WO2008124518A1 - Oxo-dihydroisoindole sulfonamide compounds as modulators of the cck2 receptor - Google Patents

Abstract

Certain oxo-dihydroisoindote sulfonamide compounds of Formula (I): wherein R1 and R2 are each independently fluoro or chloro; R3 is H or methyl; R4 is chloro or bromo; one of X and Y is a carbonyl and the other is a carbonyl or -CH2-; or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof are CCK2 receptor modulators useful in the treatment of CCK2 receptor-mediated diseases.

Description

OXO-DIHYPROISOINDOLE SULFONAMIDE COMPOUNDS AS MODULATORS OF THE CCK2 RECEPTOR

Field of the Invention

The present invention relates to certain oxo-dihydroisoindole sulfonamide compounds, pharmaceutical compositions containing them, and methods of using them for the treatment of disease states, disorders, and conditions mediated by the cholecystokinin 2 (CCK2) receptor.

Background of the Invention The gastrins and cholecystokinins are structurally related neuropeptides that exist in gastrointestinal tissue, gastrinomas and, in the case of the cholecystokinins, the central nervous system (Walsh, J. H. Gastrointestinal Hormones, L. R. Johnson, ed., Raven Press, New York, 1994, p. 1 ). Natural cholecystokinin is a 33 amino acid peptide (CCK-33), the C-terminal five amino acids of which are identical to those of gastrin. A review of CCK receptors, ligands and the activities thereof was provided by de Tullio, P. et al. (Exp. Opin. Invest. Drugs, 2000, 9(1 ), 129-146). Gastrin acts on CCK2 receptors (otherwise known as gastrin or CCK-B receptors) and cholecystokinin acts on both CCK2 and CCK1 receptors (otherwise known as cholecystokinin or CCK-A receptors).

Gastrin and cholecystokinin are key regulators of gastrointestinal function. Gastrin is one of three primary stimulants of gastric acid secretion. In addition to the acute stimulation of gastric acid, gastrin has a trophic effect on the gastrointestinal mucosa and is implicated as a trophic hormone of several adenocarcinomas, including pancreatic, gastric, colorectal, esophageal and small cell lung carcinomas. Cholecystokinin stimulates intestinal motility, gallbladder contraction, and pancreatic enzyme secretion, inhibits gastric emptying, and is known to have trophic actions on the pancreas through increasing pancreatic enzyme production. Cholecystokinin also has various effects in the central nervous system, including regulation of anxiety, satiety, and pain.

CCK2 receptor antagonists have undergone evaluation for the treatment of advanced pancreatic cancer or pancreatic adenocarcinoma (JB95008 (gastrazole) from the James Black Foundation and Janssen Pharmaceutica N. V.), pain (L-365,260 (Colycade) from ML Laboratories and Panos), gastro-esophageal reflux disease (GERD) (YF-476 from Yamanouchi and Ferring Research Institute), gastroduodenal ulcers and reflux esophagitis (Z-360 from Zeria Pharmaceuticals), and anxiety disorders, cancer (particularly colon cancer) and peptic ulcer (CR 2945 (itriglumide) from Rotta).

Thus, CCK2 receptor modulators are useful for the treatment of certain cancers, gastro-intestinal disorders, anxiety, eating disorders, and pain. Various aryl sulfonamides have been reported in: WO2002/087568,

WO2002/088073, and WO2002/100825. Sulfonamide-based CCK2 receptor modulators have been reported in: US2004/0224983, US2005/0038032, and US2005/0043310. Sulfonamide-based dual CCK1/CCK2 modulators were disclosed in US2006/069286. There remains a need for potent CCK2 receptor modulators with desirable pharmaceutical properties.

Summary of the Invention

Certain oxo-dihydroisoindole sulfonamide derivatives have now been found to have CCK2 receptor modulating activity. Thus, the invention is directed to the general and preferred embodiments defined, respectively, by the independent and dependent claims appended hereto, which are incorporated by reference herein.

In one general aspect the invention relates to a compound of the following Formula (I):

wherein R¹ and R² are each independently fluoro or chloro;

R³ is H or methyl;

R⁴ is chloro or bromo; one of X and Y is a carbonyl and the other is a carbonyl or -CH₂-; or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof. In a further general aspect, the invention relates to pharmaceutical compositions each comprising: (a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; and (b) a pharmaceutically acceptable excipient.

In another general aspect, the invention is directed to a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by CCK2 receptor activity, comprising administering to the subject in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof.

In certain preferred embodiments of the inventive method, the disease, disorder, or medical condition is selected from: cancer, gastro-intestinal disorders, anxiety, eating disorders, and pain. Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

Detailed Description

The invention may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples. For the sake of brevity, the disclosures of the publications, including patents, cited in this specification are herein incorporated by reference.

As used herein, the terms "including", "containing" and "comprising" are used herein in their open, non-limiting sense.

The term "alkyl" refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me, which also may be structurally depicted by the symbol "/"), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:

A "heterocycloalkyl" refers to a monocyclic ring structure that is saturated or partially saturated and has from 4 to 7 ring atoms per ring structure selected from carbon atoms and up to two heteroatoms selected from nitrogen, oxygen, and sulfur. The ring structure may optionally contain up to two oxo groups on sulfur ring members. Illustrative entities, in the form of properly bonded moieties, include:

The term "heteroaryl" refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of cycloalkyl, heterocycloalkyl, and heteroaryl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected. The term "halogen" represents chlorine, fluorine, bromine or iodine. The term

"halo" represents chloro, fluoro, bromo or iodo.

The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. Where the term "substituted" is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted. Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to embrace hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, lsotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶CI, ¹²⁵I, respectively. Such isotopically labeled compounds are useful in metabolic studies (preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, lsotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

When referring to any formula given herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the moiety for the variable appearing elsewhere. In other words, where a variable appears more than once, the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula.

In preferred embodiments of Formula (I), R¹ and R² are both fluoro. In other preferred embodiments, R¹ and R² are both chloro.

In preferred embodiments, R³ is H. In other preferred embodiments, R³ is methyl. In other preferred embodiments, R³ is methyl in the (R) configuration.

In preferred embodiments, R⁴ is bromo.

In preferred embodiments, X and Y are each a carbonyl. In other preferred embodiments, X is -C H ₂- and Y is a carbonyl. In other preferred embodiments, X is a carbonyl and Y is -CH₂-. In certain preferred embodiments, the compound of Formula (I) is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

The invention includes also pharmaceutically acceptable salts of the compounds of Formula (I), preferably of those described above and of the specific compounds exemplified herein, and methods of treatment using such salts.

A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented by Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, et al., "Pharmaceutical Salts", J. Pharm. ScL₁ 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley- VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. A compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, and mandelates. If the compound of Formula (I) contains a basic nitrogen, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

If the compound of Formula (I) is an acid, such as a carboxylic acid or sulfonic acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. The invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I), and treatment methods employing such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

Examples of prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of Formula (I). Examples of amino acid residues include the twenty naturally occurring amino acids, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, by derivatizing free carboxyl groups of structures of Formula (I) as amides or alkyl esters. Examples of amides include those derived from ammonia, primary Ci-ealkyl amines and secondary di(Ci-6alkyl) amines. Secondary amines include 5- or 6-membered heterocycloalkyl or heteroaryl ring moieties. Examples of amides include those that are derived from ammonia, Ci-3alkyl primary amines, and di(Ci-₂alkyl)amines. Examples of esters of the invention include Ci_-7alkyl, C₅-₇cycloalkyl, phenyl, and phenyl(Ci-₆alkyl) esters.

Preferred esters include methyl esters. Prodrugs may also be prepared by derivatizing free hydroxy groups using groups including hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following procedures such as those outlined in Adv. Drug Delivery Rev. 1996, 19, 1 15. Carbamate derivatives of hydroxy and amino groups may also yield prodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxy groups may also provide prodrugs. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester, optionally substituted with one or more ether, amine, or carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, is also useful to yield prodrugs. Prodrugs of this type may be prepared as described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including ether, amine, and carboxylic acid functionalities.

The present invention also relates to pharmaceutically active metabolites of the compounds of Formula (I), which may also be used in the methods of the invention. A "pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of a compound of Formula (I) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini, et al., J. Med. Chem. 1997, 40, 2011-2016; Shan, et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 224-331 ; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991 ).

The compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of the present invention are useful as modulators of the CCK2 receptor in the methods of the invention. As such modulators, the compounds may act as antagonists, agonists, or inverse agonists. "Modulators" include both inhibitors and activators, where "inhibitors" refer to compounds that decrease, prevent, inactivate, desensitize or down-regulate CCK2 receptor expression or activity, and "activators" are compounds that increase, activate, facilitate, sensitize, or up-regulate CCK2 receptor expression or activity.

The term "treat" or "treating" as used herein is intended to refer to administration of an active agent or composition of the invention to a subject for the purpose of effecting a therapeutic or prophylactic benefit through modulation of CCK2 receptor activity. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through modulation of CCK2 receptor activity. The term "subject" refers to a mammalian patient in need of such treatment, such as a human.

Accordingly, the invention relates to methods of using the compounds described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated by CCK2 receptor activity, such as: cancer, gastro-intestinal disorders, anxiety, eating disorders, and pain. Symptoms or disease states are intended to be included within the scope of "medical conditions, disorders, or diseases."

Cancer includes, for example, pancreatic cancer (such as pancreatic adenocarcinoma), esophageal cancer, gastric cancer, colorectal cancer, and colon cancer, and small cell lung carcinoma. Gastro-intestinal disorders include those in which lower gastric activity or lower acid secretion is desirable. Examples of gastro- intestinal disorders include gastro-esophageal reflux disease (GERD), gastrointestinal ulcers, gastroduodenal ulcers, peptic ulcers, reflux esophagitis, Barrett's esophagus, antral G cell hyperplasia, pernicious anaemia, and Zollinger-Ellison syndrome.

Particularly, as modulators of the CCK2 receptor, the compounds of the present invention are useful in the treatment or prevention of gastro-espohageal reflux disease, pancreatic cancer, colon cancer, pain, and anxiety.

In treatment methods according to the invention, an effective amount of at least one compound according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. An "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the compounds of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.

Once improvement of the patient's disease, disorder, or condition has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long- term basis upon any recurrence of symptoms.

In addition, the compounds of the invention may be used in combination with additional active ingredients in the treatment of the above conditions. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by CCK2 receptor activity or that are active against another target associated with the particular condition, disorder, or disease, such as CCK1 receptor modulators. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of a compound according to the invention), decrease one or more side effects, or decrease the required dose of the compound according to the invention.

The compounds of the invention are used, alone or in combination with one or more other active ingredients, to formulate pharmaceutical compositions of the invention. A pharmaceutical composition of the invention comprises: (a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; and (b) a pharmaceutically acceptable excipient.

A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a compound of the invention and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. Delivery forms of the pharmaceutical compositions containing one or more dosage units of the compounds of the invention may be prepared using suitable pharmaceutical excipients and compounding techniques now or later known or available to those skilled in the art. The compositions may be administered in the inventive methods by oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration, or oral administration. For oral administration, the compounds of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds may be formulated to yield a dosage of, e.g., from about 0.05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily. Oral tablets may include a compound according to the invention mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, compounds of the invention may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the compound of the invention with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol. Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceuticaliy-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents. The compounds of this invention may also be administered by non-oral routes.

For example, the compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses may range from about 1 to 1000 μg/kg/minute of compound, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1 % to about 10% of drug to vehicle. Another mode of administering the compounds of the invention may utilize a patch formulation to affect transdermal delivery.

Compounds of the invention may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.

Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formula (I). Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0 ⁰C and the reflux temperature of the solvent.

SCHEME A

Acids A1 where R is OH are commercially available or are prepared as described by Wasserman, H. H. et al. (J. Am. Chem. Soc. 1953, 75, 2527-2528). Acids A1 are converted into acyl azides A1 (where R is N₃) by reaction with thionyl chloride to form the corresponding acyl chloride, and subsequent treatment with NaN₃. Maleimides are prepared by reaction of maleic anhydride with a suitable benzyl amine to form an acrylic acid derivative, followed by cyclization to the maleimide. Reaction of acyl azides A1 with maleimides A2 in a solvent such as te/f-butanol gives protected amines A3. Deprotection provides the corresponding free amines (not shown). For example, where the protecting group is a Boc group, deprotection is accomplished by treatment with TFA or HCI, in a solvent such as DCM or dioxane. Reaction of the resulting free amines with benzothiadiazole sulfonyl chlorides in the presence of base, such as pyridine or triethylamine, gives compounds A4, which are embodiments of Formula (I). Where R³ is a chiral methyl group, suitable benzyl amines are prepared using methods known in the literature.

SCHEME B

B3 B4 Maleimides A3 are reduced to a mixture of indolones B1 and B2 by treatment with a suitable reducing agent, such as NaBH₄, in a solvent such as methanol. The intermediate isomeric hydroxyl-indolones B1 and B2 are separated and treated with a suitable reducing agent, such as triethylsilane or NaBH₄, in a solvent such as DCM or TFA, or mixtures thereof, to give indolones B3 and B4. The indolones are then converted into compounds of Formula (I), where 1 ) X is a carbonyl and Y is -CH₂-; and 2) X is -CH₂- and Y is a carbonyl, as described in Scheme A.

Additional procedures may be used to prepare compounds of Formula (I), such as those described in the following Examples and those described in US2004/0224983, US2005/0038032, and US2005/0043310, each of which is hereby incorporated by reference.

Those skilled in the art will recognize that several of the chemical transformations described above may be performed in a different order than that depicted in the above Schemes.

Compounds of Formula (I) may be converted to their corresponding salts using methods known to those skilled in the art. For example, compounds of Formula (I) may be treated with a base such as NaOH in a solvent such as methanol (MeOH) or water to provide the corresponding sodium salt forms.

Compounds prepared according to the schemes described above may be obtained as single enantiomers, diastereomers, or regioisomers, by enantio-, diastero-, or regiospecific synthesis, or by resolution. Compounds prepared according to the schemes above may alternately be obtained as racemic (1 :1 ) or non-racemic (not 1 :1) mixtures or as mixtures of diastereomers or regioisomers. Where racemic and non- racemic mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods known to one skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation. Where regioisomeric or diastereomeric mixtures are obtained, single isomers may be separated using conventional methods such as chromatography or crystallization.

The following examples are provided to further illustrate the invention and various preferred embodiments. EXAMPLES

Chemistry:

In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated. Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt). Where solutions are "dried," they are generally dried over a drying agent such as Na₂SO₄ or MgSO₄. Where mixtures, solutions, and extracts were

"concentrated", they were typically concentrated on a rotary evaporator under reduced pressure. Normal-phase flash column chromatography (FCC) was performed on silica gel

(Siθ₂) using prepackaged cartridges, eluting with EtOAc/hexanes unless otherwise noted.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model

DRX spectrometers at 400 or 500 MHz. The format of the ¹H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).

Chemical names were generated using ChemDraw Version 6.0.2 (CambridgeSoft, Cambridge, MA) or ACD/Name Version 9 (Advanced Chemistry Development, Toronto, Ontario, Canada).

EXAMPLE 1 : Benzoπ ,2.51thiadiazole-4-sulfonic acid [6-bromo-2-(2,4-dichloro-benzyl)- 1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4-vπ-amide.

Step A: Methyl 4.5-dibromo-2-furoate. Neat methyl 2-furoate (20.0 g, 158 mmol) was stirred as AICI₃ (45.0 g, 337 mmol) was carefully added in several portions. Neat Br₂ (54.0 g, 338 mmol) was then added carefully via dropping funnel over 30 min, giving a very thick, partially solid mixture. The thick mixture was allowed to stir for 30 min after addition was complete. The reaction was cooled in an ice bath as the AICI₃ was quenched by careful addition of crushed ice. The resulting mixture was extracted with Et₂θ (3x). The combined organic extracts were washed with 10% aq. Na₂S₂θ₃, dried and concentrated to give a yellow solid. The crude product was purified by FCC to provide 26.19 g (58%) of the desired dibromofuroate as a pale yellow solid. ¹H NMR (CDCI₃): 7.18 (s, 1 H), 3.90 (s, 3H). Step B: 4,5-Dibromo-2-furoic acid. To a suspension of methyl 4,5-dibromo-2- furoate (26.19 g, 92.2 mmol) in THF (60 mL) was added LiOH (3 M in water, 60 mL, 180 mmol). The biphasic mixture was stirred for 4 h. The reaction mixture was poured into 1 N HCI and extracted with DCM (4x). The combined organic layers were dried and concentrated to provide 24.59 g (99%) of the acid as an off-white solid. ¹H NMR (CD₃OD): 7.30 (s, 1 H).

Step C: 4-Bromo-2-furoic acid. 4,5-Dibromo-2-furoic acid (24.51 g, 90.8 mmol) was dissolved in a mixture of water (280 mL) and aq. NH₄OH (33% NH₃; 80 mL) and cooled in an ice bath. The mixture was stirred rapidly as zinc dust (6.23 g, 95.3 mmol) was added in portions while keeping the internal temperature below 7 ⁰C. The mixture was stirred at 0 ⁰C for 30 min. An additional portion of zinc dust (0.5 g, 7.6 mmol) was added and the mixture was allowed to stir at 0 ⁰C for 30 min. The reaction was acidified to pH 1 with cone. HCI causing precipitation of the product. The mixture was cooled to 10 ⁰C, and the product was collected by suction filtration, washed with water, and air dried to provide 8.0 g (46%) of the desired acid. Additional product could be obtained by extraction of the filtrate with DCM and recrystallization of the crude extract from water. ¹H NMR (CDCI₃): 7.76 (d, J = 0.8, 1 H), 7.14 (d, J = 0.8, 1 H). Step D: 4-Bromo-furan-2-carbonyl azide. A suspension of 4-bromo-2~furoic acid

(1.87 g, 9.8 mmol) in thionyl chloride (5 mL) was heated at reflux for 1 h. The mixture became homogeneous during reflux. The thionyl chloride was removed in vacuo, and the crude acid chloride was azeotroped three times with toluene to remove traces of thionyl chloride. The acid chloride was stirred in acetone (15 mL) at 0 ⁰C, and a solution of NaN₃ (702 mg, 10.8 mmol) in water (5 mL) was added dropwise via pipet. The mixture was allowed to stir for 1 h at 0 ⁰C then was concentrated without external heating. The residue was diluted with satd. aq. NaHCO₃ and extracted with DCM (3x). The combined organic layers were dried and concentrated without heating to give 1.85 g (87%) of the acyl azide as a white solid. ¹H NMR (CDCI₃): 7.65 (d, J = 0.9, 1 H), 7.26 (d, J = 0.9, 1 H).

Step E: 3-(2,4-Dichloro-benzylcarbamoyl)-acrylic acid. To a solution of maleic anhydride (1.0 g, 10 mmol) in acetic acid (10 mL) was added 2,4-dichlorobenzyl amine (1.34 g, 10 mmol). The mixture was allowed to stir overnight then was concentrated. Water (50 mL) was added causing precipitation of the product acid. The white solid was collected by suction filtration, washed with water, and dried to provide 1.81 g (66%) of the pure acid. ¹H NMR (CD₃OD): 7.49 (d, J = 2.1 , 1 H), 7.46 (d, J = 8.3, 1 H), 7.33 (dd, J = 8.4, 2.2, 1 H), 6.48 (d, J = 12.5, 1 H), 6.26 (d, J = 12.5, 1 H), 4.54 (s, 2H).

Step F: N-2,4-Dichlorobenzyl maleimide. A mixture of 3-(2,4-dichloro- benzylcarbamoyl)-acrylic acid (1.70 g, 6.2 mmol), NaOAc (508 mg, 6.2 mmol), and acetic anhydride (5 mL) was stirred and heated at 120 ⁰C for 30 min. The mixture was concentrated, and the residue was stirred vigorously with sat'd. aq. NaHCO₃. The resulting mixture was extracted with DCM (3x). The combined organic layers were dried and concentrated. The crude product was purified by FCC to provide 0.66 g (42%) of the desired maleimide as a yellow solid. ¹H NMR (CDCI₃): 7.39 (d, J = 2.1 , 1 H), 7.20 (del, J = 8.3, 2.1 , 1 H), 7.12 (d, J = 8.4, 1 H), 6.78 (s, 2H), 4.78 (s, 2H).

Step G: f6-Bromo-2-(2,4-dichloro-benzyl)-1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4- vn-carbamic acid tert-butyl ester. A stirred solution of 4-bromo-furan-2-carbonyl azide (200 mg, 0.93 mmol) and N-2,4-dichlorobenzyl maleimide (461 mg, 1.8 mmol) in degassed tert-butanol (2 ml_) was heated at reflux for 2 h. The resulting dark red solution was concentrated, and the residue was purified by FCC. The desired product was isolated as a pale yellow foam (150 mg, 32%). ¹H NMR (CDCI₃): 8.78 (d, J = 1.0, 1 H), 8.68 (s, 1 H), 7.59 (d, J = 1.2, 1 H), 7.41 (s, 1 H), 7.21 (d, J = 0.9, 2H), 4.90 (s, 2H), 1.53 (s, 9H).

Step H: 4-Amino-6-bromo-2-(2,4-dichloro-benzyl)-isoindole-1 ,3-dione. [6- Bromo-2-(2,4-dichloro-benzyl)-1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4-yl]-carbamic acid tert-butyl ester (130 mg, 0.26 mmol) was stirred in a mixture of DCM (2 mL) and TFA (1 mL) for 2 h. The mixture was concentrated, and purified by reverse phase HPLC (YMC ODSA Ci₈ column, 0 to 99% gradient of acetonitrile in water with 0.05% TFA) to provide 93 mg (89%) of the desired amine as a yellow solid. ¹H NMR (CDCI₃): 7.40 (d, J = 1.8, 1 H), 7.29 (d, J = 1.4, 1 H), 7.19 (dd, J = 8.4, 2.0, 1 H), 7.16 (d, J = 8.1 , 1 H)₁ 7.06 (d, J = 1.4, 1 H), 5.27 (bs, 2H), 4.88 (s, 2H).

Step I: Benzo[1 ,2,51thiadiazole-4-sulfonic acid f6-bromo-2-(2,4-dichloro-benzyl)- 1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4-vπ-amide. A mixture of 4-amino-6-bromo-2-(2,4- dichloro-benzyl)-isoindole-1 ,3-dione (35 mg, 0.09 mmol) and benzo[1 ,2,5]thiadiazole-4- sulfonyl chloride (145 mg, 0.62 mmol) in diglyme (0.15 ml) was heated at 140 ⁰C for 4 h. The mixture was allowed to cool, and the residue was diluted with satd. aq. NaHCO₃ and extracted with DCM (3x). The combined organic layers were dried and concentrated. The product was purified by FCC to provide the desired sulfonamide as a tan solid (5 mg, 10%). MS (ESI): mass calcd. for C₂IHnBrCI₂N₄O₄S₂, 595.88; m/z found, 597, 599 [M+H]⁺. HPLC: fe = 11.39 min. ¹H NMR (CDCI₃): 9.59 (bs, 1 H), 8.40 (dd, J = 7.1 , 1.0, 1 H), 8.28 (dd, J = 8.8, 1.0, 1 H), 8.16 (d, J = 1.4, 1 H), 7.76 (dd, J = 8.8, 7.0, 1 H), 7.55 (d, J = 1 .4, 1 H), 7.41 (d, J= 2.0, 1 H), 7.20 (dd, J = 8.3, 2.0, 1 H), 7.16 (d, J = 8.3, 1 H), 4.85 (s, 2H). EXAMPLE 2: Benzoπ .2.51thiadiazole-4-sulfonic acid r6-bromo-2-(2,4-difluoro-benzvn- 1 , 3-d i oxo-2, 3-d ihydro-1 H-isoindol-4-yll-amide.

Step A: 3-(2,4-Difluoro-benzylcarbamoyl)-acrylic acid. The title compound (3.90 g, 81 %) was prepared from 2,4-difluorobenzyl amine (2.86 g, 20 mmol) as described in Example 1 , Step E. ¹H NMR (CD₃OD): 7.50-7.41 (m, 1 H), 7.00-6.91 (m, 2H), 6.45 (d, J = 12.5, 1 H), 6.25 (d, J = 12.6, 1 H), 4.87 (s, 2H).

Step B: N-2,4-Difluorobenzyl maleimide. The title compound (2.87 g, 87%) was prepared from 3-(2,4-difluoro-benzylcarbamoyl)-acrylic acid (3.87 g, 16 mmol) as described in Example 1 , Step F, heating at 90 ⁰C for 2 h. ¹H NMR (CDCI₃): 7.33-7.25 (m, 1 H), 6.86-6.76 (m, 2H), 6.74 (s, 2H), 4.72 (s, 2H).

Step C: r6-Bromo-2-(2,4-difluoro-benzyl)-1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4-yli- carbamic acid tert-butyl ester and 4-Amino-6-bromo-2-(2,4-difluoro-benzyl)-isoindole- 1 ,3-dione. A stirred solution of 4-bromo-furan-2-carbonyl azide (EXAMPLE 1 , Step D) (1.58 g, 7.2 mmol) and N-2,4-difluorobenzyl maleimide (1.34 g, 6.0 mmol) in degassed tert-butanol (6 mL) was heated at 70 ⁰C for 24 h. The resulting dark red solution was concentrated, and the residue was purified by FCC to provide the two title compounds.

[6-Bromo-2-(2,4-difluoro-benzyl)-1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4-yl]-carbamic acid tert-butyl ester was obtained as a yellow foam (0.46 g, 16%). ¹H NMR (CDCI₃): 8.75 (d, J = 1.3, 1 H), 8.69 (bs, 1 H), 7.56 (d, J = 1.4, 1 H), 7.40-7.33 (m, 1 H), 6.87-6.78 (m, 2H), 4.83 (s, 2H), 1.53 (s, 9H).

4-Amino-6-bromo-2-(2,4-difluoro-benzyl)-isoindole-1 ,3-dione was obtained as a yellow foam (0.37 g, 17%). ¹H NMR (CDCI₃): 7.38-7.30 (m, 1 H), 7.26 (d, J = 1.3, 1 H), 7.04 (d, J = 1.3, 1 H), 6.86-6.77 (m, 2H), 5.25 (bs, 2H), 4.81 (s, 2H). Step D: BenzoH ,2,51thiadiazole-4-sulfonic acid f6-bromo-2-(2,4-difluoro-benzyl)-

1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4-yli-amide. The title compound (10 mg, 20%) was prepared from 4-amino-6-bromo-2-(2,4-difluoro-benzyl)-isoindole-1 ,3-dione (34 mg, 0.09 mmol) and benzo[1 ,2,5]thiadiazole-4-sulfonyl chloride (150 mg, 0.64 mmo!) as described in Example 1 , Step I, with heating at 100 ⁰C for 2 days. MS (ESI): mass calcd. TOr C_2IHnBrF₂N₄O₄S₂, 563.94; m/z found, 565, 567 [M+H]⁺. HPLC: ^ = 10.63 min. ¹H NMR (CDCI₃): 9.60 (bs, 1 H), 8.39 (dd, J = 7.0, 1.0, 1 H), 8.26 (dd, J = 8.8, 1.0, 1 H), 8.14 (d, J = 1.4, 1 H), 7.75 (dd, J = 8.8, 7.1 , 1 H), 7.53 (d, J = 1.3, 1 H), 7.38-7.28 (m, 1 H), 6.88-6.77 (m, 2H), 4.78 (s, 2H).

EXAMPLE 3: (/?)-BenzoH ,2,51thiadiazole-4-sulfonic acid (6-bromo-2-f1-(2,4-difluoro- phenyl)-ethvn-1 ,3-dioxo-2,3-dihvdro-1 H-isoindol-4-yl}-amide.

Step A: S-(S)-2-Methyl-propane-2-sulfinic acid 2,4-difluoro-benzylideneamide. A suspension of 2,4-difluorobenzaldehyde (0.61 g, 4.3 mmol), (S)-ferf-butanesulfinamide (0.47 g, 3.9 mmol), and powdered anhydrous CuSO₄ (1.24 g, 7.8 mmol) was stirred in DCM (8 mL) overnight. The reaction mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated to give the crude N-sulfinyl imine as a viscous yellow oil. Purification by FCC provided 0.81 g (84%) of the N-sulfinyl imine as a pale yellow viscous oil. ¹H NMR (CDCI₃): 8.83 (s, 1 H), 8.02 (m, 1 H), 6.98 (m, 1 H), 6.90 (m, 1 H), 1.27 (s, 9H).

Step B: S-(S)-2-Methyl-propane-2-sulfinic acid 1-(f?H1-(2,4-difluoro-phenyl)- ethylj-amide. To a stirred solution of the above N-sulfinyl imine (0.77 g, 3.1 mmol) in DCM (20 mL) at -50 ⁰C, was added a solution of MeMgBr (3.0 M in Et₂O, (2.1 mL, 6.3 mmol). The reaction mixture was stirred at -50 ⁰C for 1 h then allowed to warm to rt overnight. The reaction was quenched by the addition of satd. aq. NH₄CI, and the mixture was poured into water, and extracted with DCM (3x). The combined organic layers were dried and concentrated. Purification by FCC provided the title compound as a mixture of diastereomers: ratio of S-(S)₁I-(R) to S-(S)₁I-(S) = 95:5 by ¹H NMR; 90% de. Combined yield for both diastereomers was 0.80 g (99%) of a colorless viscous oil. Major diastereomer: ¹H NMR (CDCI₃): 7.32 (m, 1 H), 6.87 (m, 1 H), 6.80 (m, 1 H), 4.82 (dq, J = 6.8, 4.5, 1 H), 3.32 (d, J = 4.1 , 1 H), 1.56 (d, J = 6.8, 3H), 1.19 (s, 9H).

Step C: (R)-1-(2,4-Difluoro-phenyl)-ethylamine hydrochloride. To a stirred solution of the above sulfinamide (90% de) (0.80 g, 3.06 mmol) in MeOH (7 ml_) was added satd. methanolic HCI (2 mL). After 2 h, the heterogeneous mixture was concentrated to approximately 2 mL, and then the amine hydrochloride was fully precipitated by the addition of Et₂θ (10 mL). The white solid HCI salt was collected by suction filtration, washed with Et₂O, and dried under vacuum to give 573 mg (97%) of the title compound as fine white crystals. Enantiomeric purity (99% ee) was determined by chiral HPLC (Chiralcel AS column, 90:10 hexanes/isopropyl alcohol with 0.1 % diethylamine, 0.7 mL/min) on the benzamide derivative of the amine. R enantiomer: t_R = 18.1 min. S enantiomer: t_R = 21.0 min. [α]_D ²⁰ = -3.7° (H₂O, c = 4.37 g/100 mL). ¹H NMR (MeOH-CZ₄): 7.57 (m, 1 H), 7.12 (m, 1 H), 7.09 (m, 1 H), 4.72 (q, J = 7.0, 1 H), 1.65 (d, J = 6.8, 3H). Step D: 3-π-(f?)-(2,4-Difluoro-phenyl)-ethylcarbamovn-acrylic acid. A suitable quantity of the free base of (R)-1-(2,4-difluoro-phenyl)-ethylamine was obtained by dissolving the corresponding HCI salt in water, basifying with NaOH, and extracting with DCM. To a solution of maleic anhydride (5.0 g, 50 mmol) in acetic acid (50 mL) was added (R)-1-(2,4-difluoro-phenyl)-ethylamine (7.86 g, 50 mmol). The mixture was allowed to stir overnight then was partially concentrated and poured into 0.5 N HCI (300 mL). The resulting white solid was collected by suction filtration, washed with water, and dried to provide 11 .12 g (87%) of the pure acid. ¹H NMR (CD₃OD): 7.46-7.36 (m,

I H), 6.98-6.90 (m, 2H), 6.47 (d, J = 12.6, 1 H), 6.25 (d, J = 12.6, 1 H), 5.27 (q, J = 7.0, 1 H), 1.50 (d, J = 7.0, 3H). Step E: N-M -(R)-I -(2,4-difluoro-phenyl)-ethvπ maleimide. The title compound

(3.11 g, 67%) was prepared from 3-[1 -(R)-I -(2,4-difluoro-phenyl)-ethylcarbamoyl]- acrylic acid (5.0 g, 19.6 mmol) as described in Example 1 , Step F, heating at 80 ⁰C for

I I h. ¹H NMR (CDCI₃): 7.59 (dt, J = 8.7, 6.4, 1 H), 6.91-6.84 (m, 1 H), 6.79-6.73 (m, 1 H), 6.64 (s, 2H), 5.61 (q, J = 7.3, 1 H), 1.77 (d, J = 7.3, 3H). Step F: (RH6-Bromo-2-ri-(2,4-difluoro-phenyl)-ethvπ-1 ,3-dioxo-2,3-dihvdro-1 H- isoindol-4-yiy-carbamic acid tert-butyl ester. The title compound (170 mg, 8%) was obtained from 4-bromo-furan-2-carbonyl azide (EXAMPLE 1 , Step D) (1.0 g, 4.6 mmol) and N-[1 -(R)-I -(2,4-difluoro-phenyl)-ethyl] maleimide (1.1 g, 4.6 mmol) as described in Example 1 , Step G. ¹H NMR (CDCI₃): 8.73 (d, J = 1.4, 1 H), 8.70 (bs, 1 H), 7.66 (dt, J = 8.6, 6.4, 1 H), 7.52 (d, J = 1.5, 1 H), 6.95-6.87 (m, 1 H), 6.81-6.73 (m, 1 H), 5.73 (q, J = 7.2, 1 H), 1.84 (d, J = 7.3, 3H), 1.52 (s, 9H).

Step G: (f?)-4-Amino-6-bromo-2-π-(2.4-difluoro-phenvπ-ethyl1-isoindole-1 ,3- dione. (R)-{6-Bromo-2-[1 -(2,4-difluoro-phenyl)-ethyl]-1 ,3-dioxo-2,3-dihydro-1 H-isoindol- 4-yl}-carbamic acid tert-butyl ester (100 mg, 0.21 mmol) was stirred in a mixture of DCM (0.5 ml_) and TFA (0.5 ml_) for 2 h. The mixture was concentrated to provide 70 mg (88%) of the desired amine as a yellow solid. ¹H NMR (CDCI₃): 7.66 (dt, J = 8.7, 6.4, 1H), 7.21 (d, J = 1.4, 1H), 7.00 (d, J = 1.4, 1H), 6.93-6.85 (m, 1 H), 6.79-6.72 (m, 1 H), 5.72 (q, J = 7.2, 1 H), 5.22 (bs, 2H), 1.83 (d, J = 7.3, 3H).

Step H: (R)-Benzoπ ,2.51thiadiazole-4-sulfonic acid (6-bromo-2-H-(2,4-difluoro- phenyl)-ethyll-1 ,3-dioxo-2,3-dihvdro-1 H-isoindol-4-yl)-amide. A mixture of (R)-4-amino- 6-bromo-2-[1-(2,4-difluoro-phenyl)-ethyl]-isoindole-1 ,3-dione (10 mg, 0.026 mmol) and benzo[1 ,2,5]thiadiazole-4-sulfonyl chloride (200 mg, 0.85 mmol) were melted together with stirring at 170 ⁰C. After 2 h, the reaction was allowed to cool. The crude solid was purified by FCC to provide the title sulfonamide as a tan solid (12 mg, 80%). MS (ESI): mass calcd. for C₂₂Hi₃BrF₂N₄O₄S₂, 577.95; m/z found, 577, 579 [M+H]⁺. HPLC: t_R = 11.19 min. ¹H NMR (CDCI₃): 9.63 (bs, 1 H), 8.38 (dd, J = 7.0, 1.0, 1 H), 8.26 (dd, J = 8.8, 1.0, 1 H), 8.1 1 (d, J = 1.4, 1 H), 7.74 (dd, J = 8.8, 7.1 , 1 H), 7.64 (dt, J = 8.6, 6.3, 1 H), 7.47 (d, J = 1.4, 1 H), 6.95-6.88 (m, 1H), 6.78-6.71 (m, 1 H), 5.68 (q, J = 7.4, 1 H), 1.80 (d, J = 7.3, 3H).

EXAMPLE 4: Benzori .2,51thiadiazole-4-sulfonic acid r6-bromo-2-(2,4-difluoro-benzyl)- 3-oxo-2,3-dihydro-1 H-isoindol-4-yll-amide.

Step A: [6-Bromo-2-(2.4-difluoro-benzylV1-hvdroxy-3-oxo-2,3-dihydro-1 H- isoindol-4-yll-carbamic acid tert-butyl ester and r6-Bromo-2-(2,4-difluoro-benzyl)-3- hvdroxy-1-oxo-2,3-dihvdro-1 H-isoindol-4-vn-carbamic acid tert-butyl ester. To a solution of [6-bromo-2-(2,4-difluoro-benzyl)-1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4-yl]-carbamic acid tert-butyl ester (EXAMPLE 2, Step C) (154 mg, 0.33 mmol) in MeOH (3 ml_) and THF (2 ml_) was added NaBH₄ (13 mg, 0.34 mmol). After 30 min, the mixture was concentrated, diluted with 1 N HCI, and extracted with DCM (5x). The combined organic layers were dried and concentrated. Purification by FCC gave the two title compounds.

[6-Bromo-2-(2,4-difluoro-benzyl)-1-hydroxy-3-oxo-2,3-dihydro-1 H-isoindol-4-yl]- carbamic acid tert-butyl ester (97 mg, 62%): ¹H NMR (CDCI₃): 9.21 (s, 1 H), 8.50 (s, 1 H), 7.38 (dt, J = 8.6, 6.4, 1 H), 7.29-7.28 (m, 1 H), 6.89-6.80 (m, 2H), 5.65 (d, J = 11.2, 1 H), 4.90 (d, J = 15.0, 1 H), 4.55 (d, J = 15.2, 1 H), 2.38 (d, J = 11.2, 1 H), 1.53 (s, 9H). [6-Bromo-2-(2,4-difluoro-benzyl)-3-hydroxy-1-oxo-2,3-dihydro-1 H-isoindol-4-yl]- carbamic acid tert-butyl ester (42 mg, 27%): ¹H NMR (CDCI₃): 8.45 (s, 1 H), 7.53 (d, J = 1.6, 1 H), 7.37-7.31 (m, 1 H), 7.10 (s, 1 H), 6.87-6.80 (m, 2H), 5.63 (d, J = 11.6, 1 H), 4.86 (d, J = 15.0, 1 H), 4.52 (d, J = 15.0, 1 H), 2.88 (d, J = 11.6, 1 H), 1.52 (s, 9H).

Step B: 7-Amino-5-bromo-2-(2,4-difluoro-benzyl)-2,3-dihvdro-isoindol-1-one. To a solution of [6-bromo-2-(2,4-difluoro-benzyl)-1-hydroxy-3-oxo-2,3-dihydro-1 H-isoindol- 4-yl]-carbamic acid tert-butyl ester (97 mg, 0.21 mmol) in a mixture of DCM (2 ml_) and TFA (2 ml_) was added triethylsilane (0.084 ml_, 0.52 mmol). The reaction was stirred for 2 h, and then was concentrated, diluted with satd. aq. NaHCO₃, and extracted with DCM (3x). The combined organic layers were dried and concentrated to provide the title isoindolone as a white solid (72 mg, 97%). ¹H NMR (CDCI₃): 7.36-7.28 (m, 1 H), 6.89-6.80 (m, 2H), 6.80-6.78 (m, 1 H), 6.75-6.73 (m, 1 H), 5.28 (bs, 2H), 4.72 (s, 2H)₁ 4.22 (s, 2H). Step C: Benzof1 ,2,51thiadiazole-4-sulfonic acid f6-bromo-2-(2,4-difluoro-benzyl)-

3-oxo-2,3-dihvdro-1 H-isoindol-4-vπ-amide. A mixture of 7-amino-5-bromo-2-(2,4- difluoro-benzyl)-2,3-dihydro-isoindol-1-one (40 mg, 0.11 mmol) and benzo[1 ,2,5]thiadiazole-4-sulfonyl chloride (106 mg, 0.45 mmol) in pyridine (2 ml_) was heated at 95 "C for 3.5 h. The mixture was cooled to rt, diluted with H₂O, and extracted with EtOAc (3x). The combined organic layers were dried and concentrated. The residue was purified by FCC to provide the title sulfonamide as a white solid (28 mg, 45%). MS (ESI): mass calcd. for C₂₁Hi₃BrF₂N₄O₃S₂, 549.96; m/z found, 551 , 553 [M+H]⁺. HPLC: t_R = 10.72 min. ¹H NMR (CDCI₃): 10.43 (bs, 1 H), 8.39 (dd, J = 7.0, 1.0, 1 H), 8.22 (dd, J = 8.8, 1.0, 1H), 7.80 (d, J = 1.4, 1 H), 7.72 (dd, J = 8.8, 7.1 , 1 H), 7.34-7.26 (m, 1 H), 7.10 (d, J = 1.4, 1 H), 6.91-6.78 (m, 2H), 4.69 (s, 2H), 4.17 (s, 2H).

EXAMPLE 5: Benzof1.2.51thiadiazole-4-sulfonic acid r6-bromo-2-(2,4-difluoro-benzyl)- 1-oxo-2,3-dihvdro-1 H-isoindol-4-yll-amide.

Step A: 4-Amino-6-bromo-2-(2,4-difluoro-benzyl)-2,3-dihvdro-isoindol-1-one, The title compound was prepared from [6-bromo-2-(2,4-difluoro-benzyl)-3-hydroxy-1- oxo-2,3-dihydro-1 H-isoindol-4-yl]-carbamic acid tert-butyl ester (EXAMPLE 4, Step A) (42 mg, 0.089 mmol) as described in Example 3, Step G. ¹H NMR (CDCI₃): 7.42 (d, J = 1.6, 1 H), 7.36 (dt, J = 8.3, 6.4, 1 H), 6.96 (d, J = 1.6, 1 H), 6.88-6.80 (m, 2H), 4.80 (s, 2H), 4.11 (s, 2H), 3.74 (bs, 2H).

Step B: BenzoH ,2,51thiadiazole-4-sulfonic acid [6-bromo-2-(2,4-difluoro-benzyl)- 1-oxo-2,3-dihydro-1 H-isoindol-4-vn-amide. The title compound (22 mg, 71 %) was prepared from 4-amino-6-bromo-2-(2,4-difluoro-benzyl)-2,3-dihydro-isoindol-1-one (20 mg, 0.057 mmol) and benzo[1 ,2,5]thiadiazole-4-sulfonyl chloride (53 mg, 0.23 mmol) as described in Example 4, Step C. MS (ESI): mass calcd. for C_2IHi₃BrF₂N₄O₃S₂, 549.96; m/z found, 551 , 553 [M+H]⁺. HPLC: f_R = 9.78 min. ¹H NMR (CDCI₃): 8.28 (dd, J = 8.8, 0.9, 1 H), 8.23 (dd, J = 7.0, 0.9, 1 H), 7.72 (d, J = 1.6, 1 H), 7.71 (dd, J = 8.8, 7.0, 1 H), 7.30 (dt, J = 8.5, 6.4, 1 H), 7.26 (bs, 1 H), 7.24 (d, J = 1.6, 1 H), 6.92-6.84 (m, 2H), 4.74 (s, 2H), 4.20 (s, 2H).

EXAMPLE 6: (ffl-Benzori .2.51thiadiazole-4-sulfonic acid (6-bromo-2-ri-(2,4-difluoro- phenyl)-ethyl1-3-oxo-2,3-dihydro-1 H-isoindol-4-yl)-amide.

Step A: (R)-7-Amino-5-bromo-2-f1 -(2,4-difluoro-phenyl)-ethyll-2,3-dihvdro- isoindol-1-oπe and (R)-4-amino-6-bromo-2-f1-(2,4-difluoro-phenyl)-ethyl]-2,3-dihvdro- isoindol-1-one. To a solution of (R)-4-amino-6-bromo-2-[1-(2,4-difluoro-phenyl)-ethyl]- isoindole-1 ,3-dione (EXAMPLE 3, Step G) (600 mg, 1.57 mmol) in MeOH (10 mL) was added NaBH₄ (61 mg, 1.6 mmol). After 30 min, the reaction mixture was concentrated, diluted with 1 N HCI, and extracted with DCM (5x). The combined organic layers were dried and concentrated to provide a mixture of hemiaminal reduction products. The hemiaminal mixture was stirred in DCM (3 mL) and TFA (2 mL), and triethylsilane (0.29 mL, 1.8 mmol) was added. After 2 h, the mixture was concentrated, diluted with satd. aq. NaHCC>₃, and extracted with DCM (3x). The combined organic layers were dried and concentrated to provide the two regioisomeric isoindolones. (R)-7-Amino-5-bromo-2-[1-(2,4-difluoro-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one

(400 mg, 69%): ¹H NMR (CDCI₃): 7.36 (dt, J = 8.5, 6.4, 1 H), 6.91-6.84 (m, 1H), 6.81- 6.77 (m, 1 H), 6.78-6.76 (m, 1 H), 6.72-6.70 (m, 1 H), 5.69 (q, J = 7.2, 1 H), 5.27 (bs, 2H), 4.32 (d, J = 17.1 , 1 H), 4.03 (d, J = 17.1 , 1 H), 1.67 (d, J = 7.2, 3H).

(/^:?)-4-Amino-6-bromo-2-[1-(2,4-difluoro-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (69 mg, 12%): ¹H NMR (CDCI₃): 7.40 (d, J = 1.6, 1 H), 7.39 (dt, J = 8.5, 6.3, 1 H), 6.95 (d, J = 1.6, 1 H), 6.90-6.85 (m, 1 H), 6.84-6.77 (m, 1 H), 5.78 (q, J = 7.2, 1 H), 4.20 (d, J = 16.4, 1 H), 3.89 (d, J = 16.4, 1 H), 3.73 (bs, 2H), 1.71 (d, J = 7.3, 3H).

Step B: (R)-BenzoH ,2,51thiadiazole-4-sulfonic acid {6-bromo-2-ri-(2,4-difluoro- phenyl)-ethvπ-3-oxo-2,3-dihvdro-1 H-isoindol-4-yl)-amide. To a solution of (R)-7-amino- 5-bromo-2-[1-(2,4-difluoro-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (50 mg, 0.14 mmol) and pyridine (0.044 mL, 0.54 mmoi) in DCM was added benzo[1 ,2,5]thiadiazole-4- sulfonyl chloride (63 mg, 0.27 mmol). After 15 h, the mixture was poured into 1 N HCI and extracted with DCM (4x). The combined organic layers were dried and concentrated. The residue was purified by FCC to provide the title sulfonamide as a white solid (70 mg, 91 %). MS (ESI): mass calcd. for C₂₂Hi₅BrF₂N₄O₃S₂, 563.97; m/z found, 563, 565 [M-H]^". HPLC: t_R = 10.87 min. ¹H NMR (CDCI₃): 10.46 (bs, 1 H), 8.38 (dd, J = 7.0, 1.0, 1 H), 8.21 (dd, J = 8.8, 1.0, 1 H), 7.79 (bd, J = 1.2, 1 H), 7.11 (dd, J = 8.8, 7.0, 1 H), 7.35 (dt, J = 8.5, 6.4, 1 H), 7.08 (bd, J = 1.2, 1 H), 6.93-6.85 (m, 1 H), 6.83- 6.76 (m, 1 H), 5.66 (q, J = 7.1 , 1 H), 4.26 (d, J = 17.4, 1 H), 3.95 (d, J = 17.4, 1 H), 1.66 (d, J = 7.2, 3H).

EXAMPLE 7: (R)-Benzori ,2,51thiadiazole-4-sulfonic acid (6-bromo-2-ri-(2,4-difluoro- phenyl)-ethyH-1-oxo-2,3-dihvdro-1 H-isoindol-4-yl)-amide.

The title compound (19 mg, 63%) was prepared from (R)-4-amino-6-bromo-2-[1- (2,4-difluoro-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (EXAMPLE 6, Step A) (20 mg, 0.054 mmol) and benzo[1 ,2,5]thiadiazole-4-sulfonyl chloride (26 mg, 0.11 mmol) as described in Example 6, Step B. MS (ESI): mass calcd. for C₂₂H₁₅BrF₂N₄O₃S₂, 563.97; m/z found, 563, 565 [M-H]^". HPLC: t_R = 9.96 min. ¹H NMR (CDCI₃): 8.28 (dd, J = 8.8, 1.0, 1 H), 8.23 (dd, J = 7.0, 1.0, 1 H), 7.72 (dd, J = 8.8, 7.1 , 1 H), 7.70 (d, J = 1.7, 1 H), 7.39 (dt, J = 8.5, 6.1 , 1 H), 7.27 (bs, 1 H), 7.20 (d, J = 1.6, 1 H), 6.97-6.91 (m, 1 H), 6.86- 6.80 (m, 1 H), 5.72 (q, J = 7.2, 1 H), 4.31 (d, J = 17.4, 1 H), 3.95 (d, J = 17.4, 1 H), 1.67 (d, J = 7.2, 3H).

Biological Methods: I. Binding Assay a) Assay development

Zinc Finger Proteins (ZFP) specific for the CCK2R gene were identified by Sangamo Biosciences. The ZFP domain was fused with the herpes simplex virus VP16 activation domain, and the fusion protein was subsequently cloned into the pcDNA3 mammalian expression vector (Invitrogen, San Diego, CA). Tet-inducible cell lines expressing the coding region from the ZFP vector were created using the T-REx-293™ cell line (Invitrogen). After 2 weeks of selection in culture medium containing 400 mg/mL Zeocin (Invitrogen), sixty drug-resistant stable clones were isolated and analyzed for ZFP expression as well as CCK2R induction upon addition of doxycycline to the culture medium. The cell line with the most appropriate CCK2R ZFP construct was used in all further assays and was termed the HEKZFP cell line, b) Cell culture HEKZFP cells were grown in DMEM supplemented with L-glutamine (2 mM), penicillin (50 units/mL) and streptomycin (50 μg/mL) and 10% FBS (v/v). HEKZFP cells were treated with 2 mM doxycycline (Sigma-Aldrich, MO; USA) for 2 days to de-repress the tet-regulated expression of the CCK2 receptor selective zinc finger proteins and were harvested using a rubber cell scraper. c) Membrane Preparation

Membranes were prepared from the HEKZFP cells after induction. Frozen cell pellets (-40 ⁰C) were thawed in 14 ml_ of buffer A (10 mM HEPES, 130 mM NaCI, 4.7 mM KCI, 5 mM MgCI, 1 mM EGTA and 15.4 mg/100mL bacitracin at pH 7.2), adapted from Harper, E. A. et al. (Br. J. Pharmacol. 1996, 118(7), 1717-1726). The thawed pellets were homogenized using a Polytron PT-10 (7 X 1 s). The homogenates were centrifuged for 5 min at 1500 rpm (600 X g), and the resulting pellets were discarded. The supematants were re-centrifuged in order to collect the receptor-membrane pellets (25 min 15,000 rpm; 39,800 X g), which were re-suspended in buffer A. d) Incubation Conditions All assays were conducted in 96-well plates (GF/B millipore filter plates) using buffer A. For the optimal cell number determination experiments, cells in concentrations ranging from 2.5 X 10⁵ to 12.5 X 10⁵ cells/well were incubated with 20 pM [¹²⁵I]-BH- CCK-8S (50 μL 60 pM solution) in a total volume of 150 μl_. Total binding of [¹²⁵I]-BH- CCK-8S was determined in the presence of 15 μL of buffer A. Non-specific binding of [^12SI]-BH-CCK-8S was determined in the presence of 15 μL of 10 μM YF476, a CCK-2 receptor selective antagonist that is structurally unrelated to the radioligand [¹²⁵I]-BH- CCK-8S. The assay preparation was incubated for 1 h at 21 ±3 ⁰C, and then the assay was terminated by rapid filtration of the preparation under reduced pressure. The loaded filters were washed three times using undiluted PBS (100 μl_), and then 100 μL of scintillation fluid was added to the filter plate. Bound radioactivity was determined using a Topcount (Packard BioScience, Meriden, CT) with a count time of 1 min. From these experiments a cell concentration of 1 pellet in 15 ml_ of buffer was chosen for use in other assays. To validate the radioligand concentration and incubation time for the assay, saturation and kinetic binding studies were also conducted (see Morton, M. F. The Pharmacological Characterization of Cholecystokinin Receptors in the Human Gastrointestinal Tract. PhD Thesis, University of London, 2000). The affinity of novel compounds was estimated by incubating membrane preparations with 15 μL of competing ligand (0.1 pM-1 mM) for 60 min at 21 ±3 ⁰C. The assay was then terminated according to the procedure outlined above, e) Data Analysis

The pK| values were determined using the equation of Cheng, Y.-C. et al. (Biochem. Pharmacol. 1973, 22(23), 3099-3108):

To circumvent problems associated with computer-assisted data analysis of compounds with low affinity, the data obtained in the current study were weighted according to a method described by Morton. In brief, 100% and 0% specific binding were defined independently using total binding and binding obtained in the presence of a high concentration of the reference antagonist, JB93182, [[[(1 S)-[[3,5- dicarboxyphenyl)amino]carbonyl]-2-phenylethyl]amino]-carbonyl]-6-[[(1- adamantylmethyl)amino]carbonyl]-indole. The results for compounds tested in this assay are presented in Table 1 as an average of results obtained.

Table 1

Claims

What is claimed is:

1. A compound of Formula (I):

wherein

R¹ and R² are each independently fluoro or chloro; R³ is H or methyl; R⁴ is chloro or bromo; one of X and Y is a carbonyl and the other is a carbonyl or -CH₂-; or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof.

2. A compound according to claim 1 , wherein R¹ and R² are both fluoro.

3. A compound according to claim 1 , wherein R¹ and R² are both chloro.

4. A compound according to claim 1 , wherein R³ is H.

5. A compound according to claim 1 , wherein R³ is methyl.

6. A compound according to claim 1 , wherein R³ is methyl in the (R) configuration.

7. A compound according to claim 1 , wherein R⁴ is bromo.

8. A compound according to claim 1 , wherein X and Y are each a carbonyl.

9. A compound according to claim 1 , wherein X is -CH₂- and Y is a carbonyl.

10. A compound according to claim 1 , wherein X is a carbonyl and Y is -CH≥-.

11. A compound selected from the group consisting of:

Benzo[1,2,5]thiadiazole-4-sulfonic acid [6-bromo-2-(2,4-dichloro-benzyl)-1 ,3- dioxo-2,3-dihydro-1 H-isoindol-4-yl]-amide;

Benzo[1 ,2,5]thiadiazole-4-sulfonic acid [6-bromo-2-(2,4-difluoro-benzyl)-1 ,3- dioxo-2,3-dihydro-1 H-isoindol-4-yl]-amide;

(R)-Benzo[1 ,2,5]thiadiazole-4-sulfonic acid {6-bromo-2-[1-(2,4-difluoro- phenyl)-ethyl]-1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4-yl}-amide;

Benzo[1 ,2,5]thiadiazole-4-sulfonic acid [6-bromo-2-(2,4-difluoro-benzyl)-3-oxo-

2,3-dihydro-1 H-isoindol-4-yl]-amide;

Benzo[1 ,2,5]thiadiazole-4-sulfonic acid [6-bromo-2-(2,4-difluoro-benzyl)-1-oxo-

2,3-dihydro-1 H-isoindol-4-yl]-amide;

(R)-Benzo[1 ,2,5]thiadiazole-4-sulfonic acid {6-bromo-2-[1-(2,4-difluoro- phenyl)-ethyl]-3-oxo-2,3-dihydro-1 H-isoindol-4-yl}-amide; and

(R)-Benzo[1 ,2,5]thiadiazole-4-sulfonic acid {6-bromo-2-[1 -(2,4-difluoro- phenyl)-ethyl]-1 -oxo-2,3-dihydro-1 H-isoindol-4-yl}-amide; and pharmaceutically acceptable salts thereof.

12. A compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition for treating a disease, disorder, or medical condition mediated by CCK2 receptor activity, comprising:

(a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; and (b) a pharmaceutically acceptable excipient.

14. A pharmaceutical composition according to claim 13, further comprising: an active ingredient selected from the group consisting of CCK1 receptor modulators.

15. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by CCK2 receptor activity, comprising administering to the subject in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof.

16. The method according to claim 15, wherein the disease, disorder, or medical condition is selected from the group consisting of: cancer, gastro-intestinal disorders, anxiety, eating disorders, and pain.

17. The method according to claim 15, wherein the disease, disorder, or medical condition is selected from the group consising of: pancreatic cancer, esophageal cancer, gastric cancer, colorectal cancer, and colon cancer, and small cell lung carcinoma.

18. The method according to claim 15, wherein the disease, disorder, or medical condition is selected from the group consisting of: gastro-esophageal reflux disease (GERD), gastrointestinal ulcers, gastroduodenal ulcers, peptic ulcers, reflux esophagitis, Barrett's esophagus, antral G cell hyperplasia, pernicious anaemia, and Zollinger-Ellison syndrome.

19. The method according to claim 15, wherein the disease, disorder, or medical condition is selected from the group consisting of: gastro-espohageal reflux disease, pancreatic cancer, colon cancer, pain, and anxiety.