WO2015142670A1

WO2015142670A1 - Anti-diabetic compounds, pharmaceutical compositions containing them, and method to treat diabetes

Info

Publication number: WO2015142670A1
Application number: PCT/US2015/020573
Authority: WO
Inventors: J. Thomas Ippoliti; Rebecca L. KUMMER; Nick HONIGSCHMIDT
Original assignee: Medisyn Technologies, Inc.
Priority date: 2014-03-15
Filing date: 2015-03-13
Publication date: 2015-09-24

Abstract

Described are compounds of Formula I as well as anti-hyperglycemic pharmaceutical compositions containing one or more of these compounds, and method to treat diabetes using the compounds and/or compositions. Also disclosed herein is a pharmaceutical composition for treating diabetes, the composition comprising an anti-hyperglycemic-effective amount of a compound as disclosed herein, or a pharmaceutically suitable salt thereof, in combination with a pharmaceutical carrier.

Description

ANTI-DIABETIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND METHOD TO TREAT DIABETES

BACKGROUND

Despite insulin being available as an injectable treatment for diabetes mellitus since the 1920's, diabetes continues to be a chronic public health issue worldwide. Thus, intense research continues to find alternative treatments for diabetes and related metabolic disorders. In recent years, considerable research effort has been focused on incorporating glucagon- like peptide- 1 (GLP-1), or to otherwise rationally influence a GLP-1 -moderated pathway, into a viable treatment for diabetes. GLP-1 is secreted by ileal L cells. Secretion is dependent upon the presence of nutrients in the lumen of the small intestine. GLP-1 is a potent anti-hyperglycemic hormone. Additionally, GLP- 1 is known to inhibit pancreatic β-cell apoptosis and stimulate the proliferation and differentiation of insulin-secreting β- cells. It is secreted as a pro-protein, which is then post-translationally modified to yield two physiologically active forms: GLP- 1(7-37) and GLP-l(7-36)-NH₂.

GLP-l(7-36)-NH₂ is a polypeptide having 30 amino acid residues (residues 7-36 of the proglucagon precursor), with a primary amide (NH₂) bonded to the carboxy terminus. GLP- 1(7-37) is a polypeptide having 31 amino acid residues (residues 7-37 of the proglucagon precursor). Both versions have the same insulinotropic hormone secretion action. For a discussion of GLP-1 and the functionally related insulinotropic hormones extendin-3 and extendin-4, see U.S. Pat. No. 5,424,286, issued June 13, 1995 to John Eng.

GLP-1 is the natural agonist for GLP-IR, a G protein-coupled receptor (GPCR) that is displayed on the surface of pancreatic β cells. Activation of GLP-IR augments glucose-dependent insulin release from β cells and, as noted above, promotes β cell survival. These properties are attractive for treatment of type 2 diabetes. However, GLP- 1 is rapidly degraded by peptidases in vivo. Its half-life in vivo is less than two (2) minutes. Efforts to develop small-molecule agonists of GLP-IR have not been successful, presumably because receptor activation requires contact over an extended surface. All non-natural GLP-IR agonists reported to date consist exclusively of a-amino acid residues. In the non- natural GLP-1R agonists now known, in vivo activity is prolonged via several approaches, such as varying the sequence of a-amino acid residues, incorporating stabilizing appendages, and/or utilizing specialized delivery strategies. GLP-1 derivatives have been approved for sale for use in humans in the United States. See, for example, Victoza®-brand liraglutide (rDNA origin) for injection, marketed commercially by Novo Nordisk, Inc., Plainsboro, New Jersey. See also U.S. Patent Nos. 6,268,343; 6,458,924; 7,235,627; and 8,114,833.

As used herein, the term "diabetes mellitus" or simply "diabetes" is used in a very broad sense to encompass metabolic disorders in which a subject has high blood sugar (i.e. , hyperglycemia). Hyperglycemic conditions have various etiologies, such as the pancreas does not produce enough insulin, or cells do not respond to the insulin that is produced. There are several recognized sub-types of diabetes, some of which are better understood than others. Type 1 diabetes is characterized by the complete failure of the body to produce insulin or the failure of the body to produce enough insulin. Type 2 diabetes generally results from insulin resistance, a condition in which cells fail to use insulin properly. Type 2 diabetes sometimes co-presents with an insulin deficiency. Gestational diabetes occurs when pregnant women without a previous diagnosis of diabetes develop hyperglycemia. Less common forms of diabetes include congenital diabetes (due to genetic defects relating to insulin secretion), cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes (also known as maturity onset diabetes of the young). These last two terms are catch-all phrases that refer to several hereditary forms of diabetes caused by mutations in a single, autosomal dominant gene (as contrasted to more complex, polygenic etiologies resulting in hyperglycemia).

SUMMARY OF THE INVENTION

Disclosed herein are compounds of Formula I:

wherein R¹, R², and R³ are independently selected from the group consisting of hydrogen, hydroxyl, halo, Ci-C₆ linear or branched alkyl, Ci-C₆ linear or branched alkyloxy, halo-substituted Ci-C₆ linear or branched alkyl, halo- substituted Ci-C₆ linear or branched alkyloxy, amino, mono-Ci-C6 linear or branched alkylamino, and di-Ci-C₆ linear or branched alkylamino, provided that at least two of R¹, R², and R³ are not hydrogen;

R⁴ is: Ci-C₆ linear or branched alkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, amino, and halo; or C3-C8 cycloalkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Ci-C₆ linear or branched alkyl, hydroxyl, amino, and halo; and

R⁵ and R⁶ are independently selected from the group consisting of Ci-C₆ linear or branched alkyl and Ci-C₆ linear or branched halo-alkyl; and

salts thereof.

R⁴ may also be unsubstituted or substituted C3-C6 linear or branched alkyl or unsubstituted or substituted C3-C6 cycloalkyl.

R⁴ may also be unsubstituted or substituted C3-C6 cycloalkyl.

R⁴ may also be unsubstituted C3-C6 cycloalkyl.

In any of the compounds disclosed above, R¹, R², and R³ may independently be selected from CI, F, Br, and I. Alternatively, R¹, R², and R³ may be chlorine. As noted above, and in the embodiments where all of R¹, R², and R³ are halo, R⁴ may be substituted or unsubstituted cyclopropyl.

Exemplary compounds are as follows:



salts thereof.

Also disclosed herein is a pharmaceutical composition for treating diabetes, the composition comprising an anti-hyperglycemic-effective amount of a compound as disclosed herein, or a pharmaceutically suitable salt thereof, in combination with a pharmaceutical carrier.

Lastly disclosed herein is a method of treating diabetes, the method comprising administering to a subject (including a human subject) an anti-hyperglycemic-effective amount of a pharmaceutical composition as recited herein.

Numerical ranges as used herein are intended to include every number and subset of numbers contained within that range, whether specifically disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 2 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

All references to singular characteristics or limitations of the present invention shall include the corresponding plural characteristic or limitation, and vice-versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made.

All combinations of method or process steps as used herein can be performed in any order, unless otherwise specified or clearly implied to the contrary by the context in which the referenced combination is made.

The methods of the present invention can comprise, consist of, or consist essentially of the essential elements and limitations of the method described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise useful in synthetic organic chemistry.

All patents, patent publications, and peer-reviewed publications (i.e., "references") cited herein are expressly incorporated by reference to the same extent as if each individual reference were specifically and individually indicated as being incorporated by reference. In case of conflict between the present disclosure and the incorporated references, the present disclosure controls.

BRIEF DESCRIPTION OF THE DRAWINGS jure 1 shows 'Fi NMR data for compound 2.

Fi. jure 2 shows 'Fi NMR data for compound 3.

Fi. jure 3 shows 'Fi NMR data for compound 4.

Fi. jure 4 shows 'Fi NMR data for compound 5.

Fi. jure 5 shows 'Fi NMR data for compound 7.

Fi. jure 6 shows 'Fi NMR data for compound 8.

Fi. jure 7 shows 'Fi NMR data for compound 9.

Fi. jure 8 shows 'Fi NMR data for compound 10.

Fi. jure 9 shows 'Fi NMR data for compound 11.

Figure 10 shows NMR data for compound 12.

Figure 11 shows NMR data for compound 14.

Figure 12 shows NMR data for compound 15. DETAILED DESCRIPTION

Definitions:

The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a fully saturated, straight, branched chain, or cyclic hydrocarbon radical, or combination thereof, and can include di- and multi-valent radicals, having the number of carbon atoms designated (e.g. , Ci-Cio means from one to ten carbon atoms, inclusive). Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec -butyl, cyclohexyl, (cyclohexyl)ethyl, cyclopropylmethyl, and homologs, and isomers thereof, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkyl," unless otherwise noted, also includes those derivatives of alkyl defined in more detail below as "heteroalkyl" and "cycloalkyl."

The term "alkenyl" means an alkyl group as defined above containing one or more double bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl,

2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), etc., and higher homologs and isomers.

The term "alkynyl" means an alkyl or alkenyl group as defined above containing one or more triple bonds. Examples of alkynyl groups include ethynyl, 1- and 3-propynyl,

3- butynyl, and the like, including higher homologs and isomers.

The terms "alkylene," "alkenylene," and "alkynylene," alone or as part of another substituent means a divalent radical derived from an alkyl, alkenyl, or alkynyl group, respectively, as exemplified by -(¾(¾(¾(¾-.

Typically, alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups will have from 1 to 24 carbon atoms. Those groups having 10 or fewer carbon atoms are preferred in the present invention. The term "lower" when applied to any of these groups, as in "lower alkyl" or "lower alkylene," designates a group having 10 or fewer carbon atoms.

"Substituted" refers to a chemical group as described herein that further includes one or more substituents, such as lower alkyl, aryl, acyl, halogen (e.g., alkylhalo such as

CF₃), hydroxy, amino, alkoxy, alkylamino, acylamino, thioamido, acyloxy, aryloxy, aryloxyalkyl, mercapto, thia, aza, oxo, both saturated and unsaturated cyclic hydrocarbons, heterocycles and the like. These groups may be attached to any carbon or substituent of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene moieties. Additionally, these groups may be pendent from, or integral to, the carbon chain itself. The term "aryl" is used herein to refer to an aromatic substituent, which may be a single aromatic ring or multiple aromatic rings which are fused together, linked covalently, or linked to a common group such as a diazo, methylene or ethylene moiety. The common linking group may also be a carbonyl as in benzophenone. The aromatic ring(s) may include, for example phenyl, naphthyl, biphenyl, diphenylmethyl and benzophenone, among others. The term "aryl" encompasses "arylalkyl" and "substituted aryl." For phenyl groups, the aryl ring may be mono-, di-, tri-, tetra-, or penta- substituted. Larger rings may be unsubstituted or bear one or more substituents.

"Substituted aryl" refers to aryl as just described including one or more functional groups such as lower alkyl, acyl, halogen, alkylhalo (e.g., CF₃), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, phenoxy, mercapto, and both saturated and unsaturated cyclic hydrocarbons which are fused to the aromatic ring(s), linked covalently or linked to a common group such as a diazo, methylene, or ethylene moiety. The linking group may also be a carbonyl such as in cyclohexyl phenyl ketone. The term "substituted aryl" encompasses "substituted arylalkyl."

The term "halogen" or "halo" is used herein to refer to fluorine, bromine, chlorine and iodine atoms.

The term "hydroxy" is used herein to refer to the group -OH.

The term "amino" is used to designate NRR', wherein R and R' are independently H, alkyl, alkenyl, alkynyl, aryl or substituted analogs thereof. "Amino" encompasses "alkylamino," denoting secondary and tertiary amines, and "acylamino" describing the group RC(0)NR'.

THF = tetrahydrofuran. TBD = triazabicyclodecene (i.e. , 1,5,7- triazabicyclo[4.4.0]dec-5-ene).

"Pharmaceutically-suitable salt" refers to any acid or base addition salt whose counter-ions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base or free acid are not vitiated by side effects ascribable to the counter-ions. A host of pharmaceutically-suitable salts are well known in the art. For basic active ingredients, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically-suitable salt by ion exchange procedures. Pharmaceutically-suitable salts include, without limitation, those derived from mineral acids and organic acids, explicitly including hydrohalides, e.g., hydrochlorides and hydrobromides, sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates, quinates, and the like. Base addition salts include those derived from alkali or alkaline earth metal bases or conventional organic bases, such as triethylamine, pyridine, piperidine, morpholine, N-methylmorpholine, and the like.

General Synthetic Approach:

The synthesis of compound 5 was completed in four steps as shown in Scheme 1. The overall convergent synthesis involved dividing the structure in two, synthesizing each half, and joining the two halves in a final convergent step. The synthesis shown in Scheme l is different from previous convergent synthetic routes that had been attempted but did not yield compound 5.

The difluoromethyl group was added to 3-ethoxy-4-hydroxybenzaldehyde at the para position using diethyl (bromodifluoromethyl)phosphonate. This reaction proceeds through a difluorocarbene intermediate, which is trapped by a phenolate anion and protonated by water to produce the difluoromethyl ether in the para position in 70% yield. Previous studies of this reaction have not included aldehydes as a starting material, and it was found that reaction conditions must be modified from those reported by Zafrani et al. when an aldehyde is present. The aldehyde was dissolved in acetonitrile and must be cooled to -78°C before the base is added to prevent the Cannizzaro reaction from taking place, in which the hydroxide ion attacks the aldehyde and results in an alcohol and a carboxylic acid. This important modification increased yields on average by about 30 to 40%. Reductive amination of the aldehyde to form the secondary amine was carried out using sodium triacetoxyborohydride in 56.5% yield. This mild reducing agent was used instead of hydrogenation of an imine to avoid hydrogenating the cyclopropyl group to a straight chain propyl group.

Creating the amide bond in compound 4 was accomplished through an acylation of

2,4,6-trichloroaniline (6) using bromoacetyl bromide in a 77% yield. See Scheme 2.

Compounds 3 and 4 were then joined in the final synthetic step, an S 2 reaction between the amine on compound 3 and the electrophilic alpha-bromo carbon on compound 4. See Scheme 1. The final product was isolated by column chromatography in 40% yield. This low yield can be attributed to using two equivalents of 3 so that one equivalent could serve as the base.

Scheme 1. Reagents: (a) KOH, CH₃CN:H₂0 (1:1), -78°C; (b) Na(AcO)₃BH, THF; (c) THF.

Scheme 2. Reagents: (d) TBD, THF, 0°C.

Scheme 3. : (a) KOH, CH₃CN:H₂0 (1:1), -78°C; (b) Na(AcO)₃BH, THF.

7

Scheme 4. Reagents (d) TBD, THF, 0°C; (e) THF, 120°C, 10 min, Biotage® microwave reactor.

Scheme 6. Reagents: (a) KOH, CH₃CN:H₂0 (1:1), -78°C; (b) Na(AcO)₃BH, THF; (c) THF.

Scheme 7. Reagents: (a) KOH, CH₃CN:H₂0 (1:1), -78°C; (b) Na(AcO)₃BH, THF; (c) THF; (d) TBD, anh. THF, 0°C.

18

Scheme 8. Reagents: (b) Na(AcO)₃BH, THF; (c) THF.

20

Scheme 9. Reagents: (b) Na(AcO)₃BH, THF; (c) THF.

J

Scheme 10. Reagents: (b) Na(AcO)₃BH, THF; (c) THF; (d) TBD, anh. THF, 0°C. Analogous compounds can be made using the same route by using the appropriate starting materials. All of the starting materials are available commercially from a number of commercial suppliers, including Sigma-Aldrich, St. Louis, MO. Experimental:

4-(difluoromethoxy)-ethoxybenzaldehyde 2: Addition of diethyl

(bromodifluoromethyl) phosphonate to aldehyde 1 (Scheme 1). Compound 1 (1.00 g, 6.02 mmol) was dissolved in CH₃CN (30 mL). Solution of 1 was stirred and cooled to - 78°c in a bath of dry ice and acetone. KOH (6.75 g, 120.4 mmol) was dissolved in deionized H₂0 (30 mL) and dripped into the solution of 1. The flask was then sealed with a septum. Diethyl (bromodifluoromethyl) phosphonate (3.21 g, 12.04 mmol) was dripped into the sealed flask and reaction mixture was allowed to warm to rt. The reaction mixture was then left to stir overnight. The work up involved extraction with ether followed by drying the organic layer over Na₂S0₄ and gravity filtration into a round bottom flask. Solvent was removed under reduced pressure and compound 2 remained as a brown oil (910 mg, 70%). *H NMR (400 MHz): δ 9.93 (d, J = 3.1 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.45 (dd, J = 8.2, 1.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.69 (t, J = 74.5 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H). See Figure 1.

N-(4-(difluoromethyoxy)-3-ethoxybenzyl)cyclopropanamine 3: Mono- alkylation of cyclopropylamine by 2 (Scheme 1). Compound 2 was dissolved in THF (1.5 mL) and added to a 20 mL microwave vial containing a stir bar. Cyclopropylamine (52 mg, 0.90 mmol) was also dissolved in THF (2.0 mL) and added to the solution of 2 drop- wise with stirring. 1 drop of acetic acid was added to catalyze the reaction, and the flask was sealed and put under N₂ pressure to stir. After 2 hours of stirring at rt, the seal was removed and Na(AcO)₃BH (300 mg, 1.4 mmol) was added slowly. The reaction mixture was again sealed and put under N₂ pressure and allowed to stir for 18 hours at rt. The reaction was quenched with 10% NaOH, and the product was extracted with dichloromethane and dried over K₂CC>3. Solvent was removed under reduced pressure and the crude product was column chromatographed (80:20 Hexanes: Ethyl acetate) on a silica gel column using the Biotage® (Uppsala, Sweden) Isolera® One flash chromatography system. The column was then flushed with isopropanol/ethyl acetate to extract the product, and compound 3 was isolated (130 mg, 56.5%). 'H-NMR (400 MHz): δ 7.09 (d, J = 8.1

Hz, 1H), 6.92 (d, J = 1.9 Hz, 1H), 6.84 (dd, J = 8.1, 1.9 Hz, 1H), 6.73-6.35 (m, 1H), 4.10 (dq, J = 8.9, 7.1 Hz, 4H), 3.79 (s, 2H), 2.16 (d, J = 4.4 Hz, 1H), 2.16-2.12 (m, 1H), 1.45- 1.41 (m, 3H), 0.47-0.35 (m, 4H). See Figure 2.

2-bromo-N-(2,4,6-trichlorophyenyl)acetamide 4: Acetylation of amine 6 (Scheme 2). A 100 mL round bottom flask and 25 mL Erlenmeyer flask were flame dried and put under N₂ pressure. To the round bottom, compound 6 (1.00 g, 5.09 mmol) dissolved in anhydrous THF (25 mL) was added via syringe. l,5,7-triazabicyclo[4.4.0]dec- 5-ene (TBD) was added to the solution of 6 and the reaction mixture was stirred until all the TBD had dissolved. The mixture was then cooled to 0°C in an ice bath. Into the Erlenmeyer flask, anhydrous THF (15 mL) was added followed by bromoacetyl bromide (3.09 g, 15. 3 mmol). The solution of bromoacetyl bromide was then dripped into the round bottom flask and the reaction mixture was allowed to warm to rt and stir for 18 h under N₂ pressure. The liquid was decanted from the round bottom flask into water (300 mL). The solid was isolated using vacuum filtration and then washed with MeOH cooled to -78°C to rid the product of excess TBD and yield compound 4 as a white solid (1.24 g, 77%). 'H-NMR (400 MHz): δ 7.89 (s, 1H), 7.42 (s, 2H), 4.08 (s, 3H). See Figure 3.

2-(cyclopropyl(4-(difluoromethoxy)-3-ethoxybenzyl)amino)-N-(2,4,6- trichlorophenyl)acetamide 5: Alkylation of amine 3 with amide 4 (Scheme 1).

Compound 3 (130 mg, 0.51 mmol) was dissolved in THF (1 mL) and added to a microwave vial containing a stir bar. Compound 4 was dissolved in THF (1 mL) and dripped into the stirring solution of compound 3. The vial was sealed with a rubber septum and the reaction mixture was allowed to stir under N₂ pressure at rt for 64 h. The solid that had formed was removed via vacuum filtration and the liquid layer was added to a round bottom flask. Solvent was removed under reduced pressure and a yellow solid resulted as a crude product. The crude product was purified using the Biotage® Isolera™ One flash chromatography system (70:30 Hexanes: Ethyl acetate) to yield compound 5 (50 mg,

40%). 'H-NMR (400 MHz): δ 8.50 (s, 1H), 7.39 (s, 2H), 7.13-7.11 (m, 1H), 6.88 (dq, J = 4.2, 2.1 Hz, 2H), 6.56 (t, J = 75.4 Hz, 1H), 4.07 (dq, J = 5.2, 4.2 Hz, 2H), 3.88 (s, 2H), 3.47 (s, 2H), 2.14-2.09 (m, 1H), 1.42 (t, J = 6.9 Hz, 3H), 0.59 (d, J = 5.1 Hz, 4H). See Figure 4.

Compound 8: Organic synthesis of ring-closed structure (Schemes 3 and 4).

Some synthetic steps are the same as those used to reach the target molecule and can be afforded as described previously. Only those reactions that are different from reactions previously described are presented here. 2-(cyclopropylamino)-N-(2,4,6-trichlorophenyl)acetamide 7: Monoalkylation of cyclopropylamine by 4 (Scheme 4). Compound 4 (800 mg, 2.52 mmol) was added to an Erlenmeyer flask and dissolved in THF (8 mL). Cyclopropylamine (1.44 g, 25.5 mmol) was added via gas-tight syringe to a microwave vial containing a stir bar and dissolved in THF (8 mL). Next, the solution of compound 4 was dripped into the solution of cyclopropylamine using a gas-tight syringe and the mixture was micro waved at 120°C for 10 min in the Biotage® microwave reactor. White crystals were present in the mixture and were filtered away from the organic layer using a vacuum filtration. Organic solvent was removed under reduced pressure and compound 7 remained as a white solid (690 mg, 93.2% yield). 'H-NMR (400 MHz): δ 8.78 (s, 1H), 7.39 (s, 2H), 3.58 (s, 3H), 2.37 (dt, 7 = 6.8, 3.2 Hz, 1H), 1.43 (s, 1H), 0.55-0.50 (m, 5H). See Figure 5.

l-cyclopropyl-2-(4-(difluoromethoxy)-3-ethoxyphenyl)-3-(2,4,6-trichlorophen- yl)imidazolidin-4-one 8: Alkylation of amine 7 with aldehyde 2 (Scheme 3).

Compound 2 (171 mg, 0.79 mmol) was added to a round bottom flask containing a stir bar and dissolved in THF (5 mL). Compound 7 (211 mg, 0.72 mmol) was added to the solution of 2 with stirring. 20 min after the addition of compound 2, one drop of acetic acid was added and the reaction mixture was allowed to stir for an additional 30 min. Next, Na(AcO)₃BH (229 mg, 1.1 mmol) was added and the mixture was allowed to stir overnight for 21 h under N₂ pressure. Workup involved the addition of 10% NaOH until the solution was slightly basic, the addition of water to dissolve any remaining solid, and extraction DCM. The organic layer was dried over K₂CO₃, solvent was removed under reduced pressure and the crude product was column chromatographed (70:30 Hexanes : Ethyl Acetate) using the Biotage® Isolera® One flash chromatography system and an Ultra silica gel column to yield (60 mg, 17%) compound 8. *H-NMR (400 MHz): δ 7.29 (dd, 7 = 2.2, 1.0 Hz, 1H), 7.21 (dd, 7 = 2.2, 1.0 Hz, 1H), 7.11 (s, 1H), 6.94 (d, 7 = 8.1 Hz, 1H), 6.86-6.83 (m, 1H), 6.53 (td, 7 = 75.1, 1.0 Hz, 1H), 5.72 (s, 1H), 4.01 (q, 7 = 7.0 Hz, 2H), 3.92 (dd, 7 = 15.2, 0.9 Hz, 1H), 3.60-3.55 (m, 1H), 2.01-1.97 (m, 1H), 1.40 (q, 7 = 6.5 Hz, 4H), 0.88-0.82 (m, 1H), 0.47-0.41 (m, 2H), 0.25-0.20 (m, 1H). See Figure 6.

Compound 2: Addition of diethyl (bromodifluoromethyl)phosphonate to aldehyde 1 (Scheme 5). To a 250 mL round bottom flask was added 3-ethoxy-4- hydroxybenzaldehyde (1) (l.OOg, 6.018mmol) dissolved in 30 mL acetonitrile (CH₃CN).

The solution was cooled to -78°C with a dry ice and acetone bath. In a separate vial, potassium hydroxide (a) (KOH) (6.75g, 120.36mml) was dissolved in 30 mL deionized water and dripped into the reaction flask. The flask was sealed and allowed to cool down to -78°C for 10 minutes before proceeding to the next step. Bromodifluoromethyl diethylphosphonate (DBP) (3.21g, 12.036mmol) was added. The reaction solution was allowed to warm up to room temperature and stir, capped and under nitrogen, for approximately 24 hours. To work up the reaction, the solid that had formed was filtered via gravity filtration and the solution was transferred to a 250 mL separatory funnel and extracted three times with 60 mL portions of diethyl ether. The collected organic layer was dried with sodium sulfate, filtered via gravity filtration, and concentrated via rotary evaporation and high vacuum to yield the final product (2) as a yellow oil. A ¹H NMR taken in CDC1₃ showed desired product (0.710g, 55%). Ή-NMR (400 MHz): δ 9.93 (s, 1H), 7.48 (d, 7 = 1.8 Hz, 1H), 7.44 (dd, 7 = 7.9, 1.8 Hz, 1H), 7.31 (d, 7 = 8.1 Hz, 1H), 6.69 (t, 7 = 74.5 Hz, 1H), 4.18 (q, 7 = 7.0 Hz, 2H), 1.48 (t, 7 = 7.0 Hz, 4H).

Compound 9: Reductive amination (Scheme 5). To a 250 mL round bottom flask was added compound 5 (414mg, 1.91mmol) dissolved in 25 mL THF.

Cyclopentylamine (148mg, 1.74mmol) was added to the reaction flask. Four drops of acetic acid were used to catalyze the reaction. It was capped, placed under nitrogen, and allowed to stir for 15 minutes before proceeding. Then, sodium triacetoxyborohydride (b) (553mg, 2.61mmol) was added, and the solution was allowed to stir for approximately 24 hours. The solution was taken off stirring and basified with 140 drops of 10% NaOH. Work up involved extracting three times with 50 mL portions of dichloromethane, drying with potassium carbonate, filtering via gravity filtration, and concentrating via rotary evaporation. A *H NMR taken in CDC1₃ shows desired product (9)(0.480g, 88%). *H- NMR (400 MHz): δ 8.21 (s, ), 7.08 (d, 7 = 8.1 Hz, 1H), 6.95 (d, 7 = 1.8 Hz, 1H), 6.84 (dd, 7 = 8.1, 1.9 Hz, 1H), 6.73-6.35 (m, 1H), 4.13-4.07 (m, 2H), 3.73 (s, 2H), 3.10 (quintet, 7 = 6.7 Hz, 1H), 1.89-1.81 (m, 3H), 1.73-1.64 (m, 2H), 1.61-1.48 (m, 6H), 1.46-1.40 (m, 4H). See Figure 7.

Compound 10: Final S_N2 (Scheme 5). Compound 9 (480mg, 1.68mmol) was dissolved in 3 mL THF and added to a 25 mL round bottom flask. Compound 3 (267mg,

0.84mmol) was dissolved in a separate vial in 3 mL THF and dipped into the reaction flask. The flask was capped, set under nitrogen, and allowed to react for approximately 24 hours. The solution was concentrated by blowing off THF with nitrogen, then ~6 mL ether was added to crash out the protonated amine. The ether was decanted and filtered with gravity filtration into a 25 mL round bottom flask. The product was concentrated via rotary evaporation and a ¹H NMR was taken in CHCI₃. Spectrum showed a mixture of isomers. To separate, a TLC was run in 80:20 hexanes: ethyl acetate. Two spots of r.f. 0.15 and 0.26 were visible under UV light. A 50g SNAP column was run on the Biotage Isolera One flash chromatography instrument to yield the desired product (10)(0.066g, 15%). Ή-NMR (400 MHz): δ 8.92 (s, 1H), 7.37 (d, 7 = 3.4 Hz, 2H), 7.12-7.10 (m, 1H), 6.91 (dd, 7 = 5.5, 1.9 Hz, 2H), 6.55 (t, 7 = 75.5 Hz, 1H), 4.05 (q, 7 = 7.0 Hz, 2H), 3.73 (s, 2H), 3.31 (s, 2H), 3.27 (d, 7 = 8.2 Hz, 1H), 1.91-1.86 (m, 2H), 1.73-1.67 (m, 2H), 1.57 (q, 7 = 9.5 Hz, 6H), 1.41 (t, 7 = 6.9 Hz, 3H). See Figure 8.

Compound 11: Reductive animation (Scheme 6): Compound 2 (303mg, 1.40mmol) was added to a 100 mL round bottom flask and dissolved in 10 mL THF. Cyclohexylamine (347mg, 3.50mmol) was dissolved in 5 mL THF and added to the reaction flask. One drop of acetic acid was added. The reaction solution was capped, set under nitrogen, and allowed to stir for 20 minutes. Sodium triacetoxyborohydride (b) (891mg, 4.20mmol) was added and the solution was allowed to stir under nitrogen overnight. 110 drops of 10% NaOH solution were added to basify. Next, 20 mL deionized water was added and the reaction solution was extracted three times with 50 mL portions of DCM. The collected organic layer was dried with potassium carbonate, filtered by gravity, and concentrated via rotary evaporation. A ¹H NMR taken in CDCI₃ showed desired product (ll)(0.400g, 95%). *H-NMR (400 MHz): δ 7.08 (d, 7 = 8.0 Hz, 1H), 6.96 (d, 7 = 1.9 Hz, 1H), 6.84 (dd, 7 = 8.0, 2.0 Hz, 1H), 6.54 (t, 7 = 75.8 Hz, 1H), 4.13-4.07 (m, 3H), 3.77 (d, 7 = 4.2 Hz, 2H), 2.49-2.43 (m, 1H), 1.95 (s, 1H), 1.92-1.88 (m, 2H), 1.73 (td, 7 = 8.2, 4.4 Hz, 3H), 1.63-1.57 (m, 2H), 1.44 (td, 7 = 7.1, 4.5 Hz, 4H), 1.35-1.29 (m, 2H), 1.27-1.17 (m, 3H), 1.15-1.09 (m, 3H). See Figure 9.

Compound 12: Final S_N2 (Scheme 6). Compound 11 (534mg, 1.80mmol) was dissolved in 3 mL THF and added to a 25 mL round bottom flask. Compound 3 (283mg, 0.89mmol) was dissolved in 3 mL THF and added to the reaction flask. The reaction was capped, set under nitrogen, and allowed to stir for approximately 120 hours. The solution was concentrated by blowing off THF with nitrogen, and then -12 mL ether was added to crash out the protonated amine. Solid was filtered via vacuum filtration, and the filtrate was concentrated via rotary evaporation. A ¹H NMR showed crude product. To purify, the Biotage Isolera One flash chromatography system (80:20 Hexanes: Propyl Acetate) was used to yield final, pure product (12) (0.191g, 40%). *H-NMR (400 MHz): δ 8.93 (s, 1H), 7.37-7.36 (m, 2H), 7.12-7.10 (m, 1H), 6.90 (dq, 7 = 4.2, 2.1 Hz, 2H), 6.54 (t, 7 = 75.5 Hz, 1H), 4.04 (q, 7 = 7.0 Hz, 2H), 3.74-3.69 (m, 3H), 3.33 (s, 2H), 2.65 (td, 7 = 8.7, 4.6 Hz, 1H), 1.95-1.92 (m, 2H), 1.84 (d, 7 = 12.9 Hz, 2H), 1.67 (d, 7 = 12.3 Hz, 1H), 1.42-1.37 (m, 4H), 1.36-1.30 (m, 2H), 1.27-1.17 (m, 4H), 1.15-1.09 (m, 1H). See Figure 10.

Compound 14: Acetylation of tribromoaniline (Scheme 7). A 500 mL round bottom flask and a 125 mL Erlenmeyer flask were flame dried and set under nitrogen. Tribromoaniline (13)(5.00g, 15.16mmol) was dissolved in 125 mL anhydrous THF and added to the reaction flask via syringe. l,5,7-triazabicyclo[4.4.0]dec-5-ene (d)(TBD) (2.1 lg, 15.16mmol) was added to the solution. The mixture was cooled to 0°C in an ice bath. Meanwhile, bromoacetyl bromide (9.18g, 45.48mmol) was dissolved in 75 mL anhydrous THF in the Erlenmeyer flask. The mixture was canulated into the cooled reaction flask and the solution was allowed to warm to room temperature and stir for approximately 24 hours under nitrogen. The solution from the round bottom was decanted away into 1200 mL of deionized water and solid precipitated out immediately. The mixture was vacuum filtered to isolate the solid product and washed with 250 mL of methanol cooled to -78°C. Filtrate was cloudy, so 100 mL room temperature MeOH was added to crash out more precipitate, and the solid was isolate via vacuum filtration again to yield white solid product (14)(4.77g, 70%). *H-NMR (400 MHz): δ 7.83 (s, 1H), 7.80 (d, 7 = 3.8 Hz, 2H), 4.06 (s, 2H). See Figure 11.

Compound 15: Final S_N2 (Scheme 7). Compound 11 (395mg, 1.32mmol) was dissolved in 4 mL THF and added to a 25 mL round bottom flask. Compound 14 (297mg, 0.66mmol) was dissolved in 4 mL THF and added to the reaction flask. The reaction was capped, set under nitrogen, and allowed to stir for approximately 120 hours. The solution was concentrated via rotary evaporation, and some solid began to crash out. 20 mL DCM was added and the solid, protonated amine, was isolated via vacuum filtration. The filtrate was concentrated via rotary evaporation. A ^JH NMR showed crude product. To purify, the Biotage Isolera One flash chromatography system (70:30 Hexanes: Propyl Acetate) was used to yield final, pure product (15) (0.191g, 40%). *H-NMR (400 MHz): δ 8.95 (s, 1H), 7.73 (s, 2H), 7.12-7.10 (m, 1H), 6.92 (dd, 7 = 6.3, 1.9 Hz, 2H), 6.55 (t, 7 = 75.4 Hz, 1H), 4.05 (q, 7 = 7.0 Hz, 2H), 3.72 (s, 2H), 3.33 (s, 2H), 2.69-2.64 (m, 1H), 1.95 (d, 7 = 11.1 Hz, 2H), 1.85 (d, 7 = 12.8 Hz, 2H), 1.67 (d, 7 = 12.4 Hz, 1H), 1.43-1.37 (m, 4H), 1.39- 1.31 (m, 3H), 1.27-1.18 (m, 2H), 1.12 (dd, 7 = 14.0, 10.9 Hz, 1H). See Figure 12.

Compound 17: Reductive amination (Scheme 8). To a 250 mL round bottom flask was added compound 16 (500mg, 3.01mmol) dissolved in 25 mL THF. Cyclobutylamine (535mg, 7.52mmol) was added to the reaction flask. Two drops of acetic acid were used to catalyze the reaction. It was capped, placed under nitrogen, and allowed to stir for 60 minutes before proceeding. Then, sodium triacetoxyborohydride (b) (1.914g, 9.03mmol) was added, and the solution was allowed to stir for approximately 16 hours. The solution was taken off stirring and basified with 8mL 10% NaOH. Work up involved extracting three times with 40 mL portions of Ethyl Acetate, drying with potassium carbonate, filtering via gravity filtration, and concentrating via rotary evaporation. A ¹H NMR taken in CDC1₃ shows desired product (17)(0.605g, 97%).

Compound 18: Final S_N2 (Scheme 8). Compound 17 (605 mg, 2.92mmol) was dissolved in 10 mL THF and added to a 25 mL round bottom flask. Compound 4 (463mg, 1.46mmol) was dissolved in a separate vial in 10 mL THF and dripped into the reaction flask. The flask was capped, set under nitrogen, and allowed to react for approximately 24 hours. A white solid was removed via vacuum filtration. The product was concentrated via rotary evaporation and a ^JH NMR was taken in CDCI₃. Spectrum showed a mixture of isomers. To separate, a TLC was run in 70:30 hexanes: ethyl acetate. Two spots of r.f.

0.20 and 0.33 were visible under UV light. A lOOg SNAP column was run on the Biotage Isolera One flash chromatography instrument to yield the desired product (18) (0.369g, 55%).

Compound 19: Reductive amination (Scheme 9). To a 50 mL round bottom flask was added compound 16 (500mg, 3.01mmol) dissolved in 10 mL THF.

Cyclohexylamine (745.8mg, 7.52mmol) was added to the reaction flask. Two drops of acetic acid were used to catalyze the reaction. It was capped, placed under nitrogen, and allowed to stir for 60 minutes before proceeding. Then, sodium triacetoxyborohydride (b)

(1.914g, 9.03mmol) was added, and the solution was allowed to stir for approximately 16 hours. The solution was taken off stirring and basified with 8mL 10% NaOH. Work up involved extracting three times with 40 mL portions of dichloromethane, drying with potassium carbonate, filtering via gravity filtration, and concentrating via rotary evaporation. A ^!H NMR taken in CDC1₃ shows desired product (19)(0.693g, 92%).

Compound 20: Final S_N2 (Scheme 9). Compound 19 (693 mg, 2.78mmol) was dissolved in 10 mL THF and added to a 25 mL round bottom flask. Compound 4 (441mg,

1.39mmol) was dissolved in a separate vial in 10 mL THF and dripped into the reaction flask. The flask was capped, set under nitrogen, and allowed to react for approximately 24 hours. A white solid was removed via vacuum filtration. The product was concentrated via rotary evaporation and a ¹H NMR was taken in CDCI₃. Spectrum showed a mixture of isomers. To separate, a TLC was run in 65:35 hexanes: propyl acetate. Two spots of r.f. 0.13 and 0.29 were visible under UV light. A 50g SNAP column was run on the Biotage Isolera One flash chromatography instrument to yield the desired product (20)(0.445g, 66%).

Compound 14: Acetylation of tribromoaniline (Scheme 10). A 500 mL round bottom flask and a 125 mL Erlenmeyer flask were flame dried and set under nitrogen. Tribromoaniline (13)(5.00g, 15.16mmol) was dissolved in 125 mL anhydrous THF and added to the reaction flask via syringe. l,5,7-triazabicyclo[4.4.0]dec-5-ene (d)(TBD) (2.1 lg, 15.16mmol) was added to the solution. The mixture was cooled to 0°C in an ice bath. Meanwhile, bromoacetyl bromide (9.18g, 45.48mmol) was dissolved in 75 mL anhydrous THF in the Erlenmeyer flask. The mixture was canulated into the cooled reaction flask and the solution was allowed to warm to room temperature and stir for approximately 24 hours under nitrogen. The solution from the round bottom was decanted away into 1200 mL of deionized water and solid precipitated out immediately. The mixture was vacuum filtered to isolate the solid product and washed with 250 mL of methanol cooled to -78°C. Filtrate was cloudy, so 100 mL room temperature MeOH was added to crash out more precipitate, and the solid was isolate via vacuum filtration again to yield white solid product (14)(4.77g, 70%).

Compound 21 Final S_N2 (Scheme 10). Compound 17 (645mg, 2.91mmol) was dissolved in 10 mL THF and added to a 50 mL round bottom flask. Compound 14 (542mg, 1.46mmol) was dissolved in 10 mL THF and added to the reaction flask. The reaction was capped, set under nitrogen, and allowed to stir for approximately 24 hours. A white solid was isolated via vacuum filtration. The filtrate product was concentrated via rotary evaporation. A ^JH NMR showed crude product. A TLC was run in 70:30

Cyclohexane:Propyl Acetate. Two spots of r.f. 0.125 and 0.225 were visible under UV light. To purify, the Biotage Isolera One flash chromatography system was used to yield final, pure product (21) (0.372g, 43%).

Nutritional Compositions:

The present disclosure includes nutritional compositions for inhibiting hyperglycemia. Such compositions include any food or preparation for human consumption (including for enteral or parenteral consumption) which when taken into the body (a) serve to nourish or build up tissues or supply energy and/or (b) maintain, restore or support adequate nutritional status or metabolic function.

The nutritional composition comprises at least one compound as described herein admixed with an edible foodstuff and may either be in a solid or liquid form. Additionally, the composition may include edible macronutrients, vitamins and minerals in amounts desired for a particular use. The amount of such ingredients will vary depending on whether the composition is intended for use with normal, healthy infants, children or adults having specialized needs such as those which accompany hyperglycemic metabolic conditions.

Examples of macronutrients which may be added to the composition include but are not limited to edible fats, carbohydrates and proteins. Examples of such edible fats include but are not limited to coconut oil, soy oil, and mono- and diglycerides. Examples of such carbohydrates include but are not limited to glucose, edible lactose and hydrolyzed search. Additionally, examples of proteins which may be utilized in the nutritional composition include but are not limited to soy proteins, electrodialysed whey,

electrodialysed skim milk, milk whey, or the hydrolysates of these proteins.

With respect to vitamins and minerals, the following may be added to the nutritional compositions described herein: calcium, phosphorus, potassium, sodium, chloride, magnesium, manganese, iron, copper, zinc, selenium, iodine, and Vitamins A, E, D, C, and the B complex. Other such vitamins and minerals may also be added.

Examples of nutritional compositions disclosed herein include but are not limited to infant formulas, dietary supplements, dietary substitutes, and rehydration compositions. Nutritional compositions of particular interest include but are not limited to those utilized for enteral and parenteral supplementation for infants, specialist infant formulas, supplements for the elderly, and supplements for those with hyperglycemia.

The nutritional composition of the present invention may also be added to food even when supplementation of the diet is not required. For example, the composition may be added to food of any type including but not limited to margarines, modified butters, cheeses, milk, yoghurt, chocolate, candy, snacks, salad oils, cooking oils, cooking fats, meats, fish and beverages.

In a preferred version, the nutritional composition is an enteral nutritional product, more preferably, an adult or pediatric enteral nutritional product. This composition may be administered to adults or children experiencing stress or having specialized needs due to chronic or acute disease states. The composition may comprise, in addition to GLP-1 analogs described herein, macronutrients, vitamins and minerals as described above. The macronutrients may be present in amounts equivalent to those present in human milk or on an energy basis, i.e., on a per calorie basis.

Methods for formulating liquid or solid enteral and parenteral nutritional formulas are well known in the art. An enteral formula, for example, may be sterilized and subsequently utilized on a ready-to-feed (RTF) basis or stored in a concentrated liquid or powder. The powder can be prepared by spray drying the formula prepared as indicated above, and reconstituting it by rehydrating the concentrate. Adult and pediatric nutritional formulas are well known in the art and are commercially available (e.g., Similac®-brand and Ensure®-brand formulas from Ross Products Division, Abbott Laboratories, Columbus, Ohio). A GLP-1 analog produced in accordance with the present disclosure may be added to commercial formulas of this type.

The energy density of the nutritional compositions in liquid form may range from about 0.6 Kcal to about 3 Kcal per ml. When in solid or powdered form, the nutritional supplements may contain from about 1.2 to more than 9 Kcals per gram, preferably about 3 to 7 Kcals per gram. In general, the osmolality of a liquid product should be less than 700 mOsm and, more preferably, less than 660 mOsm. Pharmaceutical Compositions:

Also disclosed herein are pharmaceutical compositions comprising one or more of the compounds described herein or a pharmaceutically suitable salt thereof as described herein. More specifically, the pharmaceutical composition may comprise one or more of the compounds disclosed herein as well as a standard, well-known, non-toxic

pharmaceutically suitable carrier, adjuvant or vehicle such as, for example, phosphate buffered saline, water, ethanol, polyols, vegetable oils, a wetting agent or an emulsion such as a water/oil emulsion. The composition may be in either a liquid, solid or semisolid form. For example, the composition may be in the form of a tablet, capsule, ingestible liquid or powder, injectable, suppository, or topical ointment or cream. Proper fluidity can be maintained, for example, by maintaining appropriate particle size in the case of dispersions and by the use of surfactants. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Besides such inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, perfuming agents, and the like.

Suspensions, in addition to the active compounds, may comprise suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.

Solid dosage forms such as tablets and capsules can be prepared using techniques well known in the art of pharmacy. For example, compounds produced as described herein can be made into tablets with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. Capsules can be prepared by incorporating these excipients into a gelatin capsule along with antioxidants and the relevant GLP- 1 analog.

For intravenous administration, the compounds disclosed herein may be incorporated into commercial formulations such as Intralipid®-brand fat emulsions for intravenous injection. ("Intralipid" is a registered trademark of Fresenius Kabi AB, Uppsala, Sweden.) Where desired, the individual components of the formulations may be provided individually, in kit form, for single or multiple use. A typical intravenous dosage of a representative compound as described herein is from about 0.1 mg to 100 mg daily and is preferably from 0.5 mg to 3.0 mg daily. Dosages above and below these stated ranges are specifically within the scope of the claims.

Possible routes of administration of the pharmaceutical compositions include, for example, enteral (e.g., oral and rectal) and parenteral. For example, a liquid preparation may be administered, for example, orally or rectally. Additionally, a homogenous mixture can be completely dispersed in water, admixed under sterile conditions with

physiologically acceptable diluents, preservatives, buffers or propellants in order to form a spray or inhalant. The route of administration will, of course, depend upon the desired effect and the medical stated of the subject being treated. The dosage of the composition to be administered to the patient may be determined by one of ordinary skill in the art and depends upon various factors such as weight of the patient, age of the patient, immune status of the patient, etc., and is ultimately at the discretion of the medical professional administering the treatment. With respect to form, the composition may be, for example, a solution, a dispersion, a suspension, an emulsion or a sterile powder which is then reconstituted. The composition may be administered in a single daily dose or multiple doses.

The present disclosure also includes treating hyperglycemic disorders in mammals, including humans, by administering an anti-hyperglycemic-effective amount of one or more of the compounds described herein. In particular, the compositions of the present invention may be used to treat diabetic and hyperglycemic conditions of any and all description. To the extent the compositions impart a feeling of satiation, the compositions may also be used to treat obesity and to ease weight loss.

It should be noted that the above-described pharmaceutical and nutritional compositions may be utilized in connection with non-human animals, both domestic and non-domestic, as well as humans.

Testing for Anti-Hyperglycemic Activity:

Select compounds disclosed herein were tested for their anti-hyperglycemic activity. Eli Lilly and Company (Indianapolis, IN) operates a drug candidate testing service known as PD2 (for Phenotypic Drug Discovery), which includes testing for anti- hyperglycemic activity. This testing includes assays for glucagon-like peptide 1 (GLP-1) modulation activity, including GLP- 1 Secretion mSTC- 1 SP / CRC ( Stimulation and

ECso); GLP-1 Secretion hNCI CRC (EC₅₀); Cytolethality hNCI LDH Secretion CRC (EC5₀); GLP-1 Secretion Glu-Tag CRC (EC 50); Growth Hormone Secretion Primary Rat Hepatocyte SP / CRC (% Stimulation / EC₅₀); CSR Panel (Ki, % Efficacy); PDE Profiling (IC5₀); cAMP NCI (EC50); and Calcium Mobilization NCI (EC₅₀). The following compounds were tested using these assays and showed potent efficacy:

It is predicted that the other compounds disclosed herein have the same or similar activity.

GLP-1 is a potent anti-hyperglycemic hormone that induces glucose-dependent insulin secretion and suppresses glucagon secretion. The glucose dependency of GLP- 1 is deemed important because GLP-1 does not stimulate insulin secretion and cause hypoglycemia when plasma glucose concentrations are in the normal fasting range. Prior art ELISA's can be used to measure the ability of a compound to modulate GLP-1 secretion. See, for example, Dungan & Buse (2005) "Glucagon-Like Peptide 1 -Based Therapies for Type 2 Diabetes: A Focus on Exenatide," Clinical Diabetes 23(2):56-62; and Kim & Brubaker (2006) "Glucagon-Like Peptide 1 Secretion by the L-Cell," Diabetes 55(2):570-577.

REFERENCES CITED

The following documents are incorporated herein by reference:

Zafrani, Y., Sod-Moriah, G., Segall, Y. Diethyl bromodifluoromethylphosphonate: a highly efficient and environmentally benign difluoro carbene precursor.

Tetrahedron. 2009, 65(27): 5278-5283.

Abdel-Magid, A.F. et al. Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride: Studies on direct and indirect reductive amination procedures. /. Org. Chem. 1996, 61(11): 3849-3862.

Claims

CLAIMS What is claimed is:

1. A compound of Formula I:

R⁴ is: Ci-C₆ linear or branched alkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, amino, and halo; or C₃-C8 cycloalkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Ci-C₆ linear or branched alkyl, hydroxyl, amino, and halo; and

R⁵ and R⁶ are independently selected from the group consisting of Ci-C₆ linear or branched alkyl and Ci-C₆ linear or branched halo-alkyl; or

a salt thereof.

2. A compound as claimed in Claim 1 , wherein R⁴ is unsubstituted or substituted C₃-C6 linear or branched alkyl or unsubstituted or substituted C₃-C6 cycloalkyl.

3. A compound as claimed in Claim 1, wherein R⁴ is unsubstituted or substituted C₃-C6 cycloalkyl.

4. A compound as claimed in Claim 1, wherein R⁴ is unsubstituted C₃-C6 cycloalkyl.

5. A compound as claimed in any one of Claims 1 to 4, wherein R¹, R², and R³ are independently selected from CI, F, Br, and I.

6. A compound as claimed in Claim 5, wherein R¹, R², and R³ are chlorine.

7. A compound as claimed in Claim 5, wherein R⁴ is substituted or unsubstituted cyclopropyl.

8. A compound as claimed in Claim 1, which is:

31

32

salts thereof.

9. A pharmaceutical composition for treating diabetes, the composition comprising an anti-hyperglycemic-effective amount of a compound as recited in any one of Claims 1-8, or a pharmaceutically suitable salt thereof, in combination with a pharmaceutical carrier.

10. A method of treating diabetes, the method comprising administering to a subject an anti-hyperglycemic-effective amount of a pharmaceutical composition as recited in Claim 9.