WO2011087758A1

WO2011087758A1 - Adamantyl amide derivatives and uses of same

Info

Publication number: WO2011087758A1
Application number: PCT/US2010/061288
Authority: WO
Inventors: Hermogenes N. Jimenez; Gil Ma; Guiying Li; Michel Grenon; Dario Doller
Original assignee: H. Lundbeck A/S
Priority date: 2009-12-22
Filing date: 2010-12-20
Publication date: 2011-07-21
Also published as: TW201121941A

Abstract

The present invention provides adamantyl amide derivatives of formula (I):, wherein R¹, R², and L are as defined herein; or a pharmaceutically acceptable salt thereof; and pharmaceutical compositions and uses of same.

Description

ADAMANTYL AMIDE DERIVATIVES AND USES OF SAME

FIELD OF THE INVENTION

The present invention provides adamantyl amide derivatives, as well as pharmaceutical compositions and methods of treatment using same.

BACKGROUND OF THE INVENTION

This invention concerns adamantyl amide derivatives, which act as allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5 receptors or mGluR5), as well as pharmaceutical compositions and methods of treatment utilizing these compounds.

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. One means of modulating glutamate neurotransmission is through metabotropic glutamate receptors (mGluRs); another means being ionotropic receptors. Presently, eight mGluRs have been cloned and classified into three groups based on sequence homology, preferred signal transduction pathway and pharmacology. Group I of mGluRs includes mGluRl and mGluR5, while Group II comprises mGluR2 and mGluR3 and Group III comprises mGlu4, 6, 7 and 8 receptors.

mGlu receptors have an essential role in normal brain functions, as well as in neurological, psychiatric, and neuromuscular disorders. mGlu5 receptors are located primarily postsynaptically and highly expressed in the limbic brain regions. mGlu5 receptors also are expressed in the thalamus, spinal cord, and vagal nerve systems, as well as peripherally in the skin on nerve endings and C fibers.

Ligands to the mGlu5 receptors have been shown to have promise for peripheral and central nervous system disorders. See e.g., G. Jaeschke et al, "mGlu5 receptor antagonists and their therapeutic potential," Expert Opin. Ther. Patents, 2008, 18, 2: 123-142. Yet some proffer that glutamate analogs targeting the orthosteric binding site may be limited by low brain penetration and insufficient selectivity with respect to the different mGluRs subtypes. Synthetic agonists may lead to continuous stimulation of the receptor since they are often designed to be metabolically stable. This continuous stimulation is not necessarily desirable, due to potential receptor desensitization issues. Also, with respect to receptor occupancy, synthetic antagonists may lead to prolonged blockade of receptor function, which may not be compatible with the kinetics of the pathology of a central nervous system disorder. However, a more selective and controlled "fine-tuning" action on the mGlu5 receptor is feasible through allosteric modulation. See e.g., P. Bach et ah, "Metabotropic glutamate receptor 5 modulators and their potential therapeutic applications," Expert Opin. Ther. Patents, 2007, 17, 4: 371-381. Allosteric modulation refers to binding by a modulator ligand to a site on a receptor that is different from the orthosteric primary substrate or ligand binding site. This ligand binding process results in conformational changes, which may profoundly influence the function of the protein (e.g., G protein-coupled receptors such as mGluRs, including mGluR5). Novel mGluR5 ligands that allosterically modulate the mGlu5 receptor may improve the therapeutic window of traditional central nervous system agents and/or the treatment of central nervous system disorders. The present invention is directed to these, and other important, ends.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula (I):

(I)

wherein:

R¹ and R² are each independently, aryl, heteroaryl, alkyl, cycloalkyl, ketocycloalkyl, heterocyclyl, acyl, alkoxy, which is optionally mono-, di-, or tri- substituted independently with alkyl, halogen, hydroxy, cyano, amino, alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, trifluoromethyl; and

L is -CO-N(X)-, -NH-C(0)-N(Y)-, -(W)N-C(0)0-, -OC(0)N(Z)-, -NHS0₂-, -NH-, - heteroaryl or a bond; wherein:

X is hydrogen, or a bond that is linked to R² and taken together with the N to which it is attached forms a heterocycle;

Y is hydrogen or a bond that is linked to R² and taken together with the N to which it is attached forms a heterocycle; W is hydrogen or a bond that is linked to R² and taken together with the N to which it is attached forms a heterocycle; and

Z is hydrogen or a bond that is linked to R² and taken together with the N to which it is attached forms a heterocycle; or

a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

The present invention also provides a method of treating a disease or disorder, the method comprises administering a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof to a mammal in need thereof, wherein the disease or disorder is a central nervous system disease or disorder. In some embodiments of the method, a symptom of the disease or disorder is treated.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides adamantyl amide derivatives. The adamantyl derivatives are of formula (I):

(I) wherein:

R¹ and R² are each independently aryl, heteroaryl, alkyl, cycloalkyl, ketocycloalkyl, heterocyclyl, acyl, alkoxy, which is optionally mono-, di-, or tri- substituted independently with alkyl, halogen, hydroxy, cyano, amino, alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, trifluoromethyl; and

L is -CO-N(X)-, -NH-C(0)-N(Y)-, -(W)N-C(0)0-, -OC(0)N(Z)-, -NHS0₂-, -NH-, - heteroaryl or a bond; wherein: X is hydrogen, or a bond that is linked to R² and taken together with the N to which it is attached forms a heterocycle;

Y is hydrogen or a bond that is linked to R² and taken together with the N to which it is attached forms a heterocycle;

W is hydrogen or a bond that is linked to R² and taken together with the N to which it is attached forms a heterocycle; and

a pharmaceutically acceptable salt thereof.

The term "alkyl", employed alone or as part of a group, is defined herein, unless otherwise stated, as either a straight-chain or branched saturated hydrocarbon of 1 to 8 carbon atoms. In some embodiments, the alkyl moiety contains 8, 7, 6, 5, 4, 3, 2 or 1 carbon atoms. Where the term "alkyl" appears herein without a carbon atom range it means a range of Ci-Cs. Where the term "alkyl" appears herein with a carbon range, it means an alkyl of any number within in the carbon range identified, such as a Ci-C3alkyl means methyl, ethyl or propyl. Examples of saturated hydrocarbon alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, w-propyl, z^'sopropyl, w-butyl, tert-butyl, iso-butyl, sec-butyl, w-pentyl, n- hexyl, and the like. Alkyl also refers to alkyl moieties where the alkyl group is substituted by hydroxy, cyano, alkoxy, alkylamino, dialkylamino, alkylamide, dialkylamide, and the like, including without limitation, -OCi-C₄alkyl-OH, -OCi-C₄alkyl-OCH₃, -OCi-C₄alkyl-NHCH₃, -OCi-C₄alkyl-N(CH₃)₂, -OCi-C₄alkyl-CONHCH₃, -OCi-C₄alkyl-CON(CH₃)₂, -OCi-C₄alkyl- NHCOCH₃, and -OCi-C₄alkyl-N(CH₃)COCH₃.

The term "alkoxy", employed alone or in combination with other terms, is defined herein, unless otherwise stated, as -O-alkyl, where "alkyl" is as previously defined herein. Examples of alkoxy moieties include, but are not limited to, chemical groups such as methoxy, ethoxy, z^'so-propoxy, sec-butoxy, tert-butoxy, and homologs, isomers, and the like. Alkoxy also refers to -O-alkyl moieties where the alkyl group is substituted by hydroxy, cyano, alkoxy, alkylamino, dialkylamino, alkylamide, dialkylamide, and the like, including without limitation, -OCi-C₄alkyl-OH, -OCi-C₄alkyl-OCH₃, -OCi-C₄alkyl-NHCH₃, -OCi-C₄alkyl- N(CH₃)₂, -OCi-C₄alkyl-CONHCH₃, -OCi-C₄alkyl-CON(CH₃)₂, -OCi-C₄alkyl-NHCOCH₃, and -OCi-C₄alkyl-N(CH₃)COCH₃. The term "hydroxyalkyl", employed alone or in combination with other terms, is defined herein, unless otherwise stated, as -alkyl-OH, where "alkyl" is as previously defined herein. Non-limiting examples include methyl-OH, ethyl-OH, w-propyl-OH, and the like.

As used herein, the term "cycloalkyl", employed alone or in combination with other terms, is defined herein, unless otherwise stated, as a cyclized alkyl group having from 3 to 8 ring carbon atoms, where "alkyl" is as defined herein. Examples of cycloalkyl moieties include, but are not limited to, chemical groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term "ketocycloalkyl", employed alone or in combination with other terms, is defined herein, unless otherwise stated, as a cycloalkyl having a keto radical attached thereto, where "cycloalkyl" is as defined herein. Examples include cyclopentanone or cyclohexanone.

The terms "halo" or "halogen", employed alone or in combination with other terms, is defined herein, unless otherwise stated, as fluoro, chloro, bromo, or iodo.

The term "aryl", employed alone or in combination with other terms, is defined herein, unless otherwise stated, as an aromatic hydrocarbon of up to 14 carbon atoms, which can be a single ring (monocyclic) or multiple rings (e.g., bicyclic, tricyclic, polycyclic) fused together or linked covalently. Any suitable ring position of the aryl moiety can be covalently linked to the defined chemical structure. Examples of aryl moieties include, but are not limited to, chemical groups such as phenyl, 1-naphthyl, 2-naphthyl, and the like. An aryl group can be unsubstituted or substituted as described herein.

The term "heteroaryl" employed alone or in combination with other terms, is defined herein, unless otherwise stated, as a monocyclic or polycyclic (fused together or linked covalently) aromatic hydrocarbon ring comprising one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. A heteroaryl group comprises up to 14 carbon atoms and 1 to 6 heteroatoms. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, oxadiazolyl, 2- quinolinyl, 2-quinazolinyl, 3-phenyl-2-quinolinyl and the like. A heteroaryl group can be unsubstituted or substituted as described herein.

The term "heterocyclyl" employed alone or in combination with other terms, is defined herein, unless otherwise stated, as a univalent group formed by removing a hydrogen atom from any ring atom of a heterocycle. In some embodiments, the heterocyclyl contains 1, 2, 3 or 4 heteroatoms selected independently from O, S and N. In some embodiments, the heterocyclyl comprises 3 to 14 carbon atoms. In some embodiments, the heterocyclyl comprises 3, 4, 5, 6, 7, 9, 10, 1 1, 12, 13, or 14 carbon atoms.

The term "acyl" employed alone or in combination with other terms, is defined herein, unless otherwise stated, as groups of formula -C(0)-alkyl, where alkyl is a previously described herein; i.e., an alkylcarbonyl, such as formyl, acetyl and the like.

The term "aminoalkyl" employed alone or in combination with other terms, is defined herein, unless otherwise stated, as alkyl-amino, where the term "alkyl" is as previously defined herein and the term "amino" is -NH₂, -NH-, or -N<. Non-limiting examples include - CH₃NH-, CH₃CH2 H-, (Ci-C₃alkyl)NH-, (Ci-C₃alkyl)₂N-, and the like.

The term "alkylamino" employed alone or in combination with other terms, is defined herein, unless otherwise stated, as amino-alkyl, where the term "alkyl" is as previously defined herein and the term "amino" is -NH₂, -NH-, or -N<. Non-limiting examples include - NHCH₃, -NHCH2CH3, -NH(Ci-C₃alkyl), -N(Ci-C₃alkyl)₂, and the like.

In some embodiments, R¹ and R² of a compound of formula (I) are both aryl; in some embodiments, R¹ is heteroaryl and R² is aryl. In some embodiments, R¹ and R² of a compound of formula (I) are both heteroaryl; in some embodiments, either R¹ or R² is heteroaryl; in some embodiments, R¹ is heteroaryl and R² is heterocyclyl; in some embodiments, R¹ is heteroaryl and R² is cycloalkyl. In some embodiments, R¹ of a compound of formula (I) is aryl while R² of the compound of formula (I) is alkyl.

In some embodiments, L of a compound of formula (I) is -CO-N(X)-, where X is as defined herein; in some embodiments, L is -NH-C(0)-N(Y)-, where Y is as defined herein; in some embodiments, L is -(W)N-C(0)0-, where W is as defined herein; in some embodiments, L is -OC(0)N(Z)-, where Z is as defined herein; in some embodiments, L is -NHSO₂-; in some embodiments, L is -NH-; in some embodiments, L is a heteroaryl; and in some embodiments, L is a bond.

In some embodiments, the compound of formula (I) is a retroamide derivative.

In some embodiments, the compound of formula (I) is a urea derivative.

In some embodiments, the compound of formula (I) is a carbamate derivative.

In some embodiments, the compound of formula (I) is a heteroaryl devirative. In some embodiments, the compound of formula (I) is a sulfonamide derivative.

In some embodiments, the compound of formula (I) is an amine derivative.

In some embodiments, the compound of formula (I) is a compound disclosed in the Experimental Section below (see e.g. Tables 1-2).

Another aspect of the present invention is a composition that comprises a pharmaceutically effective amount of a compound according to the present invention, and a pharmaceutically acceptable carrier or excipient.

A composition of the present invention may be adapted to any mode of administration, such as orally (including sublingually), via implants, parentally (including intravenous, intraperitoneal, intraarticularly and subcutaneous injections), rectally, intranasally, topically, ocularly (via eye drops), vaginally, and transdermally.

A compound of the present invention can be used either as a free base or in the form of a salt derived from pharmaceutically acceptable acids or bases.

A compound of the present invention can also be used in the form of an ester, carbamate and other conventional prodrug form, which generally will be a functional derivative of the compound that is readily converted to the active moiety in vivo. Also included are metabolites of a compound of the present invention defined as active species produced upon introduction of the compound into a biological system.

When a compound of the present invention is employed as described above, it may be combined with one or more pharmaceutically acceptable excipients or carriers, e.g., solvents, diluents and the like. Such pharmaceutical preparations may be administered orally in such forms as tablets, capsules (including, e.g., time release and sustained release formulations), pills, lozenges, aerosols, dispersible powders, granules, solutions, suspensions (containing, e.g., a suspending agent, at, e.g., from about 0.05 to about 5% of suspending agent), syrups (containing, e.g., sugar or a sugar substitute such as aspartame, at, e.g., about 10 to about 50% sugar or sugar substitute), elixirs and the like, or parenterally in the form of sterile injectable solutions, suspensions or emulsions containing, e.g., from about 0.05 to about 5% suspending agent in an isotonic medium. Such preparations may contain, e.g., from about 25 to about 90% of the active ingredient in combination with the carrier, more customarily from about 5% and about 60% by weight. The effective dosage of an active ingredient (e.g., a compound or salt of the present invention and a prodrug or metabolite thereof) employed may vary depending on the particular compound, salt, prodrug or metabolite used, the mode of administration, age, weight, sex and medical condition of the patient, and the severity of the disease, disorder, condition, and/or system being treated. The selection of the appropriate administration and dosage form for an individual mammal will be apparent to those skilled in the art. Such determinations are routine to a physician, veterinarian or clinician of ordinary skill in the art (see e.g., Harrison 's Principles of Internal Medicine, Anthony Fauci et al. (eds.) 14^th ed. New York: McGraw Hill (1998)). Further, the dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the needs of the therapeutic situation.

Solid carriers, e.g., starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, liquid carriers, e.g., sterile water, polyethylene glycols, glycerol, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, may be employed as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included. Non-limiting examples of adjuvants include flavoring agents, coloring agents, preserving agents, and antioxidants, such as vitamin E, ascorbic acid, BHT and BHA.

An active compound also may be administered parenterally or intraperitoneally. Solutions or suspensions of the active compound as a free base, neutral compound or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions also can be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. These preparations may contain a preservative to prevent the growth of microorganisms under ordinary conditions of storage and use.

The pharmaceutical forms suitable for injectable or infusing use include sterile aqueous solutions, suspensions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable or infusing solutions, suspension or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy injectability and infusing exists. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, and polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil. Furthermore, active compounds of the present invention can be administered intranasally or transdermally using vehicles suitable for intranasal or transdermal delivery known to those ordinarily skilled in the art. Transdermal administration includes all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues, using carrier systems such as lotions, creams, foams, pastes, patches, suspensions, solutions, and suppositories (rectal and vaginal). Creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient also may be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semi-permeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. When using a transdermal delivery system, the dosage administration will be continuous rather than a single or divided daily dose.

A compound of the present invention can also be administered in the form of a liposome delivery system where the liposomal lipid bilayer is formed from a variety of phospholipids. A compound of the present invention also may be delivered by the use of a carrier such as monoclonal antibodies to which the compound is coupled. Other carriers to which a compound of the present invention also may be coupled are a soluble polymer or a biodegradable polymer useful in achieving controlled release of an active ingredient.

It is understood by those practicing the art that some of the compounds of formula (I) may contain one or more asymmetric centers, and thus may give rise to enantiomers and diastereomers. The present invention includes all stereoisomers including individual diastereomers and resolved, enantiomerically pure stereoisomers, as well as racemates, and all other variations of stereoisomers, and mixtures and pharmaceutically acceptable salts thereof, which possess the indicated activity. Optical isomers may be obtained in pure form by procedures known to those skilled in the art, and include, but are not limited to, chiral chromatographic separations, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. It is also understood that this invention encompasses all possible regioisomers, endo-exo isomers, and mixtures thereof that possess the indicated activity. Such isomers can be obtained in pure form by procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography. It is understood by those practicing the art that some of the compounds of formula (I) may be chiral due to hindered rotation, and give rise to atropisomers, which can be resolved and obtained in pure form by procedures known to those skilled in the art. It is further understood by those practicing the art that some of the compounds of formula (I) include structural isomers, including tautomers.

Included also in this invention are polymorphs and hydrates of the compounds of formula (I), as well as isotopically labeled analogs thereof (e.g., ²H, ³H, ^{! j}C, ^{l 3}N and the like).

Another aspect of the present invention is a method for using the compounds of the invention. The invention is to be understood as embracing all simultaneous, sequential or separate use of any combination of the compounds of the invention with any pharmaceutical composition useful in the methods described herein.

In some embodiments, the method includes administering an effective amount of a compound of formula (I), or salt thereof. In some embodiments, the method includes administering a therapeutically effective amount of a compound described herein, or salt thereof.

As used herein, the phrase "effective amount" when applied to a compound of the invention, is intended to denote an amount sufficient to cause an intended biological effect. The phrase "therapeutically effective amount" when applied to a compound of the invention is intended to denote an amount of the compound that is sufficient to ameliorate, palliate, stabilize, reverse, slow or delay the progression of a disorder or disease state, or of a symptom of the disorder or disease. In some embodiments, the method of the present invention provides for administration of combinations of compounds. In such instances, the "effective amount" is the amount of the combination sufficient to cause the intended biological effect.

In some embodiments, the method includes administering an effective amount of a combination of two or more of the compounds described herein, or salts thereof. It is specifically intended that the phrases "combination of two or more of the compounds described herein, or salts thereof," or "at least one compound as described herein, or a pharmaceutically acceptable salt thereof," or similar language describing specific compounds, includes the administration of such compounds in any proportion and combination of salt, neutral or free base forms; i.e., includes the administration of such compounds each in the base form, each in the neutral form or each in the salt form, or one or more in the base form and one or more in the neutral form, or one or more in the base form and one or more in the salt form, or one or more in the neutral form and one or more in the salt form, in any proportion of the neutral and/or basic compounds and/or salts. The term "treatment" or "treating" as used herein means ameliorating or reversing the progress of a disease or disorder, or ameliorating or reversing one or more symptoms or side effects of such disease or disorder. For example, "treatment" or "treating" can refer to slowing, interrupting, controlling, lessening, stopping, or regulating the progression or continuation of a disease or disorder. "Treatment" or "treating", as used herein, also means to, inhibit or block, as in retard, arrest, restrain, impede or obstruct, the progress of a system, condition or state of a disease or disorder. For purposes of this invention, "treatment" or "treating" further means an approach for obtaining beneficial or desired clinical results, where "beneficial or desired clinical results" include, without limitation, alleviation of a symptom, diminishment of (or reducing) the extent of a disorder or disease, stabilized (i.e., not worsening) disease or disorder state, delay or slowing of a disease or disorder state, amelioration or palliation of a disease or disorder state, and remission of a disease or disorder, whether partial or total, detectable or undetectable.

The term "prevent" or "preventing" as used herein means to keep from happening or existing. The term "administering" as used herein refers to either directly administering a compound of the present invention, or administering a prodrug, derivative, or analog of same, that will form an effective amount of the compound within a mammal.

The present invention also provides a method of treating a disease or disorder, the method comprises administering a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof to a mammal in need thereof, wherein the disease or disorder is a central nervous system disease or disorder.

A compound of the present invention can allosterically modulate the mGlu5 receptor. An allosteric modulator that enhances or potentiates the affinity of an orthosteric ligand for the mGluR5 receptor and/or enhances or potentiates an orthosteric agonist's efficacy is an allosteric enhancer (or potentiator) or positive allosteric modulator (PAM). See e.g., May, L.T. Annu. Rev. Pharmacol. Toxicol. 2007, 47, 1-51. An allosteric modulator that reduces or diminishes an orthosteric agonist's efficacy is an allosteric antagonist (or inhibitor) or negative allosteric modulator (NAM). Id. A silent allosteric modulator (SAM) binds to an allosteric site of the receptor but has no measurable intrinsic efficacy. A SAM may indirectly demonstrate efficacy by preventing an allosterically binding compound from displaying its own positive (PAM) or negative (NAM) efficacy.

In some embodiments, the mammal of the method of the invention is a human. In some embodiments of the method of the invention, the central nervous system disease or disorder is a cognitive, neurodegenerative, psychiatric or neurological disease or disorder. In some such embodiments, the cognitive, neurodegenerative, psychiatric or neurological disease or disorder is selected from a group consisting of a mood disorder, an anxiety, a schizophrenia (including schizoaffective disorders), Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's chorea, amyotrophic lateral sclerosis, Creutzfeld- Jakob disease, a trauma-induced neurodegeneration, AIDS-induced encephalopathy, another infection-related encephalopathy (i.e., a non-AIDS-induced encephalopathy), Fragile X syndrome, an autism spectrum disorder, and a combination thereof.

As used herein, the phrase "mood disorder" refers to any of several psychological disorders characterized by abnormalities of emotional state, such as, without limitation, bipolar disorders, depressive disorders, cyclothymic disorders, dysthymic disorders, mood disorders due to a general medical condition, mood disorders not otherwise specified and substance- induced mood disorders; and as characterized by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association: Arlington, VA, 1994).

As used herein, the phrase "autism spectrum disorder" (ASD) refers to a disorder that causes severe and pervasive impairment in thinking, feeling, language, and the ability to relate to others, which is often first diagnosed in early childhood and range from a severe form, called autistic disorder ("classic" autism), through pervasive development disorder not otherwise specified (PDD-NOS), to a much milder form, Asperger syndrome. The phrase, as used herein, also includes Rett syndrome and childhood disintegrative disorder, and as used herein, is synonymous with the phrase, "pervasive developmental disorders" (PDDs).

In some such embodiments, the mood disorder is a depression (i.e., a depressive disorder). In some such embodiments, the depression is selected from the group consisting of atypical depression, bipolar depression, unipolar depression, major depression, endogenous depression (i.e., acute depression with no obvious cause), involutional depression (i.e., depression that occurs in mid-life or the elderly), reactive depression (i.e., depression caused by an obvious traumatic life episode), postpartum depression, primary depression (i.e., depression that has no obvious physical or psychological cause such as a medical illness or disorder), psychotic depression, and secondary depression (i.e., depression that seems to be caused by some other underlying condition such another medical illness or disorder). In some such embodiments, the anxiety disease or disorder is selected from a group comprising generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, post-traumatic stress disorder, acute stress reaction, an adjustment disorder, a hypochondriacal disorder, separation anxiety disorder, agoraphobia, a specific phobia, anxiety disorder due to general medical condition, substance-induced anxiety disorder, alcohol withdrawal-induced anxiety, and a combination thereof.

In some embodiments, the central nervous system disease or disorder of the method of the invention is a seizure disease or disorder. In some embodiments, the seizure disease or disorder is selected from the group consisting of a convulsion, epilepsy, status epilepticus, and a combination thereof.

In some embodiments, the central nervous system disease or disorder of the method of the invention is a pain disease or disorder selected from the group consisting of inflammatory pain, neuropathic pain and migraine pain. In some embodiments, the neuropathic pain or migraine pain disease or disorder is selected from the group consisting of allodynia, hyperalgesic pain, phantom pain, neuropathic pain related to diabetic neuropathy, neuropathic pain related to migraine, and a combination thereof.

In some embodiments, the central nervous system disease or disorder of the method of the invention is a neuronal hyperexcitation state disease or disorder. In some embodiments, the neuronal hyperexcitation state disease or disorder is a neuronal hyperexcitation state in medicament withdrawal, a neuronal hyperexcitation state in intoxication, or a combination thereof.

In some embodiments of the method of the invention, at least one symptom of the cognitive neurodegenerative, psychiatric or neurological disease or disorder is treated.

In some embodiments, the cognitive, neurodegenerative, psychiatric or neurological disease or disorder is a depression. In some such embodiments, the at least one symptom of the depression is depressed feeling, depressed mood, loss of interest or pleasure in some or all activities, changes in appetite, changes in weight, changes in sleep patterns, lack of energy, fatigue, low self esteem, diminished capacity for thinking, concentration, or decisiveness, feelings of hopelessness or worthlessness, psychomotor agitation or retardation, self- reproach, inappropriate guilt, frequent thoughts of death or suicide, plans or attempts to commit suicide, or a combination thereof. In some embodiments, the cognitive, neurodegenerative, psychiatric or neurological disease or disorder is an anxiety. In some such embodiments, the at least one symptom of anxiety is apprehension, fear, trembling, muscle aches, insomnia, abdominal upsets, dizziness, irritability, persistent, recurring thoughts, compulsions, heart palpitations, chest pain, chest discomfort, sweating, tingling sensations, feeling of choking, fear of losing control, flashbacks, nightmares, intrusive thoughts, intrusive recollections, avoidance behaviors, emotional numbing, an inability to sleep, anxious feelings, overactive startle response, hypervigilance, outbursts of anger, faintness, blushing, profuse sweating, or a combination thereof.

In some embodiments, the cognitive, neurodegenerative, psychiatric or neurological disease or disorder is schizophrenia. In some such embodiments, the at least one symptom of schizophrenia is a positive symptom selected from the group consisting of hallucination, delusion, paranoia, and a combination thereof. In some such embodiments, the symptom of schizophrenia is a negative symptom selected from the group consisting of social withdrawal, flat affect, anhedonia, decreased motivation, and a combination thereof. In some such embodiments, the symptom of schizophrenia is a cognitive symptom selected from the group consisting of severe deficit in attention, severe deficit in object naming, severe deficit in working memory, severe deficit in long-term memory storage, severe deficit in executive functioning, a slowing of information processing, a slowing of neural activity, long term depression, and a combination thereof.

In some embodiments of the method of the invention, the cognitive, neurodegenerative, psychiatric or neurological disease or disorder is Parkinson's disease. In some such embodiments, the at least one symptom of Parkinson's disease is levodopa-induced dyskinesia, poor balance, Parkinsonian gait, bradykinesia, rigidity, tremor, change in speech, loss of facial expression, micrographia, difficulty swallowing, drooling, pain, dementia, confusion, a sleep disturbance, constipation, a skin problem, depression, fear, anxiety, difficulty with memory, slowed thinking, sexual dysfunction, an urinary problem, fatigue, aching, loss of energy, or a combination thereof.

In some embodiments, the cognitive, neurodegenerative, psychiatric or neurological disease or disorder is Alzheimer's disease. In some such embodiments, the at least one symptom of Alzheimer's disease is impairment in memory, impairment in attention, impairment in judgment, impairment in decision-making, impairment in orientation to physical surroundings, language impairment, impairment in speed-dependent activities, impairment in abstract reasoning, impairment in visuospatial abilities, impairment in executive functioning, impairment in behavioral disturbances, disinterest and passivity, apathy, inappropriate dressing, poor self care, agitation, violent outburst, aggression, depression, anxiety, hallucination, delusion, change in personality, change in mood, dementia, or a combination thereof.

In some embodiments, the cognitive, neurodegenerative, psychiatric or neurological disease or disorder is multiple sclerosis. In some such embodiments, the at least one symptom of multiple sclerosis is optic neuritis blurred vision, eye pain, loss of color vision, blindness, diplopia double vision, nystagmus jerky eye movements, ocular dysmetria, constant under- or overshooting eye movements, internuclear ophthalmoplegia, nystagmus, diplopia, movement and sound phosphenes, diplopia, afferent pupillary defect, motor paresis, monoparesis, paraparesis, hemiparesis, quadraparesis plegia, paraplegia, hemiplegia, tetraplegia, quadraplegia, spasticity, dysarthria, muscle atrophy, spasms, cramps, hypotonia, clonus, myoclonus, myokymia, restless leg syndrome, footdrop dysfunctional reflexes (MRSs, Babinski's, Hoffman's, Chaddock's), paraesthesia, anaesthesia, neuralgia, neuropathic pain, neurogenic pain, l'hermitte's, proprioceptive dysfunction, trigeminal neuralgia, ataxia, intention tremor, dysmetria, vestibular ataxia, vertigo, speech ataxia, dystonia, dysdiadochokinesia, frequent micturation, bladder spasticity, flaccid bladder, detrusor- sphincter dyssynergia, erectile dysfunction, anorgasmy, retrograde ejaculation, frigidity, constipation, fecal urgency, depression, cognitive dysfunction, dementia, mood swings, emotional lability, euphoria, bipolar syndrome, anxiety, aphasia, dysphasia, fatigue, uhthoffs symptom, gastroesophageal reflux, a sleeping disorder, or a combination thereof.

The present invention further provides a method of treating gastroesophageal reflux, the method comprises administering a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need thereof.

The present invention further provides a method of treating alcohol dependence, the method comprises administering a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need thereof.

In some embodiments, the compound of the present invention is used in the preparation of a medicament for treatment of a central nervous system disease or disorder. In some embodiments, the central nervous disease or disorder is as previously disclosed herein. Another aspect of the present invention is a process for producing the compounds of the present invention.

PREPARATION OF THE COMPOUNDS OF THE PRESENT INVENTION

The compounds of the present invention may be prepared, without limitation, according to one of the general methods outlined below. For example, Schemes 1-24 that follow are intended as an illustration of some embodiments of the invention and no limitation of the present invention is implied because of them.

The following defines acronyms as used herein unless specified otherwise in a particular instance.

Boc = tert-butyloxycarbonyl

BOP = Benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate, CAS No. 56602-33-6

DCM = Dichloromethane or Methylene chloride, CAS No. 75-09-2

DIEA = NN-diisopropylethylamine, CAS No. 7087-68-5

DMA = NN-dimethylacetamide, CAS No. 127-19-5

DMAP = 4-dimethylaminopyridine, CAS No. 1 122-58-3

DMC = 2-Chloro-l,3-dimethylimidazolinium chloride, CAS No.37091-73-9

DMF = NN-dimethylformamide, CAS No. 68-12-2

DMPU = l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone, CAS No. 7226-23-5

DMSO = Dimethyl sulfoxide, CAS No. 67-68-5

DPPA = Diphenylphosphoryl azide, CAS No. 26386-88-9

EDC = l-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide

EDCI = N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride, CAS No. 93128- 40-6

HATU = 2-(lH-7-Azabenzotriazol-l-yl)— 1,1,3, 3-tetramethyl uronium hexafluorophosphate Methanaminium, CAS No. 148893-10-1

HBTU = 2-(lH-Benzotriazole-l-yl)-l,l,3,3-Tetramethyluronium hexafluorophosphate, CAS No. 94790-37-1 MTBE = Methyl ?-butyl ether, CAS No. 145288-29-5

NBS = N-Bromosuccinimide, CAS No. 128-08-5

NMP = N-Methyl-pyrrolidone, CAS No. 872-50-4

PyBOP = Benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate, CAS No. 128625-52-5

rt = room temperature

RT = LC-MS retention time

TEA = Triethyl amine, CAS No.121-44-8

TFA = Trifluoroacetic acid, CAS No. 76-05-1

THF = Tetrahydrofuran, CAS No. 109-99-9

A compound of formula (I-a) can be prepared via the process outlined in Scheme 1 using customary amidation procedures from intermediate A and R²(X)NH where X is hydrogen or a bond that is linked to R² and taken N together to form a heterocycle, and R¹ and R² are as previously defined.

Scheme 1

Intermediate A

a) R²(X)NH, PyBOP (or BOP or DMC or EDCI or HBTU, etc.), DIEA or TEA, DCM (or THF or DMF or CH₃CN, etc.); or R²(X)NH, HATU, DMAP, THF

A compound of formula (I-a) can also be made via the process outlined in Scheme 2 using customary amidation procedures from intermediate B and R^C^H or R^OCl.

Scheme 2

Intermediate B

a) R COCI, DIEA or TEA, DCM; b) R C0₂H, PyBOP (or BOP or DMC or EDCI or HBTU, etc.), DIEA or TEA, DCM (or THF or DMF or CH₃CN, etc.); or R C0₂H, HATU, DMAP, THF Intermediate A can be made via the process outlined in Scheme 3.

Scheme 3

a) H₂S0₄, HN0₃, MeCN; b) HCI, H₂0; c) SOCI₂, MeOH; d) R¹COCI, TEA, DCM; or R¹C0₂H,

PyBOP, NEt₃, DCM; e) LiOH, H₂0, THF

Commercially available 1-adamantanecarboxylic acid (compound 1) can be converted to acetamide 2 via a Ritter reaction. Hydrolysis of compound 2 under acidic conditions affords the corresponding amine salt, which is then converted to methyl ester 3. Customary amidation of compound 3 affords compound 4. Hydrolysis of ester 4 under customary condition affords Intermediate A.

Intermediate B can be made via the process outlined in Scheme 4.

Scheme 4

a) (Boc)₂0, THF, 2M NaOH in water; b) R²(X)NH, PyBOP, NEt₃, DCM; c) HCI, THF/H₂0; or TFA

Boc protection of compound 5 under customary condition (see e.g., step a of Scheme 4) gives compound 6. Amidation of acid 6 with R²(X)NH using costomary procedures (see e.g., step b of Scheme 4) yields compound 7, which is then converted to intermediate B by removing Boc group under customary conditions (see e.g., step c of Scheme 4).

A compound of formula (I-b) can be prepared from the reaction of intermediate C with amine R²N(Y)H (Y is hydro gen or a bond that is linked to R² and taken N together to form a heterocycle) under customary conditions (see e.g., step a ) via the process outlined in Scheme 5. Scheme 5

Intermediate C

a) R²N(Y)H, DCM (or DMF or neat), rt or microwave at 160 °C

A compound of formula (I-b) can also be prepared from the reaction of intermediate D with carbamic chloride (Y)(R²)NC(0)C1 or isocyanate R²NCO under customary conditions (see e.g., step a or b ) via the process outlined in Scheme 6.

Scheme 6

Intermediate D

a) (Y)(R₂)NC(0)-CI, DIEA, DCM; b) R²NCO, DCM (or DMF or neat), rt or microwave at 160 °C

Intermediates C and D can be prepared via the process outlined in Scheme 7.

Scheme 7

Intermediate A Intermediate C Intermediate D

a) TEA, DPPA, Toluene, rt-90 °C; b) HCI, H₂0

Standard Curtius rearrangement of intermediate A under customary condition (see e.g., step a of Scheme 7) gives isocyante intermediate C, which upon acid hydrolysis, affords intermediate D.

A compound of formula (I-c) can be prepared from the reaction of intermediate C with alcohol R²OH or the reaction of intermediate D with chloroformate R²OC(0)Cl under customary conditions (see e.g., step a or b) via the processed outlined in Scheme 8. Scheme 8

Intermediate C Formula (l-c) Intermediate D

a) R²OH, DCM; b) R²OC(0)CI, TEA, DCM

Cyclic carbamate, a compound of formula (I-d) can be prepared via the process outlined in Scheme 9.

Scheme 9

a Formula (l-d)

Intermediate D 8 _ _

n = 1, 2

a) CI(CH₂)₂(CH₂)nOC(0)CI, TEA, THF; b) NaH, DMF, 50 °C

Amidation of intermediate D with chloroformate Cl(CH₂)₂(CH₂)nOC(0)Cl under customary conditions (see e.g., step a of Scheme 9) gives compound 8, which can be cyclized to a compound of formula (I-d) by treatment with base such as NaH in DMF at 50 °C.

A compound of formula (I-e) can be made via the process outlined in Scheme 10 using customary conditions (see e.g., step a of Scheme 10).

Scheme 10

Formula (I-e)

Intermediate D

a) R²S0₂CI, TEA, DCM

A compound of formula (I-f) can be prepared via the process outlined in Scheme 11, where Z is hydrogen, or a bond that is linked to R² and taken N together to form a heterocycle. Scheme 11

Intermediate E

a) CIC0₂CCI₃, R²(Z)NH, TEA, DCM; b) R²(Z)NC(0)CI, TEA, DCM; c) R²NCO, DCM

Reaction of intermediate E with triphosgene chloro formate and R²(Z)NH (see e.g., step a of Scheme 11) or carmabic chloride R²(Z)NC(0)C1 (see e.g., step b of Scheme 11) or isocyanate R²NCO (see e.g., step c of Scheme 11) yields a compound of formula (I-f)

Intermediate E can be prepared from compound 9 and R^C^H via the process outlined in Scheme 12 under customary amidation conditions (see e.g., step c).

Scheme 12

Intermediate E

a) R C0₂H, BOP, TEA, DCM

A compound of formula (I-g) can be prepared via the process outlined in Scheme 13.

Scheme 13

Intermediate E 10 Formula (l-g) a) MeS0₂CI, TEA, DCM, 0 °C; b) R²NH₂, 160 °C

Reaction of intermediate E with MeSC^Cl (see e.g., step a of Scheme 13) yields mesylate 10. Alkylation of R²NH₂ with compound 10 (see e.g., step b of Scheme 13) affords a compound of formula (I-g). A compound of formula (I-g) can also be made by alkylation of intermediate D with R CI or R²Br or R²I in the present of base such as TEA or K₂CO₃ in DMF via the process outlined in step a of Scheme 14.

A compound of formula (I-h) can be made by reductive amination of intermediate D with R²CHO via the process outlined in Scheme 14 (see e.g., step b of Scheme 14).

Scheme 14

Formula (l-h) Intermediate D Formula (I-g) a) R²CI or R²Br or R²I, base, DMF, rt or heated; b) R²CHO, Na(OAc)₃BH, THF

A compound of formula (I-i) and (I-j) can be prepared via the process outlined in Scheme 15.

Scheme 15

Intermediate A 12 Formula (I-i)

U is aryl or heteroaryl

with V and N are on two adjacent carbon

R30 13 atoms

V = NH or O

Formula (I-j)

R³⁰ is alkyl

a) BOP, TEA, DCM; b) 6N aq. HCI, THF, 140 °C; or 6N aq HCI (or HOAc), microwave, 150 °C;

or HOAc, reflux; c) Ammonium acetate, HOAc, DMF, 100 °C

Amidation of intermediate A with compound 11 using customary conditions (see e.g., step a of Scheme 15) gives compound 12, which upon intramolecular cyclization affords a compound of formula (I-i) (see e.g., step b of Scheme 15). Amidation of intermediate A with compound 13 using customary conditions (see e.g., step a of Scheme 15) yields compound 14, which upon treatment with ammonium acetate in HOAc/DMF at 100 °C, affords a compound of formula (I-j).

A compound of formula (I-k) can be prepared by bisalkylation of intermediate D with compound 15 in the presence of base such as K₂CO₃ in DMF via the process outlined in Scheme 16.

Schem

Formula (I-k)

is an aryl or heteroaryl

Intermediate D Two -CH₂Br groups are on the

a) K₂C0₃, DMF two adjacent carbon atoms of U

A compound of formula (1-1) can be prepared via the process outlined in Scheme 17.

Scheme 17

a) Oxalyl chloride, TEA, DCM; b) TEA, DCM

Reaction of bis-carboxylic acid 6 with oxalyl chloride (see e.g., step a of Scheme 17) yields anhydride 17, which upon treatment with intermediate D under customary conditions such as TEA in DCM, affords a compound of formula (1-1).

A compound of formula (I-m) can be prepared via the process outlined in Scheme 18. Scheme 18

Intermediate D

a) R¹C0₂H, PyBOP, DCM; b) R¹C0₂H, EDCI, 1- ydroxybenzotriazole; C) R¹COCI, TEA, DCM;

d) K₂C0₃, DMF, rt or 50-70 °C; e) NBS, 2,2'-azo-bis-/sobutyronitrile, CCI₄; f) TEA (or DIEA), DCM

Amidation of intermediate E with R^CC^H or R^OCl using customary procesures (see e.g., steps a, b, c of Scheme 18) affords a compound of formula (I-m). Alkylation/amidation of intermediate D with intermediate F or compound 19 in the presence of bases (see e.g., steps d and f of Scheme 18) also affords a compound of formula (I-m). Non-commerically available intermediate F can be made by bromination of compound 18 using customary conditions such as step e of Scheme 18.

Intermediate E can be prepared via the process outlined in Scheme 19.

Scheme 19

a) TEA, POCI₃, Toluene; b) Zn, AcOH, rt to 90 °C; c) 1 ) DPPA, Toluene, 90 °C; 2) HCI Reaction of compound 3 with anhydride 17 (see e.g., step a of Scheme 19) yields phthalimide 20. Reduction of compound 20 (see e.g., step b of Scheme 19) gives lactam 21, which upon Curtius reaction followed by acidic hydrolysis (see e.g., step d of Scheme 19) affords intermediate E.

A compound of formula (I-n) can be prepared via the process outlined in Scheme 20.

Scheme 20

a) R C0₂H, PyBOP, DCM; b) R C0₂H, EDCI, 1-hydroxybenzotriazole; C) R COCI, TEA, DCM d) PyBOP, TEA, DCM; e) Tf₂0,DCM; f) hydrazine, MeOH, 70 °C

Amidation of intermediate G with R¹C02H or R^OCl using customary procedures (see e.g., steps a, b and c of Scheme 20) affords a compound of formula (I-n). Amidation of intermediate A with hydrazide, intermediate H (see e.g., step d of Scheme 20), followed by intramolecular cyclization (see e.g., step e of Scheme 20) also affords a compound of formula (I-n). Non-commercially available intermediate H can be prepared by treatment of ester 22 with hydrazine under customary conditions (see e.g., step f of Scheme 20).

Intermediate G can be prepared via the process outlined in Scheme 21.

Scheme 21

6 Intermediate G

a) PyBOP, TEA, DCM; b) Tf₂0, DCM; c) 6 N HCI Amidation of compound 6 with intermediate H using custmary conditions followed by intramolecular cyclization and removal of Boc (see e.g., steps a, b and c of Scheme 21) affords intermediate G.

A compound of formula (I-o) can be prepared via the process of Scheme 22.

Scheme 22

a) R C0₂H, PyBOP, TEA, DCM; b) R C0₂H, EDCI, 1-hydroxybenzotriazole; C) R COCI, TEA, DCM d) TBTU, DMF, microwave, 150 °C; e) NH₂OH HCI, K₂C0₃, MeOH, reflux

Amidation of intermediate I with R^CC^H or R COCI using customary procedures (see e.g., step a, b or c of Scheme 22) affords a compound of formula (I-o). Intermolecular cyclization of intermediate A and intermediate J also affords a compound of formula (I-o) (see e.g., step d of Scheme 22). Non-commercially available J can be made from the reaction of nitrile 23 and hydroxylamine hydrochloride (see e.g., step e of Scheme 22).

Intermediate I can be prepared via the process outlined in Scheme 23.

Scheme 23

a) TBTU, DMF, microwave, 150 °C; b) HCI/MeOH

Intermolecular cyclization of compounds 6 and intermediate J, followed by removal of Boc (see e.g., steps a and b of Scheme 23), affords intermediate G.

A compound of formula (I-p) can be prepared via the process outlined in Scheme 24. Scheme 24

a) EDAC, DMAP, TEA, DCM; b) (Tf)₂0, Pyridine, DCM

Amidation of intermediate A with compound 24 under customary conditions (see e.g., step a of Scheme 24), followed by intramolecular cyclization (see e.g., step b of Scheme 24), affords a compound of formula (I-p).

EXPERIMENTAL SECTION

1. General Methods

Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. All operations were carried out at room temperature (about 18 °C to about 25 °C) under nitrogen atmosphere. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure or in a high performance solvent evaporation system HT-4X (Genevac Inc., Valley Cottage, NY, USA). Microwave oven used is an apparatus from Biotage (Initiator). The course of the reaction was followed by thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), and reaction times are given for illustration only. Silica gel chromatography was carried out on a CombiFlash^® system (Teledyne Isco, Inc., Lincoln, NE, USA) with pre-packed silica gel cartridge or performed on Merck silica gel 60 (230-400 mesh). The structure and purity of all final products was assured by at least one of the following analytical methods: nuclear magnetic resonance (NMR) and LC-MS. NMR spectra was recorded on a Bruker Avance™ 300 spectrometer (Bruker BioSpin Corp., Billerica, MA, USA) or a Varian UNITY INOVA^® 400 (Varian, Inc., Palo Alto, CA, USA) using the indicated solvent. Chemical shift (δ) is given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard. Coupling constants (J) are expressed in hertz (Hz), and conventional abbreviations used for signal shape are: s = singlet; d = doublet; t = triplet; m = multiplet; br = broad; etc. Unless stated otherwise, mass spectra were obtained using electrospray ionization (ESMS) via either a Micromass Platform II system or a Quattro micro system (both from Waters Corp., Milford, MA, USA) and (M+H)⁺ is reported. General LC-MS methods:

Method A

Mobile phase: A) water/acetonitrile (99/1) and 0.2% ammonium formate; B) acetonitrile Gradient: 20-85% B from 0 tol.7 min, 85% B from 1.7 to 1.84 min, 85-100% B from 1.84 to 1.85 min, 100% B from 1.85-1.99 min, 100-20% B from 1.99 to 2 min.

Flow rate: 5.0 mL/min

Column: Inertsil^® ODS-3, 50 x 4.6 mm, 3 μιη particle size

Method B:

Mobile phase: A) water/acetonitrile (99/1) and 0.2% ammonium formate; B) acetonitrile Gradient: 30-90% B from 0 tol.7 min, 90% B from 1.7 to 1.84 min, 90-100% B from 1.84 to 1.85 min, 100% B from 1.85-1.99 min, 100-20% B from 1.99 to 2 min.

Flow rate: 5.0 mL/min

Column: Inertsil^® C8, 50 x 4.6 mm, 3 μιη particle size

Method C:

Mobile phase: A) water/acetonitrile (99/1) and 0.2% ammonium formate; B) acetonitrile Gradient: 10-85% B from 0 tol .7 min, 85% B from 1.7 to 1.84 min, 85-100% B from 1.84 to 1.85 min, 100% B from 1.85-1.99 min, 100-20% B from 1.99 to 2 min.

Flow rate: 5.0 mL/min

Column: Inertsil^® C8, 50 x 4.6 mm, 3 μιη particle size

Method D:

Mobile phase: A) water/acetonitrile (99/1) and 0.2% ammonium formate; B) acetonitrile Gradient: 10-80% B from 0 to 4.5 minutes, 80% B from 4.5 to 4.54 min, 80-100%B from 4.54-4.85 min, 100%B from 4.85 to 4.99 min, and 100-20% B from 4.99 to 5.00 min.

Flow rate: 5.0 mL/min

Column: Inertsil® ODS-3, 50 x 4.6 mm, 3 μιη particle size

Method E: Mobile phase: A) water/acetonitrile (99/1) and 0.2% acetic acid; B) acetonitrile Gradient: 10- 80% B from 0 to 4.5 minutes, 80% B from 4.5 to 4.54 min, 80-100%B from 4.54-4.85 min, 100%B from 4.85 to 4.99 min, and 100-20% B from 4.99 to 5.00 min.

Flow rate: 5.0 mL/min

Column: Inertsil® ODS-3, 50 x 4.6 mm, 3 μιη particle size

2. Preparation of Intermediates of the Invention

Unless specified otherwise, all starting materials and reagents were obtained from commercial suppliers such as such as Sigma-Aldrich (St. Louis, MO, USA) and its subsidiaries, and used without further purification.

Intermediate 1: 3-[(Pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid

Intermediate 1 was synthesized via the process of Scheme 3, supra, as follows:

Stepl: 3-Acetylamino-adamantane-l-carboxylic acid

To a 10-L reactor was added 1 -adamantanecarboxylic acid (503 g, 2.79 mol) and 70% nitric acid (400 mL, 6.72 mol), and the resulting suspension was cooled at 0 °C with a recirculating chiller. To the mixture was slowly added 98% sulfuric acid (3.00 L, 55.5 mol) at such a rate that the temperature was kept below 10 °C. Once the addition completed, acetonitrile (2.00 L, 38.5 mol) was added at such a rate that the temperature was kept below 10 °C. After all the acetonitrile was added, the reaction was stirred at 0 °C for 1 hour. The crude reaction was then added to a 20-L reactor filled with about 10-L of ice mixed with a small amount of water and the resulting mixture was stirred and allowed to warm to room temperature. The solids were then filtered and washed with water. More solids precipitated from the acidic aqueous layer and these were filtered as well and washed with water. The combined solid material was then dried under high vacuum at 50 °C for 2 days to afford 432 g (73%) of the title compound, 3-acetylamino-adamantane-l-carboxylic acid, as a white solid.

Step 2: 3-Amino-adamantane-l-carboxylic acid hydrochloride

To a 3-neck 5-L flask equipped with a reflux condenser, a mechanical stirrer and a temperature probe was added 3-acetylamino-adamantane-l-carboxylic acid (432 g, 1.82 mol), water (1.00 L) and concentrated hydrochloric acid (2.44 L), and the resulting mixture was heated at 95 °C for 6 days. During this time, solid material precipitated from the solution. After cooling at 0 °C, the solids were filtered and washed with acetone. The solid was then dried under high vacuum at 50 °C for about 2 hours to afford 328 g (78%) of the title compound, 3-amino-adamantane-l-carboxylic acid hydrochloride, as a white solid. ^XH NMR (300 MHz, DMSO-i/₆) δ 12.35 (br s, 1H), 8.27 (br s, 3H), 2.12-2.22 (m, 2H), 1.85-1.92 (m, 2H), 1.71-1.83 (m, 6H), 1.48-1.69 (m, 4H).

Step 3: 3-Amino-adamantane-l-carboxylic acid methyl ester hydrochloride

To a 3-neck 2-L flask equipped with a reflux condenser and a temperature probe was added 3-amino-adamantane-l-carboxylic acid hydrochloride (100 g, 432 mmol) and methanol (1.0 L). To this solution was slowly added thionyl chloride (15.7 mL, 216 mmol) and the reaction was heated at 60 °C for 4 hours. Once cooled to room temperature, the crude reaction mixture was concentrated under reduced pressure to remove most of the methanol. Heptane (about 1 - L) was then added and the mixture was once again concentrated under reduced pressure at which point a solid began to precipitate. This process was repeated three more times, then the solids were filtered off, washed with heptane and allowed to dry in open air to afford 97.2 g (92%) of the title compound, 3-amino-adamantane-l-carboxylic acid methyl ester hydrochloride, as a white solid. ^XH NMR (300 MHz, CDC1₃) δ 8.46 (br s, 3H), 3.65 (s, 3H), 2.24-2.33 (m, 2H), 2.16-2.23 (m, 2H), 1.95-2.1 1 (m, 4H), 1.78-1.94 (m, 4H), 1.62-1.75 (m,

2H). Step 4: 3-[(Pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid methyl ester

To a round bottom flask was added 3-amino-adamantane-l-carboxylic acid methyl ester hydrochloride (20.0 g, 81.4 mmol) and methylene chloride (500 mL) and the solution was cooled at 0 °C. To this solution was then added triethylamine (57 mL, 0.41 mol) followed by picolinoyl chloride hydrochloride (15.2 g, 85.4 mmol) and the reaction was stirred at 0 °C for 30 minutes, then at room temperature for 6 hours. To the reaction was added saturated aqueous sodium bicarbonate (500 mL) and the biphasic mixture was stirred vigorously for a few minutes, then transferred to a 2-L separatory funnel. The mixture was extracted, the layers separated and the aqueous layer was extracted again with methylene chloride (2 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 24.8 g (97%) of the title compound, 3-[(pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid methyl ester, as a pale brown solid. ^XH NMR (400 MHz, CDC1₃) δ 8.49-8.54 (m, 1H), 8.16 (dt, J= 7.8, 1.0 Hz, 1H), 7.96 (br s, 1H), 7.83 (td, J= 7.8, 1.8 Hz, 1H), 7.40 (ddd, J= 7.6, 4.8, 1.3 Hz, 1H), 3.66 (s, 3H), 2.30-2.34 (m, 2H), 2.23-2.29 (m, 2H), 2.13-2.17 (m, 4H), 1.80-1.97 (m, 4H), 1.62- 1.78 (m, 2H). ESI-MS m/z: 315 (M+H)⁺.

Step 5: 3-[(Pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid

To a round bottom flask was added 3-[(pyridine-2-carbonyl)-amino]-adamantane-l- carboxylic acid methyl ester (24.8 g, 78.9 mmol), tetrahydrofuran (250 mL), water (250 mL) and lithium hydroxide monohydrate (14.9 g, 355 mmol) and the mixture was stirred vigorously at room temperature for 25 hours. The crude mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran, then the aqueous solution was diluted with water (200 mL) and the pH was adjusted to about 3-4 by adding solid citric acid monohydrate. A voluminous white precipitate appeared which was filtered, washed with water and dried under high vacuum at 50 °C to afford 22.1 g (93%) of the title compound, 3- [(pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid, as a white solid. ^XH NMR (400 MHz, CDC1₃) δ 8.50-8.55 (m, 1H), 8.18 (d, J= 7.7 Hz, 1H), 7.97 (br s, 1H), 7.85 (td, J= 7.8, 1.8 Hz, 1H), 7.42 (ddd, J= 7.6, 4.8, 1.3 Hz, 1H), 2.31-2.35 (m, 2H), 2.25-2.31 (m, 2H), 2.09- 2.25 (m, 4H), 1.86-2.00 (m, 4H), 1.64-1.80 (m, 2H). ESI-MS m/z: 301 (M+H)⁺.

Intermediate 2 : 3- [(6-Methyl-pyridine-2-carbonyl)-amino] -adamantane-l-carboxylic acid

In a similar manner to Intermediate 1, internmediate 2 was made at 60.8 mmol reaction scale from 3-amino-adamantane-l-carboxylic acid methyl ester hydrochloride (product of step 3 of intermediate 1) and 6-methyl-pyridine-2-carboxylic acid, and 12.2 g of the title compound was obtained. ^XH NMR (400 MHz, CDC1₃) £8.07 (br s, lH), 7.98 (d, J=7.7 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.24-7.29 (m, 1H), 2.58 (s, 3H), 1.66-2.37 (m, 14H). ESI-MS m/z: 315

(M+H) .

Intermediate 3. 3-[(6-Methyl-pyrazine-2-carbonyl)-amino]-adamantane-l-carboxylic acid

In a similar manner to intermediate 1, intermediate 3 was made at 422 mmol reaction scale from 3-amino-adamantane-l-carboxylic acid methyl ester hydrochloride and 6- methylpyrazine-2-carboxylic acid, and 66 g of the crude title compound was obtained. It was used for next step without further purification. ^XH NMR (400 MHz, CDC1₃) δ 10.2-12.3 (br s, 1H), 9.17 (s, 1H), 8.60 (s, 1H), 7.72 (br s, 1H), 2.60 (s, 3H), 2.26-2.34 (m, 4H), 2.18-2.26 (m, 2H), 2.08-2.16 (m, 2H), 1.88-1.98 (m, 4H), 1.66-1.80 (m, 2H). LC-MS (Method C): RT: 0.78 min; ESI-MS m/z: 316 (M+H)⁺.

Intermediate 4: 3-[(Pyrazine-2-carbonyl)-amino]-adamantane-l-carboxylic acid

In a similar manner to intermediate 1, intermediate 4 was made at 32.6 mmol reaction scale from 3-amino-adamantane-l-carboxylic acid methyl ester hydrochloride and 2- pyrazinecarboxylic acid, and 8.2 g of the title compound was obtained. It was used for next step without further purification. LC-MS (Method A): RT: 0.45 min; ESI-MS m/z: 302 (M+H)⁺.

Intermediate 5: 3-[(2-Methyl-pyrimidine-4-carbonyl)-amino]-adamantane-l-carboxylic acid

In a similar manner to intermediate 1, intermediate 5 was made at 27.6 mmol reaction scale from 3-amino-adamantane-l-carboxylic acid methyl ester hydrochloride and 2- methylpyrimidine-4-carboxylic acid, and 8.14 g of the crude title compound was obtained. It was used for next step without further purification. ^XH NMR (400 MHz, CDC1₃) £ 8.85 (d, J = 5.0 Hz, 1H), 7.97 (br s, 1H), 7.88 (d, J = 5.0 Hz, 1H), 2.77 (s, 2H), 1.89-2.34 (m, 12H), 1.67-1.79 (m, 2H). LC-MS (Method A): RT: 0.55 min; ESI-MS m/z: 316 (M+H)⁺.

Intermediate 6: 3-[(Pyrimidine-4-carbonyl)-amino]-adamantane-l-carboxylic acid

In a similar manner to intermediate 1, intermediate 6 was made at 32.6 mmol reaction scale from 3-amino-adamantane-l-carboxylic acid methyl ester hydrochloride and pyrimidine-4- carboxylic acid, and 7.08 g of the title compound was obtained. It was used for the next step without further purification. LC-MS (Method A): RT: 0.43 min; ESI-MS m/z: 302 (M+H)⁺.

Intermediate 7: 3-Amino-adamantane-l-carboxylic acid pyridin-2-ylamide

Intermediate 7 was synthesized via the process of Scheme 4, supra, as follows: Stepl: 3-teri-Butoxycarbonylamino-adamantane-l-carboxylic

To a round flat-bottom flask containing 3-amino-adamantane-l-carboxylic acid (1 g, 5 mmol), THF (10 mL), and 2 M of NaOH in water (3.8 mL) was added di-tert- butyldicarbonate (1.1 g, 5.1 mmol). After stirring at rt for 16 hrs, the reaction was cooled in an ice bath, neutralized with 2N aqueous HC1, and then partitioned into ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1 g of the title compound which was used without further purification. ¾ NMR (400 MHz, CDC1₃) δ 4.46 (br s, 1H), 1.80-2.23 (m, 12H), 1.61-1.67 (m, 2H), 1.43 (s, 9H). ESI-MS m/z: 296 (M+H)⁺.

Step 2: 3-Amino-adamantane-l-carboxylic acid pyridin-2-ylamide

To a vial containing 3-tert-butoxycarbonylamino-adamantane-l-carboxylic acid (47 mg, 0.15 mmol), DCM (5 mL), DMC (23.7 mg, 0.180 mmol) and DIEA (39 mg, 0.30 mmol) was added 2-pyridinamine (21 mg, 0.22 mmol). After stirring at rt for 16 hrs, the reaction mixture was partitioned into DCM and saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 5 mL of THF and treated with 6 M of HC1 in water (0.125 mL). After stirring at rt for 16 hrs, the reaction mixture was partitioned into DCM and saturated sodium bicarbonate, dried over sodium sulfate, and concentrated under reduced pressure. ESI-MS m/z: 372 (M+H)⁺. The crude product was used immediately in the next step without further purification.

Intermediate 8: 3-Amino-adamantane-l-carboxylic acid (3-chloro-phenyl)-amide

In a similar manner to intermediate 7, intermediate 8 was prepared. Amide coupling of 3-tert- butoxycarbonylamino-adamantane-1 -carboxylic acid and 3-chloro-phenylamine at 0.6 mmol reaction scale gave 155 mg (60%) of 3-(3-chloro-phenylcarbamoyl)-adamantan-l-yl]- carbamic acid tert-butyl ester after purification on a reverse phase HPLC/MS purification system (Gradient: acetonitrile in water, 18-95% in 3.6minutes with a cycle time of 5 min. A shallow gradient between 20-40% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil C8, 30 x 50 mm, 5 um particle size). ^XH NMR (400 MHz, CDC1₃) £7.67-7.71 (m, 1H), 7.31-7.36 (m, 2H), 7.22 (t, J = 8.1 Hz, 1H), 7.05-7.08 (m, 1H), 4.49 (br s, 1H), 1.64-2.31 (m, 14H), 1.43 (s, 9H). ESI-MS m/z: 405 (M+H)⁺. Removal of Boc using 4M HC1 in dioxane gave the title compound, 3-amino-adamantane-l- carboxylic acid (3-chloro-phenyl)-amide which was used in subsequent step without further purification.

Intermediate 9: 6-Methyl-pyridine-2-carboxylic acid (3-isocyanato-adamantan-l-yl)- amide

Intermediate 9 was synthesized via the process of Scheme 7, supra, as follows:

To a flask containing 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid (intermediate 2, 1600 mg, 5.0 mmol), toluene (50 mL, 500 mmol) and TEA (0.76 g, 7.5 mmol) was added diphenylphosphonic azide (1.8 g, 6.5 mmol). After stirring for 15 min at rt, the reaction was heated at 80 °C for 3 hrs. After cooled to rt, the reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned into ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica flash chromatography using 10-40% ethyl acetate in hexane to afford 1.5 g (96%) of the title compound. ^XH NMR (400 MHz, CDC1₃) δ 8.07 (br s, lH), 7.99 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.27-7.30 (m, 1H), 2.58 (s, 3H), 1.86-2.39 (m, 12H), 1.57-1.74 (m, 2H). ESI-MS m/z: 312 (M+H)⁺. Intermediate 10: Pyridine-2-carboxylic acid (3-formylamino-adamantan-l-yl)-amide

In a similar manner to intermediate 9, intermediate 10 was made at 4.2 mmol reaction scale from 3-[(pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid (intermediate 1), and 0.3 g (50%) of the title compound was obtained as an oil. ^XH NMR (400 MHz, CDC1₃) δ 8.47-8.53 (m, 1H), 8.11-8.17 (m, 1H), 7.93-8.03 (m, 1H), 7.77-7.87 (m, 1H), 7.35-7.44 (m, 1H), 1.59-2.41 (m, 14H). ESI-MS m/z: 298 (M+H)⁺.

Intermediate 11: Pyridine-2-carboxylic acid (3-amino-adamantan-l-yl)-amide

Intermediate 11 was synthesized via the process of Scheme 7, supra, as follows:

To a suspension of 3-[(pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid (intermediate 1, 10.0 g, 33.3 mmol) in toluene (100 mL) was added TEA (5.6 mL, 40 mmol), and the mixture was stirred for a few minutes until most of the solids were dissolved. To the mixture was then added diphenylphosphonic azide (7.9 mL, 37 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was transferred to an addition funnel and added dropwise to a 3 -neck round bottom flask equipped with a reflux condenser containing toluene (70 mL) at 90 °C. After the addition, the reaction was stirred at 90 °C for two more hours, and then allowed to cool down to room temperature. The reaction mixture was then slowly added to a flask containing 6.0 N aqueous HC1 (55 mL, 330 mmol) and stirred vigorously for 1 hr. The biphasic mixture was transferred to a separatory funnel and the toluene layer was discarded. The acidic aqueous layer was then slowly treated with solid sodium carbonate until a pH of 10 was reached. The aqueous layer was transferred to a 500- mL separatory funnel and extracted with methylene chloride (3 x 100 mL). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 8.38 g (93%) of the title compound, pyridine- 2-carboxylic acid (3-amino-adamantan-l-yl)-amide, as a gummy foam. 1H NMR (300 MHz,

CDC1₃) δ 8.50-8.55 (m, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.94 (br s, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.40 (ddd, J= 7.6, 4.7, 1.3 Hz, 1H), 2.21-2.31 (m, 2H), 1.97-2.13 (m, 6H), 1.51-1.71 (m, 6H). ESI-MS m/z: 272 (M+H)⁺. Intermediate 12: 6-Methyl-pyridine-2-carboxylic acid (3-amino-adamantan-l-yl)-amide

In a similar manner to intermediate 1 1, intermediate 12 was made at 31.8 mmol reaction scale from 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid (intermediate 2), and 8.48 g (93%) of the title compound, 6-methyl-pyridine-2-carboxylic acid (3-amino- adamantan-l-yl)-amide, was obtained as a white solid. ¾ NMR (400 MHz, CD₃OD) £7.81- 7.89 (m, 2H), 7.42-7.46 (m, 1H), 2.59 (s, 3H), 2.06-2.44 (m, 6H), 1.67-2.09 (m, 8H). ESI- MS m/z: 286 (M+H)⁺.

Intermediate 13: 2-Methyl-pyrimidine-4-carboxylic acid (3-amino-adamantan-l-yl)- amide

In a similar manner to intermediate 11, intermediate 13 was made at 15.8 mmol reaction scale from 3-[(2-methyl-pyrimidine-4-carbonyl)-amino]-adamantane-l-carboxylic acid (intermediate 5), and 4.6 g of the title compound was obtained. It was used for the next step without further purification. LC-MS (Method A): RT: 0.32 min; ESI-MS m/z: 287 (M+H)⁺.

Intermediate 14: 6-Methyl-pyrazine-2-carboxylic acid (3-amino-adamantan-l-yl)- amide

In a similar manner to intermediate 11, intermediate 14 was made at 15.8 mmol reaction scale from 3-[(6-methyl-pyrazine-2-carbonyl)-amino]-adamantane-l-carboxylic acid (intermediate 3), and 4.7 g of the title compound was obtained. LC-MS (Method A): RT: 0.35 min; ESI-MS m/z: 287 (M+H)⁺. Intermediate 15: 2-(3-Amino-adamantan-l-yl)-l,2-dihydro-pyrrolo[3,4-c]pyridin-3-one

Intermediate 15 was prepared via the process of Scheme 19, supra, as follows:

Stepl: 3-(l,3-Dioxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-adamantane-l-carboxylic acid methyl ester

A mixture of 3 -amino-adamantane- 1 -carboxylic acid methyl ester^»HCl (product of step 3 of intermediate 1, 3.59 g, 14.6 mmol), pyridine-3,4-dicarboxylic anhydride (2.29 g, 15.4 mmol), and TEA (6.12 mL, 43.9 mmol) in toluene (100 mL) was heated at 100 °C overnight. After cooled to rt, phosphoryl chloride (1.50 mL, 16.1 mmol) was added slowly. The reaction mixture was heated at 90 °C for 3 hours and cooled to rt. The reaction mixture was filtered to remove solid and the filtrate was concentrated under reduced pressure, which was then quenched with saturated aqueous aHC0₃ (100 mL) and basified to ~pH10 with solid a₂C0₃. The aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine, dried over MgS0_4; and concentrated under reduced pressure to give 4.89 g of the title compound, 3-(l,3-dioxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)- adamantane- 1 -carboxylic acid methyl ester, which was used for the next step without further purification. ^XH NMR (400 MHz, CDC1₃) δ 9.07 (d, J = 0.8 Hz, 1H), 9.02 (d, J = 4.8 Hz, 1H), 7.67 (dd, J = 1.2, 4.8 Hz, 1H), 3.68 (s, 3H), 2.28-2.64 (m, 8H), 1.65-1.99 (m, 6H). LC- MS (Method A): RT: 1.30 min; ESI-MS m/z: 341 (M+H)⁺.

Step2: 3-(3-Oxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-adamantane-l-carboxylic acid methyl ester

To a solution of 3-(l,3-dioxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-adamantane-l- carboxylic acid methyl ester (3.74 g, 1 1.0 mmol) in acetic acid (40.0 mL) was added zinc (3.59 g, 54.9 mmol). The reaction mixture was stirred at room temperature for 1 day. The reaction mixture was filtered to remove the solid and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and washed with saturated aqueous aHC0₃. The aqueous layer was extracted with DCM (2 x 30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by

system (30%EtOAc in DCM) to give 3.14 g (88%) of the title compound, 3-(3- oxo-1, 3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-adamantane-l-carboxylic acid methyl ester . ^XH NMR (400 MHz, CDC1₃) δ 9.04 (d, J = 0.9 Hz, 1H), 8.73 (d, J = 5.1 Hz, 1H), 7.39 (dd, J = 0.7, 5.0 Hz, 1H), 4.53 (s, 2H), 3.67 (s, 3H), 1.57-2.46 (m, 14H. LC-MS (Method A): RT: 0.92 min; ESI-MS m/z: 327 (M+H)⁺.

Step3: 3-(3-Oxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-adamantane-l-carboxylic acid

A mixture of 3-(3-oxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-adamantane-l-carboxylic acid methyl ester and LiOH (0.658 g, 27.5 mmol) in water (15 mL) and THF (45 mL) was stirred overnight at rt. THF was evaporated under reduce pressure and the aqueous layer was acidified to ~pH2 with IN HC1. The precipitates were filtered, washed with water, and dried at 50 °C under reduced pressure to give 3.17 g of the title compound, 3-(3-oxo-l,3-dihydro- pyrrolo[3,4-c]pyridin-2-yl)-adamantane-l-carboxylic acid, which was used for the next step without further purification. LC-MS (Method A): RT: 0.38 min; ESI-MS m/z: 313 (M+H)⁺.

Step 4 : 2-(3-Amino-adamantan-l-yl)-l,2-dihydro-pyrrolo [3,4-c] pyridin-3-one

A mixture of 3-(3-oxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-adamantane-l-carboxylic acid (3.17 g), diphenylphosphonic azide (2.35 g, 8.54 mmol) and TEA (1.66 g, 16.4 mmol) in toluene (32 mL) was stirred for 1 hour at rt and then for 2 hrs at 90 °C. After cooled to rt, the reaction mixture was added into cold 6M HC1 in water (16 mL), stirred vigorously at room temperature for 1 hr, and diluted with water (50 mL). The toluene layer was separated. The aqueous layer was basified with solid NaCC^ to ~pH10, and extracted with DCM (3 x 50 niL). The combined organic layers were washed with brine, dried over MgS0₄, and concentrated under reduced pressure to give 1.47 g of the title compound, 2-(3-amino- adamantan-l-yl)-l,2-dihydro-pyrrolo[3,4-c]pyridin-3-one, which was used for the next step without further purification. ^XH NMR (400 MHz, CDC1₃) δ LC-MS (Method A): RT: 0.22 min; ESI-MS m/z: 284 (M+H)⁺.

Intermediate 16: 6-(3-Amino-adamantan-l-yl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one

In a similar manner to intermediate 15, intermediate 16 was made at 14.2 mmol reaction scale from 3-amino-adamantane-l-carboxylic acid methyl ester^»HCl and pyridine-2,3-dicarboxylic anhydride, and 1.5 g of the title compound was obtained. It was used for the next step without further purification.

LC-MS (Method A): RT: 0.26 min; ESI-MS m/z: 284 (M+H)⁺.

Intermediate 17: 6-(3-Amino-adamantan-l-yl)-2-methyl-6,7-dihydro-pyrrolo[3,4- b]pyridin-5-one

Step 1: 6-methyl-pyridine-2, 3-dicarboxylic anhydride

A solution of 6-methyl-2,3-pyridinedicarboxylic acid (2.00 g, 11.0 mmol) in aectic anhydride (10.4 mL) was stirred at 100 °C for 4 h and then concentrated under the reduced pressure. The residue was diluted with EtOAc (30 mL). The organic layer was washed with saturated aqueous aHC03 and brine, dried over MgS0₄, and concentrated under reduced pressure to give 0.6 g of the title compound, 6-methyl-pyridine-2, 3-dicarboxylic anhydride. ^XH NMR (300 MHz, CDC1₃) £8.22 (d, J= 8.0 Hz, 1H), 7.65 (d, J= 8.0 Hz, 1H), 2.85 (s, 3H).

Step 2: 6-(3-Amino-adamantan-l-yl)-2-methyl-6,7-dihydro-pyrrolo[3,4-b] pyridin-5-one

In a similar manner to intermediate 15, intermediate 17 was made at 3.34 mmol reaction scale from 3-amino-adamantane-l-carboxylic acid methyl ester^»HCl and 6-methyl-pyridine-2, 3- dicarboxylic anhydride, and 203 mg of the title compound was obtained. It was used without further purification. LC-MS (Method C): RT: 0.59 min; ESI-MS m/z: 298 (M+H)⁺.

Intermediate 18: Pyridine-2-carboxylic acid (3-hydroxy-adamantan-l-yl)-amide

Intermediate 18 was synthesized via the process of Scheme 12, supra, as follows:

To a 40 ml vial was added picolinic acid (0.68 g, 5.5 mmol), DMF (15 ml), TEA (0.90 mL, 6.4 mmol), and HBTU (2.3 g, 6.0 mmol). The mixture was stirred at rt for 5 minutes to get a clear solution. 3-Amino-adamantan-l-ol (0.84 g, 5.0 mmol) was added to the above solution and the mixture was stirred at rt for 2 hours. DMF was removed in Genevac, the resulting residue was dissolved in DCM (20 mL), washed with IN aqueous NaOH, water and brine, dried over Na₂S0_4; and concentrated under reduced pressure to afford 1.32 g (97%) of the crude title compound, pyridine-2-carboxylic acid (3-hydroxy-adamantan-l-yl)-amide, as an oil, which became a colorless solid upon standing at room temperature. LC/MS Method A: RT: 0.79 min; purity (UV₂₅₄): 100%; ESI-MS m/z: 273 (M+H)⁺. It was used in the next step without further purification.

Intermediate 19: 2-Bromomethyl-nicotinic acid ethyl ester

Intermediate 19 was prepared by bromination of commercially available 2-methylnicotinic acid ethyl ester, supra, as follows:

A mixture of 2-methylnicotinic acid ethyl ester (1.00 g, 6.05 mmol), N-bromosuccinimide (1.40 g, 7.87 mmol) and 2,2'-azo-bis-isobutyronitrile (99.4 mg, 0.605 mmol) in CC1₄ (20 mL) was stirred at 90 °C overnight and then cooled to rt. The solid was filtered and washed with CCI₄. The combined organic layers were washed with saturated aqueous NaHCC and brine, dried over Na₂S0₄, and concentrated under reduced pressure. The residue was purified by CombLF/as/z^® system (DCM) to obtain 1.0 g (68%) of the title compound, 2-bromomethyl- nicotinic acid ethyl ester. ¾ NMR (400 MHz, CDC1₃) £8.71 (dd, J = 1.8, 4.8 Hz, 1H), 8.28 (dd, J = 1.8, 7.9 Hz, 1H), 7.34 (dd, J = 4.8, 7.9 Hz, 1H), 5.04 (s, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.44 (t, J= 7.2 Hz, 3H). LC-MS (Method A): RT: 0.99 min; ESI-MS m/z: 244 (M+H)⁺.

Intermediate 20: 3-Bromomethyl-pyridine-2-carboxylic acid methyl ester

In a similar manner to intermediate 19, intermediate 20 was made at 6.05 mmol reaction scale from 3-methyl-pyridine-2-carboxylic acid methyl ester, and 1.0 g of the title compound was obtained after

system (DCM). ¾ NMR (400 MHz, CDC1₃) £8.66 (dd, J = 1.7, 4.6 Hz, 1H), 7.89 (dd, J = 1.6, 7.9 Hz, 1H), 7.47 (dd, J = 4.7, 7.9 Hz, 1H), 4.94 (s, 2H), 4.03 (s, 3H). LC-MS (Method C): RT: 0.89 min; ESI-MS m/z: 230 (M+H)⁺

Intermediate 21: 3-[5-(6-Methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2-yl]-adamantan-l-yl- amine

Intermediate 21 was prepared via the process of Scheme 21, supra, as follows:

Step 1: 3-teri-Butoxycarbonylamino-adamantane-l-carboxylic acid

To a solution of 3-amino-adamantane-l-carboxylic acid methyl ester^»HCl (5.00 g, 20.3 mmol) and TEA (6.24 mL, 44.8 mmol) in DCM (100 mL) was added di-/er/-butyldicarbonate (4.88 g, 22.4 mmol) at 0 °C. The reaction mixture was stirred at rt overnight and concentrated under reduced pressure. The residue was diluted with EtOAc. The organic layer was washed with water, citric acid, saturated aqueous NaHCC , and brine, dried over MgS0₄, and concentrated under reduced pressure to give crude 3-ter/-butoxycarbonylamino-adamantane- 1-carboxylic acid methyl ester, which was used for the next step without further purification. ¾ NMR (300 MHz, CDC1₃) ^4.41 (br s, 1H), 3.65 (s, 3H), 1.79-2.22 (m, 12H), 1.63 (br s, 2H), 1.43 (s, 9H). To a solution of above methyl ester in THF (60.0 mL) was added a solution of LiOH (1.46 g, 61.0 mmol) in water (60.0 mL). The mixture was stirred at rt overnight and concentrated under reduced pressure to remove THF. The aqueous layer was acidified with citric acid. The white solid was filfered, washed with water (3x), and dried under reduced pressure at 40 °C to give 5.41 g (90%) of the title compound, 3-tert-butoxycarbonylamino- adamantane-l-carboxylic acid. ^XH NMR (400 MHz, CDC1₃) £4.45 (br s, 1H), 1.82-2.24 (m, 12H), 1.62-1.66 (m, 2H), 1.43 (s, 9H).

Step 2: 3-[5-(6-Methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2-yl]-adamantan-l-ylamine

In a 20-mL vial was added 3-tert-butoxycarbonylamino-adamantane-l-carboxylic acid (1.00 g, 3.38 mmol), 6-methylnicotinoyl hydrazide (0.512 g, 3.38 mmol) and DCM (25.0 mL), followed by the addition of PyBOP (1.85 g, 3.55 mmol) and TEA (0.94 mL, 6.77 mmol). The reaction mixture was stirred overnight at rt and diluted with DCM (50 mL). The organic layer was washed with saturated aqueous aHC0₃ and brine (30 mL), dried over Na₂S0₄, filtered, and concentrated under reduced pressure to give crude {3-[N-(6-methyl-pyridine-3- carbonyl)-hydrazinocarbonyl]-adamantan-l-yl}-carbamic acid tert-butyl ester, which was used for the following step without further purification. To a solution of above crude intermediate and pyridine (1.10 mL, 13.5 mmol) in DCM (30 mL) was added trifluoromethanesulfonic anhydride (1.14 mL, 6.77 mmol) at 0 °C. The reaction mixture was stirred overnight at rt and quenched with saturated aqueous NaHC(¾ at 0 °C. The aqueous layer was extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The resulting residue was suspended in ethyl ether and the precipitates were collected via filtration to give crude 5- [5-(3-isocyanato-adamantan-l-yl)-l,3,4-oxadiazol-2-yl]-2-methyl-pyridine. ^XH NMR (300 MHz, CDCI₃) £9.14 (d, J= 2.0 Hz, 1H), 8.26-8.32 (m, 1H), 7.37 (d, J= 8.2 Hz, 1H), 2.71 (s, 3H), 1.74-2.43 (m, 14H). LC-MS (Method A): RT: 1.35 min; ESI-MS m/z: 337 (M+H)⁺.

To a solution of 6N HC1 (5 mL) at 0 °C was added a solution of 5-[5-(3-isocyanato- adamantan-l-yl)-l,3,4-oxadiazol-2-yl]-2-methyl-pyridine in toluene (5 mL). The mixture was stirred for 1 hour at rt and basified with solid K2CO₃ to ~pH10. The aqueous layer was extracted with z^'-PrOH/CHC13 (1 :3, 3x). The combined organic layers were dried over MgS0₄ and concentrated under reduced pressure to afford 0.37 g (35%) of the crude title compound, 3-[5-(6-methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2-yl]-adamantan-l-ylamine, which was used for next step without further purification. ^XH NMR (400 MHz, CDC1₃) δ 9.1 1 (d, J = 2.0 Hz, 1H), 8.21 (dd, J = 2.3, 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 2.65 (s, 3H), 1.62-2.34 (m, 14H). LC-MS (Method A): RT: 0.42 min; ESI-MS m/z: 311 (M+H)⁺.

Intermediate 22: 6-Ethyl-nicotinic acid hydrazide

Intermediate 22 was prepared from commercially available 6-chloro-nicotinic acid methyl ester via the process of Scheme 20, supra, as follows:

Ste l: 6-Ethyl-nicotinic acid methyl ester

To a solution of methyl-6-chloronicotinate (2.00 g, 11.6 mmol) and ferric acetylacetonate (0.21 g, 0.58 mmol) in THF (36.4 mL) and N-methylpyrrolidinone (3.64 mL) was added 3.0 M of ethylmagnesium bromide in ethyl ether (4.66 mL) at rt. The reaction mixture was stirred at rt overnight and quenched with brine. The aqueous layer was extracted with EtOAc (20 mL x 3). The combinded organic layer was washed with brine, dried over MgS0₄, and concentratd under reduced pressure. The residue was purified by CombLF/as/z^® system (0 to30% EtOAc in hexanes) to give 0.9 g of the title compound, 6-ethyl-nicotinic acid methyl ester. ¾ NMR (400 MHz, CDC1₃) δ 9.13 (d, J = 1.9 Hz, 1H), 8.20 (dd, J = 2.2, 8.1 Hz, 1H), 7.25 (d, J= 8.2 Hz, 1H), 3.94 (s, 3H), 2.90 (q, J= 7.6 Hz, 2H), 1.33 (t, J= 7.6 Hz, 3H).

Step2: 6-Ethyl-nicotinic acid hydrazide

A solution of 6-ethyl-nicotinic acid methyl ester (0.9 g) and hydrazine (4.00 mL, 127 mmol) in methanol (40 mL) was stirred at 70 °C overnight and concentrated under reduced pressure to give 1.1 g of the title compound, 6-ethyl-nicotinic acid hydrazide, which was used for the next step without further purification. ¾ NMR (400 MHz, CDC1₃) δ 8.86 (d, J = 1.9 Hz, 1H), 8.01 (dd, J= 2.4, 8.1 Hz, 1H), 7.43 (br s, 1H), 7.26 (d, J= 8.0 Hz, 1H), 4.10 (br s, 2H), 2.89 (q, J= 7.6 Hz, 2H), 1.32 (t, J= 7.6 Hz, 3H).

Intermediate 23: 6-Methyl-nicotinic acid hydrazide

Using the same experimental procedures described in the synthesis of intermediate 22 (step 2), intermediate 23 was made at 9.39 mmol reaction scale from methyl-6-methylnicotinate, and 0.50 g of the title compound was obtained. It was used for the next step without further purification. ^XH NMR (400 MHz, CDC1₃) δ 8.85 (d, J = 2.2 Hz, 1H), 7.99 (dd, J

Hz, 1H), 7.68 (br s, 1H), 7.26 (d, J= 8.9 Hz, 1H), 4.13 (br s, 2H), 2.62 (s, 3H).

Intermediate 24: 5-Methyl-nicotinic acid hydrazide

Using the same experimental procedures described in the synthesis of intermediate 22 (step 2), intermediate 24 was made at 19.8 mmol reaction scale from methyl-5-methylnicotinate, and 3.3 g of the crude title compound was obtained. It was used for the next step without further purification. ^XH NMR (400 MHz, CDC1₃) δ 8.76 (d, J= 1.8 Hz, 1H), 8.58 (d, J= 1.7 Hz, 1H), 7.93 (s, 1H), 7.74 (br s, 1H), 6.86 (br s, 2H), 2.41 (s, 3H).

Intermediate 25: 6-Trifluoromethyl-nicotinic acid hydrazide

Using the same experimental procedures described in the synthesis of intermediate 22 (step 2), intermediate 25 was made at 9.75 mmol reaction scale from methyl-6- (trifluoromethyl)nicotinate, and 1.7 g of the crude title compound was obtained. It was used for the next step without further purification. ^XH NMR (400 MHz, CDC1₃) δ 8.98 (br s, 1H), 8.83 (s, 1H), 8.31 (d, J= 8.2 Hz, 1H), 8.12 (dd, J= 2.0, 8.2 Hz, 1H), 4.13 (br s, 2H). LC-MS (Method A): RT: 0.48 min; ESI-MS m/z: 2.6 (M+H)⁺.

Intermediate 26: 3-[3-(6-Methyl-pyridin-3-yl)-[l,2,4]oxadiazol-5-yl]-adamantan-l- ylamine

Intermediate 26 was prepared via the process of Scheme 23, supra, as follows:

Stepl: {3-[3-(6-Methyl-pyridin-3-yl)-[l,2,4]oxadiazol-5-yl]-adamantan-l-yl}-carbamic acid tert-butyl ester

A mixture of 3-ter/-butoxycarbonylamino-adamantane-l-carboxylic acid (0.20 g, 0.68 mmol), N-hydroxy-6-methyl-nicotinamidine (0.51 g, 3.38 mmol), N,N-diisopropylethylamine (1.47 mL, 8.46 mmol) and TBTU (1.09 g, 3.38 mmol) in DMF (7.50 mL) was microwaved at 150 °C for 20 minutes. The reaction mixture was diluted with EtOAc (50 mL). The organic layer was washed with saturated aqueous aHC03 and brine, dried ove MgS0₄, and concentrated under reduced pressure.

The residue was purified by CombLF/as/z^® system (0 to 30% EtOAc in DCM) to give 220 mg (79%) of the title compound, {3-[3-(6-methyl-pyridin-3-yl)-l,2,4-oxadiazol-5-yl]-adamantan- l-yl}-carbamic acid tert-butyl ester. ¾ NMR (400 MHz, CDC1₃) δ 9.17 (d, J= 1.7 Hz, 1H), 8.22 (dd, J = 2.2, 8.1 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 2.63 (s, 3H), 1.71-2.38 (m, 14H), 1.44 (s, 9H). LC-MS (Method C): RT: 1.65 min; ESI-MS m/z: 411 (M+H)⁺.

Step 2 : 3- [3-(6-Methyl-pyridin-3-yl)- [1,2,4] oxadiazol-5-yl] -adamantan-l-ylamine

To a solution of {3-[3-(6-methyl-pyridin-3-yl)-l,2,4-oxadiazol-5-yl]-adamantan-l-yl }- carbamic acid tert-butyl ester (200 mg, 0.487 mmol in methanol (5.00 mL, 123 mmol) was added 2.0 M of HCl in Ether (0.974 mL).The reaction mixture was stirred at rt overnight and basified with saturated aqueous aHC0₃. The aqueous layer was extracted with DCM (3x). The combined organic layers were washed with brine and concentrated under reduced pressure to give 118 mg (78%) of the crude title compound, 3-[3-(6-methyl-pyridin-3-yl)- [l,2,4]oxadiazol-5-yl]-adamantan-l-ylamine. It was used for the next step without further purification. ¾ NMR (400 MHz, CDC1₃) δ δ 9.17 (d, J= 1.9 Hz, 1H), 8.22 (dd, J= 2.2, 8.1 Hz, 1H), 7.26 (d, J= 7.9 Hz, 1H), 2.63 (s, 3H), 1.65-2.34 (m, 14H). LC-MS (Method C): RT: 0.76 min;ESI-MS m/z: 311 (M+H)⁺.

Intermediate 27: iV-Hydroxy-6-methyl-nicotinamidine

Intermediate 27 was prepared via the process of Scheme 22, supra, as follows:

To a mixture containing 5-cyano-2-picoline (5.00 g, 42.3 mmol), methanol (17 mL), and finely powdered K₂CO₃ (8.77 g, 63.5 mmol) was added a solution of hydroxylamine hydrochloride (5.88 g, 84.6 mmol) in methanol (50 mL). The reaction mixture was heated at reflux overnight and then cooled to rt. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue were triturated with cold MTBE, and the resulting solid was collected via filtration and dried under reduced pressure to give 3.6 g (56%) of the title compound, N-hydroxy-6-methyl-nicotinamidine. ^XH NMR (400 MHz, DMSO-d₆) δ 9.65 (br s, 1H), 8.72 (s, 1H), 7.90 (d, J= 8.0 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 5.91 (s, 2H), 2.47 (s, 3H)

3. Preparation of Compounds of the Invention

Unless specified otherwise, all starting materials and reagents were obtained from commercial suppliers, such as Sigma-Aldrich Corp. (St. Louis, MO, USA) and its subsidiaries, and used without further purification. Example 4: 6-Methyl-pyridine-2-carboxylic acid (3-methylcarbamoyl-adamantan-l- yl)-amide

Example 4 was synthesized from intermediate 2 via the process of Scheme 1, supra, as follows:

To a vial containing 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid (intermediate 2, 60 mg, 0.2 mmol), DCM (1 mL), DIEA (39 mg, 0.30 mmol) and TBTU (96 mg, 0.30 mmol) was added 0.5 ml of 2M methyl amine in THF (1 mmol). After stirring at rt for 16 hrs, the reaction mixture was partitioned into DCM and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 18-95% in 3.6 minutes with a cycle time of 5 min. A shallow gradient between 25-48% of acetonitrile was used between 0.7-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil CI 8, 30 x 50 mm, 5 um particle size) to afford 45 mg (70%) of the title compound, 6-methyl-pyridine-2-carboxylic acid (3-methylcarbamoyl-adamantan-l-yl)- amide.

In an analogous manner to Example 4, Examples 1-3, 5-6, 25, 26, 28 and 29 of Table 1 (below) were made from intermediate 2 and corresponding commercially available amines.

In a similar manner to Example 4, Examples 7-21, 27, and 30-32 of Table 1 were made from intermediate 1 and commercially available amines.

In a similar manner to Example 4, Examples 22 and 23 were made from commercially available 3-chlorobenzoic acid and intermediates 8 and 7 respectively. Example 24: 3-(3-Chloro-benzoylamino)-adamantane-l-carboxylic acid (6-methyl- pyridin-2-yl)-amide

Examaple 24 was prepared via the processes of Schemes 2 and 4, supra, as follows:

Step 1 : 3-Amino-adamantane-l-carboxylic acid (6-methyl-pyridin-2-yl)-amide

In a similar manner to intermediate 7, 3-amino-adamantane-l-carboxylic acid (6-methyl- pyridin-2-yl)-amide was made at 0.1 mmol reaction scale from 3-tert-butoxycarbonylamino- adamantane- 1 -carboxylic acid and 6-methylpyridin-2-amine. The crude product 3-amino- adamantane- 1 -carboxylic acid (6-methyl-pyridin-2-yl)-amide was used in the next step without further purification.

Step 2: 3-(3-Chloro-benzoylamino)-adamantane-l-carboxylic acid (6-methyl-pyridin-2- yl)-amide

In a similar manner to Example 4, 22 mg (50%) of the title compound, 3-(3-chloro- benzoylamino)-adamantane- 1 -carboxylic acid (6-methyl-pyridin-2-yl)-amide was obtained from the reaction of the crude product of step 1 and commercially available 3-chlorobenzoic acid.

Example 37: 6-Methyl-pyridine-2-carboxylic acid [3-(3-propyl-ureido)-adamantan-l- yl]-amide

Example 37 was synthesized from intermediate 9 via the process of Scheme 5, supra, as follows:

To a vial containing 6-methyl-pyridine-2-carboxylic acid (3-isocyanato-adamantan-l-yl)- amide (intermediate 9, 30 mg, 0.1 mmol) and DMF (2 mL) was added 1-propanamine (600 mg, 10 mmol). The mixture was microwaved for 15 minutes at 160 °C and then concentrated under reduced pressure. The residue was partitioned into DCM and saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 24-95% in 3.6minutes with a cycle time of 5 min. A shallow gradient between 30-60% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 39 mM of ammonium acetate. Column: Inertsil C8, 30 x 50 mm, 5 um particle size) to afford 18 mg (48%) of the title compound, 6-methyl-pyridine-2-carboxylic acid [3-(3-propyl-ureido)-adamantan-l-yl]- amide.

Example 37 was also made from intermediate 12 via the process of Scheme 6. Reaction of intermediate 12 (6-methyl-pyridine-2-carboxylic acid (3-amino-adamantan-l-yl)-amide) (60 mg, 0.2 mmol) with propyl isocyanate ( 600 mg, 7 mmol) in DCM at rt for 16 hrs, and 40 mg (50%) of the title compound was obtained after HPLC purification.

In a similar manner to Example 37, Examples 33-35 of Table 1 were made from the reaction of intermediates 13, 14 and 12 with the corresponding commercially available isocyanates, respectively; Examples 39-40 of Table 1 were made from the reaction of intermediate 11 with the corresponding commercially available isocyanates, respectively; Examples 36 and 38 of Table 1 were made from the reaction of intermediate 9 with the corresponding commercially available amines, respectively; Examples 41, 42 and 45 of Table 1 were made from the reaction of intermediate 10 with the corresponding commercially available amines, respectively. Example 43: Morpholine-4-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]- adamantan-l-yl}-amide

Example 43 was synthesized from intermediate 11 via the process of Scheme 6, supra, as follows:

To a vial containing a solution of pyridine-2-carboxylic acid (3-amino-adamantan-l-yl)- amide (intermediate 11, 20 mg, 0.07 mmol) in DCM (2 mL) and DIEA ( 19 mg, 0.15 mmol) was added dropwise morpholine-4-carbonyl chloride (16.5 mg, 0.1 1 mmol). After stirring for 16 hrs at rt, the reaction mixture was partitioned into DCM and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 20-95% in 3.4 minutes with a cycle time of 5 min. A shallow gradient between 22-48% of acetonitrile was used between 0.51-3.2 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 39 mM of ammonium acetate. Column: Inertsil C8, 30 x 50 mm, 5 um particle size) to afford 6 mg (20%) of the title compound as a white solid.

In an analogous manner to Example 43, Example 44 of Table 1 was made from intermediate 11 and piperdine-l-carbonyl chloride.

Example 54: {3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 2,2-difluoro-propyl ester

Example 54 was synthesized from intermediate 9 via the process of Scheme 8, supra, as follows:

To a vial containing 6-methyl-pyridine-2-carboxylic acid (3-isocyanato-adamantan-l-yl)- amide (intermediate 9, 30 mg, 0.1 mmol) and DMF (2 mL) was added 2,2-difluoropropanol (500 mg, 5 mmol). The solution was microwaved for 25 minutes at 165 °C. The reaction mixture was concentrated and partitioned into DCM and saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 29-95% in 3.6minutes with a cycle time of 5 min. A shallow gradient between 40-70% of acetonitrile was used between 0.75-3.4 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 39 mM of ammonium acetate. Column: Inertsil C8, 30 x 50 mm, 5 um particle size) to afford 12 mg (30%) of the title compound, {3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 2,2- difluoro-propyl ester.

In an analogous manner to Example 54, Examples 46-53 and 55 of Table 1 were made from intermediate 9 and the corresponding commercially available alcohols, respectively.

In a similar manner to Example 54, Example 59 of Table 1 was made from intermediate 10 and 2,2-difluoropropanol.

Example 57: {3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 2-methoxy-ethyl ester

Example 57 was synthesized from intermediate 12 via the process of Scheme 8, supra, as follows:

To a vial containing 6-methyl-pyridine-2-carboxylic acid (3-amino-adamantan-l-yl)-amide (intermediate 12) (30 mg, O. lmmol), DCM (2 mL) and 2-methoxyethyl chloroformate (21 mg, 0.15 mmol) was added TEA (0.028 mL, 0.20 mmol). After stitting at rt for 16 hrs, the reaction mixture was concentrated and partitioned into DCM and saturated sodium bicarbonate solution. The organic layer separated, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 27-95% in 3.6minutes with a cycle time of 5 min. A shallow gradient between 35-64% of acetonitrile was used between 0.75-3.3 min to separate close- eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil CI 8, 30 x 50 mm, 5 um particle size) to afford 15 mg (40%) of the title compound, {3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 2-methoxy-ethyl ester.

In an analogous manner to Example 57, examples 56 and 58 were made from intermediate 12 and the corresponding commercially available chloroformates, respectively.

Example 60: 6-Methyl-pyridine-2-carboxylic acid [3-(2-oxo-[l,3]oxazinan-3-yl)- adamantan-l-yl]-amide

Example 60 was prepared from intermediate 12 via the process of Scheme 9, supra, as follows:

To a vial containing containing 6-methyl-pyridine-2-carboxylic acid (3-amino-adamantan-l- yl)-amide (intermediate 12) (50 mg, 0.2 mmol), CH₃CN (5 mL) and TEA (26 mg, 0.26 mmol) was added 3- chloropropyl chloroformate (0.06 g, 0.4 mmol). After stirring at rt for 1 hr, the reaction was partitioned into DCM and saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give 65 mg (80%) of the crude intermediate (3-[(6-methyl-pyridine-2-carbonyl)- amino]-adamantan-l-yl}-carbamic acid 3-chloro-propyl ester. It was used for next step without further isolation. ^XH NMR (400 MHz, CDC1₃) δ 8.02 (br s, 1H), 7.95 (d, J= 7.6 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 4.63 (br s, 1H), 4.10-4.20 (m, 2H), 3.61 (t, J= 6.3 Hz, 2H) 2.55 (s, 3H), 1.55-2.40-1.55 (m, 14H). ESI-MS m/z: 406 (M+H)⁺.

Above intermediate (52 mg, 0.14 mmol) was taken up in DMF (3 mL) and sodium hydride (13 mg, 0.52 mmol) was added. After stirring at 50 °C for 2 hrs, the reaction mixture was concentrated and partitioned into DCM and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfat, and concentrated to dryness under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP- HPLC/MS) purification system (Gradient: acetonitrile in water, 23-95% in 3.6minutes with a cycle time of 5 min. A shallow gradient between 27-55% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil C8, 30 x 50 mm, 5 um particle size) to afford 4 mg (8%) of the title compound, 6-methyl-pyridine-2-carboxylic acid [3-(2- oxo- [ 1,3] oxazinan-3 -yl)-adamantan- 1 -yl]-amide.

Example 61: Pyridine-2-carboxylic acid (3-benze nesulfonylamino-adamantan-l-yl)- amide

Example 61 was prepared from intermediate 11 via the process of Scheme 10, supra, as follows:

To a vial containing pyridine-2-carboxylic acid (3-amino-adamantan-l-yl)-amide (20 mg, 0.07 mmol), DCM (3 ml) and DIEA (0.018 g, 0.14 mmol) was added benzenesulfonyl chloride (18 mg, 0.10 mmol). After stirring at rt for 3 hrs, the reaction mixture was washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 24-95% in 3.6minutes with a cycle time of 5 min. A shallow gradient between 35-65% of acetonitrile was used between 0.75-3.5 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil C 18, 30 x 50 mm, 5 um particle size) to afford 22 mg (80%) of the title compound, pyridine-2-carboxylic acid (3-benze nesulfonylamino- adamantan- 1 -yl)-amide. Example 62: Ethyl-carbamic acid 3-[(pyridine-2-carbonyl)-amino]-adamantan-l-yl ester

Example 62 was prepared from intermediate 18 via the process of Scheme 11, supra, as follows:

To a vial containing pyridine-2-carboxylic acid (3-hydroxy-adamantan-l-yl)-amide (intermediate 18, 20 mg, 0.07 mmol) and DMF (2 mL, 20 mmol) was added isocyanato- ethane (50 mg, 0.7 mmol). The reaction mixture was microwaved for 25 minutes at 165 °C and then concentrated under reduced pressure. The residue was partitioned into DCM and saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 24-95% in 3.6minutes with a cycle time of 5 min. A shallow gradient between 30-60% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil C 18, 30 x 50 mm, 5 um particle size) to afford 7 mg (30%) of the title compound, ethyl-carbamic acid 3-[(pyridine-2-carbonyl)-amino]- adamantan- 1 -yl ester.

Example 63: 6-Methyl-pyridine-2-carboxylic acid [3-(pyridin-2-ylamino)-adamantan-l

-yl] -amide

Example 63 was made via the process of Scheme 13, supra, as follows:

Step 1: 6-Methyl-pyridine-2-carboxylic acid (3-hydroxy-adamantan-l-yl)-amide

To a flask containing 6-methylpicolinic acid (410 mg, 3.0 mmol), DMF (10 mL), BOP (1400 mg, 3.3 mmol) and DIEA (390 mg, 3.0 mmol) was added 3-amino-adamantan-l-ol (500 mg, 3 mmol). After stirring at rt for 16 hrs, the reaction mixture was washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by CombiF/as/z^® (hexane:ethyl acetate = 1 : 1) to afford 600 mg (70%) of the title compound, 3-hydroxy- adamantane-l-carboxylic acid (6-methyl-pyridin-2-yl)-amide. ^XH NMR (400 MHz, CDC1₃) £8.06 (br s, 1H), 7.95 (d, J= 7.7 Hz, 1H), 7.70 (t, J= 7.7 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 2.55 (s, 3H), 1.54-2.35 (m, 14H). ESI-MS m/z: 287 (M+H)⁺.

Step 2: 6-Methyl-pyridine-2-carboxylic acid [3-(pyridin-2-ylamino)-adamantan-l -yl]- amide

To a vial containing 6-methyl-pyridine-2-carboxylic acid (3-hydroxy-adamantan-l-yl)-amide (700 mg, 2 mmol), DCM (5 mL, 80 mmol) and TEA (680 uL, 4.9 mmol) at 0 °C was added methanesulfonyl chloride (500 uL, 6 mmol) dropwise. After stirring at rt for 16 hrs, the reaction mixture was washed successively with water and saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 500 mg (40%) of the crude mesylate intermediate, methanesulfonic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-l- yl ester which was used in the next step without further purification. ESI-MS m/z: 365 (M+H)⁺. To a vial containing the mesylate (100 mg, 0.3 mmol) was added 2-pyridinamine (380 mg, 4.0 mmol). After heated at 160 °C for 1 hour, the reaction mixture was cooled to rt and partitioned into DCM and saturated solution of sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 28-95% in 3.6minutes with a cycle time of 5 min. A shallow gradient between 38-67% of acetonitrile was used between 0.75-3.4 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil C8, 30 x 50 mm, 5 um particle size) to afford 15 mg (20%) of the title compound, 6-methyl-pyridine-2- carboxylic acid [3-(pyridin-2-ylamino)-adamantan-l -yl]-amide.

Example 64: Pyridine-2-carboxylic acid {3-[(pyridin-2-ylmethyl)-amino]-adamantan-l- yl}-amide

Example 64 was prepared from intermediate 11 via the process of Scheme 14, supra, as follows:

To a flask containing pyridine-2-carboxylic acid (3-amino-adamantan-l-yl)-amide (intermediate 11, 140 mg, 0.52 mmol) in THF (10 mL) was added 2-pyridinecarboxaldehyde (61 mg, 0.57 mmol) and the mixture was stirred at rt for 45 minutes. Sodium triacetoxyborohydride (164 mg, 0.774 mmol) was then added and the reaction was stirred overnight (>16 hours) at rt. The reaction was quenched by adding methanol (1.0 mL) and stirring vigorously for a few minutes. The solvent was removed by concentrating under reduced pressure and the residue was purified by preparative Thin Layer Chromatography (TLC), eluting with 10% methanol in DCM (containing 1% ammonium hydroxide). The product obtained was further purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 15-95% in 3.9 minutes with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 78 mM of ammonium acetate. Column: Inertsil C8, 30 x 50 mm, 5 μιη particle size) to afford 47 mg (25%) of the title compound, pyridine-2-carboxylic acid (3-[(pyridin-2-ylmethyl)- amino]-adamantan-l-yl} -amide as a white solid.

In an analogous manner, Example 65 was prepared from intermediate 11 and commercially available benzaldehyde.

Example 66: Pyridine-2-carboxylic acid [3-(5-chloro-lH-benzoimidazol-2-yl)- adamantan-l-yl]-amide

Example 66 was synthesized from intermediate 1 via the process of Scheme 15, supra, as follows:

To a flask containing 3-[(pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid (intermediate 1, 300 mg, 1 mmol), DCM (20 mL) and DIEA (1 mL, 6 mmol) was added EDCI (230 mg, 1.2 mmol) and 4-chloro-benzene-l,2-diamine (171 mg, 1.2 mmol). After stirring at rt for 16 h, the reaction mixture was partitioned into DCM and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 16-95% in 3.95 minutes with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 96 mM of ammonium formate. Column: Inertsil C8, 30 x 50 mm, 5 um particle size.) to give a mixture of the intermediate amide regioisomers (300 mg, 70 %). ESI-MS m/z: 425 (M+H)⁺. A portion of above amide intermediate (20 mg, 0.05 mmol) was dissolved in 1 mL of THF and 2 mL of 6M HC1 and the solution was microwaved for 10 minutes at 160 °C. After cooling to rt, the reaction mixture was concentration under reduced pressure, and the resulting residue was partitioned into DCM and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 25-95% in 3.9 minutes with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil C8, 30 x 50 mm, 5 um particle size) to afford 6 mg (30%) of the title compound, pyridine-2-carboxylic acid [3-(5-chloro-lH-benzimidazol-2-yl)-adamantan-l-yl]-amide.

In a similar manner to Example 66, Example 67 of Table 1 was made from intermediate 2 and commercially available 2-aminophenol; Examples 68-71 were made from intermediate 2 and the corresponding commercially available diamines.

Example 72: 6-Methyl-pyridine-2-carboxylic acid [3-(3-methyl-3H-imidazo[4,5- b]pyridin-2-yl)-adamantan-l-yl]-amide

Example 72 was made via the process of Scheme 15 from intermediate 2 and N²- methylpyridine-2,3 -diamine, which was made by reduction of the corresponding nitro compound, supra, as follows:

To a vial containing N-methyl-3-nitro-2-pyridinamine (1.53 g, 10.0 mmol) in methanol (25 mL) was added 10% palladium on charcoal (150 mg). The mixture was hydrogenated for 16 hrs at 30 psi, filtered through Celite, and the filtrate was concentrated under reduced pressure to afford N²-methylpyridine-2,3-diamine as a brown solid in a quantitative yield. It was used in next step without purification. ¾ NMR (400 MHz, CDC1₃) £ 7.79 (dd, J = 5.2, 1.5 Hz, 1H), 6.85 (dd, J = 7.3, 1.6 Hz, 1H), 6.53 (m, 1H), 4.18 (br s, 1H), 3.17 (br s, 2H), 3.01 (s, 3H).

To a flask containing 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid (intermediate 12, 1.9 g, 6.0 mmol), DCM (50 mL), DIEA (1.9 g, 15 mmol) and TBTU (2.2 g, 7.0 mmol) was added N²-methylpyridine-2,3 -diamine (0.74 g, 6 mmol). After stirring at rt for 5 hours, the reaction mixture was concentrated, and partitioned into DCM and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification systerm (Gradient: acetonitrile in water, 23-95% in 3.6 minutes with a cycle time of 5 min. A shallow gradient between 26-56% of acetonitrile was used between 0.75-3.4 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil CI 8, 30 x 50 mm, 5 um particle size) to yield an amide intermediate as regioisomeric mixtures in a quantitative yield. ESI-MS m/z: 420 (M+H)⁺.

To a microwave vial containing above amide intermediate (80 mg, 0.19 mmol) was added 3 mL of acetic acid. The reaction mixture was microwaved at 160 °C for 25 minutes, poured slowly into an ice cold sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 28-95% in 3.6minutes with a cycle time of 5 min. A shallow gradient between 33-62% of acetonitrile was used between 0.75-3.4 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil CI 8, 30 x 50 mm, 5 um particle size) to afford 60 mg (78%) of the title compound, 6-methyl-pyridine-2- carboxylic acid [3-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-adamantan-l-yl]-amide, as a brownish solid.

Example 73: 6-Methyl-pyridine-2-carboxylic acid [3-(4-methyl-lH-imidazol-2-yl)- adamantan-l-yl]-amide

Example 73 was synthesized from intermediate 2 via the process of Scheme 15, supra as follows;

To a vial containing 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid (intermediate 2, 100 mg, 0.3 mmol), DCM (15 mL, 230 mmol), DIEA (62 mg, 0.48 mmol) and amino acetone hydrochloride (52 mg, 0.48 mmol) was added BOP (210 mg, 0.48 mmol). After stirring at rt for 3 hours, the reaction mixture was concentrated under reduced pressure, and then partitioned into DCM and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP- HPLC/MS) purification system (Gradient: acetonitrile in water, 18-95% in 3.5 minutes with a cycle time of 5 min. A shallow gradient between 20-40% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 39 mM of ammonium acetate. Column: Inertsil C8, 30 x 50 mm, 5 um particle size) to give 50 mg (40%) of an amide intermediate. ESI-MS m/z: 370 (M+H)⁺. To above intermediate (20 mg) in DMF (200 uL) was added ammonium acetate (150 mg) and acetic acid (1 mL). After heated at 100 °C for 4 hrs, the reation mixture was cooled to rt, concentrated under reduced pressure, and partitioned into DCM and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 12-95% in 3.6 minutes with a cycle time of 5 min. A shallow gradient between 20-42% of acetonitrile was used between 0.6-3.25 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil C8, 30 x 50 mm, 5 um particle size) to afford 5 mg (26%) of the title compound, 6-methyl-pyridine-2-carboxylic acid [3-(4-methyl-lH-imidazol-2-yl)-adamantan- l-yl]-amide.

Example 74: 6-Methyl-pyridine-2-carboxylic acid [3-(l,3-dihydro-isoindol-2-yl)- adamantan-l-yl]-amide

Example 74 was prepared from intermediate 12 via the process of Scheme 16, supra, as follows:

To a culture tube was added 6-methyl-pyridine-2-carboxylic acid (3-amino-adamantan-l-yl)- amide (intermediate 12, 50.0 mg, 0.175 mmol), l,2-bis(bromomethyl)-benzene (46 mg, 0.17 mmol), potassium carbonate (60 mg, 0.43 mmol) and DMF (2.0 mL), and the mixture was stirred at rt for 18 hours. To the reaction was then added water (10 mL) and ethyl acetate (10 mL), and the biphasic mixture was stirred vigorously for a few minutes. The organic layer was separated and the aqueous layer was stirred again with ethyl acetate (2 x 10 mL). The combined organic layers were then washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 20-95% in 3.5 minutes with a cycle time of 5 min. A shallow gradient between 24-52% of acetonitrile was used between 0.7-3.3 min to separate close- eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 96 mM of ammonium formate. Column: Inertsil C8, 30 x 50 mm, 5 μιη particle size) to afford 12 mg (18%) of the title compound, 6-methyl-pyridine-2-carboxylic acid [3-(l,3-dihydro-isoindol-2-yl)- adamantan-l-yl] -amide as an oil.

Example 87: 6-Methyl-pyridine-2-carboxylic acid [3-(5-oxo-5,7-dihydro-pyrrolo[3,4- b]pyridin-6-yl)-adamantan-l-yl]-amide

Example 87 was prepared from intermediate 16 via the process of Scheme 18, supra, as follows:

In a 20-mL vial was added 6-(3-amino-adamantan-l-yl)-5,6-dihydro-pyrrolo[3,4-b]pyridin-7- one (intermediate 16, 50.0 mg, 0.18 mmol), 6-methylpicolinic acid (26.6 mg, 0.19 mmol) and DCM (4.0 mL, 62.4 mmol), followed by the addition of PYBOP (110 mg, 0.21 mmol) and triethylamine (61.5 uL, 0.44 mmol). After stirred at rt overnight, the reaction mixture was diluted with DCM (30 mL). The orgainc layer was separated, washed with saturated aqueous aHC03 and brine, dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP- HPLC/MS) purification system (Gradient: acetonitrile in water, 23-95% in 3.6minutes with a cycle time of 5 min. A shallow gradient between 27-50% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 78 mM of ammonium acetate. Column: Inertsil C8, 30 x 50 mm, 5 um particle size) to give 41 mg (58%) of the title compound, 6-methyl-pyridine-2-carboxylic acid [3-(7-oxo- 5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-adamantan-l-yl]-amide.

In an analogous manner to Example 87, Examples 75-77 and 79 of Table 1 were made from intermediate 15 and commercially available 6-methylpicolinic acid, 2-methylpyrimidine-4- carboxylic acid, 5-fluoropyidine-2-carboxylic acid and 4-fluoro-pyridine-2-carboxylic acid, respectively.

In an analogous manner to Example 87, Example 78 of Table 1 was made from intermediate 15 and 4-methyl-2-pyrimidinecarboxylic acid, which was prepared by following procedure:

Step 1 : To a solution of 2-chloro-4-methylpyrimidine (3.00 g, 23.3 mmol) in ethyl ether (24 mL) was added a solution of sodium cyanide (2.86 g, 58.3 mmol) in TEA and water (1 :3, 24.0 mL). The reaction mixture was stirred at room temperature overnight. The aqueous layer was extracted with ethyl ether (3 x 20 mL). The combined organic layers were dried over MgS0₄, filtered, and concentrated under reduced pressure to give 1.8 g of 4-methyl- pyrimidine-2-carbonitrile, which was used for the next step without further purification. ^XH NMR (400 MHz, D₂0) £8.64 (d, J= 5.4 Hz, 1H), 7.59 (d, J= 5.5 Hz, 1H).

Step 2: A solution of 4-methyl-pyrimidine-2-carbonitrile (500 mg, 4.20 mmol) and sodium hydroxide (504 mg, 12.6 mmol) in water (12.5 mL) was stirred at 60 °C for 1 hour. The reaction mixture was cooled to rt and acidified up to ~pH2 with citiric acid and extracted with ΟΗ(¾:Ζ^'-ΡΓΟΗ (3: 1, 2 x 20 mL). The combined organic layers were dried over MgS0₄ and concentrated under reduced pressure to afford 0.29 g of 4-methyl-2-pyrimidinecarboxylic acid, which was used for the next step without further purification. ^XH NMR (300 MHz, D₂0) £8.50 (d, J= 5.2 Hz, 1H), 7.31 (d, J= 5.3 Hz, 1H).

In an analogous manner to Example 87, Example 80 of Table 1 was made from intermediate 15 and commercially available nicotinoyl chloride HC1 salt.

In an analogous manner to Example 87, Examples 81-82 and 86 of Table 1 were made from the reaction of intermediate 16 with commercially available 5-fluoropyidine-2-carboxylic acid, 2-methylpyrimidine-4-carboxylic acid and 2-methyl-l,3-thiazole-4-carboxylic acid, respectively.

In an analogous manner to Example 87, Examples 83-85 of Table 1 were made from the reaction of intermediate 16 with commercially available nicotinoyl chloride HC1 salt, isoxazole-5-carbonyl chloride and l,3-thiazole-2-carbonyl chloride, respectively.

In an analogous manner to Example 87, Examples 89-91 of Table 1 were made from the reaction of intermediate 17 and commercially available 2-methylpyrimidine-4-carboxylic acid, 6-methylpicolinic acid, and 5-fluoropyidine-2-carboxylic acid, respectively.

Example 87 was also made from intermediates 12 and 19 via the process of Scheme 18, supra, as follows:

To a solution of 6-methyl-pyridine-2-carboxylic acid (3-amino-adamantan-l-yl)-amide (0.33 g, 0.82 mmol) and 2-bromomethyl-nicotinic acid ethyl ester (0.20 g, 0.82 mmol) in DMF (1.00 mL, 12.9 mmol) was added potassium carbonate (0.226 g, 1.64 mmol). The reaction mixture was stirred at rt overnight and at 50 °C for 2 days. The reaction mixture was cooled to rt, and then diluted with EtOAc (50 ml). The organic layer was washed with saturated aqueous aHC03 and brine, and concentrated under reduced pressure. The residue was purified by CombiF/os/z^® system (0-10% 2 N ammonia in MeOH in DCM) and further on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 23-95% in 3.6 minutes with a cycle time of 5 min. A shallow gradient between 26-56% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 46 mM of ammonium formate. Column: Inertsil C18, 30 x 50 mm, 5 um particle size) to give 32 mg (9.7%) of the title compound, 6-methyl-pyridine-2-carboxylic acid [3-(5-oxo-5,7-dihydro- pyrrolo[3,4-b]pyridin-6-yl)-adamantan- 1 -yl]-amide.

In an analogous manner to Example 87, Example 88 of Table 1 was made from intermediates 13 and 20.

Example 92: Pyridine-2-carboxylic acid [3-(l-oxo-l,3-dihydro-isoindol-2-yl)- adamantan-l-yl]-amide

Example 92 was synthesized from intermediate 11 via the process of Scheme 18, supra, as follows:

To a vial containing pyridine-2-carboxylic acid (3-amino-adamantan-l-yl)-amide (intermediate 11, 20 mg, 0.07 mmol), DCM (5 ml), and DIEA (14 mg, 0.1 mmol) was added 2-bromomethyl-benzoyl bromide (23 mg, 0.08 mmol). After stirring for 16 hrs at rt, the reaction mixture was partitioned into DCM and saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP- HPLC/MS) purification system (Gradient: acetonitrile in water, 24-95% in 3.6 minutes with a cycle time of 5 min. A shallow gradient between 35-65% of acetonitrile was used between 0.75-3.5 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil CI 8, 30 x 50 mm, 5 um particle size) to afford 14 mg (40%) of the title compound, pyridine-2-carboxylic acid [3-(l-oxo-l,3- dihydro-isoindol-2-yl)-adamantan-l-yl] -amide. Example 93: Pyridine-2-carboxylic acid [3-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4- b]pyrazin-6-yl)-adamantan-l-yl]-amide

Example 93 was synthesized from the amino intermediate 11 via the process of Scheme 17, supra, as follows:

To a vial containing pyrazine-2,3-dicarboxylic acid (20 mg, 0.1 mmol), DCM (5 mL) and oxalyl chloride (30 mg, 0.2 mmol) was added a drop of DMF. After stirring at rt for 16 h, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in DCM (5 mL), pyridine-2-carboxylic acid (3-amino-adamantan-l-yl)-amide (intermediate 11, 20 mg, 0.07 mmol) was added, followed by TEA (7 mg, 0.07 mmol). After stirring for 16 h at rt, the reaction mixture was partitioned into DCM and saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP- HPLC/MS) purification system (Gradient: acetonitrile in water, 23-95% in 3.6 minutes with a cycle time of 5 min. A shallow gradient between 27-57% of acetonitrile was used between 0.75-3.5 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil CI 8, 30 x 50 mm, 5 um particle size) to afford 8 mg (30%) of the title compound, pyridine-2-carboxylic acid [3-(5,7-dioxo- 5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-yl)-adamantan-l-yl]-amide.

Example 101: 6-Methyl-pyridine-2-carboxylic acid [3-(5-pyridin-2-yl-[l,3,4]oxadiazol-2- yl)-adamantan-l-yl]-amide

Example 101 was prepared from intermediate 2 via the process of Scheme 20, supra, as follows: Step 1: 6-Methyl-pyridine-2-carboxylic acid {3-[iV-(pyridine-2-carbonyl)- hydrazinocarbonyl]-adamantan-l-yl}-amide

To a flask was added 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid (intermediate 2, 157 mg, 0.50 mmol), 2-picolinyl hydrazide (82 mg, 0.60 mmol) and DCM (5.0 mL), followed by PyBOP (312 mg, 0.600 mmol) and TEA (0.17 mL, 1.25 mmol). After stirring at rt for 5 hours, the reaction mixture was transferred to a separatory funnel with DCM (15 mL) and saturated aqueous sodium bicarbonate (about 30 mL). After extracting, the layers were separated and the aqueous layer was extracted again with DCM (2 x 15 mL). The combined organic layers were then washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 23-95% in 3.6 minutes with a cycle time of 5 min. A shallow gradient between 26-54% of acetonitrile was used between 0.75-3.4 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 65 mM of ammonium acetate. Column: Inertsil C8, 30 x 50 mm, 5 μιη particle size) to afford 170 mg (79%) of the title compound, 6-methyl-pyridine-2-carboxylic acid {3-[N-(pyridine-2- carbonyl)-hydrazinocarbonyl]-adamantan-l-yl} -amide, as a white solid. ^XH NMR (300 MHz, CDC1₃) δ 10.28 (br d, J = 6.6 Hz, 1H), 8.56-8.61 (m, 1H), 8.46 (br d, J = 6.4 Hz, 1H), 8.07- 8.17 (m, 2H), 7.98 (d, J= 7.7 Hz, 1H), 7.86 (td, J= 7.7, 1.6 Hz, 1H), 7.73 (t, J= 7.6 Hz, 1H), 7.46 (ddd, J= 7.6, 4.7, 1.2 Hz, 1H), 7.30-7.24 (m, 1H), 2.58 (s, 3H), 2.14-2.42 (m, 8H), 1.93- 2.07 (m, 4H), 1.67-1.86 (m, 2H). ESI-MS m/z: 434 (M+H)⁺.

Step 2: 6-Methyl-pyridine-2-carboxylic acid [3-(5-pyridin-2-yl-[l,3,4]oxadiazol-2-yl)- adamantan-l-yl]-amide

To a culture tube was added 6-methyl-pyridine-2-carboxylic acid {3-[N-(pyridine-2- carbonyl)-hydrazinocarbonyl]-adamantan-l-yl}-amide (50.0 mg, 0.16 mmol), pyridine (46 mg, 0.58 mmol) and DCM (1.0 mL). The solution was cooled at 0 °C and treated with a solution of triflic anhydride (107 mg, 0.381 mmol) in DCM (1.0 mL) and the reaction was left to gradually warm to rt. After about 25 hours, the reaction mixture was diluted with DCM (3 mL), and then stirred vigorously with saturated aqueous sodium bicarbonate (5 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by preparative Thin Layer Chromatography (TLC), eluting with 100% Ethyl acetate to afford 24 mg (44%, 88% purity) of the title compound, 6-methyl-pyridine-2-carboxylic acid [3-(5-pyridin-2-yl-[l,3,4]oxadiazol-2-yl)- adamantan- 1 -yl] -amide, as a colorless oil.

In an analogous manner, examples 94-100 and 102-103 were made from intermediate 2 and the corresponding commercially available hydazides, respectively.

In a similar manner to Example 101, Examples 104-106 were made from intermediate 3 and the corresponding commercially available hydrazides, respectively; Examples 107-108 were made from intermediate 1 and the corresponding commercially available hydrazides, respectively; Examples 109 and 1 10 were made from the reaction of intermediates 4 and 5 with commercially available nicotinohydrazide, respectively; Examples 11 1-1 14 were made from the reaction of intermediate 23 with intermediates 1, 5, 2 and 3, respectively; Examples 115-116 were made from the reaction of intermediate 24 with intermediates 1 and 5, respectively; Examples 1 17-1 18 were made from the reaction of intermediate 25 with intermediates 1 and 5, respectively; Examples 119-120 were made from the reaction of intermediate 22 with intermediates 2 and 5, respectively.

Example 121: 5-Fluoro-pyridine-2-carboxylic acid {3-[5-(6-methyl-pyridin-3-yl)-

[l,3,4]oxadiazol-2-yl]-adamantan-l-yl}-amide

Example 121 was prepared from intermediate 21 via the process of Scheme 20, supra, as follows: In a 20-mL vial was added 3-[5-(6-methyl-pyridin-3-yl)-l,3,4-oxadiazol-2-yl]-adamantan-l- ylamine (intermediate 21, 70.0 mg, 0.23 mmol), 5-fluoropyridine-2-carboxylic acid (35.0 mg, 0.25 mmol) and DCM (2.80 mL, 43.7 mmol), followed by PYBOP (129 mg, 0.248 mmol) and TEA (69.2 uL, 0.50 mmol). The reaction mixture was stirred at rt overnight and diluted with DCM (30 mL). The orgainc layer was washed with saturated aqueous aHC0₃ and brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system (Gradient: acetonitrile in water, 25-95% in 3.6 minutes with a cycle time of 5 min. A shallow gradient between 35-65% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 92 mM of ammonium formate. Column: Inertsil C8, 30 x 50 mm, 5 um particle size) to give 17 mg (17%) of the title compound, 5-fluoro-pyridine-2-carboxylic acid {3-[5-(6-methyl-pyridin-3- yl)-l,3,4-oxadiazol-2-yl]-tricyclo[3.3.1.1(3, 7)]decan-l-yl} -amide.

In a similar manner to Example 121, Examples 122 and 123 of Table 1 were made from the reaction of intermediate 21 with commercially 2-pyrazinecarboxylic acid and pyrimidine-4- carboxylic acid, respectively.

Example 124: 2-Methyl-pyrimidine-4-carboxylic acid {3-[3-(3-fluoro-phenyl)-

[l,2,4]oxadiazol-5-yl]-adamantan-l-yl}-amide

Example 124 was prepared from intermediate 5 via the process of Scheme 22, supra, as follows:

A mixture of 3-[(2-methyl-pyrimidine-4-carbonyl)-amino]-adamantan-l-carboxylic acid (intermediate 5, 50.0 mg, 0.16 mmol), 3-fluoro-N-hydroxy-benzamidine (24.4 mg, 0.16 mmol), N,N-diisopropylethylamine (69.0 uL, 0.40 mmol) and TBTU (50.9 mg, 0.16 mmol) in DMF (1.0 mL) was microwaved at 150 °C for 20 minutes. The reaction mixture was diluted with EtOAc (50 mL). The organic layer was washed with saturated aqueous aHC0₃ and brine, dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by CombLF/os/z^® system (4 g silica gel cartridge; gradient: 10 to 50% ethyl acetate in hexanes over 15 min) to give 54 mg (78%) of the title compound, 2-methyl-pyrimidine-4-carboxylic acid {3 -[3 -(3 -fluoro-phenyl)- 1 ,2,4-oxadiazol-5 -yl] -adamantan- 1 -yl} -amide.

In a similar manner to Example 124, Example 125 of Table 1 was made from intermediate 5 and commercially available 3-pyridylamidoxime.

In a similar manner to Example 124, Example 126 of Table 1 was made from intermediate 4 and commercially available 3-pyridylamidoxime.

In a similar manner to Example 124, Example 127 of Table 1 was made from intermediate 2 and commercially available 3-pyridylamidoxime.

In a similar manner to Example 124, Examples 128-131 of Table 1 were from the reaction of intermediate 27 with intermediates 2, 5, 1 and 6, respectively.

Example 134: 5-Fluoro-pyridine-2-carboxylic acid {3-[3-(6-methyl-pyridin-3-yl)-

[l,2,4]oxadiazol-5-yl]-adamantan-l-yl}-amide

Example 134 was prepared from intermediate 26 via the process of Scheme 22, supra, as follows:

To a solution of 5-fluoropyridine-2-carboxylic acid (22.7 mg, 0.16 mmol) in DCM (3.0 mL) was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (50.0 mg, 0.32 mmol) and 1- hydroxybenzotriazole (0.022 g, 0.16 mmol) at 0 °C followed by the addition of 3-[3-(6- methyl-pyridin-3-yl)-[l,2,4]oxadiazol-5-yl]-adamantan-l-ylamine (intermediate 26, 50.0 mg, 0.16 mmol) in DCM (2 mL). The reaction mixture was stirred at rt overnight and diluted with DCM. The organic layer was washed with saturated aqueous aHC03 and brine, and concentrated under reduced pressure. The residue was purified by CombLF/as/z^® system (4 g silica gel cartridge; gradient: 0 to 50% ethyl acetate in DCM over 10 min, then 50% ethyl acetate in DCM for 10 min) to give 48 mg (69%) of the title compound, 5-fluoro-pyridine-2- carboxylic acid {3 - [3 -(6-methyl-pyridin-3 -yl)- [ 1 ,2,4]oxadiazol-5 -yl] -adamantan- 1 -yl} -amide.

In a similar manner to Example 134, Examples 132 and 133 Table 1 was made from intermediate 26 and commercially available 2-pyrazinecarboxylic acid and 6-methyl-2- pyrazinecarboxylic acid, respectively. Example 135: 6-Methyl-pyridine-2-carboxylic acid {3-[5-(3-chloro-phenyl)-oxazol-2-yl]- adamantan-l-yl}-amide

Example 135 was prepared from intermediate 2 via the process of Scheme 24, supra, as follows:

Step 1: 6-Methyl-pyridine-2-carboxylic acid {3-[2-(3-chloro-phenyl)-2-oxo- ethylcarbamoyl]-adamantan-l-yl}-amide

To a flask was added 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-l-carboxylic acid (188 mg, 0.60 mmol), 2-amino-l-(3-chloro-phenyl)-ethanone hydrochloride (103 mg, 0.50 mmol) and DCM (5.0 mL). The solution was then treated successively with TEA (240 μί, 1.7 mmol), 4-dimethylaminopyridine (9 mg, 0.07 mmol) and EDCI (144 mg, 0.750 mmol). After stirring for 5 days at rt, the reaction mixture was diluted with DCM (5 mL), and then stirred vigorously with saturated aqueous sodium bicarbonate (10 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by preparative Thin Layer Chromatography (TLC), eluting with 50% Ethyl acetate in hexanes to afford 42 mg (18%) of the title compound, 6- methyl-pyridine-2-carboxylic acid {3-[2-(3-chloro-phenyl)-2-oxo-ethylcarbamoyl]- adamantan-l-yl} -amide. ESI-MS m/z: 466 (M+H)⁺. Step 2: 6-Methyl-pyridine-2-carboxylic acid {3-[5-(3-chloro-phenyl)-oxazol-2-yl]- adamantan-l-yl}-amide

To a culture tube was added 6-methyl-pyridine-2-carboxylic acid {3-[2-(3-chloro-phenyl)-2- oxo-ethylcarbamoyl]-adamantan-l-yl} -amide (42 mg, 0.09 mmol), pyridine (36 mg, 0.46 mmol) and DCM (1.0 mL). The solution was then treated with a solution of triflic anhydride (64 mg, 0.23 mmol) in DCM (1.0 mL). After stirring overnight at rt, the reaction mixture was diluted with DCM (3 mL), and then stirred vigorously with saturated aqueous sodium bicarbonate (5 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by preparative Thin Layer Chromatography (TLC), eluting with 50% ethyl acetate in hexanes to afford 30 mg (70%) of the title compound, 6-methyl-pyridine-2-carboxylic acid (3-[5-(3-chloro-phenyl)- oxazol-2-yl]-adamantan- 1 -yl} -amide.

Table 1 : Adamantyl Amide Derivatives

Synthesis

Example STRUCTURE Chemical Name Amount LC/MS Ή NMR

Yield

Pyridine-2-carboxylic acid Method C

P [3-(2-hydroxy- 9 mg RT: 0.88 min

10

ethylcarbamoyl)- 20% m/z: 344

adamantan-1 -yl]-amide (M+H)^÷

Method C

Pyridine-2-carboxylic acid

25 mg RT: 1.41 min

11 (3-cyclohexylcarbamoyl- 60% m/z: 382

adamantan-1 -yl)-amide

(M+H)^÷

Pyridine-2-carboxylic acid Method C

[3-(3-hydroxy-azetidine-1 - 46 mg RT: 0.9 min

12

carbonyl)-adamantan-1- 40% m/z: 356

yl]-amide (M+H)^÷

Method C

Pyridine-2-carboxylic acid

13 mg RT: 1.28 min

13 [3-(pyridin-2-ylcarbamoyl)-

50% m/z: 377

adamantan-1 -yl]-amide

(M+H)^÷

Pyridine-2-carboxylic acid Method C

[3-(benzothiazol-2- 12 mg RT: 1.50 min

14

ylcarbamoyl)-adamantan- 40% m/z: 433

1-yl]-amide (M+H)^÷

(400 MHz, CDCI₃) £9.90 (br s, 1 H), 8.50-8.52 (m,

Pyridine-2-carboxylic acid Method C 1H), 8.13-8.17 (m, 1H), [3-(4-methyl-thiazol-2- 19 mg RT: 1.34 min 8.00 (s, 1 H), 7.83 (t, J=

15

ylcarbamoyl)-adamantan- 80% m/z: 397 7.8 Hz, 1H), 7.38-7.43 1-yl]-amide (M+H)^÷ (m,1 H), 6.48-6.49 (m, 1 H),

1.92-2.40 (m, 15H), 1.68- 1.82 (m, 2H).

Pyridine-2-carboxylic acid Method C

[3-(1H-benzimidazol-2- 15 mg RT: 1.30 min

16

ylcarbamoyl)-adamantan- 60% m/z: 416

1-yl]-amide (M+H)^÷

Pyridine-2-carboxylic acid

Method C

[3-(1-methyl-1H-

13 mg RT: 1.41 min

17 benzimidazol-2-

50% m/z: 430

ylcarbamoyl)-adamantan- (M+H)^÷

1-yl]-amide

adamantan-1 -yl)-amide (M+H)^÷ Synthesis

Example STRUCTURE Chemical Name Amount LC/MS Ή NMR

Yield

6-Methyl-pyridine-2-

Method C

carboxylic acid [3-((R)-3-

15 mg RT: 1.27 min

26 fluoro-pyrrolidine-1-

60% m/z: 386

carbonyl)-adamantan-1- (M+H)^÷

yl]-amide

Pyridine-2-carboxylic acid Method C

[3-((R)-fluoro-pyrrolidine-1 - 13 mg RT: 1.16 min

27

carbonyl)-adamantan-1- 50% m/z: 372

yl]-amide (M+H)^÷

6-Methyl-pyridine-2-

Method A

carboxylic acid [3-(₄-

2 mg RT: 0.97 min

28 hydroxy-piperidine-1-

8% m/z: 398

carbonyl)-adamantan-1- (M+H)^÷

yl]-amide

6-Methyl-pyridine-2- Method A

carboxylic acid [3- 3 mg RT: 1.12 min

29

(morpholine-₄-carbonyl)- 10% m/z: 38₄

adamantan-1 -yl]-amide (M+H)^÷

Pyridine-2-carboxylic acid Method C

[3-(morpholine-₄- 13 mg RT: 1.00 min

30

carbonyl)-adamantan-1- 60% m/z: 370

yl]-amide (M+H)^÷

(₄00 MHz, CDCI₃) δ 8.50-8.5₄ (m, 1H), 8.15

Method C

Pyridine-2-carboxylic acid (d, =7.8 Hz, 1H), 8.00 (s,

16 mg RT: 1.32 min

31 [3-(piperidine-1-carbonyl)- 1H), 7.83 (t, = 7.8 Hz,

70% m/z: 368

adamantan-1 -yl]-amide 1H), 7.38-743 (m,1 H),

(M+H)^÷

3.60-3.66 (m, 4H), 1.50- 2.₄5 (m, 20H).

Method C

Pyridine-2-carboxylic acid

8 mg RT: 1.22 min

32 [3-(pyrrolidine-1 -carbonyl)- 30% m/z: 35₄

adamantan-1 -yl]-amide

(M+H)^÷

2-Methyl-pyrimidine-₄- Method A

-AJ / II carboxylic acid [3-(3- 22 mg RT: 1.07 min

33

propyl-ureido)-adamantan- 30% m/z: 372

1-yl]-amide (M+H)^÷

6-Methyl-pyrazine-2- Method A

carboxylic acid [3-(3- 25 mg RT: 1.10 min

3₄

propyl-ureido)-adamantan- 30% m/z: 372

1-yl]-amide (M+H)^÷

6-(3-{3-[(6-Methyl-pyridine- Method A

2-carbonyl)-aminoj- 35 mg RT: 1.38 min

35

adamantan-1 -yl}-ureido)- 40% m/z: 471

hexanoic acid ethyl ester (M+H)^÷

amide (M+H)^÷

H₃C acid hexyl ester (M+H)^÷

In a similar manner to Example 61, Examples 136-149 of Table 2 may be prepared from the reaction of amine intermediates 12, 14 and 11 with the corresponding commercially available sulfonyl chlorides, respectively.

In a similar manner to Example 62, Examples 150-156 of Table 2 may be prepared via the process of Scheme 11 from the reaction of intermediate E with triphosgene chloro formate and commercially available amines (see e.g., step a of Scheme 11), carmabic chlorides (see e.g., step b of Scheme 11) or isocyanates (see e.g., step c of Scheme 11).

In a similar manner to Example 64, Examples 157-163 and 165-167 of Table 2 may be prepared from the reaction of intermediate 12 with the corresponding commercially available aldehydes, respectively. In an analogous manner to Example 63, Examples 164 and 168 of Table 2 may be prepared using commercially available 2-aminothiazole and 4-aminotetrahydropyran, respectively.

Table 2: Hypothetical Compounds

Pyridine-2-carboxylic acid [3-

146 (pyridine-2-sulfonylamino)- adamantan-1-yl]-amide

Pyridine-2-carboxylic acid [3-

147 (pyridine-3-sulfonylamino)- adamantan-1-yl]-amide

Pyridine-2-carboxylic acid [3-

148 (pyridine-4sulfonylamino)- adamantan-1-yl]-amide

Pyridine-2-carboxylic acid [3-

149 (thiazole-2-sulfonylamino)- adamantan-1-yl]-amide

Ethyl-carbamic acid 3-[(6-methyl-

150 pyridine-2-carbonyl)-amino]- adamantan-1-yl ester

Ethyl-carbamic acid 3-[(6-methyl-

151 pyrazine-2-carbonyl)-amino]- adamantan-1-yl ester

Cyclopropyl-carbamic acid 3-[(6-

152 methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl ester

Azetidine-1-carboxylic acid 3-[(6-

153 methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl ester

Piperidine-1-carboxylic acid 3-[(6-

154 methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl ester

Morpholine-4-carboxylic acid 3-[(6-

155 methyl-pyridine-2-carbonyl)-amino]- adamantan-1-yl ester

H amide 6-Met yl-pyridine-2-carboxylic

167 acid{3-[(tetra ydro-pyran-₄-ylmet yl)-

H amino]-adamantan-1 -yl}-amide

6-Met yl-pyridine-2-carboxylic acid

168 [3-(tetra ydro-pyran-₄-ylamino)-

H adamantan-1-yl]-amide

4. Pharmacological Evaluation of Compounds of the Invention

Compounds of the present invention have been tested in vitro, and can be tested in vitro and in vivo, in the assays as described below.

In vitro Assays

Radioligand binding assays

Binding assays were performed using human metabotropic glutamate receptor 5 (hmGluR5) protein as described in [J. A. O'Brien et al. Mol Pharmacol, 2003, 64, 731-740] with slight modifications. Briefly, after thawing, the membrane homogenates were resuspended in 50 mM Tris-HCl, 0.9% NaCl binding buffer at pH 7.4 to a final assay concentration of 40 μg protein/well for [³H] 2-methyl-6-phenylethynyl-pyridine ([³H] MPEP) (American Radiolabeled Chemicals, Inc., St. Louis, MO) filtration binding. Incubations included 5 nM [³H] MPEP, membranes and either buffer or varying concentrations of compound. Samples were incubated for 60 min at room temperature with shaking. Non-specific binding was defined with 10 μΜ MPEP. After incubation, samples were filtered over a GF/C filter (presoaked in 0.25% polyethyleneimine (PEI)) and then washed 4 times using a Tomtec^® Harvester 96^® Mach III cell harvester (Tomtec, Hamden, CT) with 0.5 mL ice-cold 50 mM Tris-HCl (pH 7.4).

IC5₀ values were derived from the inhibition curve and K{ values were calculated according to the Cheng and Prusoff equation of K{ = IC50/ (1+ [L]/ a) described in [Y. Cheng and W.H. Prusoff Biochem. Pharmacol. 1973, 22, 23:3099-3108] where [L] is the concentration of radioligand and is its dissociation constant at the receptor, derived from the saturation isotherm. The K{ value for representative Examples 113, 75, 82, 68 and 85, were 8.2 nM, 35 nM, 80 nM, 130 nM, and 380 nM, respectively.

Calcium mobilization assay to test for negative or positive allosteric activity

The cDNA for rat metabotropic glutamate receptor 5 (rmGluR5) and the cDNA for human metabotropic glutamate receptor 5 (hmGluR5) were generous gifts from S. Nakanishi (Kyoto University, Kyoto, Japan). The rmGluR5 or hmGluR5 was stably expressed in a HEK 293 cell line and grown in Dulbecco's Modified Eagle Medium (DMEM) (Invitrogen, Carlsbad, CA) with supplements (10% bovine calf serum, 4 mM glutamine, 100 units/mL penicillin, 100 μg/mL streptomycin and 0.75 mM G1418) at 37 °C, 5% CO2. Twenty-four hours prior to assay, cells were seeded into 384-well black wall microtiter plates coated with poly-D- lysine. Just prior to assay, media was aspirated and cells dye-loaded (25 μΕΛνεΙΙ) with 3 μΜ Fluo-4/ 0.01% pluronic acid in assay buffer (Hank's Balanced Saline Solution (HBSS)): 150 mM NaCl, 5 mM KC1, 1 mM CaCl₂, 1 mM MgCl₂, plus 20 mM N-2- Hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), pH 7.4, 0.1% bovine serum albumin (BSA) and 2.5 mM probenicid) for 1 hour in 5% CO2 at 37 °C. After excess dye was discarded, cells were washed in assay buffer and layered with a final volume equal to 30 μΕΛνεΙΙ. Basal fluorescence is monitored in a fluorometric imaging plate reader (FLIPR) (Molecular Devices, Sunnyvale, CA) with an excitation wavelength of 488 nm and an emission range of 500 to 560 nm. Laser excitation energy was adjusted so that basal fluorescence readings were approximately 10,000 relative fluorescent units. Cells were stimulated with an EC2₀ or an ECso concentration of glutamate in the presence of a compound to be tested, both diluted in assay buffer, and relative fluorescent units were measured at defined intervals (exposure = 0.6 sec) over a 3 min period at room temperature. Basal readings derived from negative controls were subtracted from all samples. Maximum change in fluorescence was calculated for each well. Concentration-response curves derived from the maximum change in fluorescence were analyzed by nonlinear regression (Hill equation). A negative modulator can be identified from these concentration-response curves if a compound produces a concentration dependent inhibition of the ECso glutamate response. Exemplified compounds Examples 1-5, 7-24, 26-32, 39, 41, 43-45, 61, 63-83, 87, 92-1 12 and 135 were tested in the above assay for negative allosteric modulation using rmGluR5: FLIPR maximum inhibition ranged from 43 to 99% while FLIPR IC5₀ ranged from 0.94 nM to 4700 nM. Exemplified compounds Examples 6, 25, 33-38, 40, 42, 46-60, 62, 84-91, 1 12-134 were tested in the above assay using hmGluR5: FLIPR maximum inhibition ranged from 77 % to 96 %, while FLIPR IC₅₀ ranged from 0.44 nM to 770 nM.

A positive modulator (PAM) can be identified from these concentration-response curves if a compound produces a concentration dependent increase in the EC20 glutamate response.

A silent allosteric modulator (SAM) can be identified based on results from both the radioligand assay and the calcium mobilization assay. If a compound actively binds to an allosteric site of the receptor based on the radioligand assay, but has no measurable intrinsic efficacy in the calcium mobilization assay, the compound is a SAM.

In vivo Assays

An in vivo effect of a compound of the present invention may also be evaluated by using the following, non-limiting, examples of in vivo behavioral animal models. The following behavioral models are not intended as the only models useful for determining the efficacy of a compound of formula (I) to treat the corresponding disorder or disease.

A mouse marble burying (mMB) assay similar to that described in [K. Njung'e, K. and S.L. Handley, Pharmacology, Biochemistry and Behavior, 1991, 38, 63- 67] can be used to evaluate in vivo for anxiolytic effects of a compound. Example 1 12 was efficacious at 3 mpk upon SC dosing.

More specifically for the mMB testing, adult, male CD1 mice (Charles River Laboratories (Kingston, NY)), weighing 25 to 30 g, will be used. All animals will be group-housed in a standard colony room with a 12: 12 light/dark cycle (lights on at 6:00 am) for at least one week prior to testing. Food and water will be provided ad libitum. Animals will be weighed, tail marked, and randomly assigned to treatment groups before testing.

For each test, sixty minutes after the injection of vehicle or test compound, or 30 min after injection of the positive control, buspirone, mice will be individually placed into test cages containing 1.5 in of Aspen bedding (PWI brand) and two rows of 10 marbles (20 marbles per test cage total). Filter tops will be used to cover each test cage. Thirty minutes later, mice will be removed from test cages and returned to their home cages. The number of fully visible marbles (less than 2/3 covered with bedding) will be counted and subtracted from 20 to arrive at the number of marbles buried. Twelve mice can be tested per group, for example.

Testing will include multiple tests with each test performed to evaluate, e.g., buspirone hydrochloride (BUS; Sigma Aldrich) (positive control) and/or a compound of formula (I). Each compound will be dissolved immediately prior to testing in 20% beta-cyclodextrin (compound of formula (I)) or distilled water (BUS) and administered at one or more doses (such as 3, 10, and/or 30 mg/kg) via subcutaneous (SC) or intraperitoneal (IP) injection at the indicated pretreatment times (i.e., 30, 60, or 120 min pretreatment). Doses will be measured in mg drug (salt form) per kg body weight. Data will be analyzed using one-way ANOVA with post-hoc Dunnett's test. Anxiolytic effect in vivo can also be tested via a modified Geller-Seifter conflict test described in [N.A. Moore et al. Behavioural Pharmacology. 1994, 5, 196-202]. For example, more specifically, rodent operant chambers (ENV-007CT, Med Associates Inc. (Georgia, VT)) and sound-attenuating chambers (ENV-018MD, Med Associates Inc.) are used and each chamber is equipped with a house light, cue lights, grid floor to deliver foot shocks via a programmable shocker, (E V-414, Med Associates, Inc.) and food hopper. Two levers are located on either side of the food hopper. Rats are trained to only respond on the left lever. Food reinforcement is used (e.g., Dustless Precision Pellets, 45 mg, BioServ, (Frenchtown, NJ)). MED-PCIV software (Med Associates) is used to run experimental sessions and collect data.

Prior to beginning the Conflict procedure, animals are initially trained to lever press on fixed ratio schedules (FR 1, 2, 5, and 10). Once animals obtain 25 rewards on a FR 10 schedule for 2 consecutive days, animals begin training on a three component Conflict schedule. The three components are as follows: (1) an unpunished, variable interval 30 s (VI30) schedule of food reinforcement to reinforce lever pressing on a variable time schedule that averages 30 s; this period had a duration of 9 minutes and is signaled by illumination of the rear house light only; (2) immediately following is a 3 minute time out period (TO) that is signaled by total darkness; responding is recorded but is neither rewarded nor punished; (3) a punished, fixed ratio 10 (FR10) schedule of reinforcement that simultaneously presents food and foot shock (0.3 mA, 500 ms) on every tenth lever press during a 3 minute period; this component is signaled by illumination of the rear house light and cue lights above each lever. These three components are repeated twice in the same order during the daily 30 minute session.

Testing begins when stable rates of responding are observed for 5 days (no significant trends up or down). Animals are tested using a Latin-squares design, on, e.g., Wednesdays and Fridays. Animals serve as their own controls and receive all treatments. To maintain baseline performance, animals are also trained the remaining three weekdays.

Testing is performed using 12 adult, male Sprague-Dawley rats, weighing 426-567 g (Charles River Laboratories (Kingston, NY)). Animals are pair-housed in colony rooms maintained at controlled temperature (68-72°F) and a 12-h light/dark cycle (lights on 06:00). Animals are given free access to water, while food is limited to 15 g of Bacon Lover's Treats (BioServ) after training/testing Monday through Thursday. Friday through Sunday, animals have free access to Lab Diet 5012 Rat Diet (PMI Nutrition International, LLC, Brentwood, MO) until cages are changed and food removed on Sunday. Testing includes multiple tests where each test is performed to evaluate either a reference compound or a compound of formula (I). Reference anxiolytics can include chlordiazepoxide, diazepam and buspirone, which are dissolved in saline or water and administered via sc, ip, and/or p.o. Test compounds are dissolved in 20% beta-cyclodextrin, and the pH is adjusted to 7 with aHC03. For each test, the compound to be evaluated is tested at one or more doses (such as 10, 20, 30 and/or 50 mg/kg) via p.o. administration 60 minutes before the test using an injection volume of 2 mL/kg in comparison with a vehicle control group. Doses are measured in mg drug (salt form) per kg body weight. Data is analyzed using Repeated Measures ANOVA with post-hoc Dunnett's test.

The "Vogel Conflict Test" as described by J.R. Vogel et al. [Psychopharmacologia, 1971, 21, 1 : 1-7] can be used to detect anxiolytic activity of a compound of formula (I) because anxiolytics increase punished drinking. In the test, rats are deprived of water for approximately 48 hours and are then placed individually into a transparent Plexiglas^® enclosure (15 x 32 x 34 cm) with a floor consisting of stainless steel bars (0.4 cm) spaced 1 cm apart. The back wall of the enclosure is made of opaque Plexiglas^®, thereby concealing the observer from the experimental animal. In the center of the opposite wall, 5 cm above the floor, a metal water spout will be protruded into the cage and will be connected to one pole of a shock generator (Apelex: Type 01 1346). The other pole of the shock generator will be connected to the metal grid floor.

The rat is left to explore until it found the water spout. Then, every time it would drink, it would receive a slight electric shock (1.7 mA, 1 s) 2 seconds after it started lapping. The number of punished drinks is counted during a 3 minute test. The test is performed blind with 10 rats per group. Testing can include multiple tests using reference compounds and a compound of formula (I), which can be prepared and administered as described below in the LES test. Male Rj : Wistar (Hans) rats as described therein can be used after acclimatization conditions have been achieved. Data can be analyzed by comparing treated groups with appropriate controls using unpaired Student's t tests.

Compounds of the invention also can be evaluated in vivo for anxiolytic effects using a light- enhanced startle (LES) reflex method as that described in [Walker and Davis. Biol. Psychiatry, 1997, 42, 6:461-471]. The startle response is a coordinated contraction of skeletal muscle groups in response to a high intensity unexpected stimulus. Most sensory modalities can be used, but sound is most frequently employed because it is easily controlled. Thus, when a short burst of sufficient intensity occurs (e.g., 115 dB) an involuntary startle response occurs. High light levels increase the startle response in nocturnal species such as the rat and this effect does not require any pre-conditioning. Anxiolytics - an agent that relieves anxiety - decrease light-enhanced startle.

For the LES test, an apparatus consisting of a commercially available soundproofed startle chamber (e.g., SR-LAB™ Startle Response System, San Diego Instruments, San Diego, CA) can be used. All experimental events and data recording can be controlled by computer program (e.g., SR-LAB™ control unit). Rats are placed within the startle chamber in a small Perspex^® cylinder, slightly larger than the rat, which is attached to a base plate containing a strain gauge. Vertical movement of the rat such as occurs during a startle response results in deformation of the base plate, which generates a current in the strain gauge that is proportional to the size of the movement, i.e., the size of the startle response. A loudspeaker is placed directly above the rat to provide background sound and stimuli. A light source (2500 - 3500 Lux) is located in each startle chamber.

The LES test consists of two 20-minute sessions (first with lights off and then with lights on) of which the first 5 minutes are for habituation, during which background noise of 70 dB intensity is provided within the chamber. At the end of each habituation period, 10 stimulations of 110 dB are presented to habituate the animals. Thereafter, three trial types are presented in pseudo random order, 8 times each. Trials are separated by 15-25 seconds. The trial types are 100, 105 or 1 10 dB startle during which a 40 ms burst of white noise at 100, 105 or 1 10 dB is presented, resulting in a startle response. A period of 5 minutes without light or noise separates the two sessions. An appropriate rat species that can be use includes male Rj: Wister (Hans) rats (180-280 g weight at start of the testing with a maximum weight range per test of 50 g) (Elevage Janvier, Le Genest-Saint-Isle, France). The rats should be allowed to acclimatize to laboratory conditions at least 5 days before testing with free access to food and water. Acclimatization conditions should be comparable to those described in the scientific literature and/or known to those skilled in the art.

The output from the startle platform is recorded for 40 ms starting from the onset of the startle stimulus. Three variables are recorded for each trial: the average response over the whole recording period, the peak response and the time to peak response. The startle intensity is calculated for each rat by averaging the 8 trials of each type under dark or light conditions and calculating the percentage increase in startle amplitude (average and peak values) caused by light (LES). The time to peak response is a measure of reaction time. The test is performed un-blinded using, e.g., 12 rats per group. Testing includes multiple tests where each test is performed to evaluate a reference compound (e.g., chlordiazepoxide), comparative compound (e.g., pregabalin) and/or a compound of the present invention. For example, in test 1, a known anxiolytic, such as chlordiazepoxide and pregabalin, is used, followed by test 2 using the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and then test 3 is performed using a compound of the present invention. Alternatively, each test can be performed concurrently, or in some combination of sequentially and concurrently. For each test, the compound to be evaluated is tested at one or more doses (such as 1, 3, 10, 30 and/or 100 mg/kg) via p.o. administration 60 minutes before the test in comparison with a vehicle control group. Prior to testing, test compounds can be tested for solubility by cold stirring of the highest intended dose for 10 min in distilled water. If soluble, distilled water can serve as the vehicle. If insoluble, the test compounds can be suspended in 0.2% hydroxypropylmethylcellulose (HPMC) in distilled water. Doses can be prepared as weight to volume (W/V) stock solutions and then serially diluted (V/V) for compounds in solution or separately weighted (W/V) for compounds in suspension.

For each test, data is analyzed by comparing treated groups with the vehicle control using unpaired Student's t tests. LES in each group will be analyzed by comparing within each treated group the intensity of startle reaction under dark and light conditions using paired Student's t tests.

Compounds of formula (I) can be evaluated in vivo for antidepressive effects. An assessment of depression-like actions can be measured using a forced swim test similar to that described in [J.F. Cryan, et al. Neuroscience and Biobehavioral Reviews 2005, 29, 547-569.] Animals used for testing are adult, male NIH Swiss Webster mice (Harlan Laboratories (Frederick, MD)), weighing 22 to 24 g, which are acclimatized and housed as previously described with the mice used in the mMB tests.

For the mouse Forced Swim Test (mFST), mice are individually placed into clear Pyrex^ cylinders (11 cm diameter, 16.5 cm height) containing 1 1 cm deep tap water (23-25 °C) sixty min after the injection of vehicle or test compound, or 30 min after injection of the positive control, imipramine hydrochloride (IMI; Sigma Aldrich, St. Louis, MO). Imipramine is prepared with isotonic saline and test compound is prepared as described previously with mMB tests. Doses used can be as described previously with mMB tests. The percentage of time spent floating, swimming, and struggling ("climbing") is measured during a 6 min session. Swim sessions are video monitored and can be analyzed in real-time using the Biobserve Automated FST apparatus and software (Biobserve GmbH, Bonn, Germany). Group size can range from twelve to thirteen mice. Doses are measured in mg drug (salt form) per kg body weight. Data is analyzed using one-way ANOVA with post-hoc Dunnett's test.

Antidepressive effect also can be evaluated using the Flinders Sensitive Line (FSL) rat in the FST and social interaction test as described in [D.H. Overstreet and G. Griebel Pharmacol Biochem Behav., 2005, 82, 1 : 223-227]. More specifically, compounds of the invention are tested at multiple doses (e.g., 10 mg/kg, 30 mg/kg, etc.) by preparing in 20% HP-beta- cyclodextrin and against vehicle control. In addition to an FSL vehicle control group, Flinders Resistant Line rats' vehicle control group is tested. Test compounds are administered daily by IP injection (2 mg/kg injection volume) for 14 days. Animals are tested in the social interaction and forced swim tests on Day 15, 22-24 hours after the injection on Day 14, as described in Overstreet and Griebel 2005. Six to eight animals per group are tested.

Anxiolytic and antidepressive effect can also be evaluated using a paradigm for decreased HPA axis feedback (David et ah, 2001 , SFN meeting in San Diego). This model based on the chronic delivery of corticosterone in the drinking water, causes anxiety- and depression-like behaviors in mice. The model consists of a sustained administration of a high dose (35μg/mL), but not a low dose ^g/mL), of corticosterone for four or seven weeks. Such a treatment induced anxiety- and depression-like behaviour in C57B16/NTac mouse strain as indicated by a decreased time spent and number of entries into center of the arena during the 30 minutes open field test (OF), whereas total ambulation was unaltered. Also, the latency to feed was increased in corticosterone-treated mice submitted to the novelty suppressed feeding (NSF) paradigm. As the corticosterone treatment did not alter food-intake in the home cage (familiar environment), changes in feeding latency were not due to changes in appetite or an underlying metabolic abnormality. Importantly, the adrenocorticotropic hormone (ACTH) and corticosterone (CORT) response to an acute stressor (6 min forced swim test (FST)), measured as plasma-concentrations, was blunted in C57BL/6NTac mice. Theses results were confirmed in CD1 strain mice. Three weeks treatment with the antidepressant imipramine (40 mg/kg/day ip) and fluoxetine (18 mg/kg/day ip) reversed the anxiety- and depression-like effects caused by a seven weeks corticosterone treatment in the OF, NSF and FST.

In such test, for example, 240 adult male mice of C57Bl/6Ntac strain (Taconic Farms (Denmark)), 8-10 weeks old are used, who are allowed to acclimate to the facility for at least 1 week prior to testing (e.g., 5 per cage under a 12 h (06:00-18:00) light-dark cycle at 22 °C) with food and water freely available.

A compound of the invention (30 or 60 mg/kg, per day in chow), fluoxetine (18 mg/kg per day in drinking water) or vehicle (0.45% β-cyclodextrine, CD in drinking water) are administered to mice treated via drinking water with either vehicle or corticosterone (35 μg/mL). After 7 weeks of treatment as indicated below, mice are tested in the following behavioral tests: OF, NSF, FST and sucrose splash grooming test. Treatment is started with either CD or corticosterone (35 μg/mL) given via the drinking water for 3 weeks (n=200 mice per group). Thereafter, administration with CD or corticosterone will continue, and mice are divided into 8 groups of 30 mice as indicated below for 4 additional weeks.

Week 1-8 Week 3-7

vehicle ( CD) vehicle

vehicle ( CD) fluoxetine, 18 mg/kg

vehicle ( CD) test compound, 30 mg/kg

vehicle ( CD) test compound, 60 mg/kg

35μg/mL/day corticosterone vehicle

35μg/mL/day corticosterone fluoxetine, 18mg/kg

35μg/mL/day corticosterone test compound, 30 mg/kg

35μg/mL/day corticosterone test compound, 60 mg/kg

Mice are tested in the behavioral paradigms in this order: OF, NSF, sucrose splash test and then the mouse FST (15 animals/group).

The Open-field test

Motor activity is quantified in Plexiglas® open field boxes 43 x 43 cm² (MED associates, Georgia, VT) over a 10 min session. Two sets of 16 pulse-modulated infrared photo beams are placed on opposite walls 2.5 cm apart to record x-y ambulatory movements. A 40-W white bulb placed in the middle of the room provided around 200-lx illumination at floor level. Activity chambers are computer interfaced for data sampling at 100 ms resolution. The computer defined grid lines that divided each open field into center and surrounds regions, with each of four lines being 1 1 cm from each wall. Dependant measures are total time spent in the center, the numbers of entries into the center and distance travelled in the center divided by total distance travelled. Overall motor activity is quantified as the total distance travelled (cm).

The Novelty-Suppressed Feeding

The novelty suppressed feeding (NSF) is a conflict test that elicits competing motivations: the drive to eat and the fear of venturing into the center of brightly lit arena. Latency to begin eating is used as an index of anxiety-like behavior because classical anxiolytic drugs decrease it. The NSF is carried out during a 5-min period as described in (Santarelli et al, Science, 2003, 301, 5634:805-9). Briefly, the testing apparatus consisted of a plastic box 50x50x20 cm. The floor is covered with approximately 2 cm of wooden bedding. Twenty-four hours prior to behavioral testing, all food is removed from the home cage. At the time of testing, a single pellet of food (regular chow) is placed on a white paper platform positioned in the center of the box. An animal is placed in a corner of the maze and a stopwatch is immediately started. The measure of interest (chewing) is scored when the mouse is sitting on its haunches and biting with the use of forepaws. Immediately after this test, mice are transferred to their home cage and the amount of food consumed in 5 min is measured (home cage food consumption). Mice are tested during the light period. Because antidepressants are known to have various effects on appetite, the feeding drive is assessed by returning animals in their home cage (familiar environment) immediately after the test. Then, the amount of food consumed over a 5 min-period is measured.

Splash test

The grooming latency is assessed at the end of the corticosterone regimen (end of seventh week) in the presence or absence of 3 -weeks of fluoxetine treatment. This test consists in squirting 200 μΐ of a 10% sucrose solution on the mouse's snout. The grooming frequency is then recorded

The mouse Forced Swim Test

A modified forced swim test procedure as described in [Dulawa et al. Neuropsychopharmacol., 2004, 29, 7: 1321-1330; Holick et al. Neuropsychopharmacol. , 2008, 33, 2: 406-417] is used. Mice are placed individually into glass cylinders (height: 25 cm, diameter: 10cm) containing 18 cm water that is maintained at 23-25 °C and videotaping will be for 6 min via a tripod-mounted camera positioned directly on the side of the cylinder. An increase of swimming and climbing has been linked to an activation of serotoninergic and noradrenergic system in rats [see, e.g., J.F. Cryan and I. Lucki Pharmacol. & Exp. Therap., 2000, 295, 3: 1120-1 126] and in mice [see, e.g., Dulawa et al. (2004); Holick et al, (2008)], respectively. Therefore, the predominant behavior (swimming, immobility or climbing) is scored here during the last 4 min of the 6 min testing period.

Anxiolytic-like properties also can be evaluated using these additional tests: (1) social interaction described in [S.E. File and P. Seth European Journal of Pharmacology, 2003. 463, 1-3:35-53], and (2) elevated plus-maze described in [S.M. Korte and S.F. De Boer European Journal of Pharmacology , 2003, 463, 1-3: 163- 175].

Parkinson's disease (PD) can be assessed by measuring the neurotoxicity of MPTP in rats as described in [E. H. Lee et al. Chin. J. Physiol., 1992, 35, 4: 317-36]. Also experimentally induced striatal DA depletion in animals is a valid model of Parkinsonism, as described in [W. Schultz Prog. Neurobiol, 1982, 18, 2-3 : 121-66]. The capacity of certain substances to damage catecholaminergic neurons has been used extensively to produce DA deficiency in animals, as described in [L. E. Annett et al. Exp. Neurol, 1994, 125, 2: 228-46]. PD can also be assessed by measuring the neurotoxicity induced by 6-hydroxydopamine (6-OHDA) as described in [N. Breysse et al. J. Neurosci., 2002, 22, 13 : 5669-5678; D. Rylander et al. J. Pharmacol. Exp. Ther., 2009, 330, 1 : 227-235; and L. Chen et al, "Chronic, systemic treatment with a metabotropic glutamate receptor 5 antagonist in 6-hydroxydopamine partially lesioned rats reverses abnormal firing of dopaminergic neurons," Brain Res., 2009, 1286, 192-200].

Fragile X Syndrome can be assessed using the fmrl^tmlCgr mouse model as described in [Q.J. Yan et al. NeuropharmacoL, 2005, 49, 7: 1053-1066] as well as the Fmrl knockout mice with a selective reduction in mGluR5 expression as described in [G. D51en et al. Neuron, 2007, 56, 6:955-962].

Preclinically, animals also can be evaluated for blockade/attenuation of symptoms associated with schizophrenia. Positive symptoms in animal models of schizophrenia can be evaluated by measuring changes in the overall level of activity of dopamine (DA) activity with concomitant parallel changes in locomotor activity as described in [R. Depoortere et al. Neuropsychopharmacology, 2003, 28, 1 1 : 1889-902], D-amphetamine (AMPH) and phencyclidine (PCP) via induction of model psychosis or locomotor hyperactivity as described in [W. J. Freed et al. Neuropharmacology, 1984, 23, 2A: 175-81; F. Sams-Dodd Neuropsychopharmacology, 1998 19, 1 : 18-25]. For example, Depoortere et al., 2003, have described tests for evaluating locomotor activity, catalepsy, climbing and stereotypy, which relate to positive symptomology and side effect profile, by characterizing compounds with typical and atypical antipsychotic efficacy. Attenuation in apomorphine-induced climbing, stereotypy and catalepsy (AIC) can be evaluated as described in [Y. K. Fung et al. Pharmacol. Biochem. Behav., 1986, 24, 1 : 139-41 and Y. K. Fung et al. Steroids, 1987, 49, 4- 5: 287-94]. Additionally, negative symptoms of schizophrenia can be evaluated by measuring social interaction under the influence of NMDA antagonists such as PCP, as described in F. Sams-Dodd, 1998, supra.

Cognitive symptoms of memory, including those from Alzheimer's disease, can be evaluated by such models as the Fear Conditioning Paradigm described in [T. J. Gould et al. Behav. Pharmacol, 2002, 13, 4: 287-94, and A. O. Hamm et al. Brain, 2003, 126, Pt 2: 267-75] and the Radial Arm Test described in [J. P. Aggleton et al. Behav. Brain Res., 1986, 19, 2: 133- 46], while spatial reference memory and learning can be evaluated in the Morris water maze test as described in [R.G.M. Morris. Learn. Motiv., 1981, 12, 239-260; B. Bontempi et al. Eur. J. Neurosci. 1996, 8, 1 1 : 2348-60]. More specifically, in the Morris water maze test, a circular water tank (150 cm diameter and 45 cm height) is filled with about 30 cm water and maintained at 26-28 °C with an escape platform (15 cm diameter) 18 cm from the perimeter and always in the same position 1.5 cm beneath the surface of the water. The water is made opaque by addition of a non-toxic coloring agent (e.g., milk powder) rendering the platform invisible. Animals are given a single training session over a single day. The training session consists of 4 consecutive trials in the water maze, each separated by 60 seconds. For each trial, the animal is placed in the water maze at one of two starting points equidistant from the escape platform and allowed to find the escape platform. The animal is left on the escape platform for 60 seconds before starting a new trial. If the animal does not find the platform within 120 seconds, the animal is removed from the water and placed on the platform for 60 seconds. During the 4 trials, the animals start the water maze twice from each starting point in a randomly determined order per animal. Appropriate animals for testing with acclimatization conditions are, for example, the male Rj: Wistar (Hans) rats as previously described for the LES test.

The trials are video-recorded and the behavior of animals is analyzed using a video-tracking system (SMART, Panlab, S.L., Cornelia (Barcelona), Spain). The principal measure taken in each trial is the distance traveled to find the platform. Secondary measures taken are the swim speed and escape latency. The test is performed blind using, for example, 12 rats per test group. Testing includes multiple tests using reference compounds and compounds of the present invention that are prepared and administered as previously described LES test. For each test, data is analyzed by comparing treated groups with vehicle controls using one-way ANOVA followed by Dunnett's t tests. To increase comparability with the aforementioned Vogel conflict test, in all tests, rats are subjected to water-deprivation for approximately 24 h before the test (Day 1); however, testing is performed in non-water-deprived rats (Day 2).

Additionally, with respect to cognition, memory and hippocampal hypo-functioning can be assessed by measuring the restoration of synaptic plasticity in ovariectomized (OVX) female rats as described in [M. Day and M. Good Neurobiol. Learn. Mem., 2005, 83, 1 : 13-21]. Further, changes in attention function because of schizophrenia can be examined by the Five (5) Choice Serial Reaction Time Test (5CSRT) described in [J. L. Muir et al. Psychopharmacology (Bed), 1995, 118, 1 : 82-92 and T.W. Robbins et al. Ann. N. Y. Acad. Sci., 1998, 846, 222-37].

Human patients can be evaluated for cognitive diseases or disorders by any of the tests within the skill of those in the art.

Analgesic activity can be evaluated by neuropathic pain model (the "Chung model") as described in [S.H. Kim and J.M. Chung, Pain, 1992, 50, 3 :355-363]. Tight ligature of spinal nerves in rats is associated with hyperalgesia, allodynia and spontaneous pain, and therefore constitutes a model for peripheral neuropathic pain in humans. Antihyperalgesics reduce these chronic signs of pain hypersensitivity. Thus, in the Chung model, rats are anesthetized (sodium pentobarbital 50 mg/kg i.p.) and an incision at the L4-S2 level is performed to expose the left L5 nerve after cleaning the flank with chlorhexidine in spray. A cotton thread (standard, non-surgery quality), disinfected with pure alcohol, is placed around the L5 nerve and a simple ligature is tied tightly around the L5 nerve. The wound is then sutured and sprayed with CothiVet^® (hydrocotyle tincture spray) ( eogen^® Corp., Lexington, KY). The rats receive a s.c. injection of Clamoxyl (0.67 mL/kg) and are allowed to recover. At least 2 weeks after the surgery, when the chronic pain state is fully installed, rats are submitted consecutively to tactile and thermal stimulation of both hindpaws.

For tactile stimulation, the animal is placed under an inverted acrylic plastic box (18 x l l .5 x 13 cm) on a grid floor. The tip of an electronic Von Frey probe (Model 1610, BIOSEB, Vitrolles Cedex, France) is then applied with increasing force first to the non-lesioned and then the lesioned hindpaw and the force required to induce paw-withdrawal is automatically recorded. This procedure is carried out 3 times and the mean force per paw is calculated. For heat stimulation, the apparatus (No. 7371, Ugo Basile, Comerio VA, Italy) consists of individual acrylic plastic boxes (17 x 11 x 13 cm) placed upon an elevated glass floor. A rat is placed in the box and left free to habituate for 10 minutes. A mobile infrared radiant source (96 ± 10 mW/cm²) is then focused first under the non-lesioned and then the lesioned hindpaw and the paw-withdrawal latency is automatically recorded. In order to prevent tissue damage, the heat source is automatically turned off after 45 seconds.

Prior to receiving compound treatment all animals are submitted to tactile stimulation of the hindpaws and assigned to treatment groups matched on the basis of the pain response of the lesioned hindpaw. The test is performed blind using, for example, 10 water-deprived rats per group. Appropriate animals for testing are, for example, the male Rj : Wistar (Hans) rats as previously described for the LES test. Testing includes multiple tests using reference compounds and compounds of the present invention. In addition to the pregabalin and MPEP as previously described for the LES test, duloxetine can be used as a reference compound since it is an antihyperalgesic with respect to neuropathic pain associated with diabetes and fibromyalgia. Compounds are prepared and administered as previously described LES test. Testing can be performed using the same batch of operated rats repeatedly, with a minimum wash-out of 1 week between treatments. Also, to increase comparability with the aforementioned Vogel conflict test, in all tests, rats are subjected to water-deprivation for approximately 48 hours before each test. For each Chung model test, data will be analyzed by comparing treated groups with appropriate controls using unpaired Student's t tests.

Additionally, analgesic/anti-inflammatory activity can be evaluated in vivo using the Formalin Paw Test in the mouse such as that described by [H. Wheeler- Aceto et ah, Psychopharmacology (Berl), 1991, 104, 1 :35-44). For the test, mice are given an intraplantar injection of 5% formalin (25 μΐ) into the posterior left paw. This treatment induces paw licking in control animals. The time spent licking is counted for 5 minutes, beginning immediately after injection of formalin (early phase) and for 15 minutes starting 15 minutes after injection of formalin (late phase).

The test is performed blind using, e.g., 10 mice per group. Appropriate animals for testing are, for example, male Rj: NMRI mice (Elevage Janvier), weighing 20 - 30 g (max. range per experiment = 5 g) at the beginning of testing. Animals are acclimatized as described for the animals used in the LES test. Testing includes multiple tests using reference compounds (e.g., morphine), comparative compounds (e.g., gabapentin and duloxetine), and compounds of the present invention. Compounds of the invention can be evaluated at multiple doses as previously described in the LES test, and administered s.c. 60 minutes before formalin in comparison with a vehicle control group, while morphine (64 mg/kg p.o.), gabapentin (300 mg/kg p.o.) and duloxetine (10 mg/kg p.o.) are administered p.o. 60 minutes before formalin. Data is analyzed by comparing treated groups with vehicle control groups using unpaired Mann- Whitney U tests.

Multiple sclerosis can be evaluated by the experimental autoimmune encephalomyelitis (EAE) model described in [H. Y. Liu et al. J. Neurosci. Res., 2002, 70, 2: 238-48].

Those skilled in the art will recognize that various changes and/or modifications may be made to aspects or embodiments of this invention and that such changes and/or modifications may be made without departing from the spirit of this invention. Therefore, it is intended that the appended claims cover all such equivalent variations as will fall within the spirit and scope of this invention.

Each reference cited in the present application, including literature references, books, patents and patent applications, is incorporated herein by reference in its entirety.

Claims

What is claimed is:

1. A compound of formula (I):

(I)

wherein:

R¹ and R² are each independently aryl, heteroaryl, alkyl, cycloalkyl, ketocycloalkyl, heterocyclyl, acyl, alkoxy, which is optionally mono-, di-, or tri- substituted

independently with alkyl, halogen, hydroxy, cyano, amino, alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy; and

L is -CO-N(X)-, -NH-C(0)-N(Y)-, -(W)N-C(0)0-, -OC(0)N(Z)-, -NHS0₂-, -NH-,

-heteroaryl or a bond; wherein:

Y is hydrogen or a bond that is linked to R² and taken together with the N to

which it is attached forms a heterocycle;

a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is: 6-Methyl-pyridine-2-carboxylic acid [3-(2-hydroxyphenylcarbamoyl)-adamantan-l-yl]- amide;

6-Methyl-pyridine-2-carboxylic acid (3-isopropylcarbamoyl-adamantan-l-yl)-amide;

6-Methyl-pyridine-2-carboxylic acid [3 -(2-oxo-propylcarbamoyl)-adamantan- 1 -yl]- amide;

6-Methyl-pyridine-2-carboxylic acid (3-methylcarbamoyl-adamantan- 1 -yl)-amide;

6-Methyl-pyridine-2-carboxylic acid (3-carbamoyl-adamantan-l-yl)-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(2 -hydroxy -2 -phenyl-ethylcarbamoyl)- adamantan- 1 -yl]-amide;

Pyridine-2 -carboxy ic acid 3-(3-cyano-phenylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(3-chloro-phenylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(6-methyl-pyridin-2-ylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(2-hydroxy-ethylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid (3-cyclohexylcarbamoyl-adamantan-l-yl)-amide;

Pyridine-2 -carboxy ic acid 3 -(3 -hydroxy-azetidine- 1 -carbonyl)-adamantan- 1 -yl]-amide;

Pyridine-2 -carboxy ic acid 3-(pyridin-2-ylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(benzothiazol-2-ylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(4-methyl-thiazol-2-ylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(lH-benzimidazol-2-ylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-( 1 -methyl- lH-benzimidazol-2-ylcarbamoyl)-adamantan- 1 - yl] -amide;

Pyridine-2 -carboxy ic acid 3-(quinolin-3-ylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(4,5-dimethyl-thiazol-2-ylcarbamoyl)-adamantan-l-yl]- amide;

Pyridine-2 -carboxy ic acid 3-(2-hydroxy-2-methyl-propylcarbamoyl)-adamantan-l-yl]- amide;

Pyridine-2 -carboxy ic acid 3-(3,3-difluoro-cyclobutylcarbamoyl)-adamantan-l-yl]- amide; 3 -(3 -Chloro-benzoylamino)-adamantane- 1 -carboxylic acid (3 -chloro-phenyl)-amide;

3-(3-Chloro-benzoylamino)-adamantane-l-carboxylic acid pyridin-2-ylamide;

3 -(3 -Chloro-benzoylamino)-adamantane- 1 -carboxylic acid (6-methyl-pyridin-2-yl)- amide;

6-Methyl-pyridine-2-carboxylic acid (3-dimethylcarbamoyl-adamantan- 1 -yl)-amide;

6-Methyl-pyridine-2 -carboxylic acid [3-((R)-3-fluoro-pyrrolidine-l-carbonyl)- adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid [3 -((R)-fluoro-pyrrolidine- 1 -carbonyl)-adamantan- 1 -yl] - amide;

6-Methyl-pyridine-2-carboxylic acid [3 -(4-hydroxy-piperidine- 1 -carbonyl)-adamantan- 1 - yl] -amide;

6-Methyl-pyridine-2-carboxylic acid [3-(morpholine-4-carbonyl)-adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid [3-(morpholine-4-carbonyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxylic acid [3-(piperidine-l-carbonyl)-adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid [3 -(pyrrolidine- l-carbonyl)-adamantan-l-yl]-amide;

2-Methyl-pyrimidine-4-carboxylic acid [3 -(3 -propyl-ureido)-adamantan- 1 -yl]-amide;

6-Methyl-pyrazine-2-carboxylic acid [3-(3-propyl-ureido)-adamantan-l-yl]-amide;

6-(3- {3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-ureido)-hexanoic acid ethyl ester;

6-Methyl-pyridine-2-carboxylic acid [3-(3-ethyl-ureido)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(3-propyl-ureido)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(3-butyl-ureido)-adamantan-l-yl]-amide;

Pyridine-2 -carboxylic acid [3-(3-phenyl-ureido)-adamantan-l-yl]-amide;

Pyridine-2 -carboxylic acid [3-(3-propyl-ureido)-adamantan- 1 -yl] -amide;

Pyridine-2-carboxylic acid [3-(3-cyclopropyl-ureido)-adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid [3 -(3 -butyl-ureido)-adamantan- 1 -yl] -amide;

Morpholine-4-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-l-yl} -amide; Pyridine-2-carboxylic acid {3-[(piperidine-l-carbonyl)-amino]-adamantan-l-yl}-amide;

Pyridine-2-carboxylic acid {3-[(pyrrolidine-l-carbonyl)-amino]-adamantan-l-yl} -amide;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 2-(2- hydroxy-ethoxy)-ethyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 3,3,3- trifluoro-propyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 3-fluoro- propyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 4,4,4- trifluoro-butyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 2,2,2- trifluoro-ethyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 2-(2- methoxy-ethoxy)-ethyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 3-morpholin- 4-yl-propyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid

cyclopropylmethyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 2,2-difluoro- propyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 2 -hydroxy - ethyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 3-chloro- propyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 2-methoxy- ethyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid hexyl ester;

{3-[(Pyridine-2-carbonyl)-amino]-adamantan-l-yl}-carbamic acid 2,2,2-trifluoro-ethyl ester; 6-Methyl-pyridine-2-carboxylic acid [3-(2-oxo-[l,3]oxazinan-3-yl)-adamantan-l-yl]- amide;

Pyridine-2-carboxylic acid (3-benzenesulfonylaminoadamantan-l-yl)-amide;

Ethyl-carbamic acid 3-[(pyridine-2-carbonyl)-amino]-adamantan-l-yl ester;

6-Methyl-pyridine-2-carboxylic acid[3-(pyridin-2-ylamino)-adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid {3-[(pyridin-2-ylmethyl)-amino]-adamantan-l-yl}-amide;

Pyridine-2-carboxylic acid (3 -benzylamino-adamantan- 1 -yl)-amide;

Pyridine-2-carboxylic acid [3-(5-chloro-lH-benzimidazol-2-yl)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid (3-benzoxazol-2-yl-adamantan-l-yl)-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(lH-benzimidazol-2-yl)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(6-fluoro-lH-benzimidazol-2-yl)-adamantan-l- yl] -amide;

6-Methyl-pyridine-2-carboxylic acid [3-(lH-imidazo[4,5-b]pyridin-2-yl)-adamantan-l- yl] -amide;

6-Methyl-pyridine-2-carboxylic acid [3-(3H-imidazo[4,5-c]pyridin-2-yl)-adamantan- 1 - yl] -amide;

6-Methyl-pyridine-2-carboxylic acid [3-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)- adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(4-methyl-lH-imidazol-2-yl)-adamantan-l-yl]- amide;

6-Methyl-pyridine-2-carboxylic acid [3-(l,3-dihydro-isoindol-2-yl)-adamantan-l-yl]- amide;

6-Methyl-pyridine-2-carboxylic acid [3-(3-oxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)- adamantan-l-yl]-amide;

2-Methyl-pyrimidine-4-carboxylic acid [3 -(3 -oxo- 1 ,3 -dihydro-pyrrolo [3 ,4-c]pyridin-2- yl)-adamantan-l-yl] -amide;

5-Fluoro-pyridine-2-carboxylic acid [3-(3-oxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)- adamantan-l-yl]-amide; 4-Methyl-pyrimidine-2-carboxylic acid [3 -(3 -oxo- 1 ,3 -dihydro-pyrrolo [3 ,4-c]pyridin-2- yl)-adamantan- 1 -yl] -amide;

4- Fluoro-pyridine-2-carboxylic acid [3-(3-oxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)- adamantan- 1 -yl]-amide;

N-[3-(3-Oxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-adamantan-l-yl]-nicotinamide;

5- Fluoro-pyridine-2-carboxylic acid [3-(5-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)- adamantan- 1 -yl]-amide;

2-Methyl-pyrimidine-4-carboxylic acid [3-(5-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6- yl)-adamantan- 1 -yl] -amide;

N-[3-(5-Oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-adamantan-l-yl]-nicotinamide;

Isoxazole-5-carboxylic acid [3-(5-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)- adamantan-l-yl] -amide;

Thiazole-2-carboxylic acid [3-(5-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-adamantan-

1- yl] -amide;

2- Methyl-thiazole-4-carboxylic acid [3-(5-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)- adamantan-l-yl] -amide;

6- Methyl-pyridine-2-carboxylic acid [3-(5-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)- adamantan-l-yl] -amide;

2-Methyl-pyrimidine-4-carboxylic acid [3-(7-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6- yl)-adamantan- 1 -yl] -amide;

2-Methyl-pyrimidine-4-carboxylic acid [3-(2-methyl-5-oxo-5,7-dihydro-pyrrolo[3,4- b]pyridin-6-yl)-adamantan- 1 -yl] -amide;

6-Methyl-pyridine-2-carboxylic acid [3-(2-methyl-5-oxo-5,7-dihydro-pyrrolo[3,4- b]pyridin-6-yl)-adamantan- 1 -yl] -amide;

5-Fluoro-pyridine-2-carboxylic acid [3-(2-methyl-5-oxo-5,7-dihydro-pyrrolo[3,4- b]pyridin-6-yl)-adamantan- 1 -yl] -amide;

Pyridine-2-carboxylic acid [3-(l-oxo-l,3-dihydro-isoindol-2-yl)-adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid [3-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-yl)- adamantan-l-yl]-amide; 6-Methyl-pyridine-2-carboxylic acid [3 -(5 -phenyl- [1,3,4] oxadiazol-2-y l)-adamantan-l- yl] -amide;

6-Methyl-pyridine-2-carboxylic acid { 3 - [5 -(4-methoxy -phenyl)- [ 1 ,3 ,4]oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2-carboxylic acid { 3 - [5 -(3 -methoxy -phenyl)- [ 1 ,3 ,4]oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2-carboxylic acid {3 - [5 -(3 -chloro-phenyl)- [ 1 ,3 ,4] oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2-carboxylic acid {3 - [5 -(4-chloro-phenyl)- [ 1 ,3 ,4] oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2-carboxylic acid { 3 - [5 -(4-fluoro-phenyl)-[ 1 ,3 ,4] oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2-carboxylic acid { 3 - [5 -(3 -fluoro-phenyl)-[ 1 ,3 ,4] oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2-carboxylic acid [3-(5-pyridin-2-yl-[l,3,4]oxadiazol-2-yl)- adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(5-pyridin-4-yl-[l,3,4]oxadiazol-2-yl)- adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3 -(5 -pyridin-3 -yl- [ 1 ,3 ,4]oxadiazol-2-yl)- adamantan-l-yl]-amide;

6-Methyl-pyrazine-2-carboxylic acid [3-(5-pyridin-3-yl-[l,3,4]oxadiazol-2-yl)- adamantan-l-yl]-amide;

6-Methyl-pyrazine-2-carboxylic acid [3-(5-pyridin-4-yl-[l,3,4]oxadiazol-2-yl)- adamantan-l-yl]-amide;

6-Methyl-pyrazine-2-carboxylic acid [3-(5-pyridin-2-yl-[l,3,4]oxadiazol-2-yl)- adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid [3-(5-pyridin-3-yl-[l,3,4]oxadiazol-2-yl)-adamantan-l-yl]- amide; Pyridine-2-carboxylic acid [3-(5-pyridin-2-yl-[l,3,4]oxadiazol-2-yl)-adamantan-l-yl]- amide;

Pyrazine-2-carboxylic acid [3-(5-pyridin-3-yl-[l,3,4]oxadiazol-2-yl)-adamantan-l-yl]- amide;

2-Methyl-pyrimidine-4-carboxylic acid [3 -(5 -pyridin-3 -yl- [1,3,4] oxadiazol-2-yl)- adamantan- 1 -yl]-amide;

Pyridine-2-carboxylic acid {3 - [5-(6-methyl-pyridin-3 -yl)- [ 1,3,4] oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid {3-[5-(6-methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2- yl] -adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2-carboxylic acid {3-[5-(6-methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2- yl] -adamantan- 1 -yl} - amide;

6-Methyl-pyrazine-2-carboxylic acid {3-[5-(6-methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2- yl] -adamantan- 1 -yl} -amide;

Pyridine-2-carboxylic acid {3 - [5-(5-methyl-pyridin-3 -yl)- [ 1,3,4] oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid {3-[5-(5-methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2- yl] -adamantan- 1 -yl} -amide;

Pyridine-2-carboxylic acid {3 - [5-(6-trifluoromethyl-pyridin-3 -yl)- [ 1 ,3 ,4]oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid {3-[5-(6-trifluoromethyl-pyridin-3-yl)- [ 1 ,3,4]oxadiazol-2-yl]-adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2-carboxylic acid {3-[5-(6-ethyl-pyridin-3-yl)-[l,3,4]oxadiazol-2-yl]- adamantan- 1 -yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid {3-[5-(6-ethyl-pyridin-3-yl)-[l,3,4]oxadiazol-2- yl] -adamantan- 1 -yl} -amide;

5-Fluoro-pyridine-2-carboxylic acid {3-[5-(6-methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2- yl] -adamantan- 1 -yl} -amide; Pyrazine-2-carboxylic acid {3-[5-(6-methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2-yl]- adamantan- 1 -yl} -amide;

Pyrimidine-4-carboxylic acid {3 - [5-(6-methy l-pyridin-3 -yl)- [ 1 ,3 ,4]oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid { 3 - [3 -(3 -fluoro-phenyl)- [ 1,2,4] oxadiazol-5-yl] - adamantan- 1 -yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid [3-(3-pyridin-3-yl-[l,2,4]oxadiazol-5-yl)- adamantan-l-yl]-amide;

Pyrazine-2-carboxylic acid [3-(3-pyridin-3-yl-[l,2,4]oxadiazol-5-yl)-adamantan-l-yl]- amide;

6-Methyl-pyridine-2-carboxylic acid [3 -(3 -pyridin-3 -yl- [ 1 ,2,4]oxadiazol-5-yl)- adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid {3-[3-(6-methyl-pyridin-3-yl)-[l,2

,4]oxadiazol-5-yl] adamantan- 1-yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid { 3 - [3 -(6-methyl-pyridin-3 -yl)-[ 1 ,2,4]oxadiazol-5 - yl] -adamantan- 1 -yl} -amide;

Pyridine-2-carboxylic acid {3 - [3 -(6-methyl-pyridin-3 -yl)- [ 1 ,2,4] oxadiazol-5 -yl] - adamantan- 1 -yl} -amide;

Pyrimidine-4-carboxylic acid {3 - [3 -(6-methy l-pyridin-3 -yl)- [ 1 ,2,4]oxadiazol-5-yl] - adamantan- 1 -yl} -amide;

Pyrazine-2-carboxylic acid {3-[3-(6-methyl-pyridin-3-yl)-[l,2,4]oxadiazol-5-yl]- adamantan- 1 -yl} -amide;

6-Methyl-pyrazine-2-carboxylic acid {3-[3-(6-methyl-pyridin-3-yl)-l,2,4-oxadiazol-5- yl] -adamantan- 1 -yl} -amide;

5- Fluoro-pyridine-2-carboxylic acid {3-[3-(6-methyl-pyridin-3-yl)-[l,2,4]oxadiazol-5- yl] -adamantan- 1 -yl} - amide;

6- Methyl-pyridine-2-carboxylic acid {3-[5-(3-chloro-phenyl)-oxazol-2-yl]-adamantan-l- yl} -amide; 6-Methyl-pyridine-2-carboxylic acid (3 -benzenesulfonylamino-adamantan- 1 -yl)-amide;

6-Methyl-pyrazine-2-carboxylic acid (3 -benzenesulfonylamino-adamantan- 1 -yl)-amide;

Pyridine-2-carboxylic acid [3-(2-fluoro-benzenesulfonylamino)-adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid [3-(3-fluoro-benzenesulfonylamino)-adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid [3-(4-fluoro-benzenesulfonylamino)-adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid (3-methanesulfonylamino-adamantan-l-yl)-amide;

Pyridine-2-carboxylic acid (3 -ethanesulfonylamino-adamantan- 1 -yl)-amide;

Pyridine-2-carboxylic acid (3-cyclopropylmethanesulfonylamino-adamantan-l-yl)-amide;

Pyridine-2-carboxylic acid (3-cyclobutanesulfonylamino-adamantan-l-yl)-amide;

Pyridine-2-carboxylic acid [3-(tetrahydro-pyran-4-sulfonylamino)-adamantan-l-yl]- amide;

Pyridine-2-carboxylic acid [3-(pyridine-2-sulfonylamino)-adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid [3-(pyridine-3-sulfonylamino)-adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid [3-(pyridine-4sulfonylamino)-adamantan- 1 -yl]-amide;

Pyridine-2-carboxylic acid [3-(thiazole-2-sulfonylamino)-adamantan-l-yl]-amide;

Ethyl-carbamic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl ester;

Ethyl-carbamic acid 3-[(6-methyl-pyrazine-2-carbonyl)-amino]-adamantan-l-yl ester;

Cyclopropyl-carbamic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl ester;

Azetidine-l-carboxylic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl ester;

Piperidine- 1 -carboxylic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl ester;

Morpholine-4-carboxylic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl ester;

4-Methyl-piperazine- 1 -carboxylic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-l-yl ester; 6-Methyl-pyridine-2-carboxylic acid [3-(cyclohexylmethyl-amino)-adamantan- 1 -yl]- amide;

6-Methyl-pyridine-2-carboxylic acid [3-(cyclopentylmethyl-amino)-adamantan-l-yl]- amide;

6-Methyl-pyridine-2-carboxylic acid [3-(cyclobutylmethyl-amino)-adamantan-l-yl]- amide;

6-Methyl-pyridine-2-carboxylic acid (3-benzylamino-adamantan-l-yl)-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(2-fluoro-benzylamino)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(3-fluoro-benzylamino)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(4-fluoro-benzylamino)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(thiazol-2-ylamino)-adamantan- 1 -yl] -amide;

6-Methyl-pyridine-2-carboxylic acid (3-isobutylamino-adamantan-l-yl)-amide;

6-Methyl-pyridine-2-carboxylic acid (3 -propylamino-adamantan- 1 -yl)-amide;

6-Methyl-pyridine-2-carboxylic acid{3-[(tetrahydro-pyran-4-ylmethyl)-amino]- adamantan-l-yl} -amide; or

6-Methyl-pyridine-2-carboxylic acid [3-(tetrahydro-pyran-4-ylamino)-adamantan-l-yl]- amide; or

a pharmaceutically acceptable salt thereof

3. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

4. Use of a compound of claim 1 for as a medicament.

5. A compound of claim 1 for treatment of a cognitive, neurodegenerative, psychiatric or neurological disease or disorder.

6. Use of a compound of claim 1 for the manufacture of a medicament for treating a cognitive, neurodegenerative, psychiatric or neurological disease or disorder.

7. The compound of any of claims 5-6, wherein the cognitive or neurodegenerative disease or disorder is selected from a group consisting of a mood disorder, an anxiety, a schizophrenia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's chorea, amyotrophic lateral sclerosis, Creutzfeld-Jakob disease, a trauma-induced neurodegeneration, AIDS-induced encephalopathy, a non-AIDS-induced encephalopathy, Fragile X syndrome, an autism spectrum disorder, and a combination thereof.

8. A compound of claim 1 for treatment of gastroesophageal reflux.

9. A compound of claim 1 for treatment of alcohol dependence.