kg, from about 0.1 mg / kg to 4 mg / kg, from about 0.1 mg / kg to 3 mg / kg, from about 0.1 mg / kg to 2 mg / kg, from about 0.1 mg / kg to 1 mg / kg, from about 1 mg / kg to 100 mg / kg, from about 1 mg / kg to 200 mg / kg, from about 5 mg / kg to 200 mg / kg, from about 10 mg / kg to 200 mg / kg, from about 20 mg / kg to 200 mg / kg, from about 30 mg / kg to 200 mg / kg, from about 40 mg / kg to 200 mg / kg, from about 50 mg / kg to 200 mg / kg, from about 60 mg / kg to 200 mg / kg, from about 70 mg / kg to 200 mg / kg, from about 80 mg / kg to 200 mg / kg, from about 90 mg / kg to 200 mg / kg, from about 100 mg / kg to 200 mg / kg, from about 150 mg / kg to 200 mg / kg, from about 5 mg / kg to 150 mg / kg, from about 5 mg / kg to 100 mg / kg, from about 5 mg / kg to 90 mg / kg, from about 5 mg / kg to 80 mg / kg, from about 5 mg / kg to 70 mg / kg, from about 5 mg / kg to 60 mg / kg, from about 5 mg / kg to 50 mg / kg, from about 5 mg / kg to 40 mg / kg, from about 5 mg / kg to 30 mg / kg, from about 5 mg / kg to 20 mg / kg, from about 5 mg / kg to 10 mg / kg, from about 10 mg / kg to 100 mg / kg, from about 10 mg / kg to 90 mg / kg, from about 10 mg / kg to 80 mg / kg, from about 10 mg / kg to 70 mg / kg, from about 10 mg / kg to 60 mg / kg, from about 10 mg / kg to 50mg / kg, from about 10 mg / kg to 40 mg / kg, from about 10 mg / kg to 30 mg / kg, from about 10 mg / kg to 20 mg / kg, from about 10 mg / kg to 15 mg / kg.

[0196] In certain embodiments, the dosing amount of the compounds per dose or per day of the present disclosure is equivalent to or at least about 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60 mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80 mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, lOOmg / kg, 150mg / kg, 180mg / kg, or 200 mg / kg.

[0197] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the composition provided herein, including further embodiments in which (i) the compound is administered once a day; (ii) the composition provided herein is administered to the patient twice in the one day, or (iii) the composition provided herein is administered to the patient multiple times over the span of one day.

[0198] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the composition or compounds provided herein, including further embodiments in which (i) the composition or compounds provided herein is administered continuously or intermittently as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the composition or compounds provided herein is administered to the patient every 8 hours; (iv) the composition or compounds provided herein is administered to the patient every 12 hours; (v) the composition or compounds provided herein is administered to the patient every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the composition provided herein is temporarily suspended or the dose of the composition provided herein being administered is temporarily reduced; at the end of the drug holiday, dosing of the composition provided herein is resumed. In one embodiment, the length of the drug holiday varies from about 2 days to 1 year.

[0199] The term "unit dose" when used in reference to a composition refers to physically discrete units suitable as unitary dosage for humans, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent; i.e., carrier, or vehicle.

[0200] In certain instances, it is appropriate to administer composition or compounds provided herein described herein, in combination with one or more other therapeutic agents.

[0201] In one embodiment, the therapeutic effectiveness of one of the composition provided herein described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the composition provided herein described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0202] In one specific embodiment, an composition or compounds provided herein described herein is co-administered with a second therapeutic agent, wherein the composition or compounds provided herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0203] In certain embodiments, it would be understood that any of the methods described herein could be combined with one or more additional therapies for the ophthalmic disease including, but are not limited to, laser therapy (e.g., focal or grid laser photocoagulation or focal laser treatment or scatter (pan-retinal) laser photocoagulation or scatter laser treatment), cryotherapy, fluorescein angiography, vitrectomy, corticosteroids (e.g., intravitreal triamcinolone acetonide), Anti-vascular endothelial growth factor (VEGF) treatment (e.g., Pegaptanib (Macugen; Pfizer, Inc., New York, USA), Ranibizumab (Lucentis; Genentech, Inc., South San Francisco, California, USA), Bevacizumab (Avastin; Genentech, Inc.), and VEGF Trap-Eye (Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA)), vitrectomy for persistent diffuse diabetic macular edema, pharmacologic vitreolysis in the management of diabetic retinopathy, fibrates, renin- angiotensin system (ras) blockers, peroxisome proliferator-activated receptor gamma (PPAR-y) agonists, AntiProtein Kinase C (Ruboxistaurin), Islet cell transplantation; Therapeutic Oligonucleotides, Growth hormone and insulin growth factor(IGF), and control of systemic factors.

[0204] In certain embodiments, the methods described herein could be combined with one or more additional therapies for diabetes including, but are not limited to, acamprosate, almitrine, amlexanox, azelastine, baclofen, carbetapentane, cinacalcet, dexbromophenir amine, diethylcarbamazine, D- mannose, fenspiride, fexofenadine, ifenprodil, mexiletine, nicergoline, tolperisone, torasemide, triamterene, tolfenamic acid, piribedil, levosimendan, cimetidine, diprophylline, idebenone and rilmenidine, acarbose, acetohexamide, alogliptin, berberine, bezafibrate, bromocriptine, buformin, carbutamide, chlorpropamide, chromium picolinate, ciprofibrate, clofibrate, colesevelam, dexfenfluramine, dutogliptin, exenatide, fenofibrate, gemfibrozil, gemigliptin, glibenclamide, glibornuride, glicetanile, gliclazide, glimepiride, glipizide, gliquidone, glisentide, glyclopyramide, imidapril, insulin, inulin, lipoic acid, linagliptin, liraglutide, mecobalamin, metformin, miglitol, mitiglinide, nateglinide, orlistat, phenformin, pioglitazone, pramlintide, repaglinide, rosiglitazone, saxagliptin, sitagliptin, tolazamide, tolbutamide, vildagliptin and voglibose, as well as to the use of such compositions in the treatment of diabetes or a related disorder in a mammalian in need thereof.

[0205] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply be additive of the two therapeutic agents or the patient experiences a synergistic benefit.

[0206] In certain embodiments, different therapeutically-effective dosages of the compounds in the composition provided herein will be utilized in formulating pharmaceutical composition and / or intreatment regimens when the composition provided herein disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention / treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of an composition provided herein described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which an composition provided herein described herein and the second agent being used in combination are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.

[0207] It is understood that the dosage regimen to treat, prevent, or ameliorate the disease(s) for which relief is sought, is modified in accordance with a variety of factors (e.g. the disease or disorder from about which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from about the dosage regimens set forth herein.

[0208] For combination therapies described herein, dosages of the co-administered composition provided herein vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the composition provided herein provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.

[0209] In combination therapies, the multiple therapeutic agents (one of which is the composition provided herein described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).

[0210] The composition described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the formulation containing a compound varies. Thus, in one embodiment, the composition provided herein described herein is used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the composition provided herein is administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a composition provided herein described herein is administered as soon as ispracticable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.

[0211] In certain embodiments, the improvements resulting from the administration of the compounds or compositions provided herein sustained during the course of treatment or prevention.EXAMPLESExample 1: In Vivo Effects of Compound I in Treating Diabetes

[0107] Studies will be conducting using a bead-based model of rodent diabetic retinopathy (Db / Db mice) with systemic delivery of Compound 1. A total of 50 animals will be included: a. 15 Db / Db mice with administration of study drug vehicle b. 15 Db / Db mice with administration of Compound 1 c. 10 Db / + control mice with administration of study drug vehicle d. 10 DB / + control mice with administration of Compound 1

[0108] Compound 1 will be administered by an intraperitoneal route at a dose of 30 mg / kg. Data will be provided from mice at ~24 weeks of age after starting treatment at ~16 weeks (total: 8-week treatment time). It is contemplated that the following measurements will be taken: i. Blood sugar (at ~16 and 20 week timepoints) ii. Glucose tolerance test (at ~16 and 20 week timepoints) iii. Insulin tolerance test (at ~16 and 20 week timepoints).Example 2: In Vivo Effects of Compound I on Diabetes Mellitus Related Retinal Complications

[0212] An in vivo study was conducted using Db / Db mice to evaluate the protective effect of Compound 1 on diabetes mellitus related retinal complications.

[0213] Mice received intraperitoneal (IP) daily injections of Compound 1 for eight weeks, beginning at 16 weeks of age and concluding at 24 weeks. Compound 1 was administered at a concentration of 30 milligrams per kilogram body weight, dissolved in PBS containing 2% DMSO (vehicle). Control mice received daily IP injections of the vehicle solution (PBS with 2% DMSO) alone.• Cohort 1: Db / Db mice (diabetic model, 10 mice, started with 15 mice) were administered with Compound 1.• Cohort 2: Db / Db mice (12 mice, started with 15 mice) were administered with vehicle.• Cohort 3: DB / + mice (control, 8 mice, started with 8 mice) were administered with Compound 1.• Cohort 4: DB / + mice (2 mice, started with 8mice) were administered with vehicle.

[0214] All animals were housed and handled under lACUC-approved protocols. Metabolic data were collected, after which the animals were sacrificed and their eyes harvested for subsequent analyses.Metabolic Assessments

[0215] Body Weight Monitoring (FIGS. 1A-1B). Weekly body weights were recorded throughout the treatment period. No significant differences were observed between Compound 1 treated Db / Db and Db / + mice (control). Body weight remained stable, and Compound 1 treatment did not adversely affect weight gain or loss patterns.

[0216] Basa Blood Glucose Levels (FIGS. 2A-2B). Fasting blood glucose was measured at baseline and during the treatment period. Db / Db mice exhibited elevated blood glucose levels compared to Db / + mice. Compound 1 treatment did not significantly altered basal glucose levels in either group.

[0217] Glucose Tolerance Test (GTT) (FIGS. 3A-3B). A single GTT was performed during the treatment. In consultation with the attending veterinarian, repeated testing was avoided due to the poor health and high baseline glucose levels of the Db / Db mice. GTT curves indicated no improvement in the glucose clearance with Compound 1 treatment. Area under the curve (AUC) analysis confirmed no significant differences.

[0218] Insulin Tolerance Test (ITT) (FIGS. 4A-4B). Similarly, a single ITT was performed. Compound 1 treatment did not improve insulin sensitivity. Db / Db mice exhibited insulin resistance, and treatment did not ameliorate this phenotype.

[0219] Survival Outcomes (FIGS. 5A-5C). A reduction in survival was observed among Compound 1 treated Db / Db mice (re-constituted Compound 1 was administered via IP injections). This finding contrasts with prior studies and human clinical trials, suggesting that the decreased survival may be specific to this particular mouse model.Analyses of the Eye

[0220] FIGS. 6A-6B demonstrate that loss of inner retinal ganglion cells (RGCs) was observed in Db / Db mice, and treatment with Compound 1 mitigated this loss.

[0221] FIG. 7 demonstrates that loss of pattern electroretinography (pERG) responses and delayed visual evoked potentials (VEP) were observed in Db / Db mice. Treatment with Compound 1 mitigated these effects.

[0222] FIG. 8 demonstrates that loss of synaptic markers in retina was observed in Db / Db mice, and treatment with Compound 1 promotes these markers.

[0223] FIG. 9 demonstrates that loss of PSD95 (FIG. 9A) and synaptophysin (FIG. 9B) in the inner plexiform layer (IPL) was observed in Db / Db mice, and treatment with Compound 1 reduced these effects.

[0224] Without being bound by theory, it is believed that glial cell activation (or GFAP expression) represent a stress response under disease conditions. FIGS. 10A-10B demonstrates that glial cell activation (or GFAP expression) was observed in Db / Db mice, and treatment with Compound 1 reversed this effect.

[0225] Without being bound by theory, it is believed that Bcl-XL inhibits cell death, while Bax and pBad promote cell death. FIG. 11A demonstrates that increased Bax and pBad were observed in Db / Db mice, and treatment with Compound 1 suppressed these effects. Additionally or alternatively, FIG. 11A shows that decreased Bcl-XL was observed in Db / Db mice, and treatment with Compound 1 reversed this effect. FIG. 11B further supports the effect on Bax through immunofluorescence imaging.* * *

[0226] The present disclosure is not to be limited in scope by the specific embodiments described which are intended as single illustrations of individual aspects of the disclosure, and any compositions or methods which are functionally equivalent are within the scope of this disclosure. It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present disclosure without departing from about the spirit or scope of the disclosure. Thus, it is intended that the present disclosure cover the modifications and variations of this disclosure provided they come within the scope of the appended claims and their equivalents.

[0227] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

CLAIMS1. A method of treating or preventing diabetes mellitus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I or la:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscripts n and p are independently selected from 0, 1 or 2; each R1is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro;A is an arylene or heteroarylene, having 1 to 4 heteroatoms;W is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;X is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is as defined above, provided that when A is arylene, and Y is -S- or -NR2-, then X is not -S-;Y is selected from the group consisting of -O-, -S-, -SO-, S(O)2-, and -NR2-, wherein R2is as defined above; andZ is selected from the group consisting of -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R3)O)q-T, wherein subscript q is an integer from 1 to 100, R3is selected from the group consisting of hydrogen and methyl, and T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L-monosaccharide, and -L-oligosaccharide, wherein L is selected from the group consisting of a bond, phosphate, and sulfate.

2. The method of claim 1 , wherein A is phenylene or pyridylene in the compound of formula I or la.

3. The method of claim 1 , wherein X is S in the compound of formula I.

4. The method of claim 1 , wherein Y is -0- in the compound of formula I or la.

5. The method of claim 1, wherein X is S, Y is -O-, and A is phenylene in the compound of formula I.

6. The method of claim 1 , wherein the compound of formula I is a compound of formula Ik:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscripts n and p are each independently 0, 1 or 2; subscript q is an integer from 2 to 8; and each R41and each R42are independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro.

7. The method of claim 6, wherein each of subscripts n and p is 0.

8. The method of claim 1, wherein the compound is:Compound 1 or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

9. A method of treating or preventing diabetes mellitus in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula II:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein:Y is -NR33- or -S-; each R31is independently halogen, -CX31, -CHX31, -CH2X51. -OCX313, -OCHX312, -OCH2X31, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,- C(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl,heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; each R32is independently halogen, -CX323, -CHX322, -CH2X32, -OCX323, -OCHX322, -OCH2X32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R33is H, alkyl, or substituted alkyl; each of X31and X32is independently halogen; each of zl and z2 is independently an integer from 0 to 4; and z3 is an integer from 1 to 12.

10. The method of claim 9, wherein Y is S.

11. The method of claim 9, wherein each of zl and z2 is 0.

12. The method of claim 9, wherein the compound of formula II is:or a pharmaceutically acceptable salt or solvate thereof.

13. The method of claim 9, wherein Y is NH.

14. The method of claim 9, wherein zl is 1 , z2 is 0, and R31is alkyl.

15. The method of claim 9, wherein the compound is:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

16. The method of any one of claims 1-15, wherein the diabetes mellitus is type I diabetes or type II diabetes, gestational diabetes mellitus, congenital diabetes, cystic fibrosis-related diabetes, steroid diabetes, or several forms of monogenic diabetes.

17. The method of any one of claims 1-16, wherein the subject is middle aged or elderly subject.

18. The method of any one of claims 1-17, wherein the subject suffers from diabetes mellitus without symptom of retinopathy.

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