WO2019173505A1

WO2019173505A1 - Methods of treating disorders related to glycemic control

Info

Publication number: WO2019173505A1
Application number: PCT/US2019/021002
Authority: WO
Inventors: James E. Vath; Bryan Burkey
Original assignee: Zafgen, Inc.
Priority date: 2018-03-06
Filing date: 2019-03-06
Publication date: 2019-09-12

Abstract

Disclosed herein, in part, are methods for treating a patient in need of glycemic control, and/or treating a metabolic disorder in a patient in need thereof, comprising: administering a MetAP-2 inhibitor; and administering a GLP-1 agonist such as liraglutide.

Description

METHODS OF TREATING DISORDERS RELATED TO GLYCEMIC CONTROL

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Application No. 62/639,323, filed March 6, 2018, the content of which is hereby incorporated by reference in its entirety.

BACKGROUND

[0002] MetAP-2 encodes a protein that functions at least in part by enzymatically removing the amino terminal methionine residue from certain newly translated proteins such as glyceraldehyde-3 -phosphate dehydrogenase (Warder el al. (2008) J. Proteome Res. 7:4807). Increased expression of the MetAP-2 gene has been historically associated with various forms of cancer. Molecules inhibiting the enzymatic activity of MetAP-2 have been identified and have been explored for their utility in the treatment of various tumor types (Wang et al. (2003) Cancer Res. 63:7861) and infectious diseases such as microsporidiosis, leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed. Sci. 9:34). Notably, inhibition of MetAP-2 activity in obese and obese-diabetic animals leads to a reduction in body weight in part by increasing the oxidation of fat and in part by reducing the consumption of food (Rupnick et al. (2002) Proc. Natl. Acad. Sci. USA 99: 10730).

[0003] Such MetAP-2 inhibitors may be useful as well for patients with excess adiposity and conditions related to adiposity including type 2 diabetes, hepatic steatosis, and

cardiovascular disease (via e.g. ameliorating insulin resistance, reducing hepatic lipid content, and reducing cardiac workload). For example, over 1.1 billion people worldwide are reported to be overweight.

[0004] Glucagon-like peptide-l receptor agonists (also known as GLP-l receptor agonists or incretin mimetics) are agonists of the glucagon-like peptide-l (GLP-) receptor. A representative GLP-l agonist is liraglutide, a derivative of human incretin (metabolic hormone) binding to the same receptors as endogenous metabolic hormone GLP-l thereby stimulating insulin secretion.

[0005] There is an ongoing need for methods that can effectively treat metabolic disorders including obesity (and/or co-morbidities thereof), type II diabetes, nonalcoholic

steatohepatitis, nonalcoholic fatty liver disease, and cardiometabolic disease. SUMMARY

[0006] The present disclosure provides, for example, methods that include administering both a MetAP-2 inhibitor and a glucagon-like peptide- 1 receptor agonist. In particular this disclosure relates to methods of treatment that includes co-administration of MetAP-2 inhibitor and a glucagon-like peptide- 1 receptor agonist for the treatment of e.g, obesity, type 2 diabetes, and/or other obesity-associated conditions.

[0007] For example, provided herein is a method for treating a patient in need of glycemic control and/or treating a metabolic disorder in a patient in need thereof, comprising:

administering a MetAP-2 inhibitor to the patient; and administering a GLP-l agonist (and/or a DPP-4 inhibitor) to the patient; wherein the the MetAP-2 inhibitor and the GLP-l agonist are each administered in an amount that together provides an effective amount for the treatment. The MetAP-2 inhibitor and the GLP-l agonist may be administered together in the same dosage dosage form, or in separate dosage forms.

[0008] Contemplated GLP-l agonists may selected from the group consisting of:

liraglutide, dulaglutide, lixisenatide, albiglutide, semaglutide, taspoglutide and exenatide, for example, liraglutide.

[0009] Exemplary MetAP-2 inhibitors are provided herein, for example, a contemplated MetAP-2 inhibitor may be a fumagillin analog such as (3R,4S,5S,6R)-5-methoxy-4- ((2R,3R)-2-methyl-3-(3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 3-(2- morpholinoethyl)azetidine-l-carboxylate or a pharmaceutically acceptable salt or stereoisomer thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 depicts the absolute body weight in a rat model using a MetAP-2 inhibitor and liraglutide. Values are expressed as mean of n = 10 + SEM. Two-way ANOVA with Dunnett’s post-hoc test. *p < 0.05, ** p < 0.01, *** p < 0.001 compared to Veh. 1 + veh. 2.

[0011] FIG. 2 depicts body weight change in a rat model using a MetAP-2 inhibitor and liraglutide. Values are expressed as mean of n = 10 + SEM. Two-way ANOVA with

Dunnett’s post-hoc test. ***p < 0.001 compared to Veh. 1 + veh. 2.

[0012] FIG. 3 shows the 4 hr fasted blood glucose level 1 day before and 1, 3, and 5 weeks after dosing the compounds in a rat model using a MetAP-2 inhibitor and liraglutide. Values are expressed as mean of n = 10 + SEM. Two-way ANOVA with Dunnett’s post-hoc test. ** p < 0.01, *** p < 0.001 compared to Veh. 1 + veh. 2.

[0013] FIG. 4 depicts blood glucose level in 240 min after glucose was dosed PO at 0 min in a rat model using a MetAP-2 inhibitor and liraglutide. Compounds are dosed at -60 min and glucose is dosed PO at 0 min. Values are expressed as mean of n = 10 + SEM. Two-way ANOVA of last with Dunnett’s post-hoc test. *p < 0.05, ** p < 0.0l, *** p < 0.001 compared to Veh. 1 + veh. 2.

[0014] FIG. 5 depicts OGTT AETC blood glucose after dosing compounds in a rat model using a MetAP-2 inhibitor and liraglutide. Values are expressed as mean of n = 10 + SEM. Two-way ANOVA of last with Dunnett’s post-hoc test. *p < 0.05, *** p < 0.001 compared to Veh. 1 + veh. 2.

[0015] FIG. 6A depicts food intake on a DIO diet. FIG. 6B depicts food intake on a chow diet. Values are expressed as mean of n = 10 + SEM. Two-way ANOVA with Tukey’s post- hoc test (compare all groups - only significances on the last day of treatment are indicated). * p < 0.05 compared to Veh. 1 + veh. 2. &&& p < 0.001 compared to Veh. 1 + veh. 2 (chow).

[0016] FIG. 7 depicts total liver weight. Values are expressed as mean of n = 10 + SEM. Two-way ANOVA with Tukey’s post-hoc test (compare all groups). * p < 0.05, *** p <

0.001 compared to Veh. 1 + veh. 2. && p < 0.01 compared to Veh. 1 + veh. 2 (chow).

[0017] FIG. 8 depicts the change in relative body weight following administration of vehicle, compound A, liraglutide alone, and the co-administration of compound A and liraglutide.

DETAILED DESCRIPTION

[0018] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0019] Provided herein is a method for treating a patient (e.g. a human patient) in need of glycemic control and/or a method of treating a metabolic disorder in a patient in need thereof, comprising: administering a pharmaceutically acceptable amount of a MetAP-2 inhibitor; and administering a pharmaceutically acceptable amount of a GLP-l agonist; wherein the pharmaceutically acceptable amount of the MetAP-2 inhibitor and the pharmaceutically acceptable amount of the GLP-l agonist provides an effective amount for the treatment.

[0020] Such GLP-l agonists that form part of contemplated co-administration may be selected, for example, from the group consisting of: liraglutide, dulaglutide, lixisenatide, albiglutide, semaglutide, taspoglutide and exenatide. For example, in some embodiments, the GLP-l agonist is liraglutide, and the MetAP-2 inhibitor is a compound disclosed herein.

Definitions

[0021] “Treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0022] The phrase“combination therapy,” as used herein, refers to co-administering an MetAP-l inhibitor, such as disclosed herein, and a GLP-l agonist, for example, liraglutide, as part of a specific treatment regimen intended to provide the beneficial effect from the co action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the

combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually weeks, months or years depending upon the combination selected). Combination therapy is intended to embrace administration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. [0023] Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non drug therapies. Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[0024] The components of the combination may be administered to a patient

simultaneously or sequentially. It will be appreciated that the components may be present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients may be present in separate pharmaceutical carriers, such as, conventional oral dosage forms, that can be administered either simultaneously or sequentially.

[0025] The term“alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C2-6alkenyl, and C3-4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0026] The term“alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as Cl-6alkoxy, and C2-6alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

[0027] The term“alkoxyalkyl” as used herein refers to a straight or branched alkyl group attached to oxygen, attached to a second straight or branched alkyl group (alkyl-O-alkyl-). Exemplary alkoxyalkyl groups include, but are not limited to, alkoxyalkyl groups in which each of the alkyl groups independently contains 1-6 carbon atoms, referred to herein as Cl- 6alkoxy-Cl-6alkyl. Exemplary alkoxyalkyl groups include, but are not limited to

methoxymethyl, 2-methoxyethyl, l-methoxyethyl, 2-methoxypropyl, ethoxym ethyl, 2- isopropoxy ethyl etc. [0028] The term“alkyoxycarbonyl” as used herein refers to a straight or branched alkyl group attached to oxygen, attached to a carbonyl group (alkyl-O-C(O)-). Exemplary alkoxycarbonyl groups include, but are not limited to, alkoxycarbonyl groups of 1-6 carbon atoms, referred to herein as Cl-6alkoxycarbonyl. Exemplary alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.

[0029] The term“alkenyloxy” used herein refers to a straight or branched alkenyl group attached to oxygen (alkenyl-O-). Exemplary alkenyloxy groups include, but are not limited to, groups with an alkenyl group of 3-6 carbon atoms, referred to herein as C3-6alkenyloxy. Exemplary“alkenyloxy” groups include, but are not limited to allyloxy, butenyloxy, etc.

[0030] The term“alkynyloxy” used herein refers to a straight or branched alkynyl group attached to oxygen (alkynyl-O). Exemplary alkynyloxy groups include, but are not limited to, groups with an alkynyl group of 3-6 carbon atoms, referred to herein as C3-6alkynyloxy. Exemplary alkynyloxy groups include, but are not limited to, propynyloxy, butynyloxy, etc.

[0031] The term“alkyl” as used herein refers to a saturated straight or branched

hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Cl-6alkyl, Cl-4alkyl, and Cl -3 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -butyl, 3-methyl-2-butyl, 2-methyl- 1 -pentyl, 3-methyl-l- pentyl, 4-methyl- 1 -pentyl, 2-methyl-2-pentyl, 3 -methyl -2 -pentyl, 4-methyl-2-pentyl, 2,2- dimethyl- 1 -butyl, 3,3-dimethyl-l-butyl, 2-ethyl- 1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0032] The term“alkylcarbonyl” as used herein refers to a straight or branched alkyl group attached to a carbonyl group (alkyl -C(O)-). Exemplary alkylcarbonyl groups include, but are not limited to, alkylcarbonyl groups of 1-6 atoms, referred to herein as Cl-6alkylcarbonyl groups. Exemplary alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, etc.

[0033] The term“alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-6alkynyl, and C3-6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl,

methylpropynyl, etc. [0034] The term“carbonyl” as used herein refers to the radical -C(O)-.

[0035] The term“cyano” as used herein refers to the radical -CN.

[0036] The term“cycloalkoxy” as used herein refers to a cycloalkyl group attached to oxygen (cycloalkyl-O-). Exemplary cycloalkoxy groups include, but are not limited to, cycloalkoxy groups of 3-6 carbon atoms, referred to herein as C3-6cycloalkoxy groups.

Exemplary cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclohexyl oxy, etc

[0037] The terms“cycloalkyl” or a“carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C3-6cycloalkyl or C4-6cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

[0038] The terms“halo” or“halogen” as used herein refer to F, Cl, Br, or I.

[0039] The terms“heteroaryl” or“heteroaromatic group” as used herein refers to a monocyclic aromatic 5-6 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine etc.

[0040] The terms“heterocyclyl” or“heterocyclic group” are art-recognized and refer to e.g. saturated or partially unsaturated, 4-10 membered monocyclic or bicyclic ring structures, or e.g. 4-9 or 4-6 membered saturated ring structures, including bridged, fused or spirocyclic rings, and whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc.

[0041] The term“heterocyclyloxy” as used herein refers to a heterocyclyl group attached to oxygen (heterocyclyl -0-).

[0042] The term“heteroaryloxy” as used herein refers to a heteroaryl group attached to oxygen (heteroaryl-O-). [0043] The terms“hydroxy” and“hydroxyl” as used herein refers to the radical -OH.

[0044] The term“oxo” as used herein refers to the radical =0.

[0045] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0046] The term“pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0047] The term“pharmaceutical composition” as used herein refers to a composition comprising at least one compound (e.g., a MetAP-2 inhibitor) as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0048] “ Individual,”“patient,” or“subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The pharmaceutical compositions of the present disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). The mammal treated in the methods of the present disclosure is desirably a mammal in which treatment of obesity or weight loss is desired. “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.

[0049] In the present specification, the term“therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g. mammal or human) that is being sought by the researcher,

veterinarian, medical doctor or other clinician. The pharmaceutical compositions of the present disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a pharmaceutical composition is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in weight loss.

[0050] The term“pharmaceutically acceptable salt(s)” as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions.

Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l,r-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0051] The compounds included in the compositions of the present disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term“stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols“(+),”

“R” or“S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated“(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. [0052] The compounds included in the compositions of the present disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol ^. denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the“Z” or Έ” configuration wherein the terms“Z” and Έ” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the“ E” and“Z” isomers.

Substituents around a carbon-carbon double bond alternatively can be referred to as“cis” or “trans,” where“cis” represents substituents on the same side of the double bond and“trans” represents substituents on opposite sides of the double bond.

[0053] Compounds included in the compositions of the present disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the“Z” or“E” configuration wherein the terms“Z” and“E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and“E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as“cis” or“trans”, where the term“cis” represents substituents on the same side of the plane of the ring and the term“trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated“cis/trans.”

[0054] Individual enantiomers and diasteriomers of compounds included in the

compositions of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0055] The compounds included in the compositions of the present disclosure can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the present disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0056] The present disclosure also embraces isotopically labeled compounds included in the compositions of the present disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0057] Certain isotopically-labeled disclosed compounds (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-l4 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. I. MetAP-2 Inhibitors

[0058] In certain embodiments, a contemplated MetAP-2 inhibitor included in the methods of the present disclosure may be an irreversible inhibitor. In certain embodiments, the irreversible inhibitor may covalently bind, for example, to His23 l of MetAP-2 via, e.g., a spiro epoxide moiety present on the irreversible inhibitor.

[0059] For example, a contemplated MetAP-2 inhibitor included in the methods of the present disclosure may be an analog of, e.g., fumagillin.

[0060] In certain embodiments, a contemplated MetAP-2 inhibitor included in the methods of the present disclosure may be represented by:

wherein R¹ may selected from Ci_-8alkylene, C_2-8alkenylene, heterocyclyl, C3_-6cycloalkyl, - NR^a- Ci_-8alkylene, -NR^a-C_2-8alkenylene, and -NR^a- C_3-6cycloalkyl; wherein R¹ may be substituted by a substituent selected from the group consisting of: carboxy, -0-C(0)-NR^aR^b , -C(0)-0- Ci_-6alkyl, phenyl (optionally substituted by substituent selected from NR^aR^b), Ci. ₆alkoxy (optionally substituted by a substituent selected from the group consisting of NR^aR^b, Ci_-6alkyl, carboxy, and heterocyclyl)), Ci_-6alkylene (optionally substituted by hydroxyl, heterocyclyl, NR^aR^b, carboxy, and -C(0)-0- Ci_-6alkyl); wherein R^a and R^b are each independently selected from hydrogen and Ci_-6alkyl, or R^a and R^b together with the nitrogen to which they are attached may form a 4-7 membered heterocyclic ring; and pharmaceutically acceptable salts, stereoisomers, esters and prodrugs thereof.

[0061] In certain other embodiments, a contemplated MetAP-2 inhibitor included in the methods of the present disclosure may be represented by Formula II:

(P); wherein:

R¹ and R², together with the nitrogen to which they are attached, form a 4-6 membered saturated heterocyclic ring A, or a 6-8 membered bicyclic, fused, bridged or spirocyclic heterocyclic ring A, where ring A which may have an additional heteroatom selected from the group consisting of O, S(0)_w (wherein w is 0, 1, or 2), and NR^a;

heterocyclic ring A is substituted on an available carbon by a substituent represented by L-B; and wherein heterocyclic ring A is additionally and optionally substituted by one or two substituents each independently selected from the group consisting of halogen, hydroxyl, Ci-3alkyl and Ci_-3alkoxy; wherein Ci_-3alkyl and Ci_-3alkoxy may optionally be substituted by one or more fluorine atoms or a substituent selected from the group consisting of cyano, hydroxyl, and N(R^aR^b);

L is selected from the group consisting of Ci_-6alkylene and Ci_-6alkenylene; wherein Ci_-6alkylene and Ci-₆alkenylene may optionally be substituted by one or two substituents each independently selected from the group consisting of halogen and hydroxyl; and wherein one or two methylene units of L may optionally and independently be replaced by a moiety selected from the group consisting of a bond, -O-, -C(O)-, -O-C(O)-, -C(0)-0-, -NR^a-, -C(O)- NR^a-, -NR^a-C(0)-, -0-C(0)-NR^a-, -NR^a-C(0)-0-, -S(0)_w- (wherein w is 0, 1, or 2), -S(0)_w- NR^a-, and -NR^a-S(0)_w- ;

B is selected from the group consisting of R‘R^JN-, heterocyclyl, heterocyclyloxy, heteroaryl, heterocyclyl-(NR^a)-, and hydrogen; wherein said heteroaryl may optionally be substituted with one or more substituents selected from R ; and wherein said heterocyclyl is bound to L through a ring carbon and may optionally be substituted by one or more substituents selected from R^s; and wherein if said heterocyclyl contains a -NH moiety that nitrogen may optionally be substituted by R^h;

R¹ and R are selected independently for each occurrence from the group consisting of hydrogen, Ci_-6alkyl, C_2-6alkenyl, C_3-6cycloalkyl, heterocyclyl and heterocyclylcarbonyl; wherein Ci_-6alkyl, C2_-6alkenyl and C_3-6Cycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of fluorine, hydroxyl, cyano, R^aR^bN-, R^aR^bN-carbonyl- and Ci_-3alkoxy; and wherein heterocyclyl and

heterocyclylcarbonyl may be optionally substituted by one or more substituents

independently selected from the group consisting of Ci_-6alkyl, C2_-6alkenyl, C2_-6alkynyl, C_3- ₆cycloalkyl, Ci_-6alkoxy, halo-Ci_-6-alkyl, hydroxyl-Ci_-6-alkyl, R^aR^bN-Ci_-6alkyl- and Ci_-6- alkoxy-Ci-₆-alkyl group; and wherein if said heterocyclyl or heterocyclylcarbonyl contains a - NH moiety that nitrogen may optionally be substituted by one or more groups independently selected from the group consisting of Ci_-6alkyl, C_3-6alkenyl, C_3-6alkynyl, C_3-6cycloalkyl, Ci. ₆alkyl-S(0)₂- and Ci_-6-alkylcarbonyl; or R¹ and R^J taken together with the nitrogen to which they are attached form a 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ring, which may have an additional heteroatom selected from the group consisting of O, N, and S(0)_w (wherein w is 0, 1 or 2); wherein the 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ring may be optionally substituted on carbon by one, two, or more substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, Ci_-6alkyl, Ci_-6alkoxy, R^aR^bN-, R^aR^bN-S0₂- and R^aR^bN-carbonyl-; wherein said Ci. ₆alkyl or Ci_-6alkoxy may optionally be substituted the group consisting of fluorine, hydroxyl, and cyano; and wherein if said 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ring contains a -NH moiety that nitrogen may be optionally substituted by a substituent selected from the group consisting of hydrogen, Ci_-6alkyl, C_3- ₆alkenyl, C_3-6alkynyl, C_3-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci-₆alkylcarbonyl-, Ci.

6alkoxycarbonyl-, R'R'N-carbonyl- and R¹R^JN-S0₂-; wherein Ci_-6alkyl, C_3-6alkenyl, C_3- ₆alkynyl, C_3-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci_-6alkylcarbonyl-, and Ci_-6alkoxycarbonyl- may optionally be substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, and cyano;

R^a and R^b are independently selected, for each occurrence, from the group consisting of hydrogen and Ci_-3alkyl; wherein Ci_-3alkyl may optionally be substituted by one or more substituents selected from halogen, cyano, oxo and hydroxyl;

f p

R is independently selected, for each occurrence, from the group consisting of R , hydrogen, Ci_-6alkyl, C_3-6cycloalkyl, C_2-6alkenyl, C_2-6alkynyl, Ci_-6alkoxy, Ci-₆alkyl-S(0)_w-, (wherein wherein w is 0, 1 or 2), Ci_-6alkylcarbonyl-N(R^a)- and Ci_-6alkoxycarbonyl-N(R^a)-; wherein Ci_-6alkyl, C_3-6cycloalkyl, C_2-6alkenyl, C_2-6alkynyl, Ci_-6alkoxy, Ci_-6alkyl-S(0)_w-, Ci. ₆alkylcarbonyl-N(R^a)-, Ci_-6alkoxycarbonyl-N(R^a)- may be optionally substituted by one or more substituents selected from R^p;

R^s is independently selected for each occurrence from the group consisting of R^P, hydrogen, oxo, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, Ci_-6alkoxy, Ci_-6alkyl- S(0)_w- (wherein w is 0, 1 or 2), Ci_-6alkylcarbonyl-N(R^a)- and Ci_-6alkoxycarbonyl-N(R^a)-; wherein Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, Ci_-6alkoxy, Ci_-6alkyl-S(0)_w-, Ci. ₆alkylcarbonyl-N(R^a)-, and Ci_-6alkoxycarbonyl-N(R^a)- may be optionally substituted by one or more substituents selected from R^p;

R^h is independently selected for each occurrence from the group consisting of hydrogen, Ci_-6alkyl, C3_-6alkenyl, C3_-6alkynyl, C3_-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci.

6alkylcarbonyl-, Ci_-6alkoxycarbonyl-, R'R'N-carbonyl- and R¹R^JN-S0₂-; wherein Ci_-6alkyl, C3_-6alkenyl, C3_-6alkynyl, C3_-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci_-6alkylcarbonyl-, and Ci.

6alkoxycarbonyl- may optionally be substituted by one or more substituents selected from R^p; and

R^p is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, cyano, Ci_-6alkoxy, R'R'N-, R'R'N-carbonyl-, R'R'N-SCf-, and R'R'N- carbonyl-N(R^a); and pharmaceutically acceptable salts, stereoisomers, esters and prodrugs thereof.

[0062] Other contemplated MetAP-2 inhibitors include those represented by Formula III or Ilia:

wherein:

^ is a single or double bond;

Y is a bond or NR^a;

X is N or CRⁿ; wherein X is N when Y is a bond and X is CR^N when Y is NR^a; n is 0 or 1; m is 1 or 2;

Ring A may be optionally substituted by one or two substituents each independently selected from the group consisting of halogen, hydroxyl, Ci-3alkyl and Ci-3alkoxy, wherein Ci_-3alkyl and Ci_-3alkoxy may optionally be substituted by one or more fluorine atoms or a substituent selected from the group consisting of cyano, hydroxyl, and N(R^aR^b); R¹ and R², together with the carbon or carbons to which they are attached, form a 4-6 membered saturated heterocyclic ring B having one or two heteroatoms selected from the group consisting of O, S(0)_w (wherein w is 0, 1 or 2) and NR^h or form a 3-6 membered saturated carbocyclic ring B; wherein the heterocyclic or carbocyclic ring B may optionally be substituted on a free carbon by one or two substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, Ci_-3alkyl, Ci_-3alkoxy, -C(0)-NR¹R^J, -C(O)- N^-Ci-ealkylene-M^R, -Cu_f.alkylene-NR'R¹, -C^alkylene-O-CCOj-NR'R, and -O-C(O)- NR¾^j; wherein Ci_-3alkyl, Ci_-3alkoxy, -C(0)-NR'R^J, -C(0)-N(R^a)-Ci_-6alkylene-NRⁱR^j, -Ci. ₆alkylene-NR'R^J, -Ci_-6alkylene-0-C(0)-NR¹Rⁱ, and -0-C(0)-NR'R^J may optionally be substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl, or N(R^aR^b);

R¹ and R are selected independently for each occurrence from the group consisting of hydrogen, Ci_-6alkyl, C2_-6alkenyl, C_3-6cycloalkyl, heterocyclyl and heterocyclylcarbonyl; wherein Ci_-6alkyl, C2_-6alkenyl and C_3-6cycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of fluorine, hydroxyl, cyano, R^aR^bN-, R^aR^bN-carbonyl- and Ci_-3alkoxy; and wherein heterocyclyl and

heterocyclylcarbonyl may be optionally substituted by one or more substituents

independently selected from the group consisting of Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3- ₆cycloalkyl, Ci_-6alkoxy, halo-Ci_-6-alkyl, hydroxyl-Ci_-6-alkyl, R^aR^bN-Ci_-6alkyl- and Ci_-6- alkoxy-C_l-6-alkyl; and wherein if said heterocyclyl or heterocyclylcarbonyl contains a -NH moiety that nitrogen may optionally be substituted by one or more groups independently selected from the group consisting of Ci_-6alkyl, C_3-6alkenyl, C_3-6alkynyl, C_3-6cycloalkyl, Ci. ₆alkyl-S(0)₂- and Ci_-6-alkylcarbonyl; or R¹ and R^J taken together with the nitrogen to which they are attached form a 4-9 membered heterocyclic ring, which may have an additional heteroatom selected from the group consisting of N, O, and S(0)_w (wherein w is 0, 1 or 2); wherein the heterocyclic ring may be optionally substituted on carbon by one, two, or more substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, Ci_-6alkyl, Ci_-6alkoxy, R^aR^bN-, R^aR^bN- S0₂- and R^aR^bN-carbonyl-; wherein said Ci_-6alkyl and Ci_-6alkoxy may optionally be substituted the group consisting of fluorine, hydroxyl, and cyano; and wherein if said heterocyclic ring contains a -NH moiety that nitrogen may be optionally substituted by a substituent selected from the group consisting of hydrogen, Ci_-6alkyl, C_3-6alkenyl, C_3- ₆alkynyl, C_3-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci_-6alkylcarbonyl-, Ci_-6alkoxycarbonyl-, R'R'N- carbonyl- and R^N-SC ; wherein Ci_-6alkyl, C_3-6alkenyl, C_3-6alkynyl, C_3-6cycloalkyl, Ci. ₆alkyl-S(0)₂-, Ci_-6alkylcarbonyl-, and Ci_-6alkoxycarbonyl- may optionally be substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, and cyano;

R^h is independently selected for each occurrence from the group consisting of hydrogen, Ci_-6alkyl, C_3-6alkenyl, C_3-6alkynyl, C_3-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci.

6alkylcarbonyl-, Ci_-6alkoxycarbonyl-, R'R'N-carbonyl- and R'R'N-SOi-; wherein Ci_-6alkyl, C_3-6alkenyl, C_3-6alkynyl, C_3-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci_-6alkylcarbonyl-, and Ci.

6alkoxycarbonyl- may optionally be substituted by one or more substituents selected from R^p;

R^p is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, cyano, Ci_-6alkoxy, R'R'N-, R'R'N-carbonyl-, R'R'N-SO?-, and R'R'N- carbonyl-N(R^a)-;

R^N is selected from the group consisting of hydrogen, halogen, hydroxyl, and Ci. ₆alkyl; and

R^a and R^b are independently selected, for each occurrence, from the group consisting of hydrogen and Ci_-4alkyl; wherein Ci_-4alkyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

[0063] Other contemplated MetAP-2 inhibitors include a pharmaceutically acceptable base salt of a compound represented by Formula (IV):

wherein:

L¹ is -NR^XR²;

R¹ is H or Ci_-3alkyl, and R² is selected from the group consisting of: a 4-9 membered monocyclic heterocyclic ring, heteroaryl, -Ci_-2alkylene-heteroaryl, phenyl, -Ci. ₂alkylene-phenyl and -Ci_-6alkylene; wherein -Ci_-6alkylene may be straight or branched and may optionally be substituted with one or more substituents each independently selected from R^P; or

R¹ and R² taken together with the nitrogen to which they are attached form a

4-9 membered monocyclic, fused bicyclic, or spirocyclic heterocyclic ring; wherein the 4-9 membered monocyclic, fused bicyclic, or spirocyclic heterocyclic ring is optionally substituted with one or more substituents each independently selected from R^h;

L² is selected from the group consisting of: Ci_-4alkylene, -0-Ci_-6alkylene, - NR^a-Ci_-4alkylene, -S-Ci- alkylene, - S(0)₂-Ci- alkylene, -S(0)-Ci- alkylene, =CR^a-, -Ci. 2alkylene-heteroaryl, a 4-9 membered monocyclic heterocyclic ring, and a bond; wherein Ci. ₄alkylene and -0-Ci-₆alkylene may be straight or branched and may optionally be substituted with one or more substituents each independently selected from R^p;

T is selected from the group consisting of: -C(0)OH, tetrazole, -S0₃H, isoxazol-3-ol, isothiazol-3-ol, l-alkyl-lH-pyrazol-3-ol, l,2,4-oxadiazol-5-ol, l,2,4-thiadiazol-

5-ol, lH-imidazole-2,5-dione, oxazolidine-2,4-dione-5-yl, thiazolidine-2,4-dione-5-yl, 1,2,4- oxadiazolidine-3,5-dione-2-yl, 4-hydroxy- l,5-dihydro-2H-pyrrol-2-one-l-yl, 6-hydroxy-4H- l,3-dioxin-4-one-2-yl, -C(0)NHS(0)₂-Ci-₃alkyl, -NH-S(0)₂-Ci-₃alkyl, -S(0)₂-NH-Ci-₃alkyl, and -P(0)(OH)(OR^b); wherein -C(0)NHS(0)₂-Ci_-3alkyl, -NH-S(0)₂-Ci_-3alkyl and -S(0)₂- NH-Cusalkyl may optionally be substituted with one or more substituents each independently selected from R^p;

R^p is independently selected, for each occurrence, from the group consisting of fluorine, hydroxyl, cyano, and -C(0)NR^aR^b; or two R^p are taken together to form =0;

R^h is independently selected, for each occurrence, from the group consisting of hydrogen, Ci_-3alkyl, fluoro and hydroxyl; or two R^h are taken together to form =0; and

R^a and R^b are independently selected, for each occurrence, from the group consisting of hydrogen and Ci-3alkyl.

[0064] For example, a contemplated MetAP-2 inhibitor of the present disclosure may be selected from the group consisting of, e.g., (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 3 -(3 -methylbut-2-en- 1 -yl)oxiran-2-yl)- 1 -oxaspiro[2.5]octan-6-yl (E)-3 -(4-(2- (dimethylamino)ethoxy)phenyl)acrylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3- (3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 3-(2- morpholinoethyl)azetidine-l-carboxylate (Compound A), (3R,4S,5S,6R)-5-methoxy-4- ((2R,3R)-2-methyl-3-(3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 3-(2- (3,3-difluoroazetidin-l-yl)ethyl)azetidine-l-carboxylate, (3R,4S,5S,6R)-4-((2R,3R)-3- isopentyl-2-methyloxiran-2-yl)-5-methoxy-l-oxaspiro[2.5]octan-6-yl 3-hydroxy-3- methylazetidine-l-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3- methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 3 -hydroxy-3 -methylazeti dine- 1- carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-l- yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl ((S)-2-methyl-l-(l-(((R)-l-methylpyrrolidin-3- yl)methyl)-lH-imidazol-4-yl)propyl)carbamate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2- methyl-3-(3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl (S)-3-(2- morpholinoethyl)pyrrolidine-l-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-

3-(3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 7-oxa-2- azaspiro[3.5]nonane-2-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3- methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl (3aR,6aS)-tetrahydro-lH- furo[3,4-c]pyrrole-5(3H)-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3- methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl (3aR,6aS)-5-(2,2- difluoroethyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate, (3R,4S,5S,6R)-5-methoxy-

4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 3-(2- (lH-pyrazol-l-yl)ethyl)azetidine-l-carboxylate, (4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 3 -(3 -methylbut-2-en- 1 -yl)oxiran-2-yl)- 1 -oxaspiro[2.5 ] octan-6-yl 3 -(2-(8-oxa-3 - azabicyclo[3.2.l]octan-3-yl)ethyl)azetidine-l-carboxylate, (3R,4S,5S,6R)-5-methoxy-4- ((2R,3R)-2-methyl-3-(3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 3- azabicyclo[3. l.0]hexane-3-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3- (3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 6-(morpholinomethyl)-2- azaspiro[3.3]heptane-2-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3- methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 6-(2,2-difluoroethyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3- methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 3-

((dimethylcarbamoyl)oxy)azetidine-l-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2- methyl-3-(3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 3- ((ethylcarbamoyl)oxy)azetidine-l-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2- methyl-3-(3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 6-morpholino-2- azaspiro[3.3]heptane-2-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3- methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl (R)-3-

((dimethylcarbamoyl)oxy)pyrrolidine-l-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)- 2-methyl-3-(3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl (S)-3- ((dimethylcarbamoyl)oxy)pyrrolidine-l-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)- 2-methyl-3-(3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 4- ((dimethylcarbamoyl)oxy)piperidine-l-carboxylate, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2- methyl-3-(3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 7-(2,2- difluoroethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate, sodium 2-((l-((((3R,4S,5S,6R)-5- methoxy-4-((2R,3R)-2 -methyl-3 -(3-methylbut-2-en-l -yl)oxiran-2-yl)-l -oxaspiro[2.5]octan- 6-yl)oxy)carbonyl)azetidin-3-yl)oxy)acetate, and sodium 2-(((R)-l-((((3R,4S,5S,6R)-5- methoxy-4-((2R,3R)-2 -methyl-3 -(3-methylbut-2-en-l -yl)oxiran-2-yl)-l -oxaspiro[2.5]octan- 6-yl)oxy)carbonyl)pyrrolidin-3-yl)oxy)acetate and pharmaceutically acceptable salts or stereoisomers thereof.

[0065] In an embodiment, a contemplated MetAP-2 inhibitor of the present disclosure, upon administration, may degrade to metabolites resulting from one or more metabolic pathways selected from the group consisting of CYP-mediated oxidation, GSH conjugation, and epoxide hydrolase-mediated hydrolysis.

[0066] Also provided herein is a METAP-2 inhibitor compound represented by:

pharmaceutically acceptable salt or stereoisomer thereof.

[0067] As part of the disclosed methods, a disclosed METAP-2 inhibitor may be administered about every other day, every three or four days, or weekly, and may be administered orally, subcutaneously or intravenously. Contemplated methods may include administering a disclosed MetAP-2 inhibitor, such as described above, at a dosage of about 0.5 mg to 3.0mg, or about 0.9mg to about 1.8 mg per dose, or e.g., about .6mg, .7mg, .8mg, .9 mg, l. lmg, l.2mg, 1.3 mg, 1.4 mg, 1.5 or about 1,6 mg. II. GLP-1 Agonists

[0068] In certain embodiments, a contemplated GLP-l agonist, e.g., as part of the disclosed methods, is selected from one of the following: liraglutide, dulaglutide, lixisenatide, albiglutide, semaglutide, taspoglutide and exenatide. Such GLP-l agonists can be, for example, injected subcutaneously in the abdomen, thigh, or upper arm.

[0069] In certain embodiments, a contemplated method may include administering semaglutide with a dose that starts at 0.25 mg once weekly to 0.5 mg once weekly after 4 weeks, and further to 1 mg once weekly if additional treatment is needed. In certain embodiments, a contemplated method may include administering lixisenatide with dose starting at 10 meg once daily for 14 days and, for example, on Day 15, the dosage increases to 20 meg once daily. In another embodiment, a contemplated method includes administering liraglutide with dose starting at 0.6 mg once daily for 1 week then increases to 1.2 mg once daily. Such liraglutide dosing may further increase to 1.8 mg once daily for additional treatment. Alternatively, a liraglutide dose can start at 0.6 mg daily for 1 week, and optionally, in weekly intervals the dose may be increased until a dose of 3 mg is reached.

[0070] A contemplated method, in an exemplary embodiment, may include administering exenatide with a dose that starts at 5 meg per dose twice daily for 1 month and then increases to 10 meg twice daily based on clinical response, may include administering dulaglutide with a dose that starts at 0.75 mg once weekly and then increases to 1.5 mg once weekly for additional treatment, or may include administering albiglutide with a dose that starts at 30 mg once weekly and then increases to 50 mg once weekly in a patient requiring additional treatment.

[0071] Contemplated methods may additionally include administration of a dipeptidyl peptidase (DPP-4) inhibitor, such as one or more of alogliptin, linagliptin, saxagliptin, sitagliptin, and/or vildagliptin. In another embodiment, a method for treating a patient in need of glycemic control and/or treating a metabolic disorder in a patient in need thereof is provided, comprising: administering a pharmaceutically acceptable amount of a MetAP-2 inhibitor; and administering a pharmaceutically acceptable amount of a DPP-4 inhibitor; wherein the pharmaceutically acceptable amount of a MetAP-2 inhibitor and the

pharmaceutically acceptable amount of the DPP -4 inhibitor provides an effective amount for the treatment. For example, contemplated methods may include administering alogliptin orally with ta dose of 25 mg once daily, administering saxaliptin orally with a dose of 2.5 mg or 5 mg once daily, administering sitaliptin orally with a dose based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg and/or administering vildaliptin orally with a dose of 50 mg once daily or 100 mg twice daily (50 mg - 50 mg). Other contemplated DPP -4 inhibitors that may be used in the disclosed methods include gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and/or dutogliptin.

[0072] Another aspect of the present disclosure provides pharmaceutical compositions comprising a MetAP2- inhibitor and a GLP-l agonist (and/or a DPP -4 inhibitor) as as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.

[0073] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation

compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0074] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0075] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0076] Pharmaceutical compositions of this disclosure suitable for parenteral

administration comprise a subject composition in combination with one or more

pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0077] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0078] In another aspect, the present disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the

gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present invention. III. Methods

[0079] Provided herein, in one aspect, is a method for treating a patient (e.g. human) in need of glycemic control and/or treating a metabolic disorder in a patient in need thereof, comprising: administering a pharmaceutically acceptable amount of a MetAP-2 inhibitor; and administering a pharmaceutically acceptable amount GLP-l agonist (or GLP-l /glucagon dual receptor agonist, or DPP-4 inhibitor); wherein the pharmaceutically acceptable amount of the MetAP-2 inhibitor and the pharmaceutically acceptable amount of the GLP-l agonist or GLP-l /glucagon dual receptor agonist or DPP-4 inhibitor provides an effective amount for the treatment. For example, the MetAP-2 inhibitor and/or the GLP-l agonist may be each administered in a sub-therapeutic amount (e.g., as compared to administration of the active alone) or may be administered in an effective amount (e.g., the amount administered if administered alone). The MetAP-2 inhibitor and the GLP-l agonist (or DPP-4 inhibitor or GLP-l /glucagon dual receptor agonist) may be co-administered for example, together in the same dosage form, or in separate dosage forms. In certain embodiments, the contemplated combination therapy provides for a synergistic effect.

[0080] In certain embodiments, the present disclosure provides for methods of treating and/or controlling obesity in a patient in need thereof, comprising administering to the patient administering a MetAP-2 inhibitor such as a MetAP-2 inhibitor disclosed herein (e.g., For example, the MetAP-2 inhibitor may be one of e.g., (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2- methyl-3-(3-methylbut-2-en-l-yl)oxiran-2-yl)-l-oxaspiro[2.5]octan-6-yl 3-(2- morpholinoethyl)azetidine-l-carboxylate or a pharmaceutically acceptable salt or

stereoisomer thereof; and administering a GLP-l agonist, such as disclosed herein, e.g., litagluratide. Other GLP-l agonists contemplated may include semaglutide; ITCA 650; CJC- 1134-PC ; langlenatide; PB1023, VRS 859; TTP054; ZYOG1; N 9924 / OG217SC; NN9926 / OG987GT ; NN9927 / OG987SC; and ARI-1732TS.

[0081] Also provided herein is a method of inducing weight loss in a patient in need thereof, and/or method of substantially preventing weight gain in a patient in need thereof comprising administering to the patient a MetAP-2 inhibitor such as a MetAP-2 inhibitor disclosed herein; and administering a GLP-l agonist.

[0082] In certain embodiments, the patient is a human, or a cat or dog.

[0083] In certain embodiments, the patient has a body mass index greater than or equal to about 30 kg/m2 before the administration. [0084] Other contemplated methods of treatment include method of treating or ameliorating an obesity-related condition or co-morbidity, by co-administering a MetAP-2 inhibitor such as a MetAP-2 inhibitor disclosed herein; and a GLP-l agonist as described herein. For example, contemplated herein are methods for treating type 2 diabetes in a patient in need thereof.

[0085] In an aspect, a method for treating a patient in need of glycemic control and/or treating a metabolic disorder in a patient in need thereof is provided, comprising:

administering a pharmaceutically acceptable amount of a MetAP-2 inhibitor; and

administering a pharmaceutically acceptable amount of a DPP -4 inhibitor; wherein the pharmaceutically acceptable amount of the MetAP-2 inhibitor and the pharmaceutically acceptable amount of the DPP-4 inhibitor provides an effective amount for the treatment. Contemplated DPP -4 inhibitors may be selected from the group consisting of alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin.

[0086] In another aspect, a method for treating a patient in need of glycemic control and/or treating a metabolic disorder in a patient in need thereof, comprising: administering a pharmaceutically acceptable amount of a MetAP-2 inhibitor; and administering a

pharmaceutically acceptable amount of a GLP-l/glucagon dual receptor agonist; wherein the pharmaceutically acceptable amount of the MetAP-2 inhibitor and the pharmaceutically acceptable amount of the GLP-l/glucagon dual receptor agonist provides an effective amount for the treatment. Contemplated GLP-l/glucagon receptor agonists may include

oxyntomodulin, G49, HM12525, LY2944876 / TT-401; ZP2929; MEDI0382, or analogs thereof.

[0087] Exemplary methods contemplated herein methods of treating cardiac disorders, endocrine disorders, respiratory disorders, hepatic disorders, skeletal disorders, psychiatric disorders, metabolic disorders, and reproductive disorders. For example, methods contemplated provided herein may be in some embodiments, methods of treating

nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). For example, a method for treating nonalcoholic steatohepatitis in a patient in need thereof, is provided, comprising: administering a pharmaceutically acceptable amount of a MetAP-2 inhibitor; and administering a pharmaceutically acceptable amount of a GLP-l agonist;

wherein the pharmaceutically acceptable amount of the MetAP-2 inhibitor and the pharmaceutically acceptable amount of the GLP-l agonist provides an effective amount for the treatment.

[0088] Also disclosed herein is a pharmaceutical composition comprising:

a) a MetAP-2 inhibitor represented by:

wherein:

R¹ and R², together with the nitrogen to which they are attached, form a 4-6 membered saturated heterocyclic ring A or form a 6-8 membered bicyclic, fused, bridged or spirocyclic heterocyclic ring A, which may have an additional heteroatom selected from the group consisting of O, S(0)_w (wherein w is 0, 1, or 2), and NR^a;

L is selected from the group consisting of Ci_-6alkylene and Ci_-6alkenylene; wherein Ci_-6alkylene and Ci-₆alkenylene may optionally be substituted by one or two substituents each independently selected from the group consisting of halogen and hydroxyl; and wherein one or two methylene units of L may optionally and independently be replaced by a moiety selected from the group consisting of a bond, -0-, -C(O)-, -O-C(O)-, -C(0)-0-, -NR^a-, -C(O)- NR^a-, -NR^a-C(0)-, -0-C(0)-NR^a-, -NR^a-C(0)-0-, -S(0)_w- (wherein w is 0, 1, or 2), -S(0)_w- NR^a-, and -NR^a-S(0)_w- ;

R¹ and R^J are selected independently for each occurrence from the group consisting of hydrogen, Ci_-6alkyl, C2_-6alkenyl, C3_-6cycloalkyl, heterocyclyl and heterocyclylcarbonyl; wherein Ci_-6alkyl, C2_-6alkenyl and C3_-6cycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of fluorine, hydroxyl, cyano, R^aR^bN-, R^aR^bN-carbonyl- and Ci_-3alkoxy; and wherein heterocyclyl and

heterocyclylcarbonyl may be optionally substituted by one or more substituents

independently selected from the group consisting of Ci_-6alkyl, C2_-6alkenyl, C2_-6alkynyl, C3- ₆cycloalkyl, Ci_-6alkoxy, halo-Ci_-6-alkyl, hydroxyl-Ci_-6-alkyl, R^aR^bN-Ci_-6alkyl- and Ci_-6- alkoxy-C_l-6-alkyl group; and wherein if said heterocyclyl or heterocyclylcarbonyl contains a - NH moiety that nitrogen may optionally be substituted by one or more groups independently selected from the group consisting of Ci_-6alkyl, C3_-6alkenyl, C3_-6alkynyl, C3_-6cycloalkyl, Ci. ₆alkyl-S(0)₂- and Ci_-6-alkylcarbonyl; or R¹ and R^J taken together with the nitrogen to which they are attached form a 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ring, which may have an additional heteroatom selected from the group consisting of O, N, and S(0)_w (wherein w is 0, 1 or 2); wherein the 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ring may be optionally substituted on carbon by one, two, or more substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, Ci_-6alkyl, Ci_-6alkoxy, R^aR^bN-, R^aR^bN-S0₂- and R^aR^bN-carbonyl-; wherein said Ci. ₆alkyl or Ci_-6alkoxy may optionally be substituted the group consisting of fluorine, hydroxyl, and cyano; and wherein if said 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ring contains a -NH moiety that nitrogen may be optionally substituted by a substituent selected from the group consisting of hydrogen, Ci_-6alkyl, C_3- ₆alkenyl, C3_-6alkynyl, C3_-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci_-6alkylcarbonyl-, Ci.

6alkoxycarbonyl-, R'R'N-carbonyl- and R¹R^JN-S0₂-; wherein Ci_-6alkyl, C3_-6alkenyl, C_3- ₆alkynyl, C3_-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci_-6alkylcarbonyl-, and Ci_-6alkoxycarbonyl- may optionally be substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, and cyano; R^a and R^b are independently selected, for each occurrence, from the group consisting of hydrogen and Ci_-3alkyl; wherein Ci_-3alkyl may optionally be substituted by one or more substituents selected from halogen, cyano, oxo and hydroxyl;

f p

R¹ is independently selected, for each occurrence, from the group consisting of R , hydrogen, Ci_-6alkyl, C_3-6cycloalkyl, C_2-6alkenyl, C_2-6alkynyl, Ci_-6alkoxy, Ci-₆alkyl-S(0)_w-, (wherein wherein w is 0, 1 or 2), Ci-₆alkylcarbonyl-N(R^a)- and Ci-₆alkoxycarbonyl-N(R^a)-; wherein Ci_-6alkyl, C_3-6cycloalkyl, C_2-6alkenyl, C_2-6alkynyl, Ci_-6alkoxy, Ci_-6alkyl-S(0)_w-, Ci. ₆alkylcarbonyl-N(R^a)-, Ci_-6alkoxycarbonyl-N(R^a)- may be optionally substituted by one or more substituents selected from R^p;

R^s is independently selected for each occurrence from the group consisting of R^P, hydrogen, oxo, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, Ci_-6alkoxy, Ci_-6alkyl- S(0)_w- (wherein w is 0, 1 or 2), Ci_-6alkylcarbonyl-N(R^a)- and Ci_-6alkoxycarbonyl-N(R^a)-; wherein Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, Ci_-6alkoxy, Ci-₆alkyl-S(0)_w-, Ci. ₆alkylcarbonyl-N(R^a)-, and Ci-₆alkoxycarbonyl-N(R^a)- may be optionally substituted by one or more substituents selected from R^p;

6alkylcarbonyl-, Ci_-6alkoxycarbonyl-, R'R'N-carbonyl- and R'R'N-S0₂-; wherein Ci_-6alkyl, C_3-6alkenyl, C_3-6alkynyl, C_3-6cycloalkyl, Ci-₆alkyl-S(0)₂-, Ci-₆alkylcarbonyl-, and Ci.

R^p is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, cyano, Ci_-6alkoxy, R'R'N-, R'R'N-carbonyl-, R'R'N-SCf-, and R'R'N- carbonyl-N(R^a)-; or a pharmaceutically acceptable salt, stereoisomer, ester or prodrug thereof; b) a GLP-l agonist and/or a DPP -4 inhibitor; and c) a pharmaceutically acceptable excipient.

[0089] Exemplary cardiac disorders include hypertension, dyslipidemia, ischemic heart disease, cardiomyopathy, cardiac infarction, stroke, venous thromboembolic disease and pulmonary hypertension. Exemplary endocrine disorders include type 2 diabetes and latent autoimmune diabetes in adults. Exemplary respiratory disorders include obesity- hypoventilation syndrome, asthma, and obstructive sleep apnea. An exemplary hepatic disorder is nonalcoholic fatty liver disease. Exemplary skeletal disorders include back pain and osteoarthritis of weight-bearing joints. Exemplary metabolic disorders include Prader- Willi Syndrome and polycystic ovary syndrome. Exemplary reproductive disorders include sexual dysfunction, erectile dysfunction, infertility, obstetric complications, and fetal abnormalities. Exemplary psychiatric disorders include weight-associated depression and anxiety.

[0090] In particular, in certain embodiments, the present disclosure provides methods of treating type 2 diabetes and adults with a body mass index (BMI) of 30 or greater (obesity) or a BMI of 27 or greater (overweight) who have at least one weight-related condition, for example, hypertension, type 2 diabetes mellitus, or dyslipidemia.

[0091] In particular, in certain embodiments, the present disclosure provides a method of treating one or more of the above medical indications comprising administering to a subject in need thereof a MetAP-2 inhibitor and a GLP-l agonist wherein the combination provides a therapeutically effective of amount.

[0092] Obesity or reference to“overweight” refers to an excess of fat in proportion to lean body mass. Excess fat accumulation is associated with increase in size (hypertrophy) as well as number (hyperplasia) of adipose tissue cells. Obesity is variously measured in terms of absolute weight, weightheight ratio, distribution of subcutaneous fat, and societal and esthetic norms. A common measure of body fat is Body Mass Index (BMI). The BMI refers to the ratio of body weight (expressed in kilograms) to the square of height (expressed in meters). Body mass index may be accurately calculated using either of the formulas:

weight(kg) / height²(m²) (SI) or 703 X weight(lb) / height²(in²) (ETS).

[0093] In accordance with the ET.S. Centers for Disease Control and Prevention (CDC), an overweight adult has a BMI of 25 kg/m2 to 29.9 kg/m2, and an obese adult has a BMI of 30 kg/m2 or greater. A BMI of 40 kg/m2 or greater is indicative of morbid obesity or extreme obesity. Obesity can also refer to patients with a waist circumference of about 102 cm for males and about 88 cm for females. For children, the definitions of overweight and obese take into account age and gender effects on body fat. Patients with differing genetic background may be considered“obese” at a level differing from the general guidelines, above. [0094] The pharmaceutically acceptable methods of the present disclosure also may be useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy. Methods for treating patients at risk of obesity, such as those patients who are overweight, but not obese, e.g. with a BMI of between about 25 and 30 kg/m2, are also contemplated. In certain embodiments, a patient is a human.

[0095] BMI does not account for the fact that excess adipose can occur selectively in different parts of the body, and development of adipose tissue can be more dangerous to health in some parts of the body rather than in other parts of the body. For example,“central obesity”, typically associated with an“apple-shaped” body, results from excess adiposity especially in the abdominal region, including belly fat and visceral fat, and carries higher risk of co-morbidity than“peripheral obesity”, which is typically associated with a“pear-shaped” body resulting from excess adiposity especially on the hips. Measurement of waist/hip circumference ratio (WHR) can be used as an indicator of central obesity. A minimum WHR indicative of central obesity has been variously set, and a centrally obese adult typically has a WHR of about 0.85 or greater if female and about 0.9 or greater if male.

[0096] Methods of determining whether a subject is overweight or obese that account for the ratio of excess adipose tissue to lean body mass involve obtaining a body composition of the subject. Body composition can be obtained by measuring the thickness of subcutaneous fat in multiple places on the body, such as the abdominal area, the subscapular region, arms, buttocks and thighs. These measurements are then used to estimate total body fat with a margin of error of approximately four percentage points. Another method is bioelectrical impedance analysis (BIA), which uses the resistance of electrical flow through the body to estimate body fat. Another method is using a large tank of water to measure body buoyancy. Increased body fat will result in greater buoyancy, while greater muscle mass will result in a tendency to sink.

[0097] The pharmaceutically acceptable methods of co-administering combinations of compounds of the present disclosure may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. For treating clinical conditions and diseases noted above, a pharmaceutically acceptable composition of this present disclosure may be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections or infusion techniques.

[0098] Treatment can be continued for as long or as short a period as desired. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely. A treatment period can terminate when a desired result, for example a weight loss target, is achieved. A treatment regimen can include a corrective phase, during which dose sufficient to provide reduction of weight is administered, and can be followed by a maintenance phase, during which a e.g. a lower dose sufficient to prevent weight gain is administered. A suitable maintenance dose is likely to be found in the lower parts of the dose ranges provided herein, but corrective and maintenance doses can readily be established for individual subjects by those of skill in the art without undue experimentation, based on the disclosure herein.

Maintenance doses can be employed to maintain body weight in subjects whose body weight has been previously controlled by other means, including diet and exercise, bariatric procedures such as bypass or banding surgeries, or treatments employing other

pharmacological agents.

[0099] In certain embodiments, provided methods include methods for treating a metabolic disorder, e.g., a disorder occurring when abnormal chemical reactions in the body alter the normal metabolic process. Such metabolic disorders include lipid metabolism disorders, glucose metabolism disorders (e.g. diabetes mellitus), malabsorption syndromes and the like.

[0100] In certain embodiments, provided methods include methods for treating a metabolic disease, chronic inflammatory disease, cardiac disorders, endocrine disorders, respiratory disorders, hepatic disorders, skeletal disorders, and/ or impaired wound healing and/or for example, a inflammatory disease. For example, the inflammatory disease may be selected from the group consisting of inflammatory bowel disease, Kawasaki disease, Sjogren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, chronic obstructive pulmonary disease, and psoriasis. [0101] Exemplary co-morbidities that may accompany e.g., an overweight or obese patient include cardiac disorders, endocrine disorders, respiratory disorders, hepatic disorders, skeletal disorders, psychiatric disorders, metabolic disorders, and reproductive disorders.

[0102] Exemplary cardiac disorders that may be treated using the disclosed methods include hypertension, dyslipidemia, ischemic heart disease, cardiomyopathy, cardiac infarction, stroke, venous thromboembolic disease and pulmonary hypertension. Exemplary endocrine disorders include type 2 diabetes and latent autoimmune diabetes in adults.

Exemplary respiratory disorders include obesity-hypoventilation syndrome, asthma, and obstructive sleep apnea. An exemplary hepatic disorder is nonalcoholic fatty liver disease. Exemplary skeletal disorders include back pain and osteoarthritis of weight-bearing joints. Exemplary metabolic disorders include Prader-Willi Syndrome and polycystic ovary syndrome. Exemplary reproductive disorders include sexual dysfunction, erectile dysfunction, infertility, obstetric complications, and fetal abnormalities. Exemplary psychiatric disorders include weight-associated depression and anxiety.

EXAMPLES

[0103] The examples which follow are intended in no way to limit the scope of this disclosure but are provided to illustrate aspects of the present disclosure. Many other embodiments of this disclosure will be apparent to one skilled in the art.

[0104] All animal experiments are conducted in accordance with bioethical guidelines, which are fully compliant to internationally accepted principles for the care and use of laboratory animals Animals are obtained from Janvier (France), Taconic (Denmark) or Charles River (Germany). ETnless otherwise stated, animals are typically fed regular chow (Altromin 1324, Brogaarden, Denmark) and tap water. The animal room environment will be controlled (targeted ranges: temperature 21 ± 2°C; relative humidity 50 ± 10%). Male Rattus Norvegicus rat of Sprague Dawley strain of 25 weeks of age were individually housed at the testing facility.

Example 1 - A DIO Rat Study.

[0105] A diet inducation period before the rat study was introduced to establish a DIO and a lean rat model. On the day before dosing, 4 hour fasting was conducted and blood glucose (BG) and plasma insulin were measured as described beow. Day 0 was the first dosing as indicated below (Table 2). At weeks 1-5, blood glucose was measured at 4 hour fasting (Figure 3). At week 4 OGTT was tested (Figure 4 and Figure 5) and the model was terminated at week 5 (after a test for plasma insulin). At termination, the following assays were conducted: 4 hr fast insulin, OGTT-Insulin, OGTT-GLP1, Plasma TG and TC, GLP1, Leptin, FGF-21, Adiponectin, Ghrelin, Liver TG and TC, Liver glycogen. The study is described below:

[0106] Models and Groups. Table 1 indicates the animal model and protocols used.

Detailed information of each group is summarized in Table 2.

Table 1. Model

Table 2. Groups

[0107] Formulation. Table 3 indicates the formulations used. The vehicle is 5% mannito in water, wherein the formulation with compound A is dissolved in 5% mannitol and the dosing is prepared daily. Stock is thawed in the morning and gently agitated. Stock is diluted in vehicle prior to dosing. Liraglutide dissolves in PBS + 0.1% BSA and the dosing is prepared weekly. Table 3. Formulation

[0108] Samples. Both in vivo sample and sample on termination are collected to assess the targeted parameters in the study. Samples are taken using sublingural capillaries, cardiac puncture, or other means at the designated time points both in vivo or on termination for all of the 5 groups. For example, for 4 hr fast BG study, 10 mΐ of samples are collected on Day - 2, 5, 12, 19, 26, and 33 to assess blood glucose level for all of the 5 groups. Details about the sample taken in vivo and on termination are listed in Table 4 and Table 5 below. BG = blood glucose, OGTT = oral glucose tolerance test. Table 4. In vivo samples.

Table 5. Termination samples.

[0109] Measurements. Different measurements such body weights, food intake, 4 hr fast BG, OGTT-BG, liver histology, brian, epididymal fat are taken to evaluate in vivo pharmacology as well as histology for all of the 5 groups. Details about all sample analysis that are performed during the study are listed below.

Table 6. In vivo pharmacology

Table 7. Histology

[0110] Results. The results of the study are shown in Figures 1-7 and Table 8. Figures 1 and 2 indicate the change in body weight as a function of administration of compound A, liraglutide alone, and the co-administration of compound A and liraglutide. All groups differ except liraglutide alone and Compound A alone=NS. Figure 3 shows the 4 hr fasted blood glucose level 1 day before and 1, 3, and 5 weeks after dosing the compounds. Figure 4 depicts blood glucose level in 240 min after glucose was dosed PO at 0 min. Figure 6 depicts food intake for each group (A DIO diet; C chow diet). Compound A tended to reduce cumulative DIP diet and increase standard chow intake; liraglutide decreased DIO diet intake with no effect on standard chow. The combination markedly reducted the DIO diet with significantly increasing chow intake; no significant difference between Compound A and liraglutide on cumulative food intake was found. Figure 7 depicts the total liver weight of the animals.

[0111] Figure 5 and Table 8 shows the Tukey’s multiple comparison test of veh.l, veh 2, Liraglutide, and Compound A. Table 8.

Example 2 - 8 week, Q3D, SC dosing, DIO mouse Study

[0112] Day 0 is the first dosing as indicated below (Table 9). Primary endpoints for the study are body weight and food intake. Secondary endpoints for the study include fasting plasma glucose (FPG), glucose tolerance, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and body composition. The study is described below:

[0113] Groups. Detailed information of each group is summarized in Table 9.

Table 9. Groups

[0114] Formulation. The vehicle is 5% mannitol in water.

[0115] Results. Q3D administration may translate to weekly administration for humans.

Example 3 - 12 week DIO mouse NASH combination with liraglutide Study.

[0116] The Gubra diet-induced obesity (DIO) mouse model of NASH (DIO-NASH) includes wild-type C57BL/6 mice offered a diet high in fat, fructose and cholesterol 26+ weeks prior to pre-biopsy collection. Only animals demonstrating hepatosteatosis and fibrosis are enrolled into study groups.

[0117] Day 0 is the first dosing as indicated below (Table 10). The study evaluates the benefit of administering Compound A alone or in combination with liraglutide on fibrosis and associated pathology. A primary endpoint for the study may be an improvement in fibrosis. The study is described below:

Table 10. Groups

[0118] Figure 8 indicates the change in relative body weight as a function of administration of vehicle, compound A, liraglutide alone, and the co-administration of compound A and liraglutide.

INCORPORATION BY REFERENCE

[0119] All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

EQUIVALENTS

[0120] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0121] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term“about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

[0122] What is claimed is:

Claims

1. A method for treating a patient in need of glycemic control and/or treating a metabolic disorder in a patient in need thereof, comprising:

administering a pharmaceutically acceptable amount of a MetAP-2 inhibitor; and administering a pharmaceutically acceptable amount of a GLP-l agonist; wherein the pharmaceutically acceptable amount of the MetAP-2 inhibitor and the pharmaceutically acceptable amount of the GLP-l agonist provides an effective amount for the treatment.

2. The method of claim 1, wherein the MetAP-2 inhibitor and the GLP-l agonist are administered together in the same dosage form.

3. The method of claim 1, wherein the MetAP-2 inhibitor and the GLP-l agonist are administered in separate dosage forms.

4. The method of claim 1 or 2, wherein the patient is a human.

5. The method of any one of claims 1-4, wherein the GLP-l agonist is selected from the group consisting of: liraglutide, dulaglutide, lixisenatide, albiglutide, semaglutide, taspoglutide and exenatide.

6. The method of any one of claims 1-5, wherein the GLP-l agonist is liraglutide.

7. The method of any one of claims 1-6, comprising administering 0.6 mg of liraglutide per day for at least one week, then increasing to 1.2 mg or 1.8 mg of liraglutide per day.

8. The method of any one of claims 1-7, further comprising administering one or more of: metformin, a sulfonylurea, a thiazolidinedione, or insulin.

9. The method of any one of claims 1-8, further comprising administering of a DPP-4 inhibitor.

10. The method of claim 9, wherein the DPP -4 inhibitor is selected from the group consisting of: alogliptin, linagliptin, saxagliptin, sitagliptin, and/or vildagliptin.

11. The method of any one of claims 1-4, wherein the GLP-l agonist is a GLP-l receptor/glucagon receptor dual agonist.

12. A method for treating a patient in need of glycemic control and/or treating a metabolic disorder in a patient in need thereof, comprising:

administering a pharmaceutically acceptable amount of a MetAP-2 inhibitor; and administering a pharmaceutically acceptable amount of a DPP -4 inhibitor; wherein the pharmaceutically acceptable amount of the MetAP-2 inhibitor and the pharmaceutically acceptable amount of the DPP-4 inhibitor provides an effective amount for the treatment.

13. The method of claim 11, wherein the DPP -4 inhibitor is selected from the group consisting of alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin.

14. A method for treating a patient in need of glycemic control and/or treating a metabolic disorder in a patient in need thereof, comprising: administering a pharmaceutically acceptable amount of a MetAP-2 inhibitor; and administering a pharmaceutically acceptable amount of a GLP-l/glucagon dual receptor agonist; wherein the pharmaceutically acceptable amount of the MetAP-2 inhibitor and the pharmaceutically acceptable amount of the GLP-l/glucagon dual receptor agonist provides an effective amount for the treatment.

15. The method of claim 14, wherein the GLP-l/glucagon receptor agonist is

oxyntomodulin, G49, HM12525, or analogs thereof.

16. The method of any one of claims 1-15, wherein the MetAP-2 inhibitor is an irreversible inhibitor.

17. The method of claim 16, wherein the irreversible inhibitor covalently bonds to His231 of MetAP-2 via a spiro epoxide moiety present on the irreversible inhibitor.

18. The method of claim 16, wherein the MetAP-2 inhibitor is an analog of fumagillin.

19. The method of any one of claims 1-18, wherein the MetAP-2 inhibitor is represented by:

wherein R¹ is selected from Ci_-8alkylene, C2-8alkenylene, heterocyclyl, C3-6cycloalkyl, -NR^a- Cuxalkylene, -NR^a-C2-8alkenylene, and -NR^a- C3-6cycloalkyl wherein R¹ is substituted by a substituent selected from the group consisting of: carboxy, -C(0)-0- Ci_-6alkyl, -O- C(0)-NR^aR^b, phenyl (optionally substituted by substituent selected from NR^aR^b), Ci_-6alkoxy (optionally substituted by a substituent selected from the group consisting of NR^aR^b, Ci. ₆alkyl, carboxy and heterocyclyl)), Ci_-6alkylene (optionally substituted by halogen, hydroxyl, heterocyclyl, NR^aR^b, carboxy, -0-C(0)-N R^aR^b, and -C(0)-0- Ci_-6alkyl), wherein R^a and R^b are each independently selected from hydrogen, and Ci_-6alkyl, or together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring; and pharmaceutically acceptable salts, stereoisomers, esters and prodrugs thereof.

20. The method of any one of claims 1-18, wherein the MetAP-2 inhibitor is represented by Formula I:

(i);

wherein:

R¹ and R², together with the nitrogen to which they are attached, form a 4-6 membered saturated heterocyclic ring A or form a 6-8 membered bicyclic, fused, bridged or spirocyclic heterocyclic ring A, which may have an additional heteroatom selected from the group consisting of O, S(0)_w (wherein w is 0, 1, or 2), and NR^a; heterocyclic ring A is substituted on an available carbon by a substituent represented by L-B; and wherein heterocyclic ring A is additionally and optionally substituted by one or two substituents each independently selected from the group consisting of halogen, hydroxyl, Ci-3alkyl and Ci_-3alkoxy; wherein Ci_-3alkyl and Ci_-3alkoxy may optionally be substituted by one or more fluorine atoms or a substituent selected from the group consisting of cyano, hydroxyl, and N(R^aR^b);

L is selected from the group consisting of Ci_-6alkylene and Ci-₆alkenylene; wherein Ci_-6alkylene and Ci_-6alkenylene may optionally be substituted by one or two substituents each independently selected from the group consisting of halogen and hydroxyl; and wherein one or two methylene units of L may optionally and independently be replaced by a moiety selected from the group consisting of a bond, -0-, -C(O)-, -O-C(O)-, -C(0)-0-, -NR^a-, -C(O)- NR^a-, -NR^a-C(0)-, -0-C(0)-NR^a-, -NR^a-C(0)-0-, -S(0)_w- (wherein w is 0, 1, or 2), -S(0)_w- NR^a-, and -NR^a-S(0)_w- ;

R¹ and R^J are selected independently for each occurrence from the group consisting of hydrogen, Ci_-6alkyl, C2_-6alkenyl, C3_-6cycloalkyl, heterocyclyl and heterocyclylcarbonyl; wherein Ci_-6alkyl, C_2-6alkenyl and C_3-6cycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of fluorine, hydroxyl, cyano, R^aR^bN-, R^aR^bN-carbonyl- and Ci_-3alkoxy; and wherein heterocyclyl and

heterocyclylcarbonyl may be optionally substituted by one or more substituents

independently selected from the group consisting of Ci_-6alkyl, C2_-6alkenyl, C2_-6alkynyl, C_3- ₆cycloalkyl, Ci_-6alkoxy, halo-Ci_-6-alkyl, hydroxyl-Ci_-6-alkyl, R^aR^bN-Ci_-6alkyl- and Ci_-6- alkoxy-C_l-6-alkyl group; and wherein if said heterocyclyl or heterocyclylcarbonyl contains a - NH moiety that nitrogen may optionally be substituted by one or more groups independently selected from the group consisting of Ci_-6alkyl, C_3-6alkenyl, C_3-6alkynyl, C_3-6Cycloalkyl, Ci. ₆alkyl-S(0)₂- and Ci_-6-alkylcarbonyl; or R¹ and R^J taken together with the nitrogen to which they are attached form a 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ring, which may have an additional heteroatom selected from the group consisting of O, N, and S(0)_w (wherein w is 0, 1 or 2); wherein the 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ring may be optionally substituted on carbon by one, two, or more substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, Ci_-6alkyl, Ci_-6alkoxy, R^aR^bN-, R^aR^bN-S0₂- and R^aR^bN-carbonyl-; wherein said Ci. ₆alkyl or Ci_-6alkoxy may optionally be substituted the group consisting of fluorine, hydroxyl, and cyano; and wherein if said 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ring contains a -NH moiety that nitrogen may be optionally substituted by a substituent selected from the group consisting of hydrogen, Ci_-6alkyl, C_3- ₆alkenyl, C_3-6alkynyl, C_3-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci_-6alkylcarbonyl-, Ci. ₆alkoxycarbonyl-, R'R'N-carbonyl- and R'R'N-S0₂-; wherein Ci_-6alkyl, C_3-6alkenyl, C_3- ₆alkynyl, C_3-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci_-6alkylcarbonyl-, and Ci_-6alkoxycarbonyl- may optionally be substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, and cyano;

f p

R¹ is independently selected, for each occurrence, from the group consisting of R , hydrogen, Ci_-6alkyl, C_3-6cycloalkyl, C_2-6alkenyl, C_2-6alkynyl, Ci_-6alkoxy, Ci-₆alkyl-S(0)_w-, (wherein wherein w is 0, 1 or 2), Ci_-6alkylcarbonyl-N(R^a)- and Ci_-6alkoxycarbonyl-N(R^a)-; wherein Ci_-6alkyl, C_3-6cycloalkyl, C_2-6alkenyl, C_2-6alkynyl, Ci_-6alkoxy, Ci_-6alkyl-S(0)_w-, Ci. ₆alkylcarbonyl-N(R^a)-, Ci_-6alkoxycarbonyl-N(R^a)- may be optionally substituted by one or more substituents selected from R^p;

6alkylcarbonyl-, Ci_-6alkoxycarbonyl-, R'R'N-carbonyl- and R'R'N-S0₂-; wherein Ci_-6alkyl, C_3-6alkenyl, C_3-6alkynyl, C_3-6cycloalkyl, Ci-₆alkyl-S(0)₂-, Ci_-6alkylcarbonyl-, and Ci.

R^p is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, cyano, Ci_-6alkoxy, R'R'N-, R'R'N-carbonyl-, R'R'N-S0₂-, and R'R'N- carbonyl-N(R^a)-; or apharmaceutically acceptable salt, stereoisomer, ester or prodrug thereof.

21. The method of any one of claims 1-18, wherein the MetAP-2 inhibitor is

(3R,4S, 5 S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3 -(3 -methylbut-2-en- 1 -yl)oxiran-2-yl)- 1 - oxaspiro[2.5]octan-6-yl 3-(2-morpholinoethyl)azetidine-l-carboxylate or a pharmaceutically acceptable salt or stereoisomer thereof.

22. The method of any one of claims 1-21, comprising administering the MetAP-2 inhibitor about every other day, every three or four days, or weekly.

23. The method of any one of claims 1-22, comprising administering the MetAP-2 inhibitor with a dosage of about 0.5 mg to 3.0 mg, or about 0.9 mg to about 1.8 mg per dose.

24. The method of any one of claims 1-23, wherein the patient has a BMI of 30 kg/m2 or greater, or a BMI of 25 kg/m2 to 29.9 kg/m2 and an obesity related co-morbidity.

25. The method of anyone of claims 1-24, wherein the disorder or co-morbidity is a metabolic disease.

26. The method of claim 25, wherein the disorder or co-morbidity is nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).

27. The method of any one of claims 1-24, wherein the disorder is obesity and/or a co morbidity thereof.

28. The method of any one of claims 1-24, wherein the disorder or co-morbidity is type 2 diabetes or latent autoimmune diabetes.

29. The method of any one of claims 1-24, wherein the disorder is chronic inflammatory disease or impaired wound healing.

30. The method of any one of claims 1-24, wherein the disorder is an inflammatory disease.

31. The method of any one of claims 1-24, wherein the method reduces the risk of major cardiovascular disease.

32. The method of claim 31, wherein the patient has established cardiovascular disease and type II diabetes.

33. A method for treating nonalcoholic steatohepatitis in a patient in need thereof, comprising:

34. A pharmaceutical composition comprising: a) a MetAP-2 inhibitor represented by:

wherein:

R¹ and R², together with the nitrogen to which they are attached, form a 4-6 membered saturated heterocyclic ring A or form a 6-8 membered bicyclic, fused, bridged or spirocyclic heterocyclic ring A, which may have an additional heteroatom selected from the group consisting of O, S(0)_w (wherein w is 0, 1, or 2), and NR^a; heterocyclic ring A is substituted on an available carbon by a substituent represented by L-B; and wherein heterocyclic ring A is additionally and optionally substituted by one or two substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_-3alkyl and Ci_-3alkoxy; wherein Ci_-3alkyl and Ci_-3alkoxy may optionally be substituted by one or more fluorine atoms or a substituent selected from the group consisting of cyano, hydroxyl, and N(R^aR^b);

L is selected from the group consisting of Ci_-6alkylene and Ci_-6alkenylene; wherein Ci_-6alkylene and Ci_-6alkenylene may optionally be substituted by one or two substituents each independently selected from the group consisting of halogen and hydroxyl; and wherein one or two methylene units of L may optionally and independently be replaced by a moiety selected from the group consisting of a bond, -O-, -C(O)-, -O-C(O)-, -C(0)-0-, -NR^a-, -C(O)- NR^a-, -NR^a-C(0)-, -0-C(0)-NR^a-, -NR^a-C(0)-0-, -S(0)_w- (wherein w is 0, 1, or 2), -S(0)_w- NR^a-, and -NR^a-S(0)_w- ;

R¹ and R^J are selected independently for each occurrence from the group consisting of hydrogen, Ci_-6alkyl, C_2-6alkenyl, C_3-6cycloalkyl, heterocyclyl and heterocyclylcarbonyl; wherein Ci_-6alkyl, C2_-6alkenyl and C3_-6cycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of fluorine, hydroxyl, cyano, R^aR^bN-, R^aR^bN-carbonyl- and Ci_-3alkoxy; and wherein heterocyclyl and

heterocyclylcarbonyl may be optionally substituted by one or more substituents

independently selected from the group consisting of Ci_-6alkyl, C2_-6alkenyl, C2_-6alkynyl, C_3- ₆cycloalkyl, Ci_-6alkoxy, halo-Ci_-6-alkyl, hydroxyl-Ci_-6-alkyl, R^aR^bN-Ci_-6alkyl- and Ci_-6- alkoxy-C_l-6-alkyl group; and wherein if said heterocyclyl or heterocyclylcarbonyl contains a - NH moiety that nitrogen may optionally be substituted by one or more groups independently selected from the group consisting of Ci_-6alkyl, C_3-6alkenyl, C_3-6alkynyl, C_3-6Cycloalkyl, Ci. ₆alkyl-S(0)₂- and Ci_-6-alkylcarbonyl; or R¹ and R^J taken together with the nitrogen to which they are attached form a 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ring, which may have an additional heteroatom selected from the group consisting of O, N, and S(0)_w (wherein w is 0, 1 or 2); wherein the 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ring may be optionally substituted on carbon by one, two, or more substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, Ci_-6alkyl, Ci_-6alkoxy, R^aR^bN-, R^aR^bN-S0₂- and R^aR^bN-carbonyl-; wherein said Ci. ₆alkyl or Ci_-6alkoxy may optionally be substituted the group consisting of fluorine, hydroxyl, and cyano; and wherein if said 4-9 membered monocyclic, bridged bicyclic, fused bicyclic or spirocyclic heterocyclic ring contains a -NH moiety that nitrogen may be optionally substituted by a substituent selected from the group consisting of hydrogen, Ci_-6alkyl, C_3- ₆alkenyl, C_3-6alkynyl, C_3-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci_-6alkylcarbonyl-, Ci.

6alkoxycarbonyl-, R'R'N-carbonyl- and R'R'N-SCb-; wherein Ci_-6alkyl, C_3-6alkenyl, C_3- ₆alkynyl, C_3-6cycloalkyl, Ci_-6alkyl-S(0)₂-, Ci_-6alkylcarbonyl-, and Ci_-6alkoxycarbonyl- may optionally be substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, and cyano; R^a and R^b are independently selected, for each occurrence, from the group consisting of hydrogen and Ci_-3alkyl; wherein Ci_-3alkyl may optionally be substituted by one or more substituents selected from halogen, cyano, oxo and hydroxyl;

f p

R^p is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, cyano, Ci_-6alkoxy, R'R'N-, R'R'N-carbonyl-, R'R'N-SO?-, and R'R'N- carbonyl-N(R^a)-; or apharmaceutically acceptable salt, stereoisomer, ester or prodrug thereof; b) a GLP-l agonist and/or a DPP -4 inhibitor; and c) a pharmaceutically acceptable excipient.