WO2007135527A2 - Benzimidazolyl compounds - Google Patents

Abstract

Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of formula (I): or pharmaceutically acceptable salts thereof. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

Description

BENZIMIDAZOLYL COMPOUNDS

FIELD OF THE INVENTION

The present invention comprises a novel class of benzimidazolyl compounds having the structure of formula I (including tautomers and salts of those compounds) and pharmaceutical compositions comprising a compound of formula I. The present invention also comprises- methods of treating a subject by administering a therapeutically effective amount of a compound of formula I to the subject. These compounds are useful for the conditions disclosed herein. The present invention further comprises methods for making the compounds of formula I and corresponding intermediates. BACKGROUND OF THE INVENTION

The present invention provides potentiators of glutamate receptors (compounds of formula I), pharmaceutical compositions thereof, and methods of using the same, processes for preparing the same, and intermediates thereof.

Glutamate is an abundant and important neurotransmitter in mammalian CNS that is involved in a variety of normal CNS functions and has been suggested to be involved in CNS disorders. The functions of glutamate as a neurotransmitter are mediated by two families of glutamate receptors on cells in the CNS - the ionotropic glutamate receptor family, which contain integral ion channels, and the metabotropic glutamate receptor family whose members are linked to G-proteins (Ozawa et al., Prog. Neurobiol., 1998, 54, 581-618). The mGlu receptors are part of the Type III G-protein coupled receptor (GPCR) superfamily, which also includes the GABA-B receptors, calcium-sensing receptor, putative pheromone receptors, and taste receptors (Pin et al., Pharmacol. Then, 2003, 98, 325-354.

A key feature in the understanding of many members of the Type III GPCR superfamily that has emerged recently is the recognition of multiple binding sites on these receptors for different classes of pharmacological agents. One class of agents bind to the extracellular endogenous ligand binding site on the receptor (the orthosteric site) - both pharmacological agonists and antagonists that bind to this site have been described for members of the Type III receptor superfamily (Conn and Pin, Ann. Rev. Pharmacol. Toxicol., 1997, 37, 205-237). More recently, for many receptors in the Type III superfamily (including multiple types of mGlu receptors), compounds have been described that bind to regions of the receptor distinct from the orthosteric site (Pin et al., MoI. Pharmacol., 2001 , 60, 881-884). These are termed allosteric ligands, and for many type III receptors the discovery of allosteric ligands has provided pharmacological tools, which can be differentiated in chemical structure from orthosteric ligands. Allosteric compounds may also provide pharmacological distinctions not possible with orthosteric ligands. For example, allosteric compounds may not directly activate a receptor, but rather modulate (by enhancing or reducing) the activity of the endogenous ligand upon its binding to the orthosteric site. In addition, pharmacological distinctions include the potential for pharmacological specificity between related receptors types that share the same endogenous ligand. For example, the structural similarity of the glutamate binding site on closely related members of the mGlu receptor family has resulted in the development of agonist and antagonist compounds that bind to this site which are similar in potency toward multiple receptor within a family. There may be advantages to targeting the development of novel, selective pharmacological agents for these receptors that bind at allosteric sites, since other regions of the receptors show less homology across receptor subtypes than the glutamate binding site. The metabotropic glutamate (mGlu) receptors include eight subtypes which have been categorized into three groups based on their structural homologies, the second messenger systems to which they are linked, and their pharmacology. The mGlu receptors are found on both CNS neurons and glia, and have been implicated in a variety of CNS functions. Because of the key role of glutamate in CNS function, pharmacological manipulation of this class of glutamate receptors has been suggested as an avenue to treat a variety of diseases (Conn and Pin, Ann. Rev. Pharmacol. Toxicol., 1997, 37, 205-237; Schoepp and Conn, Trends Pharmacol. ScL, 1993, 14, 13-20).

The present invention relates to the mGluR2 subtype of mGlu receptor, which together with mGluR3 receptors comprise the group Il mGlu receptors. mGluR2 receptors have been shown to modulate synaptic transmission at both excitatory glutamate-releasing and inhibitory GABA-releasing neurons (Schoepp, J Pharmacol Exp. Ther., 2001 , 299, 12- 20). The pharmacological tools that have been used to probe the functions of mGluR2 receptors are direct agonist and competitive antagonist compounds that have activity at both mGluR2 and mGluR3 receptors. Compounds that bind to allosteric sites of the mGluR2 receptor may allow differentiation from the activities of these orthosteric ligands. Pharmacological manipulation of mGluR2 receptors has been suggested to be useful for a variety of disorders (Marek, Current Opinion in Pharmacology, 2004, 4, 18-22). These include anxiety and related disorders (Tizzano et al., Pharmacol Biochem., Behav., 2002, 73, 367- 374), stress disorders (Eur J. Pharmacol., 2002, 435, 161-170), depression (Feinberg et al., Pharmacol Biochem, Behav., 2002, 73, 467-474), schizophrenia (Klodzinska et al., Pharmacol Biochem, Behav., 2002, 73, 327-332; Moghaddam and Adams, Science, 1998, 281 , 1349-1352), pain disorders including chronic pain syndromes (Varney and Gereau, Curr. Drug Target CNS Neurol. Disorders, 2002, 1 , 283-296), seizure disorders and epilepsy (Moldrich et al., Neuropharmacol., 2001 , 41 , 8-18), Parkinson's (Bradley et al., J. Neurosci., 2000, 20, 3085-3094), neurodegenerative disorders and brain injury (Bond et al., J. Pharmacol Exp. Ther., 2000, 294, 800-809; Allen et al., J. Pharmacol Exp. Ther., 1999, 290, 112-290), and substance abuse (Helton et al., Neuropharmacol., 1998, 36, 1511-1516). Pin et al., European J. Pharmacology 375 (1999), pp. 277-294, describes the role of mGluR2 agonists and antagonists in regulating the activity of many synapses in the central nervious system, thereby affecting a wide number of physiological and pathological processes. Johnson et al., J. Med. Chem. 2003, 46, 3189-3192, describes mGluR2 potentiators that have antianxiolytic activity.

All journal articles cited hereinabove are incorporated by reference herein in their entirety.

WO 01/56990 states that mGluR2 receptor potentiators may be effective in the treatment of neurological and psychiatric disorders associated with glutamate dysfunction, including: acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder. A need still exists for new drug therapies for the treatment of subjects suffering from or susceptible to the above disorders or conditions. In particular, a need still exists for new drugs having one or more improved properties (such as safety profile, efficacy, or physical properties) relative to those currently available. SUMMARY OF THE INVENTION

The invention is directed to a class of compounds, including the pharmaceutically acceptable salts of the compounds, having the structure of formula I:

Formula I wherein:

Y₁ is selected from the group consisting of O, C(H)R¹⁸ and NR¹⁸, wherein R¹⁸ is selected from the group consisting of hydrogen, S(O)R 103 , S(O)₂R ,103 , alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl, wherein the R¹⁸ alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R¹⁰¹, -OR¹⁰¹, and -NR¹⁰¹R¹⁰²;

-X²- represents a bond or is -C(O)-, -S(O)₂ or -(CHR¹)_n1- n1 = 1 , 2, or 3; n = 0, 1 , 2, or 3 each R¹ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, and cycloalkenyl, wherein each R¹ alkyl, alkenyl, cycloalkyl, or cycloalkenyl is optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R¹⁰¹, -OR¹⁰¹, -NR¹⁰¹R¹⁰², C(O)NR¹⁰¹R¹⁰², NR¹⁰¹C(O)R¹⁰³, and C(O)R¹⁰³; each R¹⁰¹ and each R¹⁰² is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; wherein each R¹⁰¹ and R¹⁰² alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl optionally substituted with one or more halogen or alkoxy or aryloxy, aryl optionally substituted with one or more halogen or alkoxy or alkyl or trihaloalkyl, heterocycloalkyl optionally substituted with aryl or heteroaryl or =0 or alkyl optionally substituted with hydroxy, cycloalkyl optionally substituted with hydroxy, heteroaryl optionally substituted with one or more halogen or alkoxy or alkyl or trihaloalkyl, hydroxyalkyl, alkoxy, aryloxy ; each R¹⁰³ is independently at each occurrence selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl and is independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl optionally substituted with one or more halogen or alkoxy or aryloxy, aryl optionally substituted with one or more halogen or alkoxy or alkyl or trihaloalkyl, heterocycloalkyl optionally substituted with aryl or heteroaryl or =0 or alkyl optionally substituted with hydroxy, cycloalkyl optionally substituted with hydroxy, heteroaryl optionally substituted with one or more halogen or alkoxy or alkyl or trihaloalkyl, hydroxyalkyl, alkoxy, aryloxy ;

R² is selected from the group consisting of alkyl, aryl, heterocycloalkyl, cycloalkyl and heteroaryl wherein the R² substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R²⁰¹, - C(O)R²⁰³, -C(O)NR²⁰¹R²⁰², -OR²⁰¹, -NR²⁰¹R²⁰², -NR²⁰¹C(O)R²⁰³, -NR²⁰¹C(O)OR²⁰³; each R²⁰¹ and each R²⁰² is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; each R²⁰³ is independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R²⁰¹, R²⁰² and R²⁰³ alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, -R²¹¹, -C(O)R²¹³, -C(O)OR²¹³ , -C(O)NR²¹¹R²¹², -OR²¹¹, -OC(O)R²¹³, -NR²¹¹R²¹², -NR²¹¹C(O)R²¹³, -NR²¹¹C(O)OR²¹³, -NR²¹¹S(O)₂R²¹³, -S(O)₈R²¹³, -S(O)₂NR²¹¹R²¹² ; s is 0, 1 or 2; each R²¹¹ and each R²¹² is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyi, aryl, heterocycloalkyl and heteroaryl, each R²¹³ is independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R²¹¹, R²¹² and R²¹³ alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl substituents are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkenyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl; R¹⁷ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, and cycloalkenyl, wherein the R¹⁷ alkyl, alkenyl, cycloalkyl, or cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R⁵⁰¹, -OR⁵⁰¹, -NR⁵⁰¹R⁵⁰², -S(O)_VR⁵⁰³ , -S(O)₂ NR⁵⁰¹R⁵⁰², -NR⁵⁰¹ S(O)₂R⁵⁰³, OC(O)R⁵⁰³,-C(O)OR⁵⁰³, C(O)NR⁵⁰¹R⁵⁰², NR⁵⁰¹C(O)R⁵⁰³, and C(O)R⁵⁰³; v is O, 1 or 2; wherein each R⁵⁰¹ and each R⁵⁰² is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl; and wherein each R⁵⁰³ is independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl;

R⁴, R⁵, R⁶ and R⁷ are each independently selected from the group consisting of halogen, cyano, -R⁴⁰¹, -C(O)OR⁴⁰¹, -C(O)NR⁴⁰¹R⁴⁰², -OR⁴⁰¹, -OC(O)R⁴⁰², -NR⁴⁰¹R⁴⁰², and -NR⁴⁰¹C(O)R⁴⁰²; wherein each R⁴⁰¹ and each R⁴⁰² is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl; wherein the R⁴⁰¹ and R⁴⁰² alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl substituents are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R⁴¹¹, -C(O)R⁴¹³-C(O)OR⁴¹³ , -C(O)NR⁴¹¹R⁴¹², -OR⁴¹¹, -OC(O)R⁴¹³, -NR⁴¹¹R⁴¹², -NR⁴¹¹C(O)R⁴¹³, -NR⁴¹¹C(O)OR⁴¹³, -NR⁴¹¹S(O)₂R⁴¹³, -S(O)₁R⁴¹³, -S(O)₂NR⁴¹¹R⁴¹²; t is O, 1 or 2; each R⁴¹¹ and each R⁴¹² is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl ; each R⁴¹³ is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R⁴¹¹, R⁴¹² and R⁴¹³ alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl substituents are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl; or wherein

(a)R¹⁷ and R⁷, taken together with the atoms connecting R¹⁷ and R⁷, form a 5-8 membered heterocyclic ring or

(b) R⁴ and R⁵, taken together with the atoms connecting R⁴ and R⁵, form a 5-8 membered heterocyclic or carbocyclic ring; or (c) R⁵ and R⁶, taken together with the atoms connecting R⁵ and R⁶, form a 5-8 membered heterocyclic or carbocyclic ring; or (d) R⁶ and R⁷, taken together with the atoms connecting R⁶ and R⁷, form a 5-8 membered heterocyclic or carbocyclic ring; and

R⁸ is hydrogen, flourine or alkyl optionally substituted with one or more fluorines.

In one embodiment of the invention, Y-i is O. In another embodiment of the invention, Y-, is C(H)R¹⁸.

In another embodiment of the invention, Y₁ is NR¹⁸.

In another embodiment of the invention, -X²- is -C(O)- or -(CHR¹)_n1- wherein n1 = 1 , or 2.

In another embodiment of the invention, -X²- is -(CHR¹)_nr wherein n1 = 1 , or 2. In another embodiment of the invention, n = 0 or 1.

In another embodiment of the invention, R² is selected from the group consisting of aryl, heterocycloalkyl, cycloalkyl and heteroaryl, optionally substituted as defined in formula I. in another embodiment of the invention, the compound of formula I has the formula Il

formula Il or a pharmaceutically acceptable salt thereof wherein

-X²- is a bond or -CO-; and

R¹⁷ is selected from the group consisting of alkyl and cycloalkyl; wherein the R¹⁷ alkyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, -R¹⁰¹, -OR¹⁰¹, -NR¹⁰¹R¹⁰², -S(O)₇R¹⁰¹, and -C(O)OR¹⁰¹; or R¹⁷ and R⁷, taken together with the atoms connecting R¹⁷ and R⁷, can form a 5-8 membered heterocyclic ring. In another embodiment of the compound of formula II, each of R⁴, R⁵, R⁶ and R⁷ is independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, wherein the R⁵, R⁶ or R⁷ alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl are optionally substituted as in the compound of formula I. Preferably, each of R⁴, R⁵, R^δ and R⁷ is independently is selected from the group consisting of hydrogen, cyano and halogen.

In another embodiment of the compound of formula II, R¹⁷ is selected from the group consisting of alkyl and cycloalkyl, wherein the R¹⁷ alkyl and cycloalkyl substituent is optionally substituted as in the compound of formula II.

In another embodiment of the compound of formula II, R¹⁷ and R⁷ together with the atoms connecting them form a 5-8-membered heterocyclic ring.

In another embodiment of the invention, the compound of formula i has the formula

formula III or a pharmaceutically acceptable salt thereof wherein:

R¹⁷ is selected from the group consisting of alkyl and cycloalkyl; wherein the R¹⁷ alkyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl;

R⁴ is selected from the group consisting of hydrogen and halogen; R⁵ is selected from the group consisting of hydrogen, halogen, cyano, alkyl, amino, heterocycloalkyl and heteroaryl ;

R⁶ is selected from the group consisting of hydrogen, halogen, cyano, alkyl, heterocycloalkyl and heteroaryl;

R⁷ is selected from the group consisting of hydrogen, halogen, alkyl, aryl, heterocycloalkyl and heteroaryl; and wherein the R⁵, R⁶, or R⁷ alkyl, heterocycloalkyl, heteroaryl and aryl are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl.

In an exemplary embodiment of the compound of formula III, R² is aryl, optionally substituted as in the compound of formula 111. The aryl is preferably phenyl or naphthalenyl, optionally substituted as in the compound of formula III. More preferably, the phenyl or naphthalenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R²⁰¹, -C(O)R²⁰¹, -C(O)OR²⁰¹, -OR²⁰¹, -NR²⁰¹R²⁰²;

R²⁰¹, R²⁰² are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R²⁰¹ and R²⁰² alkyl, cycloalkyl, aryl , heterocycloalkyl and heteroaryl substituents are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R²¹¹, -C(O)R²¹¹,-OR²¹¹, -NR²¹¹R²¹², -S(O)₃R²¹¹; S = O, 1 , 2;

R²¹¹, R²¹² are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; and wherein the R²¹¹, R²¹² and R²¹³ alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl substituents are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkenyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl.

As an example, R² is phenyl or naphthalenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R²⁰¹, -OR²⁰¹; each R²⁰¹substituent is independently selected from the group consisting of alkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R²⁰¹ alkyl, aryl , heterocycloalkyl and heteroaryl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R²¹¹, -C(O)R²¹¹, and -0R^211; each R²¹¹ is independently selected from the group consisting of alkyl and aryl, wherein R²¹¹ alkyl and aryl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl. In another exemplary embodiment of the compound of formula III, R² is tetrahydronaphthalenyl, optionally substituted as in the compound of formula III.

In another exemplary embodiment of the compound of formula III, R² is heterocycloalkyl or heteroaryl optionally substituted as in the compound of formula III. As an example, the R² heterocycloalkyl or heteroaryl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen and alkyl, wherein the alkyl is optionally substituted with one or more halogen substituents.

In another embodiment of the compound of formula III, R¹⁷ is selected from the group consisting of alkyl and cycloalkyl; wherein the R¹⁷ alkyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl; R² is selected from the group consisting of alkyl, aryl, heterocycloalkyl, cycloalkyl and heteroaryl, wherein R² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl, where R² is preferably aryl or heteroraryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl;

R⁴ is selected from the group consisting of hydrogen and halogen;

R⁵ is selected from the group consisting of hydrogen, halogen, cyano, alkyl, haloalkyl, amino, heterocycloalkyl and heteroaryl; R⁶ is selected from the group consisting of hydrogen, halogen, cyano, alkyl, aryl, heterocycloalkyl and heteroaryl; and

R⁷ is selected from the group consisting of hydrogen, halogen, alkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R⁵, R⁶ or R⁷ alkyl heterocycloalkyl and heteroaryl are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl.

As another example, R¹⁷ is alkyl, cycloalkyl, haloalkyl or alkoxyalkyl and R² is selected from the group consisting of heterocycloalkyl and heteroaryl which are pptionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryi, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl.

In another embodiment of the compound of formula III,

R¹⁷ is methyl;

R² is phenyl; wherein the R² substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl;

R⁴ is hydrogen, fluoro or bromo; R⁵ is hydrogen, cyano, halogen, methyl or amino; R⁶ is selected from the group consisting of hydrogen, bromo, fluoro, cyano, methyl, methoxy and methoxypyridinyl; and R⁷ is selected from the group consisting of bromo, fluoro, phenyl and methoxypyridinyl.

In another embodiment of the compound of formula III,

R¹⁷ is methyl, cyclopropyl, fluoroethyl, fluoromethyl, methoxyethyl or methoxymethyl; R² is selected from the group consisting of alkyl, aryl, heterocycloalkyl, cycloalkyl and heteroaryl, wherein R² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl. Preferably, R² is aryl, cycloalkyl, heterocycloalkyl, aryl and heteroraryl wherein R² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl; R⁴ is hydrogen; R⁵ is hydrogen; R⁶ is hydrogen; and R⁷ is hydrogen. Exemplary embodiments of the invention include embodiments wherein -X²- is a bond and R² is selected from the group consisting of the following substituents:

2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2-chloro-4,5- dimethylphenyl, 2-chloro-4-butylphenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 2- chloro-5-trifluoromethyl, 2-fluoro-4-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl, 2-fluoro-6- chlorophenyl, 2-trifluoromethylphenyl, phenyl, phenylphenyl, quinolinyl, tetrahydronaphthalenyl, 2,3,6-trifluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6- difluorophenyl, 2-chloro-5-trifluoromethylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3,4- difluorophenyl , 3,5-dichlorophenyl, 3,5-ditrifluoromethylphenyl, 3-chlorophenyl, 3- fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-chloro-5- trifluoropheπyl, 3-phenylphenyl, 2,5,6-trifluorophenyl, 2,4-dichlorophenyl, 3,5- trifluoromethylphenyl, isoquinolinyl, ([3-fluorophenyl, 5-propyl]triazolyl)phenyl, 1-chloro-5- methylphenyl, 2,3,4-trifluorophenyl, 2,3,5-trimethylphenyl, 2,3-dichloro-4-fluorophenyl, 2,3- difluoro-4-methylphenyl, 2,3-dimethyl-4-fluorophenyl, 2,3-dimethylphenyl, 2,4- dimethoxyphenylphenyl, 2,4-dimethylphenyl, 2,5-dimethoxyphenylphenyl, 2,5-dimethylphenyl, 2,5-dimethylphenylphenyl, 2,6-difluoro-3-methylphenyl, 2,6-difluorophenyl, 2,5- difluorophenylphenyl, 2-benzisoxazolyl-4-chloro-5-methylphenyl, 2-benzotriazolyl-4- methylphenyl, 2-benzthiazolyl-4-methoxyphenyl, 2-benzthiazolyl-5-methylphenyl, 2- benzthiazolyl-6-methylphenyl, 2-bromo-4-phenylphenyl, 2-chloro-3,4-difluorophenyl, 2-chloro- 3-cyano-4-fluorophenyl, 2-chloro-3-ethenyl-4-fluorophenyl, 2-chloro-3-ethyl-4-fluorophenyl, 2- chloro-3-fluorophenyl, 2-chloro-3-methyl-4-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-4- phenylphenyl, 2-cyano-3-chloro-4-fluorophenyl, 2-cyano-4-fluorophenyl, 2-cyanophenyl, 2- cyclopropyl-4-fluorophenyl, 2-ethoxyphenyl, 2-ethyl-3-chloro-4-fluorophenyl, 2-ethyl-4,5- dimethylphenyl, 2-ethyl-4-methylphenyl, 2-fluoro-3-chlorophenyl, 2-fluoro-4- methylphenylphenyl, 2-fluoro-5-methylcarbonylphenylphenyl, 2-fluoro-5-methylphenyl, 2- fluoro-5-methylphenylphenyl, 2-fluorophenylphenyl, 2-isoxazolyl-4,6-dichlorophenyl, 2- isoxazolyl-4-bromophenyl, 2-isoxazolyl-4-chlorophenyl, 2-isoxazolyl-4-methylphenyl, 2- methoxy-3-methyl-4-fluorophenyl, 2-methoxy-4-cyanophenyl, 2-methoxy-4-fluorophenyl, 2- methoxy-4-methylphenyl, 2-methoxy-5-chlorophenylphenyl, 2-methoxy-5-cyanophenylphenyl, 2-methoxy-5-fluoropheny!phenyl, 2-methoxy-5-methylphenyl, 2-methoxy-6-fluorophenyl, 2- methoxyphenyl, 2-methoxyphenylphenyl, 2-methyl-3,4-difluorophenyl, 2-methyl-3-chloro-4- fluorophenyl, 2-methyl-3-methoxy-4-fluorophenyl, 2-methyl-4-chlorophenyl, 2-methyl-4- fluorophenyl, 2-methyl-4-methylphenyl, 2-methyl-5-fluorophenylphenyl, 2-methyl-6- chlorophenyl, 2-methylphenyl, 2-methylphenylphenyl, 2-methylpyrimidinyl, 2-phenyI, 4- butylphenyl, 2-propylphenyl, 2-trifluoromethoxyphenylphenyl, 2-trifluoromethylphenylphenyl, 3,4-dichlorophenyl, 3,4-dichlorophenylcarbonyl, 3,4-dicyanophenyl, 3,4-difluorophenyIphenyl, 3,4-dimethoxyphenylphenyl, 3,4-dimethylphenyl, 3,5-difluorophenyl, 3,5-dibutylphenylphenyl, 3,5-difluorophenyl, 3,5-dimethyl-4-cyanophenyl, 3,5-dimethylphenyl, 3-butylphenyl, 3-chloro- 4-cyanophenylphenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methylphenyl, 3-cyano-4- fluorophenylphenyl, 3-cyano-4-methoxyphenylphenyl, 3-cyanophenyl, 3-ethoxyphenyl, 3- ethylphenyl, 3-fIuoro-4-chIorophenyl, 3-fluoro-4-cyanophenyl, 3-fluoro-4-cyanophenylphenyl, 3-fluoro-4-methoxyphenylphenyl, 3-fluoro-4-methylphenylphenyl, 3-fluorophenylphenyl, 3- methoxyphenyl, 3-methoxyphenylphenyl, 3-methyl-4-chlorophenyl, 3-methyI-4-fluorophenyl, 3-methyl-4-methoxyphenylphenyl, 3-propylphenyl, 3-trifluoromethyl-4-methoxyphenylphenyl, 3-trifluoromethylphenylphenyl, 4-butylphenyl, 4-chlorophenylcarbonyl, 4-cyanoethylphenyl, 4- cyanomethylphenyl, 4-cyanophenyl, 4-cyanophenylphenyl, 4-ethylphenyl, 4-fluoro-3- methylphenylphenyl, 4-fluorophenylcarbonyl, 4-fluorophenylphenyl, 4-methoxy-3- fluorophenylphenyl, 4-methoxy-3-trifluoromethylphenylphenyl, 4-methoxymethylphenyl, 4- methoxyphenyl, 4-methoxyphenylcarbonyl, 4-methoxyphenylphenyl, 4-methylphenyl, 4- propylphenyl, benzo[d][1 ,3]dioxolylphenyl, benzofuranylphenyl, benzthiazolylphenyl, bromopyridinyl, chlorophenyltriazolylphenyl, chloropyridinyl, cyanophenylphenyl, dibenzo[b,d]furanyl, difluoromethoxyphenylphenyl, dihydro-1H-indenyl, dihydrobenzofuranyl, ethoxyphenyl, fluorodihydrobenzofuranyl, fluorodihydroindenyl, fluoronaphthalenyl, imidazolylphenyl, isoxazolylphenyl, methoxyphenylphenyl, methylbenzothiazolylphenyl, methylcarbonylbenzofuranylphenyl, methylcarbonylphenylphenyl, methylcarbonylthiophenyl, methyldihydro-1 H-indenyl, methyldihydrobenzo[b][1 ,4]oxazinylphenyl, methylindolyl, methylphenylphenyl, methylpyrazolylphenyl, methylpyridinyl, methylquinolinylphenyl, methylthiazolylphenylphenyl, methylthiopyrimidinyl, naphthalenyl, oxazolylphenylphenyl, oxodihydro-1 H-indenylphenyl, phenylcarbonyl, propylphenyl, propylphenylphenyl, propylpyridinyl, pyridinyl, pyrrolylphenyl, quinolinylphenyl, quinoxalinyl, quinoxalinylphenyl, thiadiazolylphenyl, thiadiazolylphenylphenyl, triazolylphenyl, trifluoromethoxyphenylphenyl, trifluoromethylphenyl, trifluoromethylphenylphenyl, trifluoromethylpyridinyl and 2,4,5- trifluorophenyl. Exemplary embodiments of the invention also include embodiments wherein R¹⁷ is selected from the group consisting of cyclopropyl, fluoroethyl, fluoromethyl, methoxyethyl, methoxymethyl and methyl. Exemplary embodiments of the invention also include embodiments wherein R⁴ is selected from the group consisting of fluoro and bromo.

Exemplary embodiments of the invention also include embodiments wherein R⁵ is selected from the group consisting of fluoro, bromo, cyano, methoxy, methoxypyridinyl and methyl,

Exemplary embodiments of the invention also include embodiments wherein R⁶ is selected from the group consisting of fluoro, bromo, cyano, methoxy, methoxypyridinyl and methyl.

Exemplary embodiments of the invention also include embodiments wherein R⁷ is selected from the group consisting of fluoro, bromo, methoxypyridinyl and methyl.

Exemplary embodiments of the invention also include embodiments wherein R¹⁷ and R⁷, taken together with the atoms connecting R¹⁷ and R⁷, form a 5-8 membered heterocyclic ring.

In another embodiment of the invention, the compound of formula I has the formula IV,

formula IV or a pharmaceutically acceptable salt thereof wherein: R¹⁷ is selected from the group consisting of alky! and cycloalkyl; wherein R¹⁷ is optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl;

R² is aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R²⁰¹ and -OR²⁰¹; R²⁰¹ is independently selected from the group consisting of hydrogen and alkyl; wherein the R²⁰¹ alkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl; R⁴ is selected from the group consisting of hydrogen and halogen;

R⁵ is selected from the group consisting of hydrogen, halogen, cyano, alkyl and ammo;

R⁶ is selected from the group consisting of hydrogen, halogen, cyano, alkyl, heterocycloalkyl, and heteroaryl;

R⁷ is selected from the group consisting of hydrogen, halogen, aryl heterocycloalkyl, and heteroaryl; and wherein the R⁵, R⁶ and R⁷ alkyl, aryl, heterocycloalkyl, and heteroaryl substituents are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl.

In another embodiment of the invention, the compound of formula I has the formula V,

formula V or a pharmaceutically acceptable salt thereof wherein:

R² is selected from the group consisting of alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl wherein R² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R²⁰¹, -C(O)R²⁰³, -C(O)OR²⁰³, -C(O)NR²⁰¹R²⁰² -OR²⁰¹, -OC(O)R²⁰³, -NR²⁰¹R²⁰², -NR²⁰¹C(O)R²⁰³, -NR²⁰¹C(O)OR²⁰³;

R²⁰¹, R²⁰² are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;

R²⁰³ is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; wherein the R²⁰¹, R²⁰² and R²⁰³ alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl substituents are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, -R²¹¹, -C(O)R²¹¹, - C(O)OR²¹¹ , -C(O)NR²¹¹R²¹², -OR²¹¹, -OC(O)R²¹², -NR²¹¹R²¹², -NR²¹¹C(O)R²¹², - NR²¹¹C(S)R²¹³, -NR²¹¹C(O)OR²¹², -NR²¹¹C(S)OR²¹², -NR²¹¹S(O)₂R²¹³, -NR²¹¹C(O)NR²¹²R²¹³, - S(O)₃R²¹³, and -S(O)₂NR²¹¹R²¹²; s is 0, 1 or 2;

R²¹¹, R²¹² are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;

R²¹³ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; wherein the R²¹¹, R²¹² and R²¹³ alkyl, alkenyl, cycloalkyl, aryl , heterocycloalkyl, and heteroaryl substituents are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl.

In the compound of formula V, R² is preferably selected from the group consisting of aryl, heterocycloalkyl and heteroaryi wherein the R² substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R²⁰¹, -C(O)R²⁰³, -C(O)OR²⁰³, -C(O)NR²⁰¹R²⁰², -OR²⁰¹, -OC(O)R²⁰³,

-NR²⁰¹R²⁰², -NR²⁰¹C(O)R²⁰³, -NR²⁰¹C(O)OR²⁰³.

In another embodiment of the invention, the R¹⁰¹ is heterocycloalkyl containing a nitrogen directly bonded to R¹, and the R¹⁰¹ heterocycloalkyl nitrogen is optionally substituted as defined in formula I.

In another embodiment of the invention, R¹⁰¹ is heteroaryl that containing a nitrogen directly bonded to R¹, and the R¹⁰¹ heterocycloalkyl nitrogen is optionally substituted as defined in formula I.

In another embodiment of the invention, -C(O)R¹⁰³ is -CO-heterocycloalkyl, wherein the heterocycloalkyl contains a nitrogen directly bonded to CO, wherein the R¹⁰³ heterocycloalkyl in the C(O)R¹⁰³ is optionally substituted as defined in formula I.

In another embodiment of the invention, -C(O)R¹⁰³ is -CO-heteroaryl, wherein the heteroaryl contains a nitrogen directly bonded to CO, wherein the R¹⁰³ heteroaryl in the C(O)R¹⁰³ is optionally substituted as defined in formula I. In another embodiment of the invention, the R²⁰¹ is heterocycloalkyl containing a nitrogen directly bonded to R², and the R²⁰¹ heterocycloalkyl nitrogen is optionally substituted as defined in formula I.

In another embodiment of the invention, the R²⁰¹ is heteroaryl containing a nitrogen directly bonded to R², and the R²⁰¹ heteroaryl nitrogen is optionally substituted as defined in formula I.

In another embodiment of the invention, R⁸ is hydrogen or alkyl. Exemplary compounds according to the invention include the compounds disclosed in Table 1 herein or pharmaceutically acceptable salts thereof.

The compounds of formula I are useful for the treatment or prevention of a variety of neurological and psychiatric disorders associated with glutamate dysfunction, including: acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder. Accordingly, in one embodiment, the invention provides a method for treating or preventing a condition in a mammal, such as a human, selected from the conditions above, comprising administering a compound of formula I to the mammal. The mammal is preferably a mammal in need of such treatment or prevention. As an example, the invention provides a method for treating or preventing a condition selected from migraine, anxiety disorders, schizophrenia, and epilepsy. Exemplary anxiety disorders are generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive-compulsive disorder.

In another embodiment, the invention comprises methods of treating or preventing a condition in a mammal, such as a human, by administering a compound having the structure of formula I, wherein the condition is selected from the group consisting of cardiovascular diseases, such as atherosclerotic cardiovascular diseases, cerebrovascular diseases and peripheral arterial diseases, to the mammal. The mammal is preferably a mammal in need of such treatment or prevention. Other conditions that can be treated or prevented in accordance with the present invention include hypertension and angiogenesis. In another embodiment the present invention provides methods of treating or preventing neurological and psychiatric disorders associated with glutamate dysfunction, comprising administering to a patient in need thereof an amount of a compound of formula I effective in treating or preventing such disorders. The compound of formula I is optionally used in combination with another active agent. Such an active agent may be, for example, a metabotropic glutamate receptor agonist.

The invention is also directed to a pharmaceutical composition comprising a compound of formula I, and a pharmaceutically acceptable carrier. The composition may be, for example, a composition for treating or preventing a condition selected from the group consisting of acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder, wherein the composition contains an amount of the compound of formula I that is effective in the treatment or prevention of such conditions. The composition may be, as another example, a composition comprising an mGluR2 antagonizing amount of the compound of formula I.

The composition may also further comprise another active agent. Such an active agent may be, for example, a metabotropic glutamate receptor agonist. DETAILED DESCRIPTION OF THE INVENTION This detailed description of embodiments is intended only to acquaint others skilled in the art with Applicants' invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as it may be best suited to the requirements of a particular use. This invention, therefore, is not limited to the embodiments described in this specification, and may be variously modified.

Abbreviations and Definitions TABLE A - Abbreviations

1-HOAT 1 -hydroxy-7-azabenzotriazole

1-HOBt 1-hydroxybenzotriazole hydrate

The term "alkyl" refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing in one embodiment, from one to twenty carbon atoms; in another embodiment from one to twelve carbon atoms; in another embodiment, from one to ten carbon atoms; in another embodiment, from one to six carbon atoms; and in another embodiment, from one to four carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, iso-amyl, hexyl and the like.

The term "alkenyl" refers to a linear or branched-chain hydrocarbyl substituent containing one or more double bonds and from two to twenty carbon atoms; in another embodiment, from two to twelve carbon atoms; in another embodiment, from two to six carbon atoms; and in another embodiment, from two to four carbon atoms. Examples of alkenyl include ethenyl (also known as vinyl), allyl, propenyl (including 1-propenyl and 2- propenyl) and butenyl (including 1-butenyl, 2-butenyl and 3-butenyl). The term "alkenyl" embraces substituents having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.

The term "benzyl" refers to methyl radical substituted with phenyl, i.e., the following

structure: ^1"α>v

The term "carbocyclic ring" refers to a saturated cyclic, partially saturated cyclic, or aromatic ring containing from 3 to 14 carbon ring atoms ("ring atoms" are the atoms bound together to form the ring). A carbocyclic ring typically contains from 3 to 10 carbon ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. A "carbocyclic ring system" alternatively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as "tetralinyl"), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as "phenalenyl"), fluorenyl, and decalinyl.

The term "heterocyclic ring" refers to a saturated cyclic, partially saturated cyclic, or aromatic ring containing from 3 to 14 ring atoms ("ring atoms" are the atoms bound together to form the ring), in which at least one of the ring atoms is a heteroatom that is oxygen, nitrogen, or sulfur, with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.

The term "cycloalkyl" refers to a saturated carbocyclic substituent having three to fourteen carbon atoms. In another embodiment, a cycloalkyl substituent has three to ten carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkyl" also includes substituents that are fused to a C₆-C₁₀ aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyl group as a substituent is bound to a carbon atom of the cycloalkyl group. When such a fused cycloalkyl group is substituted with one or more substituents, the one or more substitutents, unless otherwise specified, are each bound to a carbon atom of the cycloalkyl group. The fused C₆-C₁₀ aromatic ring or to a 5-10-membered heteroaromatic ring may be optionally substituted with halogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or =0.

The term "cycloalkenyl" refers to a partially unsaturated carbocyclic substituent having three to fourteen carbon atoms, typically three to ten carbon atoms. Examples of cycloalkenyi include cyclobutenyl, cyclopentenyl, and cyclohexenyl.

A cycloalkyl or cycloalkenyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyi, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. Alternatively, 2 or 3 rings may be fused together, such as bicyclodecanyl and decalinyl. The term "aryl" refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may have six to eighteen carbon atoms. As an example, the aryl substituent may have six to fourteen carbon atoms. The term "aryl" may refer to substituents such as phenyl, naphthyl and anthracenyl. The term "aryl" also includes substituents such as phenyl, naphthyl and anthracenyl that are fused to a C₄-C₁₀ carbocyclic ring, such as a C₅ or a C_δ carbocyclic ring, or to a 4-10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group. When such a fused aryl group is substituted with one more substituents, the one or more substitutents, unless otherwise specified, are each bound to an aromatic carbon of the fused aryl group. The fused C₄-C₁₀ carbocyclic or 4-10-membered heterocyclic ring may be optionally substituted with halogen, C₁-C₆ alkyl, C₃-Ci₀ cycloalkyl, or =0. Examples of aryl groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as "tetralinyl"), indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (also known as "phenalenyl"), and fluorenyl.

In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, etc.) is indicated by the prefix "C_x-Cy-," wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "C_rC₆-alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C₃-C₆-cycloalkyl refers to saturated cycloalkyl containing from 3 to 6 carbon ring atoms. In some instances, the number of atoms in a cyclic substituent containing one or more heteroatoms (e.g., heteroaryl or heterocycloalkyl) is indicated by the prefix "X-Y- membered", wherein wherein x is the minimum and y is the maximum number of atoms forming the cyclic moiety of the substituent. Thus, for example, 5-8-membered heterocycloalkyl refers to a heterocycloalkyl containing from 5 to 8 atoms, including one ore more heteroatoms, in the cyclic moiety of the heterocycloalkyl.

The term "hydrogen" refers to hydrogen substituent, and may be depicted as -H. The term "hydroxy" refers to -OH. When used in combination with another term(s), the prefix "hydroxy" indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds bearing a carbon to which one or more hydroxy substituents include, for example, alcohols, enols and phenol.

The term "hydroxyalkyl" refers to an alkyl that is substituted with at least one hydroxy substituent. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.

The term "nitro" means -NO₂.

The term "cyano" (also referred to as "nitrile") -CN, which also may be

depicted:

Th

e term "carbonyl" means -C(O)-, which also may be depicted as:

The term "amino" refers to -NH₂.

The term "alkylamino" refers to an amino group, wherein at least one alkyl chain is bonded to the amino nitrogen in place of a hydrogen atom. Examples of alkylamino substituents include monoalkylamino such as methylamino (exemplified by the formula

-NH(CH₃)), which may also be depicted:

and dialkylamino such as dimethylamino, (exemplified by the formula

-N(CH₃)₂, which may also be depicted:

.

The term "aminocarbonyl" means -C(O)-NH₂, which also may be depicted

as:

The term "halogen" refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -Cl), bromine (which may be depicted as -Br), or iodine (which may be depicted as -I). In one embodiment, the halogen is chlorine. In another embodiment, the halogen is a fluorine. The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen substituents. For example, haloalkyl refers to an alkyl that is substituted with at least one halogen substituent. Where there is more than one hydrogen replaced with halogens, the halogens may be the identical or different. Examples of haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl. Illustrating further, "haloalkoxy" refers to an alkoxy that is substituted with at least one halogen substituent. Examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), and 2,2,2-trifluoroethoxy. It should be recognized that if a substituent is substituted by more than one halogen substituent, those halogen substituents may be identical or different (unless otherwise stated).

The prefix "perhalo" indicates that each hydrogen substituent on the substituent to which the prefix is attached is replaced with an independently selected halogen substituent. If all the halogen substituents are identical, the prefix may identify the halogen substituent. Thus, for example, the term "perfluoro" means that every hydrogen substituent on the substituent to which the prefix is attached is replaced with a fluorine substituent. To illustrate, the term "perfluoroalkyl" refers to an alkyl substituent wherein a fluorine substituent is in the place of each hydrogen substituent. Examples of perfluoroalkyl substituents include trifluoromethyl (-CF₃), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, and perfluorodecyl. To illustrate further, the term "perfluoroalkoxy" refers to an alkoxy substituent wherein each hydrogen substituent is replaced with a fluorine substituent. Examples of perfluoroalkoxy substituents include trifluoromethoxy (-0-CF₃), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, and perfluorodecoxy. The term "oxo" refers to =0.

The term "oxy" refers to an ether substituent, and may be depicted as -O-. The term "alkoxy" refers to an alkyl linked to an oxygen, which may also be represented as

-O-R, wherein the R represents the alkyl group. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.

The term "alkylthio" means -S-alkyl. For example, "methylthio" is -S-CH₃. Other examples of alkylthio include ethylthio, propylthio, butylthio, and hexylthio. The term "alkylcarbonyl" means -C(O)-alkyl. For example, "ethylcarbonyl" may be

depicted as:

. Examples of other alkylcarbonyl include methylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcabonyl, and hexylcarbonyl.

The term "aminoalkylcarbonyl" means -C(O)-alkyl-NH₂. For example,

"aminomethylcarbonyl" may be depicted as:

'

The term "alkoxycarbonyl" means -C(O)-O-alkyl. For example, "ethoxycarbonyl" may

be depicted as:

. Examples of other alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and hexyloxycarbonyl. In another embodiment, where the carbon atom of the carbonyl is attached to a carbon atom of a second alkyl, the resulting functional group is an ester.

The terms "thio" and "thia" mean a divalent sulfur atom and such a substituent may be depicted as -S-. For example, a thioether is represented as "alkyl-thio-alkyl" or, alternatively, alkyl-S-alkyl.

The term "thiol" refers to a sulfhydryl substituent, and may be depicted as -SH. The term "thione" refers to =S.

The term "sulfonyl" refers to -S(O)₂-, which also may be depicted as:

Thus, for example, "alkyl-sulfonyl-alkyl" refers to alkyl-S(O)₂-alkyl. Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.

The term "aminosulfonyl" means -S(O)₂-NH₂, which also may be depicted

The term "sulfinyl" or "sulfoxido" means -S(O)-, which also may be depicted as:

Thus, for example, "alkylsulfinylalkyl" or "alkylsulfoxidoalkyl" refers to alkyl-S(O)-alkyl. Exemplary alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfinyl, and hexylsulfinyl. The term "heterocycloalkyl" refers to a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heterocycloalkyl alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (e.g., nitrogen, oxygen, or sulfur). In a group that has a heterocycloalkyl substituent, the ring atom of the heterocycloalkyl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heterocycloalkyl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.

The term "heterocycloalkyl" also includes substituents that are fused to a C₆-C₁₀ aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused heterocycloalkyl group as a substituent is bound to a heteroatom of the heterocyclocalkyl group or to a carbon atom of the heterocycloalkyl group. When such a fused heterocycloalkyl group is substituted with one more substituents, the one or more substitutents, unless otherwise specified, are each bound to a heteroatom of the heterocyclocalkyl group or to a carbon atom of the heterocycloalkyl group. The fused C₆-Ci_O aromatic ring or to a 5-10-membered heteroaromatic ring may be optionally substituted with halogen, C₁-C₆ alkyl, C₃-C-_I0 cycloalkyl, or =0.

The term "heteroaryl" refers to an aromatic ring structure containing from 5 to 14 ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1 ,2,3-, 1 ,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazoiyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1 ,4-benzoxazinyl. In a group that has a heteroaryl substituent, the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heteroaryl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. The term "heteroaryl" also includes pyridyl N-oxides and groups containing a pyridine N-oxide ring.

Examples of single-ring heteroaryls include furanyl, dihydrofuranyl, tetradydrofuranyl, thiophenyl (also known as "thiofuranyl"), dihydrothiophenyl, tetrahydrothiophenyi, pyrrolyl, isopyrrolyi, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiaβdiazolyl, oxathiazolyl, oxadiazolyl (including oxadiazolyl, 1 ,2,4-oxadiazolyl (also known as "azoximyl"), 1 ,2,5-oxadiazolyl (also known as "furazanyl"), or 1 ,3,4-oxadiazolyl), oxatriazolyl (including 1 ,2,3,4-oxatriazolyl or 1 ,2,3,5-oxatriazolyl), dioxazolyl (including 1 ,2,3-dioxazolyl, 1 ,2,4-dioxazolyl, 1 ,3,2-dioxazolyl, or 1 ,3,4-dioxazolyI), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (including 1 ,2-pyranyl or 1 ,4-pyranyl), dihydropyranyl, pyridinyl (also known as "azinyl"), piperidinyl, diazinyl (including pyridazinyl (also known as "1 ,2-diazinyl"), pyrimidinyl (also known as "1,3-diazinyl" or "pyrimidyi"), or pyrazinyl (also known as "1 ,4-diazinyl"), piperazinyl, triazinyl (including s-triazinyl (also known as "1 ,3,5-triazinyl"), as-triazinyl (also known 1 ,2,4-triazinyI), and v-triazinyl (also known as "1 ,2,3-triazinyl"), oxazinyl (including 1 ,2,3-oxazinyl, 1 ,3,2-oxazinyl, 1 ,3,6-oxazinyl (also known as "pentoxazolyl"), 1 ,2,6-oxazinyl, or 1 ,4-oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyl or 1 ,2,6-oxathiazinyl), oxadiazinyl (including 1 ,4,2-oxadiazinyl or 1 ,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

Examples of 2-fused-ring heteroaryls include, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl.

Examples of 3-fused-ring heteroaryls or heterocycloalkyls include 5,6-dihydro-4H- imidazo[4,5,1-ij]quinoline, 4,5-dihydroimidazo[4,5,1-hi]indole, 4,5,6,7-tetrahydroimidazo[4,5,1- jk][1]benzazepine, and dibenzofuranyl.

Other examples of fused-ring heteroaryls include benzo-fused heteroaryls such as indolyl, isoindolyl (also known as "isobenzazolyl" or "pseudoisoindolyl"), indoleninyl (also known as "pseudoindolyl"), isoindazolyl (also known as "benzpyrazolyl"), benzazinyl (including quinolinyl (also known as "1 -benzazinyl") or isoquinolinyl (also known as "2-benzazinyl")), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as "1 ,2-benzodiazinyl") or quinazolinyl (also known as "1 ,3-benzodiazinyl"), benzopyranyl (including "chromanyl" or "isochromanyl"), benzothiopyranyl (also known as "thiochromanyl"), benzoxazolyl, indoxazinyl (also known as "benzisoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as "coumaronyl"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl," "thionaphthenyl," or "benzothiofuranyl"), isobenzothienyl (also known as "isobenzothiophenyl," "isothionaphthenyl," or "isobenzothiofuranyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1 ,3,2-benzoxazinyl), 1 ,4,2-benzoxazinyI, 2,3,1 -benzoxazinyl , or 3,1 ,4-benzoxazinyl ), benzisoxazinyl (including 1 ,2-benzisoxazinyl or 1 ,4-benzisoxazinyl), tetrahydroisoquinolinyl , carbazolyl, xanthenyl, and acridinyl.

The term "heteroaryl" also includes substituents such as pyridyl and quinolinyl that are fused to a C₄-C₁₀ carbocyclic ring, such as a C₅ or a C₆ carbocyclic ring, or to a 4-10- membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. When such a fused heteroaryl group is substituted with one more substituents, the one or more substitutents, unless otherwise specified, are each bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. The fused C₄-Ci₀ carbocyclic or 4-10-membered heterocyclic ring may be optionally substituted with halogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or =0.

A substituent is "substitutable" if it comprises at least one carbon, sulfur, oxygen or nitrogen atom that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano do not fall within this definition.

If a substituent is described as being "substituted," a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon, oxygen, sulfur or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro substituent, and difluoroalkyl is alkyl substituted with two fluoro substituents. it should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated). If a substituent is described as being "optionally substituted," the substituent may be either (1) not substituted, or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent. If a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent there are any) may each be replaced with an independently selected optional substituent. One exemplary substituent may be depicted as - N R' R," wherein R' and R" together with the nitrogen atom to which they are attached, may form a heterocyclic ring. The heterocyclic ring formed from R' and R" together with the nitrogen atom to which they are attached may be partially or fully saturated. In one embodiment, the heterocyclic ring consists of 3 to 7 atoms. In another embodiment, the heterocyclic ring is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, pyridyl and thiazolyl.

This specification uses the terms "substituent," "radical," and "group" interchangeably. If a group of substituents are collectively described as being optionally substituted by one or more of a list of substituents, the group may include: (1 ) unsubstitutable substituents, (2) substitutable substituents that are not substituted by the optional substituents, and/or (3) substitutable substituents that are substituted by one or more of the optional substituents.

If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen substituents, that substituent may be either (1 ) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non- hydrogen substituents, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen substituent. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen substituents, then the nitrogen will be optionally substituted with up to 2 non-hydrogen substituents if the amino nitrogen is a primary nitrogen, whereas the amino nitrogen will be optionally substituted with up to only 1 non-hydrogen substituent if the amino nitrogen is a secondary nitrogen. A prefix attached to a multi-moiety substituent only applies to the first moiety. To illustrate, the term "alkylcycloalkyl" contains two moieties: alkyl and cycloalkyl. Thus, a C₁-C₆- prefix on C_rC₆-alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the CrCβ- prefix does not describe the cycloalkyl moiety. To illustrate further, the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyl substituent is substituted with one or more halogen substituents. If the halogen substitution may only occur on the alkyl moiety, the substituent would be described as "alkoxyhaloalkyl." If the halogen substitution may occur on both the alkyl moiety and the alkoxy moeity, the substituent would be described as "haloalkoxyhaloalkyl." When a substituent is comprised of multiple moieties, unless otherwise indicated, it is the intention for the final moiety to serve as the point of attachment to the remainder of the molecule. For example, in a substituent A-B-C, moiety C is attached to the remainder of the molecule. In a substituent A-B-C-D, moiety D is attached to the remainder of the molecule. Similarly, in a substituent aminocarbonylmethyl, the methyl moiety is attached to the remainder of the molecule, where the substituent may also be be depicted as

. In a substituent trifluoromethylaminocarbonyl, the carbonyl moiety is attached to the remainder of the molecule, where the substituent may also be depicted as

If substituents are described as being "independently selected" from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).

Isomers

When an asymmetric center is present in a compound of formulae I through V, hereinafter referred to as the compound of the invention, the compound may exist in the form of optical isomers (enantiomers). In one embodiment, the present invention comprises enantiomers and mixtures, including racemic mixtures of the compounds of formulae I through V. In another embodiment, for compounds of formulae I through V that contain more than one asymmetric center, the present invention comprises diastereomeric forms (individual diastereomers and mixtures thereof) of compounds. When a compound of formulae I through V contains an alkenyl group or moiety, geometric isomers may arise. Tautomeric Forms

The present invention comprises the tautomeric forms of compounds of formulae I through V. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula 1 containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. The various ratios of the tautomers in solid and liquid form is dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound. Salts

The compounds of this invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.

Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of formulae I - V with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound. For use in medicine, the salts of the compounds of this invention are non-toxic "pharmaceutically acceptable salts." Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.

Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.

Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. In another embodiment, base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.

Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl (C₁-C₆) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates

(e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.

In one embodiment, hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

Prodrugs Also within the scope of the present invention are so-called "prodrugs" of the compound of the invention. Thus, certain derivatives of the compound of the invention which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into the compound of the invention having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs." Further information on the use of prodrugs may be found in "Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association). Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of any of formulae I through V with certain moieties known to those skilled in the art as "pro-moieties" as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985). Isotopes

The present invention also includes isotopically labelled compounds, which are identical to those recited in formula I , but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶CI, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labelled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, le_±, ³H, and carbon-14, Le., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, Le₁, ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

Administration and Dosing

Typically, a compound of the invention is administered in an amount effective to treat or prevent a condition as described herein. The compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment or prevention intended. Therapeutically effective doses of the compounds required to treat or prevent the progress of the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

In another embodiment, the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

In another embodiment, the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the invention can also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may be administered rectally or vaginally. In another embodiment, the compounds of the invention may also be administered directly to the eye or ear.

The dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment or prevention of the above-indicated conditions. In one embodiment, the total daily dose of a compound of the invention (administered in single or divided doses) is typically from about 0.01 to about 100 mg/kg. In another embodiment, total daily dose of the compound of the invention is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg (i.e., mg compound of the invention per kg body weight). In one embodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment, dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired. For oral administration, the compositions may be provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1mg to about 100 mg of active ingredient. Intravenously, doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Suitable subjects according to the present invention include mammalian subjects.

Mammals according to the present invention include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development. Use in the Preparation of a Medicament

In another embodiment, the invention comprises the use of one or more compounds of the invention for the preparation of a medicament for the treatment or prevention of the conditions recited herein.

Pharmaceutical Compositions For the treatment or prevention of the conditions referred to above, the compound of the invention can be administered as compound per se. Alternatively, pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound.

In another embodiment, the present invention comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the invention presented with a pharmaceutically-acceptable carrier. The carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compounds. A compound of the invention may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be present.

The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment or prevention intended. The active compounds and compositions, for example, may be administered orally, rectally, parenterally, or topically. Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of formulae I through V are ordinarily combined with one or more adjuvants. Such capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agentsor may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.

In another embodiment, the present invention comprises a parenteral dose form. "Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneal^, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.

In another embodiment, the present invention comprises a topical dose form. "Topical administration" includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J. Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).

Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in suitable carrier. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed- linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 , 2,3,3, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

In another embodiment, the present invention comprises a rectal dose form. Such rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3^rd Ed.), American Pharmaceutical Association, Washington, 1999.

Co-administration The compounds of the present invention can be used, alone or in combination with other therapeutic agents, in the treatment or prevention of various conditions or disease states. The compound(s) of the present invention and other therapeutic agent(s) may be may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially. An exemplary therapeutic agent may be, for example, a metabotropic glutamate receptor agonist.

The administration of two or more compounds "in combination" means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two or more compounds may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration.

The phrases "concurrent administration," "co-administration," "simultaneous administration," and "administered simultaneously" mean that the compounds are administered in combination.

Kits The present invention further comprises kits that are suitable for use in performing the methods of treatment or prevention described above. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present invention and a container for the dosage, in quantities sufficient to carry out the methods of the present invention. In another embodiment, the kit of the present invention comprises one or more compounds of the invention.

Intermediates

In another embodiment, the invention relates to the novel intermediates useful for preparing the compounds of the invention General Synthetic Schemes

The compounds of the formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatisations that are familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or may be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-lnterscience)). Preferred methods include, but are not limited to, those described below.

During any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 , and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference. Compounds of formula I, or their pharmaceutically acceptable salts, can be prepared according to the reaction schemes discussed herein. Unless otherwise indicated, the substituents in the schemes are defined as above. Isolation and purification of the products are accomplished by standard procedures, which are known to a chemist of ordinary skill.

The following schemes are exemplary of the processes for making compounds of formula I. In the schemes below, numerals from (I) to (LXXIII), including numerals from (I) to (V), are used for convenience to designate the formulae in the schemes. The use of numerals from (I) to (V) in the schemes below is not intended to imply that the compounds designated by such numerals correspond to the compounds of formulae I - V that are disclosed hereinabove and that are recited in the appended claims.

Scheme I illustrates a method for the preparation of compounds of formula I, where R² is phenyl, substituted phenyl or heteroaryl, -X²- is a bond, and R¹⁷, and R⁴ through R⁷ are defined as above.

Referring to scheme I, a compound of formula (I) [SynLett, 1996, 1097] can be treated with (BOC)₂O in the presence of a suitable base such as triethylamine, in solvents such as CH₂CI₂, to produce the desired carbamate of formula (II). Compounds of formula (II) can be coupled with phenols, alcohols or carboxylic acids of formula (III) in the presence of a suitable coupling reagent such as diethylazodicarboxylate (DEAD) and triarylphosphines, such as triphenylphosphines, in solvents such as THF, toluene or ether at or about room temperature, to produce the corresponding ethers or esters (not depicted). Other suitable coupling reagents for this transformation include di-tert-butylazodicarboxylate (DBAD), diphenylazodicarboxylate and the like. Other suitable triarylphosphines include polymer bound triphenylphosphine, and the like. The corresponding ether or ester compounds can be treated with acids such as trifluoroacetic acid, hydrochloric acid and the like, in solvents such as methylene chloride, dioxane, ethyl acetate, THF, dichloroethane and the like, to produce the secondary amine compounds of formula (IV). Compounds of formula (IV) can be treated with aldehydes of formula (V) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene chloride, dichloroethane, DMF or THF and the like, at about room temperature, to produce the corresponding tertiary amines of formula (Vl). Other suitable conditions for this transformation include treatment of the amine of formula (IV) with aldehydes of formula (V) in solvents such as methanol or ethanol at room temperature, followed by treatment with reducing agents such as NaBH₄ Or NaCNBH₃, which also produce the desired compounds of formula (Vl). Scheme I

Alternatively, scheme Il illustrates a method for the preparation of compounds of formula I₁ where R² is an optionally substituted phenyl and heteroaryl, -X²- is a bond, and R¹⁷ and R⁴ through R⁷ are defined as above. Referring to scheme Il below, a boronic acid of formula (VIII) can be reacted with an aryl bromide, heterocyclic bromide or heteroaryl bromide of formula (IX) in the presence of a suitable palladium catalyst such as tetrakis triphenylphosphine palladium (O) and a suitable base such as sodium, potassium or cesium carbonate, and the like, in suitable solvent mixtures such as ethanol/water, with or without microwave irradiation, at elevated temperatures around 75 ⁰C to 150 ⁰C, to produce the corresponding substituted phenyl compounds of formula (X). Compounds of formula (X) can be coupled with the alcohol of formula (II) in the presence of a suitable coupling reagent such as diethylazodicarboxylate (DEAD) and triarylphosphines, such as triphenylphosphines, in solvents such as THF or ether at or about room temperature, to produce the corresponding ethers (not depicted). The ether compounds can be treated with a suitable acid such as trifluoroacetic acid or hydrochloric acid in solvents such as methylene chloride, dioxane, ethyl acetate, and the like, to produce the secondary amine compounds of formula (Xl). Compound of formula (Xl) can be treated with aldehydes of formula (V) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene chloride, dichloroethane, DMF or THF, at about room temperature, to produce the corresponding tertiary amines of formula (XII). Scheme Il

.OH

THF

Alternatively, scheme illustrates a method for the preparation of compounds of formula I, where R² is an optionally substituted phenyl or heteroaryl, -X²- is a bond, and R¹⁷, and R⁴ through R⁷ are defined as above. Referring to scheme III below the alcohol of formula (II) can be coupled with the borate-phenol of formula (XIII) in the presence of a suitable coupling reagent such as diethylazodicarboxylate (DEAD) and triarylphosphines, such as triphenylphosphine, in solvents such as THF or ether at or about room temperature, to produce the corresponding ether of formula (XIV). Compounds of formula (XV) can be prepared by treatment of the borate ester of formula (XIV) and an aryl bromide, heterocyclic bromide or heteroaryl bromide of formula (IX) with a suitable palladium catalyst such as tetrakis triphenylphosphine palladium (0) and a suitable base such as sodium, potassium or cesium carbonate, and the like, in suitable solvent mixtures such as ethanol/water, with or without microwave irradiation, at elevated temperatures around 75 ⁰C to 150 ⁰C, to produce the corresponding substituted phenyl compounds of formula (XV). Compounds of formula (XV) can be treated with a suitable acid such as trifluoroacetic acid or hydrochloric acid and the like in solvents such as methylene chloride, dioxane, ethyl acetate, and the like, to produce the secondary amine compounds of formula (XVI). Compounds of formula (XVI) can be treated with aldehydes of formula (V) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene chloride, dichloroethane, DMF or THF, at about room temperature, to produce the corresponding tertiary amines of formula (XVII). Scheme III

Alternatively, scheme IV illustrates a method for the preparation of compounds of formula I, where R² is an optionally substituted phenyl or heteroaryl, -X²- is a bond, and R¹⁷, and R⁴ through R⁷ are defined as above. Referring to scheme IV below, the [3.1.0] amino alcohol (I) can be treated with aldehydes of formula (V) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene chloride or THF, at about room temperature, to produce the corresponding tertiary amines of formula (XVIII). The alcohol of compound (XVIII) can be then converted to a good leaving group X such as mesylate, tosylate or halogen such as chloride using well-defined literature procedures to give compounds of formula (XIX). Compound (XIX) was then treated with R²-OH (III) in the presence of a suitable base, such as cesium carbonate, potassium t-butoxide, in a suitable solvent such as acetonitrile with or without microwave irradiation at elevated temperature around 100 ⁰C to 180 ⁰C to yield compound of formula (Vl). Scheme IV

(XVIIl) (XlX)

X= OMs, OTs , Cl

HO — R² ^

(Vl)

Alternatively, scheme V illustrates a method for the preparation of compounds of formula I, where R² is an optionally substituted heteroaryl including but not limited to 2-pyridyl, 2-pyrimidine, or 2-pyrazine, -X²- is a bond, and R¹⁷, and R⁴ through R⁷ are defined as above.

Referring to scheme V below, alcohol (XVIII) can be treated with halo-heteroaryl (formula XX) in the presence of suitable base such as potassium t-butoxide or sodium hydride, in solvents such as THF, DMF or DMSO, at elevated temperature around 70 ⁰C to 180 ⁰C with or without microwave heating to yield a compound of formula (XXI). Scheme V

(XXI)

Aldehydes of formula (V) are either commercially available or can be prepared, but not limited to, by a general procedure illustrated by scheme Vl, wherein R¹⁷, and R⁴ through R⁷ are defined as above. Referring to scheme Vl below, substituted 2-halo-nitrobenzene

(XXII) can be treated with primary amine of formula XXIII in the presence of a suitable base such as potassium carbonate and in a suitable solvent such as dichloromethane at a reaction temperature ranging from room temperature to 100 ⁰C to give aniline of formula (XXIV). Reduction of the nitro group using well-precedented conditions such as Pd/C under hydrogen or Fe/EtOH/CaCI₂ can yield dianiline of formula (XXV). The imidazole ring can then be formed by treating dianiline (XXV) with acetimidate of formula (XXVI) in the presence of acetic acid, in a suitable solvent such as MeOH. The acetal of compound (XXVII) can be removed with acids such as HCI to give the desired aldehyde of formula (V). Alternatively, dianiline (XXV) can be condensed with glycolic acid under strong acidic conditions, such as aqueous hydrochloric acid, at elevated temperature such as reflux. The resultant alcohol of formula (XXVb) can then be oxidized using a suitable oxidation reagent, such as MnO₂ in a suitable solvent such as methylene chloride, to yield the desired aldehyde of formula (V). In addition, dianiline (XXV) can cyclize with triethylorthoacetate in a suitable solvent such as ethanol at elevated temperature with or without microwave heating to produce imidazole of formula (XXVa), which can be subsequently oxidized to the desired aldehyde of formula (V) using selenium dioxide. Other known literature procedures on synthesis of methylbenzimidazole aldehydes or small variations of the synthesis described above can also be used.

Scheme Vl

(V)

Alternatively, a compound of formula I can also be synthesized as illustrated in scheme VII. A compound of formula (XXX) can be generated by treating a compound of formula (XXVIII) with a reagent of formula (XXIX), wherein M is defined as a boronic acid, boronic ester, trialkylstanane, magnesium halogen, or zinc, with a palladium catalyst such as but not limited to palladium(O) tetrakis(triphenylphosphine), palladium(ll) acetate, tris(dibenzylideneacetone) dipalladium(O), dichloro[1 ,1'-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct, in the presence of a phosphine ligand such as but not limited to triphenyiphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, 1,1'-bis(diphenyl- phsophino)ferrocene, 1 ,2-bis(diphenyl-phsophino)ethane, 1 ,3-bis(diphenylphsphino)-propane, 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl (BINAP), in the presence or absence of a base such as but not limited to potassium or sodium acetate, sodium or potassium or cesium carbonate, potassium phosphate, cesium fluoride and sodium tert-butoxide. This reaction is typically carried out in an inert solvent such as 1 ,4-dioxane, ethyl ether, tetrahydrofuran (THF), benzene, toluene, DMF, DMSO in the presence or absence of 1%-10% water at a temperature from 0 ⁰C to 200 ⁰C.

Scheme VII

CX_γ.R² X₂ r^αχ ₂ ^'R2

(XXXII)

Referring to scheme VII, a compound of formula I is prepared by treating a compound of formula (XXVIII) with alcohol (III) wherein R⁴, R⁵, R⁶ or R⁷ is chlorine, bromine, or iodine. The reaction is usually carried out in the presence of a copper salt such as, but not limited to, copper(l) chloride (CuCI), copper(ll) triflate and copper(l) iodide (CuI), in the presence or absence of a ligand such as, but not limited to, 2,2,6,6-tetramethylheptane-3,5-dione (TMHD), 1 ,10-phenanthroline, 8-hydroxyquinoline, 2-aminopyridine and pentane-2,4-dione (acac), and in the presence or absence of a base such as cesium carbonate, potassium phosphate, potassium acetate, sodium acetate, cesium acetate, sodium carbonate, lithium carbonate, potassium carbonate, preferably cesium carbonate, using the reacting alcohol as solvent or in an inert solvent such as, but not limited to, benzene, toluene, xylene, N,N-dimethylformamicie (DMF), dimethylsulfoxide (DMSO) and N-methylpyrrolidinone (NMP) at a temperature from about O⁰C to about 200⁰C. Referring to scheme VII, a compound of formula (XXXIII) is prepared by treating a compound of formula (XXVIII), wherein R⁴, R⁵, R⁶ or R⁷is chlorine, bromine, or iodine, with amine (XXXI). The reaction is carried out in the presence or absence of a palladium catalyst such as palladium(ll) acetate, tris(dibenzylidene acetone)dipalladium(O), dichloro-[1 ,1'-bis(diphenylphosphino)ferrocene] palladium (II) dichloro methane adduct, in the presence or absence of a phosphine ligand such as BINAP, 1,3-bis (diphenylphsphino)-propane, or 1,1'-bis(diphenyiphsophino)ferrocene, in the presence of a strong base such as sodium tert-butoxide in a suitable solvent such as toluene at a temperature from 6O⁰C to 11O⁰C.

Alternatively, scheme VIII illustrates a method for the preparation of compounds of formula I, where X² is a methylene, and R¹⁷, and R⁴ through R⁷ are defined as above. Referring to scheme VIII below, alcohol (XVIII) can be treated with halo-benzyl (formula XXXIV) in the presence of suitable base such as potassium t-butoxide or sodium hydride, in solvents such as THF, DMF or DMSO, at elevated temperature around 50 ⁰C to 180 ⁰C with or without microwave heating to yield compound of formula (XXXV).

Scheme VIII

(^xvι") (XXXV)

Scheme IX illustrates a method for the preparation of compounds of formula I, where R¹⁷ and R⁴ through R⁷ are defined as above, and R is hydrogen or any one of the substituents, defined above, that may optionally substitute R². Oxidation of Boc-protected [3.1.0] amino alcohol (II) via common oxidizing methods well known in the art, such as Swern oxidation and Dess-Martin oxidation, yields aldehyde of formula (XXXVI). Wittig olefination using phosphonium salt of formula (XXXVII) in the presence of a suitable base, such as BuLi, NaHMDS, in a solvent such as THF at a reaction temperature from -78⁰C to room temperature, provides olefin of formula (XXXVIII) as a mixture of ZJE isomers. Hydrogenation of the olefin under hydrogen in the presence of a suitable catalyst, such as Pd/C, Pd(OH)₂ and PtO₂, followed by removal of the Boc protecting group under acidic conditions, such as trifluoroacetic acid or HCI, give amine of formula (XXXIX). Amine (XXXIX) then can be treated with aldehydes of formula (V) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene chloride or THF to yield the product of formula (XL).

Scheme IX

H₂

XXXIX XL

Alternatively, compounds of formula I can be prepared via the synthetic route illustrated in scheme X. Aldehyde (XXXVI) can be treated with bromomethyl triphenylphosphonium bromide in the presence of suitable base such as BuLi or NaHMDS, in a suitable solvent such as THF, at reaction temperature from -78⁰C to room temperature to yield vinyl bromide of formula (XLI) as a mixture of Z/E isomers. A compound of formual (XXXVIII) then can be prepared via Suzuki coupling of vinylbromide (XLI) and boronic acids with a catalyst such as palladium (O) tetrakis(triphenylphosphine), palladium (II) acetate, allyl palladium chloride dimer, tris(dibenzylideneacetone)dipalladium (0), tris(dibenzylideneacetone)dipailadium (0) chloroform adduct, palladium (II) chloride or dichloro[1 ,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct, in the presence or absence of a base such as potassium phosphate, potassium acetate, sodium acetate, cesium acetate, sodium carbonate, lithium carbonate, potassium carbonate, cesium fluoride or cesium carbonate, preferably sodium carbonate. This reaction is typically carried out in a reaction inert solvent such as dimethyl ethylene glycol ether (DME), 1 ,4-dioxane, acetonitrile, methyl sulfoxide, tetrahydrofuran, ethanol, methanol, 2-propanol, or toluene, in the presence or absence of from about 1 % - about 10% water, preferably about 5% water, with or without microwave assisted heating at a temperature from about O⁰C to about 200°C, preferably from about 60°C to about 100°C. Hydrogenation of (XXXVIII) under hydrogen in the presence of a suitable catalyst, such as Pd/C, Pd(OH)₂ and PtO₂, followed by removal of the Boc protecting group under acidic conditions, such as trifluoroacetic acid or HCl, give amine of formula (XXXIX). Amine (XXXIX) then can be treated with aldehydes of formula (V) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene chloride or THF to yield the product of formula (XL).

Scheme X

XXXVI XLI III

XXXIX

Scheme Xl illustrates a method for the preparation of compounds of formula VL, wherein R², R⁴ through R⁷, R¹⁷ and R¹⁸, are defined as above. Referring to scheme Xl, a compound of formula (I) [SynLett, 1996, 1097] can be treated with aldehydes of formula (V) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene chloride or THF, at about room temperature, to produce the corresponding tertiary amines of formula (XVIII). Other suitable conditions for this transformation include treatment of the amine of formula (I) with aldehydes of formula (V) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH₄, to also produce the desired compounds of formula (XVIII). Compounds of formula (XVIII) can undergo a Swern oxidation by treatment with oxalyl chloride and dimethyl sulfoxide (DMSO) in solvents such as methylene chloride or THF at temperatures ranging from about -78⁰C to room temperature, followed by the addition of a suitable base such as triethylamine and warming the reaction to about room temperature to produce the corresponding aldehydes of formula (XLIII). Compounds of formula (XLIII) can be treated with amines of formula (XLIV) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene chloride, 1 ,2-dichloroethane or THF,^' with or without 4A° molecular sieves, at about room temperature, to produce the corresponding secondary and tertiary amines of formula (VL). Other suitable conditions for this transformation include treatment of the aldehydes of formula (XLIII) with amines of formula (XLIV) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBhU, to also produce the desired compounds of formula (VL).

Scheme Xl

XLIlI _VL

Alternatively, Scheme XII illustrates a method for the preparation of compounds of formula I, where X² is sulfone, R¹⁸ is hydrogen, alkyl, phenyl, substituted phenyl, aryl, or heterocycle; R² is alkyl, phenyl, substituted phenyl, aryl or heterocycle; R⁴ through R⁷ and R¹⁷ are defined as above. Referring to scheme XII, a compound of formula (I) [SynLett, 1996, 1097] can be treated with aldehydes of formula (V) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene chloride or THF, at about room temperature, to produce the corresponding tertiary amines of formula (XVIII). Other suitable conditions for this transformation include treatment of the amine of formula (I) with aldehydes of formula (V) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH₄, to also produce the desired compounds of formula (XVIII). Compounds of formula (XVIII) can undergo a Swern oxidation by treatment with oxalyl chloride and dimethyl sulfoxide (DMSO) in solvents such as methylene chloride or THF at temperatures ranging from about -78 ⁰C to room temperature, followed by the addition of a suitable base such as triethylamine and warming the reaction to about room temperature to produce the corresponding aldehydes of formula (XLIII). Compounds of formula (XLIII) can be treated with amines of formula (XLIVa) in the presence of suitable reducing agents such as NaBH₃CN, in solvents such as methanol or ethanol, with or without the presence of an acid such as acetic acid, at about room temperature, to produce the corresponding secondary amines of formula (XLVI). Other suitable conditions for this transformation include treatment of the aldehydes of formula (XLIII) with amines of formula (XLIVa) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH₄, to also produce the desired compounds of formula (XLVI). Compounds of formula (XLVI) can be treated with sulfonyl chlorides of formula (XLVII) in solvents such as methylene chloride, 1 ,2-dichloroethane or THF, in the presence of a suitable base such as pyridine, triethylamine or Hunig's base, at temperatures ranging from about room temperature to 90 ⁰C to produce the corresponding sulfonamides of formula (XLVIII).

Scheme XII

DMSO

^XLlM

Alternatively, scheme XIII illustrates a method for the preparation of compounds of formula I, where X² is sulfone, R² is alkyl, phenyl, substituted phenyl, aryl, or heterocycle; R⁴ through R⁷ and R¹⁷ are defined as above. Referring to scheme XIII₁ a compound of formula (XLIII), as prepared in a manner described previously, can be treated with dibenzylamine in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene chloride, 1 ,2-dichloroethane or THF, with or without the presence of an acid such as acetic acid, at about room temperature, to produce the corresponding tertiary amines of formula (IL). Other suitable conditions for this transformation include treatment of the aldehydes of formula (XLIII) with dibenzylamine in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH₄, to also produce the desired compounds of formula (IL). Compounds of formula (IL) can be debenzylated with catalysts such as palladium hydroxide in the presence of ammonium formate in a suitable solvent such as ethanol or methanol at temperatures ranging from around room temperature to 90 C to produce the primary amines of formula (L). Compounds of formula (L) can be treated with sulfonyl chlorides of formula (XLVII) in solvents such as methylene chloride, 1 ,2-dichloroethane or THF, in the presence of a suitable base such as pyridine, triethylamine or Hunig's base, at temperatures ranging from about room temperature to 9O⁰C to produce the corresponding sulfonamides of formula (Ll).

Scheme XIII

XLIII IL

^u Li

Alternatively, scheme XIV illustrates a method for the preparation of compounds of formula I, where X² is carbonyl, R² is alkyl, phenyl, substituted phenyl, aryl, or heterocycle; R⁴ through R⁷ and R¹⁷ are defined as above. Referring to scheme XIV, a compound of formula (L), as prepared in a manner described previously, can be treated with carboxylic acids of formula (LIl) in the presence of suitable coupling reagents such as 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), in solvents such as methylene chloride, 1 ,2-dichloroethane, THF or DMF, with or without the presence of 1-hydroxybenzotriazole hydrate (HOBT), at about room temperature, to produce the corresponding amides of formula (LIII). Other suitable coupling conditions for this transformation include activation of the carboxylic acid LII with HATU (O-(7-azabenzotriazole- 1yl)-1 ,1 ,3,3,-tetramethyluronium hexafluorophosphate) or PyBOP (benzotriazole-i-yl)-oxy- tris-pyrrolidino-phosphonium hexafluorophosphate) or HBTU (O-benzotriazole-1yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate) /trialkylamine, or 2-(1 H-benzotriazole-1-yl)-1 , 1 ,3,3- tetramethyluronium tetrafluoroborate (TBTU)/ trialkylamine, or alkyl chloroformate (for example, isobutyl chloroformate) / N-methyl morpholine or trialkylamine ( for example, Et₃N) in an appropriate solvent such as methylene chloride, THF, acetonitrile, DMF. Scheme XIV

Alternatively, scheme XV illustrates a method for the preparation of compounds of formula I₁ where X² is a bond, R² is alkyl, phenyl, substituted phenyl, aryl, or heterocycle; R⁴ through R⁷ and R¹⁷ are defined as above. Referring to Scheme V, a compound of formula (XLVIa), as prepared in a manner described previously, can be treated with formaldehyde and/or formic acid in solvents such as THF and H₂O, at about room temperature, to produce the corresponding secondary amines of formula (LIV).

Scheme XV

Scheme XVI illustrates a method for the preparation of compounds of formula I, where X² is a bond, R¹⁸ is hydrogen, alkyl, phenyl, substituted phenyl, aryl, or heterocycle; R² is hydrogen, alkyl, phenyl, substituted phenyl, aryl or heterocycle; R⁴ through R⁷ and R¹⁷ are defined as above. Referring to scheme Vl, aldehyde (XXXVI) can be treated with amines of formula (XLIV) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene choride, 1 ,2-dichloroethane or THF, at about room temperature, to produce the corresponding secondary or tertiary amines of formula (LV). Other suitable conditions for this transformation include treatment of the aldehydes of formula (XXXVI) with amines of formula (XLIV) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH₄, to also produce the desired compounds of formula (LV). Compounds of formula (LV) can be boc-deprotected with treatment of an acid such as hydrochloric acid or trifluoroacetic acid in a suitable solvent such as 1 ,4-dioxane or methylene chloride, at about room temperature to produce the secondary amines of formula (LVI). Compounds of formula (LVI) can be treated with aldehydes of formula (V) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene choride, 1 ,2- dichloroethane or THF, at about room temperature, to produce the corresponding tertiary amine of formula (VL). Other suitable conditions for this transformation include treatment of the amines of formula (LVI) with aldehydes of formula (V) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH₄, to also produce the desired compounds of formula (VL).

Scheme XVI

LVI

XXXVI LV

Alternatively, scheme XVII illustrates a method for the preparation of compounds of formula I₁ where R² is an optionally substituted phenyl or heteroaryl, X² is a bond, and R¹⁷, and R⁴ through R⁷ are defined as above. Referring to scheme XVII below, alcohol of formula (XVIII) can be converted to a good leaving group such as mesylate, tosylate or halogen such as chloride using well-defined literature procedures to give compounds of formula (LVII). Compound (LVII) is then treated with amine (XLIV) in the presence of a suitable base, such as potassium carbonate or cesium carbonate in a suitable solvent such as THF or acetonitrile with or without microwave irradiation at elevated temperature around 100 ⁰C to 250 ⁰C to yield compound of formula (VL). Scheme XVII

LVII

XVIII VL

X= OMs, OTs , Cl

Scheme XVIII illustrates a method for the preparation of compounds of formula I₁ where X² is sulfonyl, R¹⁸ is alkyl, phenyl, substituted phenyl, aryl, or heterocycle; R² is alkyl, phenyl, substituted phenyl, aryl, or heterocycle; R⁴ through R⁷ and R¹⁷ are defined as above. Referring to scheme Vll.aldehyde (XXXVI) can be treated with amines of formula (XLIVa) in the presence of suitable reducing agents such as NaBH₄, in solvents such as methanol or ethanol, at about room temperature, to produce the corresponding secondary amines of formula (LVIII). Other suitable conditions for this transformation include treatment of the aldehydes of formula (XXXVI) with amines of formula (XLIVa) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH₃CN or NaBH(OAc)₃ to also produce the desired compounds of formula (LVIII). Compounds of formula (XIX) can be treated with sulfonyl chlorides of formula (XLVII) in solvents such as methylene chloride, 1 ,2-dichloroethane or THF, in the presence of a suitable base such as pyridine, triethylamine or Hunig's base, at temperatures ranging from about room temperature to 9O⁰C to produce the corresponding sulfonamides of formula (LIX). Compounds of formula (LIX) can be Boc-deprotected with treatment of a suitable acid such as hydrochloric acid or trifluoroacetic acid in a suitable solvent such as 1 ,4-dioxane or methylene chloride, at about room temperature to produce the secondary amines of formula (LX). Compounds of formula (LX) can be treated with aldehydes of formula (V) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene choride, 1 ,2-dichloroethane or THF, at about room temperature, to produce the corresponding tertiary amine of formula (XLVIII). Other suitable conditions for this transformation include treatment of the amines of formula (LX) with aldehydes of formula (V) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH₄, to also produce the desired compounds of formula (XLVIII). Scheme XVIII

LVIII

XXXVI LIX

V

HCI, 1 ,4-dioxane

Alternatively, scheme XIX illustrates a method for the preparation of compounds of formula I₁ where X² is CH₂, R² is alkyl, phenyl, substituted phenyl, aryl, or heterocycle; R⁴ through R⁷ and R¹⁷ are defined as above. Referring to scheme XIX, aldehyde of formula (XXXVI) as described previously, can be treated with N-methylbenzylamine in the presence of a suitable reducing agent such as NaHB(OAc)₃, in solvents such as methylene chloride, 1 ,2- dichloroethane or THF, at about room temperature, to produce the corresponding product of formula (LXI). Other suitable reducing agents include NaBH₄ and NaBH₃CN in solvents such as methanol or ethanol at room temperature. A compound of formula (LXI) can be debenzylated with catalysts such as palladium hydroxide in the presence of ammonium formate in a suitable solvent such as ethanol or methanol at temperatures ranging from around room temperature to 9O⁰C to produce the corresponding product of formula (LXII). A compound of formula (LXII) can be treated with varying aldehydes of formula (LXIII) in the presence of a suitable reducing agent such as NaHB(OAc)₃, in solvents such as methylene chloride, 1 ,2-dichloroethane or THF, at about room temperature, to produce the corresponding products of formula (LXIV). Other suitable reducing agents include NaBH₄ and NaBH₃CN in solvents such as methanol or ethanol at room temperature. Compounds of formula (LXIV) can be boc-deprotected with treatment of an acid such as hydrochloric acid or trifluoroacetic acid in a suitable solvent such as 1 ,4-dioxane or methylene chloride, at about room temperature to produce the intermediate of formula (LXV). Compounds of formula (LXV) can be treated with aldehydes of formula (V) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene choride, 1 ,2-dichloroethane or THF, at about room temperature, to produce the corresponding products of formula (LXVI). Other suitable conditions for this transformation include treatment of the amines of formula (LXV) with aldehydes of formula (V) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH₄, to also produce the desired compounds of formula (LXVI).

Scheme XlX

H

Scheme XX illustrates the synthesis of compound of formula I, wherein R²⁰¹, R¹⁰¹, R⁴ through R⁷ and R¹⁷ are defined as above. Referring to scheme XX, commercially available amine LXVII can be treated with aldehydes of formula (V) in the presence of suitable reducing agents such as NaHB(OAc)₃, in solvents such as methylene chloride, dichloroethane or THF, at about room temperature, to produce the corresponding tertiary amines of formula (LXVIII). Boc protecting group can be removed under acidic conditions, such as hydrochloric acid and trifluoroacetic acid. The resultant amine (LXIX) can then be treated with aldehyde of formula (LXX) in the presence of a suitable catalyst, such as Pd/C, under hydrogen (25-50 PSI) in a solvent such as ethanol with a suitable base, such as triethylamine, at about room temperature to produce the corresponding secondary amine of formula (LXXI). Treatment of amine LXXI with aldehyde of formula LXXII in the presence of a suitable reducing agent such as NaHB(OAc)₃, in solvents such as methylene chloride, 1 ,2-dichloroethane or THF, with or without base such as triethylamine at about room temperature, to produce the desired compounds of formula (LXXlII). Scheme XX

LXXI LXXIII

N. Working Examples

The following illustrate the synthesis of various compounds of the present invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art.

METHOD A (SCHEME \)

PREPARATION 1 6-Hvdroxymethyl-3-aza-bicvclor3.1.0lhexane-3-carboxylic acid tert-butyl ester

To a solution of (3-aza-bicyclot3.1.0]hex-6-yl)-methanol-HCI (11.8 gm, 78.7 mmol) in

350 mL of anhydrous CH₂CI₂ at room temperature was added Et₃N (32.9 mL, 236 mmol), followed by (BOC)₂O (18.9 gm, 86.6 mmol) in portions. The reaction was stirred at room temperature for 18 hours. The mixture was washed with saturated NaHCO₃, water, brine and dried over anhydrous MgSO₄. The mixture was filtered and concentrated under reduced pressure to yield the crude material, which was purified via flash chromatography with 10 %

IVIeOHZCH₂CI₂. The product containing fractions were collected and concentrated to yield

6-hydroxymethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (15.6 g). 400

MHz ¹H NMR (CDCI₃) δ 3.4-3.6 (m, 4H), 3.2-3.7 (m, 2H), 1.72 (brs, 1 H), 1.4-1.4 (m, 10 H), 0.9-0.9 (m, 1H); MS (M+1) 213.2.

PREPARATION 2 ^β-fS-Chloro-pyridin^-yloxymethvD-S-aza-bicvclofS.I.OIhexane

In a flame-dried flask under N₂, was combined 807 mg (6.24 mmol, 1.33 eq) of 5- chloro 2-pyridyl phenol and 1.64 g (6.23 mmol, 1.33 eq) of triphenylphosphine in 20 mL of anhydrous THF at room temperature. To this solution was added 1.86 g (6.233 mmol, 1.33 eq) of DBAD, followed by 1.0 g (4.69 mmol, 1.0 eq) of 6-hydroxymethyl-3-aza- bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester in 5 ml_ of anhydrous THF. The yellow solution was stirred at room temperature overnight. To this solution was added 6.3 mL (25.2 mmol, 5.4 eq) of 4M HCI in 1 ,4-dioxane and the resulting solution was stirred at room temperature overnight. The solution was concentrated under reduced pressure and the resulting residue was dissolved in 95 mL methylene chloride. The solution was extracted with 63 mL of 15% aqueous citric acid. The aqueous layer was extracted with 95 mL of methylene chloride. The aqueous layer was basified with 32 mL of cone. NH4OH and extracted three times with 65 mL of methylene chloride. The combined organic layers were dried over anhydrous MgSO4, filtered and stripped in vacuo to give yellow oil which crystallized while drying under high vaccum (588 mg). The crude material was purified via flash chromatography, eluting with 5% methanol/ methylene chloride- with 0.1 % triethyl amine to yield 242 mg of desired compound. 400 MHz ¹H NMR (CDCI₃) δ 8.0 (d, 1 H), 7.5 (m, 1H), 6.7 (d, 1 H), 4.1 (d, 2H), 3.1 (d, 2H), 2.9-3.0 (m, 3H), 1.5 (m, 2H), 1.2 (m, 1H); MS (M+1) 225, 227.

EXAMPLE 1 2-(((1R,5S,6R)-6-((5-Chloropyridin-2-yloxy)methyl)-3-aza-bicyclor3.1.01hexan-3- vDmethylH -methyl-1 H-benzordiimidazole

In a flask under N₂, added 173 mg (1.08 mmol) of 1-methyl-1 H-benzo[d]imidazole-2- carbaldehyde to a suspension of 242 mg (1.08 mmol) of 6-(5-chloro-pyridin-2-yloxymethyl)-3- aza-bicyclo[3.1.0]hexane in 5 mL of anhydrous CH₂CI₂ at room temperature. After 15 minutes of stirring, 687 mg (3.24 mmol, 3 eq) of sodium triacetoxyborohydride was added and the suspension was stirred at room temperature for 67 hours. The suspension was diluted with CH₂CI₂ and extracted three times with 1N NaOH. The organic layer was dried over anhydrous MgSO4, filtered and stripped in vacuo to yellow oil. The crude material was purified via flash chromatography, eluting with EtOAc to yield 277 mg of desired compound. 400 MHz ¹H NMR (CDCl₃) δ 8.0 (d, 1 H), 7.7 (d, 1 H), 7.5 (m, 1 H), 7.2- 7.3 (m, 3H), 6.7 (d, 1 H), 4.0 (d, 2H), 4.0 (s, 2H), 3.8 (s, 3H), 3.0 (broad s, 2H), 2.6 (broad s, 2H), 1.5 (s, 2H), 1.2 (s, 1 H); MS (M+1 ) 369, 371.

The HCI salt was prepared - added 3.0 mL of 1 M HCI in diethyl ether to the desired compound dissolved in EtOAc then evaporated in vacuo, triturated with CH₃OH, evaporated in vacuo, triturated with CH₂CI₂, evaporated in vacuo and dried under high vacuum to give 343 mg of a pale yellow glass.

Alternatively, compounds of general formula I can be prepared as highlighted below in method B, utilizing parallel chemistry or high-speed synthesis methods.

METHOD B 19.5 mmol of triphenyl phosphine was dissolved in 9.75 mL of anhydrous THF and vortexed. 75 μl (0.15 mmol) of this solution was added to each 0.1 mmol of varying phenols of general foumula (III) in 2-dram vials. 13.0 mmol of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3- aza-bicycio[3.1.0]hexane-3-carboxylate (Preparation 1 ) was dissolved in 6.5 mL of anhydrous THF and vortexed. 50 μL (0.10 mmol) of this solution was added to each vial. 19.5 mmol of Diethylazodicarboxylate (DEAD) was dissolved in 9.75 mL of anhydrous THF and vortexed. 75 μL (0.15 mmol) of this solution was added to each vial. The vials were sealed and placed on shaker at room temperature for 64 hours. 200 μL of 4 M HCI in 1 ,4-dioxane was then added to each vial and the vials were placed on a shaker at room temperature for 16 hours. The reactions were evaporated under nitrogen. MCX SPE columns were conditioned by eluting twice with 4 mL of CH₃OH. The reaction residues were dissolved with 1.0 mL of CH₃OH, vortexed, and the reaction residues were added to the MCX columns. The reaction vials were rinsed two times with 1.0 mL of CH₃OH, vortexed, and the reaction residues were added to the columns. The columns were eluted three times with 4.0 mL of CH₃OH. 4.0 mL of 2 M NH₃ in CH₃OH was added to each vial with the eluent collected in tared 2-dram vials. The vials were evaporated under nitrogen, tared, and used without further purification in the next reaction. To each of the vials prepared above were added 500 μL of 1 ,2-dichloroethane and 28 μL (0.2 mmol) of triethylamine. 4.3 mmol of an aldehyde of general formula (V) was dissolved in 4.3 mL of 1 ,2-dichloroethane and 0.1 mL (0.1 mmol) was added to the vials. 0.3 mmol of sodium triacetoxyborohydride was added to vials. The vials were sealed and placed on shaker at room temperature for 16 hours. 1.5 mL of 1 N NaOH, followed by 1.0 mL of 1 ,2- dichloroethane was added to each vial and vortexed for 4 minutes. The layers were allowed to separate and 1.5 mL was removed from the lower layer to empty SPE barrels, which were allowed to drip into tared 2-dram vials. 1.0 mL of 1 ,2-dichloroethane was added and the mixture was vortexed for 4 minutes. The layers were allowed to separate and 1 mL was removed from the lower layer to empty SPE barrels, which were allowed to drip into the tared 2-dram vials. 1.0 mL of 1 ,2-dichloroethane was added to the each vial and vortexed for 4 minutes. The layers were allowed to separate and 1 mL was removed from the lower layer to empty SPE barrels, which were allowed to drip into tared 2-dram vials. The combined SPE eluents remaining in the 2 dram tared vials were evaporated in a Savant SpeedVac Plus. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (Vl).

Alternatively, compounds of formula I can be prepared as highlighted below in method C, utilizing parallel chemistry or high-speed synthesis methods.

METHOD C Prepared a 2 M stock solution of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3-aza- bicyclo[3.1.0]hexane-3-carboxyiate (Preparation 1 ) in THF. Prepared 2 M stock solutions of varying phenols of a general formula (III) in THF. Prepared a 0.5 M stock solution of DEAD in toluene. To each reaction vial, added 0.200 ml_ of the varying phenol followed by 0.075 mL of (1S,5R,6R)-tert-butyl 6- (hydroxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate. Added 0.600 mL of the DEAD solution, followed by 0.750 mL of toluene. Added 140 mg of triphenylphosphine-polystyrene resin. Vials were capped and shaken at room temperature for 17 hours. Added 2.5 mL of THF to each reaction vial. The top layer was transferred to empty 6 mL SPE cartridges over collection tubes. Added 3.0 mL of THF to the reaction vials and then aspirated the top layer to the SPE cartridges over collection tubes. Transferred solutions from collection tubes to new reaction vials and evaporated. Added 0.600 mL of CH3OH followed by 0.300 mL of 4 M HCI in 1 ,4-dioxane to each reaction vial. Vials were capped and shaken at room temperature for 24 hours. The solvent was evaporated and the intermediates used without further purification in the next reaction.

Prepared a 0.25 M solution of an aldehyde of general formula (V) in 1 ,2- dichloroethane. Prepared a 0.25 M solution of sodium triacetoxyborohydride in 1 ,2- dichloroethane. Added 0.600 mL of the aldehyde solution to each of the reaction vials from the step above, followed by 0.070 mL of DIPEA. Added 2.0 mL of the sodium triacetoxyborohydride solution, capped vials and shaken at room temperature for 17 hours. Added 1.0 mL of 1 ,2-dichloroethane followed by 2.0 mL of 10% NaOH. Vials were vortexed and/or shaken and removed top layer. Added 2.0 mL of 10% NH4OH, with vials shaken well and/ or vortexed. The bottom layers were aspirated to empty 6 mL SPE cartridges over tared collection tubes. Added 1.0 mL of 1 ,2-dichloroethane to the aqueous layer and aspirated the bottom layer to the SPE cartridge over the collection tubes. Evaporated solutions to dryness. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (Vl) Alternatively, compounds of formula I can be prepared as highlighted below in method D utilizing parallel chemistry or high-speed synthesis methods.

METHOD D

Prepared a 2 M stock solution of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3-aza- bicyclo[3.1.0]hexane-3-carboxylate (Preparation 1) in THF. Prepared 2 M stock solutions of varying phenols of a general formula (III) in THF. Prepared a 2 M stock solution of DBAD (di-t- butylazodicarboxylate) in THF. To each reaction vial, added 0.075 mL of the varying phenol followed by 0.075 mL of 2 M solution of triphenylphosphine in THF. The prepared solutions of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate and DBAD were mixed in 3:4 ratio and 0.1313 mL of this mixture was added to each reaction vial. Vials are capped and shaken at room temperature for 1 hour. Added 0.15 mL of 4 M HCI in 1 ,4- dioxane to each reaction vial. Vials are capped and shaken at room temperature for 16 hours. The solvent was evaporated and to each vial was added 3 mL of dichloromethane and 2 mL of 15% aqueous citric acid solution. The vials were shaken and centrifuged followed by removal of the lower organic layer. 3 mL of dichloromethane was added too each via) and the vials were shaken and centrifuged followed by removal of the lower organic layer. The last operation was repeated. To each vial was added 2 mL of 28% aqueous NH₄OH. After cooling, 2 mL of dichloromethane was added. The vials were shaken and centrifuged followed by collecting of the lower organic layer. The solvent was evaporated and the obtained products were used in the next step without further purification.

Prepared a 0.25 M solution of an aldehyde of general formula (V) in 1 ,2- dichloroethane. Prepared a 0.25 M solution of sodium triacetoxyborohydride in chloroform. To each vial from the step above was added 0.45 mL of 1 ,2-dichoroethane and, following dissolution, 0.45 mL of the aldehyde followed by 1.51 mL of the sodium triacetoxyborohydride solution. The vials were capped and shaken at room temperature for 17 hours. To each vial was added 2 mL of 10% aqueous NaOH. Vials were shaken and centrifuged followed by transfer of the lower organic layer to phase separation cartridges. Organic layer was collected and the solvent was removed by evaporation. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (Vl).

Alternatively, compounds of formula I can be prepared as highlighted below in method E, utilizing parallel chemistry or high-speed synthesis methods.

Method E (Scheme II) To 2-5 mL microwave test tubes was added 0.2 mmol of an aryl bromide of general formula (IX). 20.0 mmol of 2-hydroxyphenyl boronic acid was dissolved in 100 mL of EtOH, vortexed, and 1.0 mL (0.2 mmol) of the solution was added to each tube. 100 mmol of sodium carbonate was dissolved in 40 mL of water and 0.4 mL (1.0 mmol, 5eq) was added to each tube. 12 mg of tetrakis (triphenylphosphine) palladium (0) was added to each tube. The tubes were sealed and degassed under high vacuum followed by charging with nitrogen gas. The tubes were microwaved for 300 seconds at 150⁰C. The reaction mixtures were poured into empty 6 mL SPE barrels positioned over tared 2-dram vials and the tubes were rinsed with 1.0 mL of EtOH twice. The solutions were evaporated and the vials were tared.

30 mmol of triphenylphosphine was dissolved in 15.0 mL of THF, vortexed, and 150 μL (0.3 mmol, 1.5 eq) of the solution was added to each vial from above. 18.0 mmol of (1 S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate was dissolved in 9.0 mL of THF, vortexed, and 100 μL (0.2 mmol, 1.0 eq) was added to each vial. 30.0 mmol of DEAD was dissolved in 15.0 mL of THF, vortexed, and 150 μL (0.3 mmol, 1.5 eq) was added to each vial. The vials were sealed and placed on shaker at room temperature for 16 hours. 0.4 mL of 4 M HCI in 1 ,4-dioxane was added to each vial and sealed and placed on shaker at room temperature for 16 hours. The vials were evaporated and then 1.0 mL of CH₃OH was added to each and vortexed for 10 minutes. MCX SPE columns were conditioned by eluting twice with 4 ml_ of CH₃OH. The reaction solutions were transferred to the conditioned MCX SPE columns. The vials were rinsed twice with 1.0 mL of CH₃OH and transferred to the columns. The columns were eluted three times with CH₃OH. The SPE columns were placed over tared 2-dram vials. The SPE columns were eluted with 5.0 mL of 2 M NH₃ in CH₃OH. The eluents were evaporated under nitrogen at room temperature, tared and used without further purification in the next step.

1.4 mL of triethylamine was diluted with 10 mL of 1 ,2-dichloroethane, vortexed, and 100 μL (0.1 mmol) was added to each of the vials prepared above. 10.0 mmol of an aldehyde of general formula (V) was dissolved in 50 mL of 1 ,2-dichloroethane, vortexed, and 500 μL (0.1 mmol) was added to each vial. 0.3 mmol of sodium triacetoxyborohydride was added to each vial, sealed, and placed on a shaker at room temperature for 16 hours. 1.5 mL of 1 N NaOH was added to each vial, followed by 1.5 mL of 1 ,2-dichloroethane and the mixture was vortexed for 10 minutes. The layers were allowed to separate and the lower layers were removed and added to empty 6 mL SPE barrels, which were allowed to drip into tared 2-dram vials. 1.0 mL of 1 ,2-dichloroethane was added to each vial, vortexed, and the layers were allowed to separate. The lower layers were removed and added to the empty SPE barrels. 1.0 mL of 1 ,2-dichloroethane was added to each vial and the layers were allowed to separate. The lower layers were removed and added to the empty SPE barrel. The combined eiuents remaining in the 2 dram tared vials were evaporated in a Savant SpeedVac Plus. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (XII).

Alternatively, compounds of general formula I can also be prepared as highlighted below in preparation 3, and utilizing parallel chemistry or high-speed synthesis methods as described in method F. PREPARATION 3

(1 R.5S.6R)-tert-butyl 6-((4-(4,4,5.5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)methyl)-3-aza-bicvclor3.1.01hexane-3-carboxylate

Under nitrogen was combined 2.13 g (10.0 mmol) of (1 R,5S,6r)-tert-butyl-6- (hydroxymethyO-S-aza-bicycIofS.I .OJhexane-S-carboxylate with 2.20 g (10.0 mmol) of 3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol, and 3.93 g of triphenyl phosphine (15.0 mmol) in 25 mL of THF. 2.4 mL (15.0 mmol) of DEAD was added and the reaction was stirred under nitrogen for 16 hours. The reaction was stripped in vacuo to an orange oil and partitioned twice between EtOAc and 1 N NaOH. The combined organics were dried and stripped in vacuo to give an orange oil. Purification via flash chromatography, eluting with 20% EtOAc/hexane, gave 1.9 g of the desired compound. 400 MHz ¹H NMR (CDCI₃) δ 7.4 (d, 1 H), 7.3 (m, 2H), 7.0 (m, 1 H), 3.9 (broad d, 2H), 3.6 (d, 2H),3.3 (d, 2H), 1.1 - 1.6 (m, 24 H); MS (P-99) 316.3. METHOD F (SCHEME III)

0.15 mmol of aryl bromides of general formula (IX) were dissolved in EtOH and each was transferred to a 2-5 ml. microwave tube. 1.9 g of (1 R,5S,6R)-tert-butyl 6-((4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)methyl)-3-aza- bicyclo[3.1.0]hexane-3-carboxylate (preparation 3) was dissolved in 45.8 ml. EtOH, vortexed, and 1.0 mL (0.1 mmol) was added to each tube. 2.65 g of sodium carbonate was dissolved in 10 mL of water and 0.2 mL (0.5 mmol, 5 eq) was added to each tube. 12 mg of tetrakis (triphenylphosphine) palladium (0) was added to each tube, sealed, and microwaved for 300 seconds at 150⁰C. Each tube was poured into an empty 6 mL SPE barrel and filtered into a tared 2-dram vial. The tubes were rinsed twice with 1.0 mL of EtOH and added to the SPE barrel. The vials were evaporated and tared.

To the samples in the vials prepared above was added 400 μL of anhydrous THF and placed on a shaker for 10 minutes. 400 μl of 4 M HCI in 1 ,4-dioxane was added to each vial, which were sealed and placed on a shaker at room temperature for 65 hours. The samples were evaporated under nitrogen, followed by the addition of 1.0 mL of 1 ,2 dichloroethane and 1.0 mL of 1 N NaOH. The mixtures were vortexed for 5 minutes and then the layers were allowed to separate. The lower layers were added to a pre-conditioned (washed 3x with 4.5 mL of CH₃OH) MCX SPE column. 1.0 mL of 1 ,2-dichloroethane was added to each vial, the solution was vortexed for 5 minutes, and then the layers were allowed to separate. The lower layers were added to the MCX columns. 1.0 mL of 1 ,2-dichloroethane was added to each vial, the solutions were vortexed for 5 minutes, and then the layers were allowed to separate. The lower layers were added to the MCX columns. The SPE columns were rinsed three times with 4.5 mL of CH₃OH. The columns were placed over tared 2-dram vials and eluted with 4.5 mL of 2 M NH₃ in CH₃OH. The eluents were evaporated under nitrogen at room temperature for 17 hours, tared and used without further purification in the next step.

4.6 mmol of an aldehyde of general formula (V) was dissolved in 23 mL of anhydrous 1 ,2-dichloroethane, vortexed, and 500 μL (0.1 mmol) of the solution was added to each vial prepared above. 63.6 mg (0.3 mmol, 3 eq) of sodium triacetoxyborohydride was added to each vial, which were sealed and placed on shaker at room temperature for 16 hours. 1.0 mL of 1 ,2-dichloroethane followed by 1.0 mL of 1 N NaOH was added to each vial and vortexed for 5 minutes. The layers were allowed to separate and the lower layers were added to an empty SPE barrels placed over tared 2-dram vials. 1.0 mL of 1 ,2-dichloroethane was added to each vial and vortexed for 5 minutes. The layers were allowed to separate and the lower layers were added to the empty 6mL SPE barrels placed over tared 2-dram vials. An additional 1.0 mL of 1 ,2-dichloroethane was added to each vial and vortexed for 5 minutes. The lower layers were added to the empty SPE barrels placed over the tared 2-dram vials. The vials were evaporated and tared. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (XVII).

METHOD G (SCHEME IV)

One example representative of synthetic method G is described below. Other examples using method G are listed in Table 1.

Example 2 (corresponding to Entry 506 in Table 1)

2-r6-(3-Chloro-2-Fluoro-Phenoxymethvπ-3-aza-bicvclor3.1.01hexan-3-yl)methyl)- 1-methyl-1H-benzo[d1imidazole

In a flask under N₂, added 2.15 g (13.4 mmol) of 1-methyl-1 H-benzo[d]imidazole-2- carbaldehyde, 15 mL (107 mmol) of Et₃N and 200 mg MgSO₄ to a solution of 2.0 g (13.4 mmol) of (3-aza-bicyclo[3.1.0]hex-6-yl)-methanol in 50 mL of anhydrous CH₂CI₂ at room temperature. After 30 minutes of stirring, 4.25 g (20.1 mmol, 1.5 eq) of sodium triacetoxyborohydride was added and the suspension was stirred at room temperature for 18 hours. The suspension was diluted with CH₂CI₂ and washed with saturated NaHCO₃ aqueous solution and brine. The organic layer was dried with sodium sulfate, filtered and stripped in vacuo to give 3.55 g light yellow solid of [3-(1-methyl-1H-benzoimidazol-2-ylmethyl)-3-aza- bicyclo[3.1.0]hex-6-yl]-methanol, which was used without further purification. 400 MHz ¹H NMR (CD₃OD) δ 7.7 (d, 1 H), 7.5 (m, 1H), 7.2- 7.3 (m, 2H), 3.9 (s, 2H), 3.8 (s, 3H), 3.3 (d, 2H), 2.9 (d, 2H), 2.5 (broad d, 2H), 1.4 (m, 1 H), 1.3 (s, 2H); MS (M+1 ) 258. [3-(1-methyl-1 H-benzoimidazol-2-ylmethyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol

(1.55 g, 6.02 mmol) was dissolved in 50 mL CH₂CI₂ and stirred under N₂ at room temperature. To this solution was added 1.26 mL of Et₃N (9.04 mmol) and 515 uL (6.63 mmol) of mesyl chloride. The mixture was stirred at room temperature for 3 hours. The suspension was diluted with CH₂CI₂ and washed with saturated NaHCO₃ aqueous solution and brine. The organic layer was dried with sodium sulfate, filtered and stripped in vacuo to give 1.75 g (5.22 mmol) of light brown solid, which was dissolved in 26 mL acetonitrile and to this solution was added 555 uL (5.22 mmol) of phenol and 3.40 g (10.44 mmol) cesium carbonate. The mixture was then heated to 120 ⁰C for 10 min using a microwave reactor and the cooled to room temperature. The suspension was diluted with CH₂CI₂ and washed with saturated NaHCO₃ aqueous solution and brine. The organic layer was dried with sodium sulfate, filtered and stripped in vacuo. The residue was purified with 60% to 100% EtOAc in hexane to give 1.07 g viscous oil, which was then converted to mono-HCI salt (1.15 g). 400 MHz ¹H NMR (CD₃OD) free base: δ 7.6 (d, 1 H), 7.5 (d, 1 H), 7.2 (m, 2H), 7.1 (1 H), 7.0 (m, 2H), 3.9 (s, 2H), 3.8 (s, 3H), 3.0 (d, 2H), 2.5 (broad d, 2H), 1.6 (m, 1 H), 1.5 (s, 2H); MS (M+1 ) 386. METHOD H (SCHEME IV)

One example representative of synthetic method H is described below. Other examples using method H are listed in Table 1.

Example 3 (corresponding to Entry 508 in Table 1) 2-(((1 S,5R,6R)-3-((1 -methyl-1 H-benzo[d]imidazol-2-yl)methyl)-3-aza- bicyclo[3.1.0]hexan-6-yl)methoxy)-5-fluorobenzonitrile

2-(((1S,5R,6R)-6-(chloromethyl)-3-aza-bicyclo[3.1.0]hexan-3-yl)methyl)-1 -methyl-1 H- benzo[d] imidazole: In a flask under N₂, was combined 2.3 gm (8.9 mmol, 1 eq) of ((1 R,5S,6R)-3-((1 -methyl-1 H-benzo[d]imidazol-2-yl)methyl)-3-aza-bicyclo[3.1.0]hexan-6- yl)methanol and 10 ml. (51 mmol, 5.7 eq) of thionyl chloride at room temperature. The solution was stirred at 60°C for 30 minutes, cooled, poured into water, extracted with ethyl acetate, dried over sodium sulfate, filtered, stripped in vacuum to 2.08 gm of desired compound. 400 MHz ¹H NMR (CDCI₃) δ 7.7 (d, 1 H), 7.21-7.31 (m, 3H), 3.88 (s, 2H), 3.78 (s, 3H), 3.82 (s, 3H), 3.36 (d, 2H), 2.93 (d, 2H), 2.52 (d, 2H), 1.55-1.57 (m, 1 H), 1.42 (s, 2H); MS (M+1). 276.0

In a 10 mL CEM microwave vial was combined 30 mg (0.11 mmol, 1 eq) of 2- (((IS.SR.δRVΘ-^hloromethyO-S-aza-bicycloCS.I .Olhexan-S-yOmethyO-i -methyl-1 H- benzo[d]imidazole, 18 mg (0.13 mmol, 1.2 eq) of 5-fluoro-2-hydroxybenzonitrile and 30 mg of potassium carbonate (0.22 mmol, 2 eq) in 1 mL of anhydrous acetonitrile at room temperature. The vial was heated to 170⁰C for 10 minutes under microwave (CEM Explorer). The mixture was purified via flash chromatography, eluting from 0% diethyl ether / hexanes to 100% diethyl ether / hexanes to yield 25 mg of desired compound. 400 MHz ¹H NMR (CDCI₃) δ 7.7 (d, 1 H), 7.3 (d, 1 H), 7.22 - 7.28 (m, 4H), 6.8 (d, 1 H), 3.95 (s, 2H), 3.88 (d, 2H), 3.82 (s, 3H), 3.0 (d, 2H), 2.6 (d, 2H), 1.67 (m, 1H), 1.51 (s, 2H); MS (M+1). 377.1 METHOD KSCHEME V)

One example representative of synthetic method I is described below. Other examples using method I are listed in Table 1.

Example 4(corresponding to Entry 532 in Table 1) i-Methyl^-tθ-tS-trifluoromethyl-pyridin^-yloxymethyO-S-aza-bicycloIS.I.Olhex-S- ylmethyl]-1 H-benzoimidazole

To a stirred solution of (3-aza-bicyclo[3.1.0]hex-6-yl)-methanol (50 mg, 0.175 mmol) in dimethylformamide (5 ml) was added 14 mg of 60% sodium hydride in mineral oil. After 1 h 2-chloro-5-trifluoromethylpyridine (35 mg, 0.193 mmol) was added and the mixture was stirred for 24 h. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with a gradient of 50% to 80% ethylacetate in hexane to give 19 mg of the title compound as a clear colorless oil. 400 MHz ¹H NMR (CD₃OD) free base: 68.4 (s, 1H), 7.86 (dd, 1H), 7.58 (d, 1 H), 7.45 (d, 1H), 7.25 (m, 2H), 6.86 (d, 1 H), 4.17 (d, 2H), 3.89 (s, 2H), 3.92 (s, 3H), 2.92 (d, 2H), 2.51 (d, 2H), 1.63 (m, 1H), 1.50 (s, 2H); MS (M + 1) 403.

METHOD J(SCHEME VIIl) One example representative of synthetic method J is described below. Other examples using method J are listed in Table 1.

Example 5 (corresponding to Entry 533 in Table 1)

2-(((1S,5R,6R)-6-((2,5-bis(trifluoromethyl)benzyloxy)methyl)-3-aza-bicyclo[3.1.0]hexan- 3-yl)methyl)-1 -methyl-1 H-benzo[d]imidazole In a 10 mL CEM microwave vial was combined 50 mg (0.19 mmol, 1.0 eq) of

((1S,5R,6R)-3-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)-3-aza-bicyclo[3.1.0]hexan-6- yl)methanol, 0.19 mL of 1 M in THF of potassium tert-butoxide (0.19 mmol, 1.0 eq), stirred for 20 minutes at room temperature, added 59 mg (0.19 mmol, 1.0 eq) of 2-(bromomethyl)-1 ,4- bis(trifluoromethyl) benzene. The vial was heated to 130⁰C for 10 minutes under microwave (CEM Explorer). The mixture was purified via flash chromatography, eluting from 0% Ethyl Acetate / hexanes to 50% Ethyl Acetate / hexanes to yield 22 mg of desired compound. 400 MHz ¹H NMR (CDCI₃) δ 7.9 (s, 1 H), 7.72 - 7.76 (m, 2H), 7.6 (d, 1 H), 7.30 - 7.37 (m, 3H), 4.67 (s, 2H), 4.15 (s, 2H), 3.88 (s, 3H), 3.4 (d, 2H), 3.1 (m, 2H), 2.93 (m, 2H), 1.67 (m, 1 H), 1.50 (s, 2H); MS (M+1). 484.4 METHOD K (Scheme VIH

One example representative of synthetic method K is described below. Other examples using method K are listed in Table 1.

Example 6 (corresponding to Entry 540 in Table 1)

6-bromo-1 -methyl-2-(((1 S,5R,6R)-6-(phenoxymethvO-3-aza-bicyclor3.1.01hexan-3- vPmethylH H-benzoldiimidazole

PREPARATION 4

4-bromo-2-fluoro-1 -nitrobenzene: To a solution of hydroxy peroxide (46.5 ml, 480 mmol) under 0⁰C, trifluoroacetic anhydride (76.8 ml, 550 mmol) in 160 ml dichloromethane was added drop wisely over one and half hour. After addition, 4-bromo-2-fluorobenzenamine (10 g, 52.6 mmol) in 160 ml dichloromethane was added dropwise and the reaction mixture was gradually warmed up to room temperature and stirred over night. The mixture was extracted by dichloromethane and dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated under reduced pressure to yield 4-bromo-2-fluoro-1 -nitrobenzene (10.59 g). 400 MHz ¹H NMR (CDCI₃) δ 8.0 (t, 1 H), 7.4-7.6 (m, 2H); MS⁺ 219, 221. PREPARATION 5

N-methyl-(5-bromo-2-nitrophenyl)amine: To a solution of bromo-2-fluoro-1- nitrobenzene (10 g, 45.45 mmol) in 20 ml of ethanol under O⁰C, 30 ml methylamine (33 wt% in ethanol) was added dropwise. After addition, reaction mixture was gradually warmed up to room temperature and stirred for 25 minutes. The mixture was concentrated under reduced pressure to yield N-methyl-(5-bromo-2-nitrophenyl)amine (9.13 g). 400 MHz ¹H NMR (CDCI₃) δ 8.0 (d, 1 H), 7.0 (d, 1 H), 6.7 (dd, 1 H); MS⁺ 230, 232. PREPARATION 6

5-Bromo-N1-methylbenzene-1 ,2-diamine: To a solution of 120 ml ethanol and 30 ml water, 5-bromo-N-methyI-2-nitrobenzenamine (10.5 g, 45.4 mmol), iron powder (11.4 g, 204.5 mmol) and calcium chloride (4.54 g, 40.9 mmol) was added sequentially. The mixture was heated to reflux for 2 hours. After cooling down to room temperature, the mixture was filtered over celite and concentrated under reduced pressure to yield 5-bromo-N1-methylbenzene- 1 ,2-diamine (9.13 g). MS (M+1) 201 , 203.

PREPARATION 7

(6-Bromo-1-methyl-1H-benzo[d]imidazol-2-yl)methanol: To a solution of 42 ml 6N HCI and 63 ml water, 5-bromo-N1-methylbenzene-1 ,2-diamine (9.1 g, 45.4 mmol) and glycolic acid (17.2 g, 227.2 mmol) was added sequentially. The mixture was heated to reflux for 2 hours. After cooling down to room temperature, the mixture was neutralized to PH 9 by ammonium hydroxide. Precipitate formed, filtered, rinsed by water and dried by vacuum to yield (6-bromo-1-methyl-1 H-benzo[d]imidazol-2-yl)methanol (8.5 g). 400 MHz ¹H NMR (CDCI₃) δ 7.5 (d, 1 H), 7.46 (m, 1 H), 7.35 (dd, 1 H), 4.92 (s, 2H), 4.74(b, 1H), 3.8 (s, 3H); MS (M+1 ) 241 , 243.

PREPARATION 8

6-Bromo-1-methyl-1H-benzo[d]imidazole-2-carbaldehyde: To a solution of 8 ml dichloromethane, (6-bromo-1-methyl-1 H-benzo[d]imidazol-2-yl)methanol (1.0 g, 4.1 mmol) and manganese(iV) oxide (activated, 1.8 g, 20.7 mmol) was added sequentially. The mixture was irradiated by microwave under 90⁰C for 30 minutes. After cooling down to room temperature, the mixture was filtered over a short pad of silica gel and concentrated under reduced pressure to yield 6-bromo-1-methyI-1 H-benzo[d]imidazole-2-carbaldehyde (0.64 g). 400 MHz ¹H NMR (CDCI₃) δ 10.5 (s, 1 H), 7.8 (d, 1 H), 7.6 (s, 1 H), 7.5 (d, 1 H), 4.1 (s, 3H); MS (M+1) 239, 241. PREPARATION 9 e-Bromo-i-methyl^^iS.SR.eRJ-e^phenoxymethyO-S-aza-bicyclop.i .Olhexan-S- yl)methyl)-1 H-benzo[d]imidazole: To a solution of 6-bromo-1-methyl-1 H-benzo[d]imidazole-2- carbaldehyde (636 mg, 2.66 mmol) in 13 ml dichloroethane, (1S,5R,6R)-6-(phenoxymethyl)-3- aza-bicyclo[3.1.0]hexan-3-yl (504 mg, 2.66 mmol) was added and the mixture was stirred under Nitrogen for one hour at room temperature. Then, 13 ml of dichloroethane and sodium triacetoxyborohydride (1.96 g, 9.3 mmol) was added into the mixture sequentially. The mixture was stirred at room temperature over night. The mixture was first treated by 1N HCI (8 ml), followed by water and finally by ammonium hydroxide to adjust pH as 9. The mixture was extracted by dichloromethane, washed by brine and dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated under reduced pressure to yield 6-bromo-1-methyl-2- (((IS.δR.δRJ-e-fphenoxymethyO-S-aza-bicycloIS.I .OJhexan-S-yOmethylJ-I H- benzo[d]imidazole (1.03 g). 400 MHz ¹H NMR (CDCI₃) δ 7.55 (d, 1 H), 7.46 (d, 1 H), 7.32 (d, 1 H), 7.24 (m, 2H), 6.9(t, 1 H), 6.84 (d, 2H), 3.58 (s, 2H), 3.55 (m, 5H), 3.0 (d, 2H), 2.52 (d, 2H), 1.53 (m, 1 H), 1.49 (s, 2H); MS (M+1 ) 412, 414.

METHOD UScheme VII)

Example 7 (corresponding to Entry 534 in Table 1) i.e-dimethyl^-^IS^R.eRJ-e^phenoxymethylJ-S-aza-bicyclofS.I.Olhexan-S- yl)methyl)-1 H-benzo[d]imidazole

A mixture of 6-bromo-1-methyl-2-(((1S,5R,6R)-6-(phenoxymethyl)-3-aza- bicyclo[3.1.0]hexan-3-yl)methyl)-1H-benzo[d]imidazole (50 mg), dimethyl zinc (0.12 ml), Pd(dppf)CI₂ (26 mg) and 1 ml of dioxane was heated to 120⁰C for 10 minutes under microwave (CEM). The mixture filtered over diatomaceous earth and the solvent was removed in vacuo. The residue purified using silica gel chromatography (0% to 3% MeOH/CH₂CI₂) followed by reversed phase HPLC to yield 15 mg of product. MS (M+1) 348.1.

METHOD M (Scheme VIh

Example 8 (corresponding to Entry 541 in Table 1) S-methyl^^^iS.SR.βRJ-δ^phenoxymethyO-S-aza-bicyclop.i.OJhexan-S- yl)methyl)-3H-benzo[d]imidazole-5-carbonitrile

A mixture of 6-bromo-1-methyl-2-(((1S,5R,6R)-6-(phenoxymethyl)-3-aza- bicyclo[3.1.0]hexan-3-yl)methyl)-1H-benzo[d]imidazoIe (50 mg), zinc cyanide (21.3 mg), Pd(dppf)CI₂ (17 mg) and 1 ml of dimethyl formamide was heated to 12O⁰C for 10 minutes under microwave (CEM). The mixture filtered over diatomaceous earth and the solvent was removed in vacuo. The residue purified using silica gel chromatography (0% to 2% MeOH/CH₂CI₂) to yield 9 mg of product. MS (M+1) 359.1.

METHOD N (Scheme VII)

Example 9 (corresponding to Entry 538 in Table 1) 6-methoxy-1 -methyl-2-(((1 S,5R,6R)-6-(phenoxymethyl)-3-aza- bicyclo[3.1.0]hexan-3-yl)methyl)-1 H-benzo[d]imidazole

A mixture of 6-bromo-1-methyl-2-(((1S,5R,6R)-6-(phenoxymethyl)-3-aza- bicyclo[3.1.0]hexan-3-yl)methyl)-1H-benzo[d]imidazole (50 mg), copper(l) iodide (2.3 mg),

CsCO₃ (43 mg), 1 ,10-phenanthroline (4.3) and 1 ml of methonal was heated to 125°C for 1.5 hours, followed by 140⁰C for 30 minutes under microwave (CEM). The mixture filtered over diatomaceous earth and the solvent was removed in vacuo. The residue purified using silica gel chromatography (0% to 5% MeOH/CH₂CI₂) followed by reversed phase HPLC to yield 6 mg of product. MS (M+1) 364.1.

METHOD O (Scheme VII)

Example 10 (corresponding to Entry 536 in Table 1) 1-methyl-2-(((1S,5R,6R)-6-(phenoxymethyl)-3-aza-bicyclo[3.1.0]hexan-3" yl)methyl)-7-phenyl-1H-benzo[d]imidazole

A mixture of 7-bromo-1-methyl-2-(((1S,5R,6R)-6-(phenoxymethyl)-3-aza- bicyclo[3.1.0]hexan-3-yl)methyl)-1 H-benzo[d]imidazole (50 mg), phenylboronic acid (22 mg), Tetrakis(triphenyl phosphine) palladium (0) (7 mg), 0.1 ml saturated NaHCO₃ solution, 0.5 ml of toluene and 0.5 ml of ethanol was heated to 12O⁰C for 10 minutes under microwave (CEM). The mixture filtered over diatomaceous earth and the solvent was removed in vacuo. The residue purified using silica gel chromatography (0% to 3% MeOH/CH₂CI₂) followed by reversed phase HPLC to yield 14 mg of product. MS (M+1 ) 410.1.

METHOD P (Scheme VII) Example 11 (corresponding to Entry 542 in Table 1)

S-methyl^-flliSjSRjβRJ-e-lphenoxymethyO-S-aza-bicycloIS.I.OJhexan-S- yl)methyl)-3H-benzo[d] imidazol-5-amine

PREPARATION 10

3-methyl-2-(((1S,5R,6R)-6-(phenoxymethyl)-3-aza-bicyclo[3.1.0]hexan-3-yl)methyI)- N-(diphenyl methylene)-3H-benzo[d]imidazol-5-amine: A mixture of 6-bromo~1-methyl-2- (((1S,5R,6R)-6-(phenoxymethyl)-3-aza-bicyclo[3.1.0]hexan-3-yl)methyl)-1 H- benzo[d]imidazole (200 mg), diphenylmethanimine (105.5 mg), Pd₂(dba)₃ (111 mg), NaOtBu (65 mg), BINAP (226 mg) and 3 ml of toluene was heated to 11O⁰C for 10 minutes under microwave (CEM). The mixture was diluted by saturated NaHCO₃ solution and extracted by dichloromethane. The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The residue purified using silica gel chromatography (0% to 100% EtOAc/Hexane) to yield product. MS (M+1 ) 513.3.

PREPARATION 11

3-methyl-2-(((1S,5R,6R)-6-(phenoxymethy[)-3-aza-bicyclo[3.1.0]hexan-3-yl)methyl)- 3H-benzo[d] imidazol-5-amine: A mixture of 3-methyl-2-(((1S,5R,6R)-6-(prιenoxymethyl)-3- aza-bicyclo[3.1.0]hexan-3-yl)methyl)-N-(diphenylmethylene)-3H-benzo[d]imidazol-5-amine (from preparation 10), 10 ml of 1 N HCI and 10 ml of THF was refluxed for 1.5 hours. The mixture was extracted by dichloromethane and the aqueous phase was basified by 1 N NaOH to pH 14. Then, the aqueous phase was extracted by dichloromethane and the organic phase was concentrated and purified by ion exchange resin to 70 mg of product. MS (M+1) 349.1. METHOD QfScheme VII)

Example 12 (corresponding to Entry 544 in Table 1)

6-fluoro-1-methyl-2-(((1S,5R,6R)-6-(phenoxymethyl)-3-aza-bicyclo[3.1.0]hexan-3- yl)methyl)-1H-benzo[d]imidazole: A solution of 3-methyl-2-(((1S,5R,6R)-6-(phenoxymethy!)-3-aza-bicyclo[3.1.0] hexan-

3-yl)methyl)-3H-benzo[d]imidazol-5-amine (69 mg), 0.45 ml concentrated HCI and 3 ml of water was heated at 100⁰C for 10 minutes. Then the mixture was cooled to 0°C and a solution of NaNO₂ (16.4 mg) in 0.15 ml water was added into dropwise and stirred for 10 minutes. Then, HPF₆ was added drop wisely and the mixture was stirred for 30 minutes under 0°C. Precipitate was formed, filtered, and dried over vacuum. Then, the precipitate was heated in oil bath at 180°C for 20 minutes. The mixture was purified by reversed phase HPLC to yield 0.3 mg of product. MS (M+1 ) 352.1.

Preparations of substituted benzimidazole aldehydes:

PREPARATION 12 5,6-Dif luoro-1 -methyI-1 /-/-benzimidazole-2-carbaldehyde Hydrochloride Hydrate:

Sodium methylate (54 g, 1 mol) was added to a solution of diethoxyacetonitrile (139 ml_, 1 mol) in methanol (500 ml_). The reaction mixture was kept at room temperature for 24 g, then the reaction mixture was evaporated, treated with water (500 mL), and the product was extracted with ether (2x300 mL). The combined organic extracts were dried over anhydrous K₂CO₃ and evaporated to give 114.62 g (60% purity) of methyl 2,2- diethoxyethanimidoate. The obtained crude product was used for the next stage without additional purification.

10% Pd/C (2 g) was added to a solution of 4,5-difluoro-2-nitroaniline (40 g, 0.229 mol) in methanol (500 mL). The reaction mixture was hydrogenated at room temperature for 3 h and treated with the mixture of compound methyl 2,2-diethoxyethanimidoate (71 g, 0.23 mol) with acetic acid (60 g). After 16 h at room temperature, the reaction mixture was evaporated, washed with the 10% K₂CO₃ solution (1 L), and the product was extracted with ether (300 mL). The organic extract was evaporated, and the residue was purified on silica gel (ethyl acetate/hexane 1 :5) to give 48 g of 2-(diethoxymethyl)-5,6-difluoro-1H-benzimidazole. Cs₂CO₃ (67.21 g, 0.206 mol) and methyl iodide (27 g, 0.19 mol) were added to a solution of 2-(DiethoxymethyI)-5,6-difluoro-1H-benzimidazoIe (48 g, 0.1875 mol) in DMF (250 mL). The reaction mixture was stirred at room temperature for 16 h and evaporated. Ethyl acetate (300 mL) was added to the residue, and the reaction mixture was washed with water (1 L). The organic layer was separated, dried, and evaporated. The residue was purified on silica gel (ethyl acetate/hexane 1 :5) to give 40.8 g of 2-(diethoxymethyl)-5,6-difluoro-1-methyl- 1 /-/-benzimidazole. 2-(Diethoxymethyl)-5,6-difluoro-1-methyl-1W-benzimidazole was treated with 5 M HCI (300 ml_), and the reaction mixture was kept at 60 ⁰C for 6 h. Then the reaction mixture was evaporated to a volume of 100 ml_ and treated with acetone (200 mL). Then the mixture was kept in a refrigerator, and white crystals precipitated. The crystals were separated by filtration and dried under a reduced pressure to give 5,6-Difluoro-1-methyl-1H-benzimidazole-2- carbaldehyde Hydrochloride Hydrate in 72% (26.77 g, 21.4 g of free base) yield. Satisfactory C, H, Λ/-analysis was obtained.

PREPARATION 13

1 -(Fluoromethyl)-I H-benzimidazole-2-carbaldehyde Hydrochloride Hydrate: Formaldehyde (37% solution in water, 315 mL, 4.208 mol) was added to a stirred solution of 2-methylbenzimidazole (97.0 g, 734 mmol) in MeOH (500 mL). The mixture was refluxed overnight. The formed precipitate was separated by filtration and dried in vacuo to afford (2-Methyl-1H-benzimidazoM-yl)methanol (88.0 g, 74%).

DAST (29.6 mL, 224 mmol) was added dropwise to a stirred solution of (2-Methyl-1 H- benzimidazol-1-yl)methanol (33.0 g, 203 mmol) in CH₂CI₂ (700 mL) at -80 ⁰C. The mixture was stirred overnight at room temperature. The reaction mixture was poured into ice-cold water, and pH was adjusted to 9 with a 10% NaOH solution. The organic phase was separated, dried with Na₂SO₄, and concentrated to afford 1-(Fluoromethyl)-2-methyl-1/-/- benzimidazole (23.3 g, 70%). Selenium dioxide (94.6 g, 853 mmol) was added to a stirred solution of 1-

(FIuoromethyl)-2-methyl-1H-benzimidazole (70.0 g, 426 mmol) in dioxane (1.5 L), and the mixture was refluxed overnight. The solids were filtered off, and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, CHCI₃/MeOH 15:1 ) and dried. The resulting product was dissolved in concentrated HCI (100 mL), and the solution was concentrated in vacuo to afford 1-(Fluoromethyl)-1/-/-benzimidazole-2-carbaldehyde Hydrochloride Hydrate (32.1 g, 32%).

PREPARATION 14

5,6-Dihvdro-4A/-imidazor4,5,1-//lquinoline-2-carbaldehyde Hydrochloride Hydrate: A mixture of 8-aminoquinoline (90.O g, 624 mmol) and PtO₂ (2.84 g, 12.5 mmol) in glacial acetic acid (1.1 L) was stirred under a hydrogen pressure of 1.3 bars for 24 h at room temperature. The solvent was removed in vacuo at 40 ⁰C, and then CH₂CI₂ (1.5 L) and a saturated aqueous solution of NaHCO₃ (600 mL) were added to the resulting crude red oil. The obtained solution was extracted with CH₂Cl₂ (3 * 300 mL). The combined organic layers were washed with H₂O (3 * 300 mL) and dried over Na₂SO₄. The solvent was evaporated under reduced pressure at 40 ⁰C. The residue was purified by column chromatography (silica gel, CHCI₃/MeOH 100:1 ) to afford 1 ,2,3,4-tetrahydroquinolin-8-amine (55.27 g, 60%). 1 ,2,3,4-Tetrahydroquinolin-8-amine (55.27 g, 373 mmol) was dissolved in MeOH (600 mL). AcOH (67.2 g, 1.119 mol) was added, and the mixture was stirred for 10 min. A solution of methyl 2,2-diethoxyethanimidoate (60.12 g, 373 mmol) in MeOH (10O mL) was added dropwise for 1 h. The reaction mixture was stirred for 24 h and concentrated in vacuo. The residue was purified by column chromatography (silica gel, CHCI₃/MeOH 100:1) to afford 2-(diethoxymethyl)-5,6-dihydro-4H-imidazo[4,5,1-//]quinoline (43.92 g, 45%).

A solution of 2-(diethoxymethyl)-5,6-dihydro-4/-/-imidazo[4,5,1-/)]quinoline (43.92 g, 169 mmol) in 4 M aqueous HCI (169 mL) was stirred overnight at 60 ⁰C. The reaction mixture was evaporated to dryness in vacuo. The residual oil crystallized at -10 ⁰C after 4 days and was triturated with acetone/ether mixture (1 :1 ). The formed precipitate was separated by filtration and dried to afford target 5,6-Dihydro-4H-imidazo[4,5,1-//]quinoline-2-carbaldehyde Hydrochloride Hydrate (33.57 g, 83%).

PREPARATION 15

1 -(2-Methoxyethyl)-1 W-benzimidazole-2-carbaldehyde Hydrochloride Hydrate: 2-(Diethoxymethyl)-1W-benzimidazole (50 g, 0.227 mol) was suspended in DMF (200 mL), and Cs₂CO₃ (81.4 g, 0.227 mol) was added. 1-Bromo-2-methoxyethane (21.4 mL, 0.25 mol) was added dropwise, and the mixture was stirred overnight. Then the precipitate was filtered through Celite, and DMF was rotary evaporated. Water (300 mL) and diethyl ether (500 mL) were added to the residue. The organic layer was washed with water (2x300 mL), dried over Na₂SO₄, and ether was evaporated. The residue was the virtually pure 2- (Diethoxymethyl)-1-(2-methoxyethyl)-1f/-benzimidazole obtained in 97% (61 g) yield.

2-(Diethoxymethyl)-1-(2-methoxyethyI)-1H-benzimidazole (61 g, 0.219 mol) was dissolved in 6 M aqueous HCI (150 mL). The solution was kept at 60-70⁰C for 12 h. Most of water and acid was rotary evaporated, and the product crystallized from the residue. The product was filtered, washed with acetone and ether, and vacuum-dried to give 1-(2- methoxyethyl)-1/-/-benzimidazole-2-carbaldehyde Hydrochloride Hydrate in 64% (36.1 g) yield.

Similar procedure was used to prepare:

1 -(2-Fluoroethyl)-1 H-benzimidazole-2-carbaldehyde Hydrochloride Hydrate PREPARATION 161 -(Methoxymethyl)-I H-benzimidazole-2-carbaldehyde:

A mixture of tartaric acid (94.5 g, 630 mmol), o-phenylenediamine (163.5 g, 1512 mmol), water (158 mL), ethanol (94.5 mL), 12N hydrochloric acid (157.5 mL), and 85% phosphoric acid (63 mL) was kept at 135 ⁰C for 12 h. The solid phase was filtered and dissolved in water, and charcoal was added. The mixture was refluxed for 2 h, filtered, and alkalized with ammonium hydroxide. The solid phase was filtered, washed with acetone, and dried to give 1 ,2-bis(1/-/-Benzimidazol-2-yl)ethane-1 ,2-diol in 51 % (114g) yield. 60% NaH in oil (29.4 g, 734 mmol) was added in portions to a stirred suspension of 1 ,2- bis(1H-Benzimidazol-2-yl)ethane-1 ,2-diol (108.0 g, 367 mmol) in DMF (2 L). The mixture was stirred for 1 h, and chloromethyl methyl ether (59.1 g, 734 mmol) was added dropwise, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuum, poured into water (2 L), and HCI was added to pH 3. The mixture was extracted with chloroform (3x200 mL), and ammonium hydroxide was added to pH 10. The product was extracted with chloroform (4x200 mL). The extracts were combined, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, CHCI₃/MeOH 25:1 ,) and the resulted product was recrystallized from /-PrOH to give 1 ,2-bis[1-(Methoxymethyl)-1/-/-benzimidazol-2-yl]ethane-1 ,2-diol in 21% (28.9 g) yield.

NaIO₄ (16.16 g, 76 mmol) was added to a solution of 1 ,2-bis[1-(Methoxymethyl)-1/-/- benzimidazol-2-yl]ethane-1 ,2-diol (28.9 g, 76 mmol) in 1 N H₂SO₄ (1 L), and the reaction mixture was stirred at room temperature overnight. The solution was neutralized with NaHCO₃, and the product was extracted with EtOAc (4x200 mL). The combined extracts were dried over sodium sulfate, concentrated, and poured into hexane. The solid phase was filtered, washed with hexane, and dried to give 1-(Methoxymethyl)-1/-/-benzimidazole-2- carbaldehyde in 89% (25.6 g) yield.

PREPARATION 17 1 -Cyclopropyl-1 AY-benzimidazole-2-carbaldehyde Hydrochloride Hydrate: 1-Chloro-2-nitrobenzene (47.3 g, 0.300 mol) was dissolved in hexametapol (50 mL), and cyclopropylamine (51.4 g, 0.900 mol) was added. The mixture was boiled for 7 h. The 70% degree of conversion was attained according to ¹H NMR data. The reaction mixture was diluted with water (500 mL) and extracted with ether (2x200 mL). The ether layer was washed with water (2x300 mL). The organic layer was dried over Na₂SO₄. Ether was evaporated to give a mixture (53 g) containing 30% 1-chloro-2-nitrobenzene and A/-Cyclopropyl-2- nitroaniline in 70% yield.

Λ/-Cyclopropyl-2-nitroaniline (53.0 g, 0.297 mol) was dissolved in methanol (500 mL), and 10% Pd/C (2.5 g) was added in argon. The mixture was hydrogenated in a Parr apparatus at 20 psi for 1 h. The mixture self-heated, therefore hydrogen was supplied in portions so that the temperature was no higher than 50°C. After the reaction mixture was completely decolorized, the catalyst was filtered off, and acetic acid (60 mL) was added to the residue. This mixture containing Λ/-Cyclopropylbenzene-1 ,2-diamine was used at the next step.

Methyl 2,2-Diethoxyethanimidoate (61.1 g, 0.446 mol) was added to the solution containing Λ/-Cyclopropylbenzene-1 ,2-diamine and the mixture was kept at room temperature for 24 h. Then methanol was evaporated, and the residue was dissolved in ether (500 mL). The solution was washed with the 5% solution of Na₂CO₃ (2x300 mL), and ether was dried over Na₂SO₄. Ether was evaporated, and the residue was subjected to chromatography on silica gel (dichloromethane→dichloromethane/10% diethyl ether) to give 1-Cyclopropyl-2- (diethoxymethyl)-IH-benzimidazole in 28% (22 g) yield.

1-Cyclopropyl-2-(diethoxymethyl)-1/-/-benzimidazole (22.0 g, 0.0845 mL) was dissolved in 20% aqueous HCI (150 mL). The solution was heated at 60-70 ⁰C for 4 h. The main portion of water and acid was rotary evaporated. Acetone (200 mL) and ether (50 mL) was added to the residue. The precipitate was separated by filtration, washed with acetone and ether, and vacuum-dried to give i-Cyclopropyl-IH-benzimidazole-2-carbaldehyde Hydrochloride Hydrate in 96% (19.7 g) yield. PREPARATION 18

2-Formyl-1 -methyl-1 H-benzoimidazole-5-carbonitrile:

4-Chloro-3-nitro-benzonitrile (30 g, 165 mmol) was suspended in EtOH (60 mL), and methylamine (33% in EtOH, 24 ml, 165 mmol) was added. The mixture was stirred at room temperature for 1 h, then heated to 7O⁰C overnight. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was suspended in Et₂O and filtered to give 42 g of A- methylamino-3-nitro-benzonitrile, which was used in the next step without further purification.

4-methylamino-3-nitro-benzonitrile (42 g, 0.297 mol) was suspended in EtOH/H₂O (10:1, 1000 mL) under N₂ at rt. Iron powder (53 g, 948 mmol) and CaCI₂ (24 g, 216 mmol) were added and the mixture was heated at reflux for 2 hours. TLC showed no starting material was left. The mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was re-dissolved in CH₂CI₂ (400 mL) and washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuo to give 20.5 g of the desired product, 3-amino-4-methylamino-benzonitrile.

Methyl 2,2-Diethoxyethanimidoate (56.2 g, 349 mmol) and acetic acid (24 mL, 420 mmol) were added to the solution of 3-amino-4-methylamino-benzonitrile in MeOH and the mixture was kept at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc (500 mL). The solution was washed with the 5% solution of Na₂CO₃ (2 x 300 mL), and dried over Na₂SO₄. EtOAc was evaporated, and the residue was subjected to chromatography on silica gel (3:1 hexane:EtOAc) to give 35 g of 2- Diethoxymethyl-1 -methyl-1 H-benzoimidazole-5-carbonitrile.

2-Diethoxymethyl-1 -methyl-1 H-benzoimidazole-5-carbonitrile (35 g, 135 mmol) was dissolved in 4N HCI in dioxane (135 mL) and the solution was heated at 60⁰C for 8 h. The mixture was concentrated in vacuo and the residue was suspended in Et₂O (200 mL). The precipitate was separated by filtration, washed with hexane, and vacuum-dried to give 25 g of 2-Formyl-1 -methyl-1 H-benzoimidazole-5-carbonitrile Hydrochloride Hydrate as a tan solid. Similar procedure was used to prepare: 4-Bromo-1-methyl-1 H-benzoimiclazole-2-carbaldehyde from 1-Bromo-3-fluoro-2-nitro- benzene;

5-Bromo-1-methyl-1 H-benzoimidazole-2-carbaldehyde from 4-Bromo-1-fluoro-2-nitro- benzene; 5-Fluoro-1 -methyl-1 H-benzoimidazole-2-carbaldehyde from 1 ,4-Difluoro-2-nitro- benzene;

5-Trifluoromethyl-1 -methyl-1 H-benzoimidazole-2-carbaldehyde from 1 -Chloro-2-nitro- 4-trifluoromethyl-benzene;

5-Chloro-1 -methyl-1 H-benzoimidazole-2-carbaldehyde from 1 ,4-Dichloro-2-nitro- benzene.

METHOD R (Scheme IX)

PREPARATION 19

To a stirred solution of 6-Hydroxymethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (550 mg, 2.12 mmol) in CH₂CI₂ (10 mL) under nitrogen at room temperature was added Dess-Martin Periodinane (1.2 g, 2.75 mmol). The resulted milky white suspension was stirred at room temperature for 4 h. TLC showed no starting material left. A mixture of NaHCO₃ saturated aqueous solution and Na₂S₂O₃ saturated aqueous solution (10 mL, 1 :1 ) was then added and the mixture was stirred until CH₂CI₂ layer became clear. The mixture was diluted with EtOAc (100 mL) and washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuo to give 509 mg of 6-formyl-3-aza-bicyclo[3.1.0]hexane-3- carboxylic acid tert-butyl ester without further purification. 1 H-NMR (CD3OD, 400 MHz) δ (ppM): 9.25 (d, 1 H, J = 4.6 Hz), 3.60 (d, 2H, broad), 3.27-3.47 (m, 2H), 2.25 (s, 2H, broad), 1.69 (m, 1H), 1.42 (s, 9H).

PREPARATION 20 Benzyl triphenyiphosphonium chloride was dissolved in THF (15 mL). The solution was stirred under nitrogen at -78⁰C. BuLi (2.5 M in hexane, 1.42 mL, 3.55 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at -78⁰C for 1 h, then a solution of 6-formyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (507 mg, 1.97 mmol) in THF (3 mL) was added. The mixture was slowly warmed up to room temperature and stirred overnight. The reaction was quenched by water (5 mL) and diluted with EtOAc (100 mL) and washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash column (silica gel, 0% to 30% EtOAc in hexane) to give 277 mg residue. The residue was dissolved in 10 mL MeOH and to this solution was added Pd/C (10%, 100 mg). The mixture was put on a hydrogenation shaker under H₂ (45 PSI) for 5 h. TLC showed a slightly less polar spot that was much less UV-active. The mixture was filtered through a pad of celite and the filtrate was concentrated to give 280 mg of 6-Phenethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. 1H- NMR (CD3OD, 400 MHz) δ (ppM): 7.1-7.2 (m, 5H)₁ 3.40 (d, 2H₁ broad), 3.20-3.27 (m, 2H), 2.67 (t, 2H, J = 7.5 Hz), 1.54 (m, 2H), 1.40 (s, 9H), 1.22 (m, 1 H), 1.20 (m, 2H).

PREPARATION 21

To a stirred solution of 6-phenethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert- butyl ester (280 mg, 0.98 mmol) in CH₂CI₂ (5 mL) under N₂ at room temperature was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and the residue was dissolved in CH₂CI₂ (20 mL) and the pH was adjusted to 10 by 1 N NaOH. The aqueous layer was further extracted with a mixed solvent of CH₂CI₂IiPrOH (5:1 , 20 mL). The organic layer was combined and dried over sodium sulfate. The solvent was removed in vacuo to give 108 mg of 6-Phenethyl-3-aza- bicyclo[3.1.0]hexane. MS (APCI) for C₁₃Hi₇N m/z 188 (M+H)⁺ Example 13 (corresponding to entry 885 in table 1):

1 -Methyl-2-(6-phenethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-1 H-benzoimidazole: To a stirred solution of 6-phenethyl-3-aza-bicyclo[3.1.0]hexane (25 mg, 0.13 mmol) in CH₂CI₂ (2 mL) under N₂ at room temperature was added 1-Methyl-1 H-benzoimidazole-2- carbaldehyde (22 mg, 0.13 mmol), Et₃N (150 uL, 1.1 mmol) and MgSO₄ (5 mg). The mixture was stirred for 30 min and then Na(OAc)₃BH (43 mg, 0.20 mmol) was added. After being stirred at room temperature for 12 h, the mixture was diluted with CH₂CI₂ (30 mL) and washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified with flash column (silica gel, 70% to 100% EtOAc in hexane) to give 26 mg thick oil, which was dissolved in 1 mL MeOH and treated with 50 uL 4N HCI in dioxane. The mixture was concentrated and triturated with ethyl ether to give 31 mg solid as the HCI salt of 1-methyl-2-(6-phenethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-1 H-benzoimidazole. MS (ESI⁺) for C₂₂H₂₅N₃ m/z 332 (M+H)⁺. The following examples were prepared following similar procedures:

Example 14 (corresponding to entry 886 in table 1): 2-(6-Phenethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-5,6-dihydro-4H- imidazo[4,5,1-ij]quinoline. MS (ESI⁺) for C₂₄H₂₇N₃ZnZz 358 (M+H)⁺.

Example 15 (corresponding to entry 887 in table 1): 1 -Methyl-2-(6-phenethyI-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-1 H-benzoimidazole-

5-carbonitrile. MS (ESI⁺) for C₂₃H₂₄N₄ m/z 357 (M+H)⁺.

METHOD S (Scheme X)

PREPARATION 22

To a stirred solution of 6-Hydroxymethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2.03 g, 7.84 mmol) in CH₂CI₂ (100 mL) under nitrogen at room temperature was added Dess-Martin Periodinane (4.33 g, 10.2 mmol). The resulted milky white suspension was stirred at room temperature for 4 h. TLC showed no starting material left. A mixture of NaHCO₃ saturated aqueous solution and Na₂S₂O₃ saturated aqueous solution (50 ml_, 1 :1) was then added and the mixture was stirred until CH₂CI₂ layer became clear. The mixture was then diluted with EtOAc (300 ml_) and washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuo to give 1.95 g of 6-formyl-3-aza- bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester without further purification. 1 H-NMR (CD3OD, 400 MHz) δ (ppM): 9.25 (d, 1H, J = 4.6 Hz), 3.60 (d, 2H, broad), 3.27-3.47 (m, 2H), 2.25 (s, 2H, broad), 1.69 (m, 1H), 1.42 (s, 9H).

PREPARATION 23 To a stirred solution of Bromomethyl triphenylphosphonium bromide (4.30 g, 9.9 mmol) in THF (100 mL) at -78⁰C was added Sodium hexamethyldisilylazide (NaHMDS) (1 M in THF, 9.9 mL, 9.9 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at -78⁰C for 30 min, then a solution of 6-formyl-3-aza- bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.95 g, 7.59 mmol) in THF (10 mL) was added. The mixture was slowly warmed up to room temperature and stirred for 5 h. The reaction was quenched by water (10 mL). The mixture was then diluted with EtOAc (300 mL) and washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash column (silica gel, 10% to 70% EtOAc in hexane) to give 830 mg of the desired product as a mixture of (ZJE) isomers and 498 mg of recovered starting material. Part of the product (210 mg, 0.73 mmol) was dissolved in a mixed solvent (10 mL, DME: H₂O 2:1 ). To this stirred solution at room temperature under nitrogen was added 4-trifluoromethyl phenylboronic acid, sodium carbonate and Pd(PPh₃)₄. The mixture was heated to reflux and stirred overnight. The mixture was cooled to room temperature, diluted with EtOAc(IOO mL) and washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified with flash column (silica gel, 2 % to 30 % EtOAc in hexane) to give 89 mg of the desired product. 1 H-NMR (CD3OD, 400 MHz) δ (ppM): 7.61 (d, 2H₁ J = 8.3 Hz), 7.50 (d, 2H, J = 8.3 Hz), 6.43 (d, 1 H, J = 11.6 Hz), 5.34 (dd, 1 H, J = 11.6 Hz, 9.5 Hz), 3.60 (d, 2H, broad), 3.30-3.40 (m, 2H), 1.71 (s, 2H, broad), 1.45 (m, 1 H), 1.39 (s, 9H).

PREPARATION 24 The product from the previous step (89 mg, 0.25 mmol) was dissolved in 10 mL

MeOH and to this solution was added Pd/C (10%, 28 mg). The mixture was then put on a hydrogenation shaker under H₂ (45 PSI) for 4 h. TLC showed no starting material was left. The mixture was filtered through a pad of celite and the cake was further washed with MeOH (10 mL). The filtrate was concentrated to give 82 mg of 6-[2-(4-Trifluorornethyl-phenyl)-ethyrj- 3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. 1 H-NMR (CD3OD, 400 MHz) δ (ppM): 7.53 (d, 2H, J = 8.3 Hz), 7.36 (d, 2H, J = 8.3 Hz), 3.40 (d, 2H, broad), 3.20-3.30 (m, 2H), 2.76 (t, 2H, J = 7.9 Hz), 1.60 (m, 2H), 1.40 (s, 9H), 1.26 (m, 2H), 0.40 (m, 1H). PREPARAT1ON 25

To a stirred solution of 6-[2-(4-Trifluoromethyl-phenyl)-ethyl]-3-aza- bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (82 mg, 0.23 mmol) in CH₂CI₂ (5 mL) under N₂ at room temperature was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated in vacuo and the residue was directly used without further purification. MS (APCI) for C₁₄Hi₆F₃N m/z 256 (M+H)⁺

Example 16 (corresponding to entry 888 in table 1): i-Methyl^^e-p^-trifluoromethyl-phenylJ-ethylJ-S-aza-bicyclotS.I.Olhex-S- ylmethyl}-1 H-benzoimidazole: To a stirred solution of 6-[2-(4-Trifluoromethyl-phenyl)-ethyl]-

3-aza-bicyclo[3.1.0]hexane (0.077 mmol) in CH₂CI₂ (2 mL) under N₂ at room temperature was added 1-Methyl-1 H-benzoimidazole-2-carbaldehyde (12.5 mg, 0.078 mmol), Et₃N (88 uL,

0.62 mmol) and MgSO₄ (5 mg). The mixture was stirred for 30 min and then Na(OAc)₃BH (25 mg, 0.12 mmol) was added. After being stirred at room temperature for 12 h, the mixture was diluted with CH₂CI₂ (20 mL) and washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified with flash column (silica gel, 20% to 100% EtOAc in hexane) to give 23 mg white solid, which was dissolved in MeOH (1 mL) and treated with 50 uL 4N HCI in dioxane. The mixture was concentrated and triturated with ethyl ether to give 26 mg glassy solid as the HCI salt of 1-Methyl-2-{6-[2-(4-trifluoromethyl- phenyl)-ethyl]-3-aza-bicyclo[3.1.0]hex-3-ylmethyl}-1 H-benzoimidazole. MS (ESI⁺) for

C₂₃H₂₄F₃N₃ m/z 400 (M+H)⁺.

The following examples were prepared following similar procedures: Example 17(corresponding to entry 889 in table 1): 2-{6-[2-(4-Trifluoromethyl- phenylJ-ethyO-S-aza-bicyclofS.I .OJhex-S-ylmethylJ-δ.e-dihydro^H-imidazo^.S.I-ijlquinoline. MS (ESI⁺) for C₂₅H₂₆F₃N₃ m/z 426 (M+H)⁺.

Example 18 (corresponding to entry 890 in table 1): 2-{6-[2-(4-Fluoro-phenyl)- ethyll-S-aza-bicyclop.i .Olhex-S-ylmethylϊ-δ.e-dihydro^H-imidazoμ.δ.i-ijlquinoline. MS (ESI⁺) for C₂₄H₂₆FN₃ m/z 376 (M+H)⁺.

Example 19 (corresponding to entry 891 in table 1): 2-{6-[2-(4-Fluoro-phenyl)- ethyl]-3-aza-bicyclo[3.1.0]hex-3-ylmethyl}-1-methyl-1 H-benzoimidazole. MS (ESI⁺) for C₂₂H₂₄FN₃ m/z 350 (M+H)⁺.

METHOD A' (SCHEME Xl)

PREPARATION 26

[S^I-methyl-IH-benzoimidazol-Z-ylmethylJ-S-aza-bicyclofS.I .OJhex-θ-yl] methanol

To a solution of 1.13 g (10.0 mmol) (3-Aza-bicyclo[3.1.0]hex-6-yl)-methanol-HCI in 10 mL of anhydrous methylene chloride under nitrogen was added 1.78 g (11.1 mmol) of 1- methyl-1H-benzo[d]imidazole-2-carbaldehyde and the mixture was stirred at room temperature for 15 minutes. 6.36 g (30.0 mmol) of sodium triacetoxyborohydride was added and the reaction was stirred for 16 hours at room temperature. The reaction was diluted with methylene chloride and partitioned with 1 N NaOH and a white precipitate formed in the aqueous layer. The precipitate was filtered to give 1.63 g of the title compound. The organic layer was then separated from the aqueous layer, washed with 1 N NaOH, dried over anhydrous sodium sulfate, filtered and stripped in vacuo to provide an additional 1.11 g of impure product. 400 MHz ¹H NMR (CD₃OD) δ 7,6 (d, 1 H)₅ 7.4 (d, 1H), 7.2-7.3 (m, 2H), 3.9 (s, 2H), 3.8 (s, 3H), 3.3 (m, 2H), 2.9 (d, 2H), 2.5 (d, 2H), 1.4 (m, 1 H), 1.3 (t, 2H); MS (M+1 ) 258.2. PREPARATION 27

S^I-methyMH-benzofmidazoI-Σ-ylmethylJ-S-aza-bicycloIS.I .Olhexane-θ- carbaldehyde

In a flame-dried, 3-neck flask equipped with a thermometer and N₂ inlet, was dissolved 435 μl_ (5.0 mmol) of oxalyl chloride in 15 mL of anhydrous methylene chloride. The mixture was chilled in a dry ice/acetone bath to -78 ⁰C and 770 μl_ (10.85 mmol) of anhydrous DMSO was added dropwise via syringe. After the addition was complete, the mixture was stirred for 15 minutes. In a separate flask, 515 mg (2.0 mmol) of [3-(1-methyl-1H- benzoimidazol-2-yI methyI)-3-aza-bicyclo[3.1.0]hex-6-yI] methanol was dissolved in 10 mL of anhydrous THF and added to the reaction dropwise via syringe. The reaction was stirred at - 78 ⁰C for 1 hour. 2.9 mL (20.8 mmol) of TEA was added via syringe and stirred at -78 ⁰C for 10 minutes. The reaction was allowed to warm to 0 ⁰C in an ice/methanol bath. The reaction was stirred for 1 hour and then warmed to room temperature and stirred for 1 hour. The reaction was partitioned twice between saturated NaHCO₃ and methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and stripped in vacuo to give 503 mg of a pale yellow solid. 400 MHz ¹H NMR (CDCI₃) δ 9.2 (d, 1 H), 7.7 (m, 1 H), 7.2 -7.3 (m, 3H), 3.9 (s, 2H), 3.8 (s, 3H)₁ 3.0 (d, 2H), 2.2 (m, 1 H), 2.1 (t, 2H); MS (M+1) 256.1.

PREPARATION 28 1.09 g (4.28 mmol) of 3-(1-methyl-1H-benzoimidazol-2-yl methyI)-3-aza- bicyclo[3.1.0]hexane-6-carbaldehyde was dissolved in 17.12 mL of 1 ,2-dichloroethane. Added 200 μL (0.05 mmol) to each vial that contained 0.05 mmol of various amines. Then added a spatula amount of activated 4A molecular sieves powder. The vials were sealed and placed on a shaker at room temperature for 16 hours. To each vial was added 0.15 mmol of sodium triacetoxyborohydride and shaken at room temperature for 72 hours. To each vial was added 1.0 mL of 1 N NaOH followed by 1.0 mL of 1 ,2-dichloroethane. The vials were placed on a shaker for 10 minutes and the layers were allowed to separate. The lower layers were removed and added to SPE columns containing anhydrous sodium sulfate with eluents collected in tared 2-dram vials. The aqueous layers were extracted twice more with 1.0 mL of 1 ,2-dichloroethane and added to the SPE columns. Solvent was evaporated overnight and samples were purified by mass trigger preparative HPLC.

Examples prepared using method A' are listed in table 1. METHOD B' (SCHEME Xl)

Added 4.5 μL (0.078 mmol) of glacial acetic acid to each vial that contained 0.05 mmol of varying amines. Dissolved 970 mg of 3-(1-methyl-1 H-benzoimidazol-2-yl methyl)-3- aza-bicyclo[3.1.0]hexane-6-carbaldehyde in 19 mL of methanol and added 250 μL (0.05 mmol) of this solution to each vial. Dissolved 478 mg of sodium cyanoborohydride in 7.6 mL of methanol and added 100 μL of this solution to each vial. The vials were sealed and placed on a shaker at room temperature for 16 hours. The reactions were concentrated in a Savant and the residues were partitioned three times between 1.0 mL each of saturated NaHCO₃ and CH₂CI₂. The organic layers were added to SPE barrels containing anhydrous sodium sulfate with eluents collected into tared 2-dram vials. The SPE barrels were rinsed with 1.0 mL of CH₂CI₂- The solvent was removed overnight and samples were purified by mass trigger preparative HPLC.

Examples prepared using method B' are listed in table 1.

METHOD C (SCHEME XII)

PREPARATION 29 4-(Fluorophenyl)-[3-(1 -methyl-1 H-benzoimidazol-2-ylmethyl)-3-aza- bicyclo[3.1.0]hex-6-ylmethyl]-amine

Combined 111 mg (1.0 mmol) of p-fluoroaniline with 90 μL (1.57 mmol) of glacial acetic acid and 255 mg (1.0 mmol) of 3-(1 -methyl-1 H-benzoimidazol-2-yl methyl)-3-aza- bicyclo[3.1.0]hexane-6-carbaldehyde in 6.4 mL of anhydrous methanol under nitrogen. Added 68 mg (1.08 mmol) of sodium cyanoborohydride and the reaction was stirred at room temperature overnight for 17 hours. The reaction was concentrated in vacuo to a white solid residue. The residue was partitioned three times between 20 mL each of saturated aqueous NaHCO₃ and CH₂CI₂. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to an oily residue. The residue was flash chromatographed using 98:2 methylene chloride: methanol as eluent and the fractions containing product were combined and evaporated to give 300 mg of the title compound. 400 MHz ¹H NMR (CDCI₃) δ 7.7 (d, 1 H), 7.2 -7.3 (m, 3H), 6.8-6.9 (m, 2H)₁ 6.5 (m, 2H), 3.9 (s, 2H), 3.8 (s, 3H), 2.9 (d, 2H), 2.9 (d, 2H), 2.5 (d, 2H), 1.4 (m, 1 H), 1.3 (d, 2H); MS (M+1 ) 351.2. Example 20(corresponding to entry 555 in table 1):

2,2,2-Trif luoro-ethanesulfonic acid 4-(f luorophenyl)-[3-(1 -methyl-1 H- benzoimidazol-2-ylmethyl)-3-aza-bicyclo[3.1.0]hex-6-ylmethyl]-amide

In a 2-dram vial was combined 35 mg (0.10 mmol) of 4-(F)uorophenyl)-[3-(1-methyl- IH-benzoimidazol^-ylmethyO-S-aza-bicyclop.i .OJhex-θ-ylmethyll-amine with 500 μl_ of methylene chloride and 250 μL of pyridine. 22.1 μl_ (36.5 mg, 0.20 mmol) of 2,2,2- trifluroethane sulfonyl chloride was added. The sealed vial was placed on a shaker at room temperature for 16 hours. The reaction was concentrated and the residue was partitioned three times between saturated aqueous NaHCO₃ and CH₂CI₂. The combined organic layers were added to an SPE containing anhydrous sodium sulfate, and the eluent was evaporated. The residue was flash chromatographed using 1 :1 EtOAc/hexanes as eluent. The fractions containing product were combined and evaporated to give 31 mg of the title compound. 400 MHz ¹H NMR (CDCI₃) 57.7 (d, 1 H), 7.2 -7.3 (m, 5H), 7.1 (m, 2H), 3.8 (s, 2H), 3.7 (m, 5H), 3.5 (d, 2H), 2.8 (d, 2H), 2.4 (d, 2H), 1.2 (m, 1 H), 1.2 (s, 2H); MS (M+1 ) 497.2. PREPARATION 30

Benzyl-[3-(1 -methyl-1 H-benzoimidazol-2-ylmethyl)-3-aza-bicyclo[3.1.0]hex-6- ylmethyl]- amine

Combined under nitrogen, 511 mg (2.0 mmol) of crude 3-( 1 -methyl-1 H- benzoimidazol-2-yl methyl)-3-aza-bicyclo[3.1.0]hexane-6-carbaldehyde in 14 mL of methanol with 218 μL (2.0 mmol) of benzylamine and 179 μL (3.12 mmol) of glacial acetic acid. The reaction was stirred at room temperature for 10 minutes, followed by the addition of 139 mg (2.2 mmol) of sodium cyanoborohydride. The solution was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo and then partitioned twice between saturated aqueous NaHCO₃ and methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and evaporated in vacuo to give the crude product. Purification via flash chromatography used an eluent gradient of 99:1 to 9:1 CH₂CI₂ZCH₃OH and yielded 139 mg of the title compound. 400 MHz ¹H NMR (CDCI₃) δ7.7 (d, 1 H), 7.2 -7.3 (m, 8H), 3.9 (s, 2H), 3.8 (d, 5H), 2.9 (d, 2H), 2.4-2.5 (m, 4H), 1.3 (m, 1H), 1.2 (t, 2H); MS (M+1 ) 347.2. Example 21 (corresponding to entry 892 in table 1) : 2,2,2-Trifluoro-ethanesulfonic acid benzyl-[3-(1 -methyl-1 H-benzoimidazol-2- ylmethyl)-3-aza-bicyclo[3.1.0]hex-6-ylmethyl]- amide

In a 2-dram vial was combined 35 mg (0.10 mmol) of Benzyl-[3-(1 -methyl-1 H- benzoimidazol-2-ylmethyl)-3-aza-bicyclo[3.1.0]hex-6-ylmethyl]- amine with 500 μL of 1 ,2- dichlorethane and 250 μL of pyridine. 22.1 μL (36.5 mg, 0.20 mmol) of 2,2,2-trifluroethane sulfonyl chloride was added. The sealed vial was placed on a shaker at room temperature for 16 hours. The reaction mixture was partitioned three times between saturated aqueous NaHCO₃ and CH₂CI₂. The combined organic layers were evaporated. The crude residue was purified via flash chromatography, first with 95:5 CH₂CI₂ZCH₃OH, followed by 1 :1 EtOAc/hexanes and yielded 29 mg of the title compound. 400 MHz ¹H NMR (CDCI₃) 57.7 (d, 1H), 7.2 -7.3 (m, 7H), 7.0 (t, 1H), 4.4 (s, 2H), 3.8 (s, 2H), 3.6 - 3.8 (q, 2H), 3.6 (s, 3H), 3.1 (d, 2H), 2.6 (d, 2H), 2.4 (d, 2H), 1.2 (s, 2H), 1.1 (m, 1 H); MS (M+1 ) 493.2. METHOD D' (SCHEME XIII)

PREPARATION 31

Dibenzyl-[3-(1 -methyl-1 H-benzoimidazol-2-ylmethyl)-3-aza-bicyclo[3.1.0]hex-6- ylmethyl]- amine

3.45 g (17.5 mmol) of dibenzylamine was added to 14.6 mmol of 3-(1 -methyl-1 H- benzoimidazol-2-ylmethyl)-3-aza-bicyclo[3.1.0]hexane-6-carbaldehyde which was dissolved in 100 mL of anhydrous methylene chloride under nitrogen. The reaction mixture was stirred for 5 minutes, followed by the addition of 6.17 g (29.1 mmol) of sodium triacetoxyborohydride. The reaction was stirred at room temperature for 16 hours. The reaction was diluted with methylene chloride and extracted with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, stripped in vacuo, and flash chromatographed to give 3.8 g of the title compound. 400 MHz ¹H NMR (CDCI₃) 67.7 (d, 1H), 7.1 -7.4 (m, 13H), 3.8 (s, 2H), 3.8 (s, 3H), 3.6 (s, 4H), 2.8 (d, 2H), 2.4 (d, 2H), 2.3 (d, 2H), 1.1 -1.2 (m, 3H); MS (M+1 ) 347.2.

PREPARATION 32 C-[3-(1 -Methyl-1 H-benzoimidazol-2-ylmethyl)-3-aza-bicyclo[3.1.0]hex-6-yl]- methylamine

In a flask was combined 5.1 g (80 mmol) of ammonium formate with 2.0 g of Pd(OH)₂, and 3.5 g (8.0 mmol) of Dibenzyl-[3-(1-methyl-1H-benzoimidazol-2-ylmethyl)-3-aza- bicyclo[3.1.0]hex-6-ylmethyl]- amine and dissolved in 200 mL of EtOH. The reaction was heated at reflux for 3 hours and monitored by TLC. After the reaction was completed, EtOAc was added to the reaction, causing a white precipitate and the reaction was allowed to stir for 5 minutes. The reaction was filtered and concentrated to provide 2.0 g of the title compound. 400 MHz ¹H NMR (CD₃OD) δ 7,6 (d, 1H), 7.5 (d, 1H), 7.2-7.3 (m, 2H), 3.9 (s, 2H), 3.8 (s, 3H), 2.9 (d, 2H), 2.4 - 2.5 (dd, 4H), 1.3 (m, 3H); MS (M+1 ) 257.3. PREPARATION 33

513 mg of C-[3-(1 -Methyl-1 H-benzoimidazol-2-ylmethyl)-3-aza-bicyclo[3.1.0]hex-6-yl]- methylamine was dissolved in 20 mL of 1 ,2-dichloroethane, followed by the addition of 10 mL of pyridine. 750 μL (0.05 mmol) of this solution was added to 1-dram vials containing 0.1 mmol of varying sulfonyl chlorides. The sealed vials were placed on a shaker at room temperature for 16 hours. The reaction mixtures were partitioned three times with 1.0 mL of 1 ,2-dichloroethane and 1.0 mL of 1 N NaOH. The lower layers were added to SPE columns containing anhydrous sodium sulfate and the eluents collected. The solvent was removed overnight and samples were purified by mass trigger preparative HPLC. Examples prepared using method D' are listed in table 1.

METHOD E' (SCHEME XIV) PREPARATION 34

1.17 g of C-[3-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-3-aza-bicyclo[3.1.0]hex-6-yl]- methylamine was dissolved in 18.3 ml_ of DMF and vortexed to give a colorless solution. 200 μL (0.05 mmol) of this solution was added to each 0.1 mmol of varying carboxylic acids. 1.37 g of 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was dissolved in 35.6 mL of DMF with heat. 375 μL (0.075 mmol) of this EDCI solution was added to each reaction vial. 321 mg of 1-hydroxybenzotriazole hydrate (HOBT) was dissolved in 11.9 ml of DMF. 125 μL of this HOBT solution was added to each reaction vial. The sealed vials were placed on a shaker at room temperature for 16 hours. The reactions were partitioned three times between 1.0 mL of 1 N NaOH and 1 mL of EtOAc. The organic layers were added to SPE columns containing anhydrous sodium sulfate and eluents were collected into tared vials. The solvent was evaporated in a Savant and purification of products was achieved via mass triggered prep HPLC.

Examples prepared using method E' are listed in table 1. METHOD F' (SCHEME XV)

One example representative of synthetic method F' is described below. Other examples using method F' are listed in Table 1.

Example 22 (corresponding to entry 556 in table 1):

4-(Fluoro-phenyl)-methyl-r3-(1-methyl-1H-benzoimidazol-2-ylmethyl)-3-aza- bicvclo[3.1.01hex-β-ylmethyll-amine

In a 2-dram vial was combined 35 mg (0.1 mmol) of 4-(Fluorophenyl)-[3-(1-methyl- 1H-benzoimidazol-2-ylmethyl)-3-aza-bicyclo[3.1.0]hex-6-ylmethyl]-amine, 656 μL of THF, and 328 μL of water. To the reaction was added 12 μL (0.16 mmol) of 37% aqueous formaldehyde and 8 μL (0.21 mmol) of formic acid. The vial was sealed and placed on a heater/shaker at 80 ⁰C for 20 hours and then allowed to cool to room temperature. The reaction was diluted with methylene chloride and extracted with saturated aqueous NaHCO₃. The layers were separated and the aqueous layer was extracted twice with methylene chloride. The combined organic layer was added to a SPE column containing anhydrous sodium sulfate, and the eluent was collected in a tared 2-dram vial. The solvent was evaporated. Purification using flash chromatography with an eluent of 1 :1 EtOAc/hexanes provided 28 mg of the title compound. 400 MHz ¹H NMR (CDCI₃) 57.7 (d, 1 H), 7.2 -7.3 (mm, 3H), 6.9 (t, 2H), 6.7 (m, 2H), 3.9 (S, 2H), 3.7 (s, 3H), 3.1 (d, 2H), 2.9 (d, 2H), 2.8 (s, 3H), 2.5 (d, 2H), 1.3 (m, 3H); MS (M+1 ) 365.2.

METHOD G'(SCHEME XVI)

PREPARATION 35

2.54 g (12.0 mmol) of 6-formyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester was dissolved in 40 mL of anhydrous 1 ,2-dichloroethane and 500 μl_ (0.15 mmol) of this aldehyde solution was added to 0.15 mmol of each varying amine previously weighed into 2- dram vials. 95 mg (0.45 mmol) of sodium triacetoxyborohydride was added to each vial. The vials were sealed, vortexed, and placed on a shaker at room temperature for 16 hours. 1.0 mL of 1 ,2-dichloroethane was added to each vial, followed by 2.0 mL of 1 N NaOH. The vials were vortexed, and the layers were allowed to separate. The lower layers were removed and added to SPE columns containing anhydrous sodium sulfate, placed over tared 2-dram vials.

The aqueous layer was extracted two more times with 1.0 mL of 1 ,2-dichloroethane and the lower layers were added to the SPE columns. The eluted solvent in the vials was evaporated.

300 μL of THF was added to each vial, followed by 300 μL of 4 M HCI in 1 ,4-dioxane. The vials were sealed and placed on a shaker at room temperature for 16 hours. The reactions were concentrated and then diluted with 500 μL of 1 ,2-dichlorethane and 42 μL (0.3 mmol) of triethylamine.

PREPARATION 36

1.92 g of 1-methyl-1 H-benzo[d]imidazole-2-carbaldehyde was dissolved in 12.0 mL of

1 ,2-dichloroethane and vortexed to give a yellow solution. 150 μL (0.15 mmol) of this solution was added to each intermediate solution from Preparation 35. The reactions were shaken for 5 minutes. 95 mg (0.45 mmol) of sodium triacetoxyborohydride was added to each vial. The sealed vials were placed on a shaker at room temperature for 64 hours. To each vial was added 1.0 mL of 1 ,2-dichloroethane, followed by 1.5 mL of 1 N NaOH. The vials were vortexed and the layers were allowed to separate. The lower layers were removed and added to SPE columns containing anhydrous sodium sulfate, with eluents collected into tared 2- dram vials. The aqueous layer was extracted two more times with 1.0 mL of 1 ,2- dichloroethane and the lower layers were removed and added to the SPE columns. The solvent was removed via evaporation and products were purified via mass trigger preparative HPLC.

Examples prepared using method G' are listed in table 1. METHOD H' (SCHEME XVIlI) PREPARATION 37

3.2 g (15.15 mmol) of 6-Formyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert- butyl ester was dissolved in 7.6 ml. of anhydrous MeOH and vortexed to give a yellow solution. 0.3 mL (0.6 mmol) of this solution was added to 0.6 mmol of primary amines weighed into vials. The vials were sealed and placed on a shaker at room temperature for 64 hours. 45 mg (1.2 mmol) of sodium borohydride was added to each vial. The sealed vials were placed on a shaker at room temperature for 16 hours. 2.0 mL of 1 ,2-dichloroethane was added to each vial, followed by 2.0 mL of 1 N NaOH. The vials were vortexed and the layers were allowed to separate. The organic layers were removed and added to blank SPE columns with eluents collected into tared 2-dram vials. 2.0 mL of 1 ,2-dichloroethane was added to the aqueous layers and the organic layers were removed and added to the SPEs. The solvent was evaporated on a Savant for 16 hours.

PREPARATION 38

The products from Preparation 37 were diluted with 1.2 mL of 1 ,2-dichloroethane and placed on a shaker for 10 minutes to dissolve the samples. The products were aliquoted into 300 μL portions of each and transferred to new 2-dram vials. 250 μL of pyridine was added to each vial. Prepared 1.5 M solutions of sulfonyl chlorides in 1 ,2-dichloroethane. To the reaction vials was added 200 μL of a sulfonyl chloride solution. The vials were sealed and placed on a shaker at room temperature for 64 hours. 1 mL of 1 N NaOH followed by 1 mL of 1 ,2- dichloroethane was added to each vial. The vials were vortexed for 5 minutes. The layers were allowed to separate and the lower layers were removed to empty SPE barrels with eluents collected into tared 2-dram vials. The aqueous layer was extracted with an additional 1 ml_ of 1 ,2-dichloroethane, the layers were separated and the lower layers were added to the SPE barrels. The solvent was removed through evaporation in a Savant for 16 hours. The crude reaction residues were each diluted with 300 μl_ of THF, followed by 300 μL of 4 M HCI in 1 ,4-dioxane. The vials were sealed and placed on a shaker at room temperature for 16 hours. The reactions were concentrated in a Savant overnight.

PREPARATION 39

Prepared a triethylamine solution of 1.40 mL of triethylamine that was diluted with 10 mL of 1 ,2-dichloroethane. Added 100 μL (0.1 mmol) of this triethylamine solution to the crude products from Preparation 38. Dissolved 1.6 g (10.0 mmol) of 1-methyl-1 H-benzo[d]imidazole- 2-carbaldehyde in 50 mL of 1 ,2-dichloroethane, and added 500 μL (0.1 mmol) to each vial. 0.3 mmol of sodium triacetoxyborohydride was added to each vial and the sealed vials were placed on a shaker at room temperature for 16 hours. 1.5 mL of 1 N NaOH, followed by 1.4 mL of 1 ,2-dichloroethane was added to each vial, and the vials were vortexed for 10 minutes. The layers were allowed to separate and the organic layers were added to empty SPE columns with eluents collected into tared 2-dram vials. An additional 1.0 mL of 1 ,2- dichloroethane was added to the aqueous layers, vortexed, and the organic layers were added to the SPEs. The solvent was evaporated in a Savant for 16 hours. Products were purified through mass triggered preparative HPLC. Examples prepared using method H' are listed in table 1.

METHOD I' (SCHEME XIX)

PREPARATION 40

6-r(Benzyl-methyl-amino)-methvπ-3-aza-bicvclo T3.1.Oihexane -3-carboxylic acid tert-bυtyl ester 913 μL (7.1 mmol) of N-methylbenzyl amine was added to 1.5 g (7.1 mmol) of (6-

Formyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester which was dissolved in 35 mL of anhydrous methylene chloride under nitrogen. The reaction mixture was stirred for 10 minutes, followed by the addition of 4.5 g (21.3 mmol) of sodium triacetoxyborohydride. The reaction was stirred at room temperature for 16 hours. The reaction was diluted with methylene chloride and extracted twice with 100 mL of 1 N NaOH. The organic layer was dried over anhydrous sodium sulfate, filtered, stripped in vacuo, and dried under high vacuum to give 1.97 g of the title compound as a pale yellow oil. 400 MHz ¹H NMR (CDCI₃) δ 7.2 -7.3 (m, 5H), 3.6 (d, 1H)₁ 3.5 (m, 3H), 3.3 (m, 2H), 2.3 (t, 2H), 2.2 (s, 3H), 1.4 (s, 9H), 1.3 (m, 2H), 0.7 (m, 1H); MS (M+1) 317.2.

PREPARATION 41

6- Methylaminomethyl-3-aza-bicvclo F3.1.01hexane -3-carboxylic acid tert-butyl ester

Under nitrogen was combined 1.97 g of 6-[(Benzyl-methyl-amino)-methyl]-3-aza- bicyclo [3.1.0]hexane -3-carboxylic acid tert-butyl ester, 3.92 g (62.1 mmol) of ammonium formate and 1.36 g (9.69 mmol) of 10% palladium hydroxide in 180 mL of EtOH. The suspension was heated to reflux for 4 hours. The reaction was cooled to room temperature, filtered over. Celite, and the solid was rinsed twice with EtOH. 25 drops of concentrated ammonium hydroxide was added to the filtrate. The filtrate was concentrated in vacuo, dried under high vacuum for 16 hours to give 1.35 g of the title compound as a colorless oil. 400

MHz ¹H NMR (CDCI₃) δ 3.6 (d, 1H), 3.5 (d, 1 H), 3.3 (t, 2H), 2.5 (m, 2H), 2.4 (s, 3H), 2.1

(broad s, 1 H), 1.4 (s, 9H), 1.3 (m, 2H), 0.8 (m, 1 H); MS (M+1 ) 227.2. PREPARATION 42

Dissolved 1.35 g (5.97 mmol) of 6- Methylaminomethyl-3-aza-bicyclo [3.1.0]hexane -3- carboxylic acid tert-butyl ester in 29.8 mL of 1 ,2-dichloroethane and added 500 μL (0.1 mmol) of this solution to 0.1 mmol of each aldehyde previously weighted into 2-dram vials. Added 0.3 mmol of sodium triacetoxyborohydride to the reactions, sealed the vials and placed them on a shaker at room temperature for 64 hours. To each vial was added 1.0 mL of 1 N NaOH and 1.0 mL of 1 ,2-dichloroethane. The mixtures were vortexed, the layers were allowed to separate, and the organic layers were removed and added to empty SPE barrels with eluents collected into tared 2-dram vials. The aqueous layers were extracted twice more with 1.0 mL of 1 ,2-dichloroethane and added to the SPEs. The samples were concentrated by evaporation and then were each diluted with 300 μL of THF followed by 300 μL of 4 M HCI in 1 ,4-dioxane. The vials were sealed and placed on a shaker at room temperature for 16 hours. The reactions were concentrated by evaporation.

PREPARATION 43

Combined 838 μL (6.0 mmol) of TEA with 5.2 mL of 1 ,2-dichloroethane and added

100 μL (0.1 mmol) of this solution to each product from Preparation 42. 961 mg (6.0 mmol) of 1-methyl-1 H-benzo[d]imidazole-2-carbaldehyde was dissolved in 30 mL of 1 ,2-dichloroethane and 500 μL (0.1 mmol) of this solution was added to each reaction vial followed by the addition of 0.3 mmol of sodium triacetoxyborohydride to each vial. The vials were sealed and placed on a shaker at room temperature for 64 hours. 1.0 mL of 1 ,2-dichloroethane was added to each vial, followed by 1.0 mL of 1 N NaOH, and the vials were vortexed for 4.5 minutes. The layers were allowed to separate and the organic layers were removed and transferred to empty SPE barrels, with eluents collected into tared 2-dram vials. The aqueous layer was extracted one more time with 1.0 mL of 1 ,2-dichloroethane, and the organic layers were transferred to the SPE barrels. The solvent was evaporated in a Savant for 16 hours. Products of Structure XXVII were purified by mass triggered preparative HPLC.

Examples prepared using method I' are listed in table 1. METHOD I2'

Example 23 (corresponding to entry 893 in table 1): (2,5-bis(trifluoromethvnphenvn-N-methyl-N-(((1S.5R.6r)-3-((1-methyl-1H- benzordiimidazol-Σ-vOmethvh-S-aza-bicvclorS.I.OIhexan-β-vOmethvQmethanamine

In a flask under N₂, added 720 mg (2.82 mmol) of (1 R,5S,6R)-3-((1-methyl-1H- benzofdJimidazol^-yOmethylJ-S-aza-bicyclop.i .OJhexane-δ-carbaldehyde to a solution of

1100 mg (4.28 mmol) of (2,5-bis(trifluoromethyl)phenyl)-N-methylmethanamine, 1.6 mL (11.2 mmol) of triethylamine in 10 mL of anhydrous 1 ,2-Dichloroethane at room temperature. After

15 minutes of stirring, 712 mg (3.36 mmol, 1.2 eq) of sodium triacetoxyborohydride was added and the suspension was stirred at room temperature for 67 hours. The suspension was diluted with CH₂CI₂ and extracted three times with 1 N NaOH. The organic layer was dried over anhydrous MgSO₄, filtered and stripped in vacuo to yellow oil. The crude material was purified via flash chromatography, eluting from 0% Methanol/Dichloromethane to 10%

Methanol/Dichloromethane to yield 830 mg of desired compound. 400 MHz ¹H NMR (CDCI₃) δ 8.2 (s, 1H), 7.7 (m, 2 H), 7.5 (d, 1H), 7.2- 7.3 (m, 3H), 3.9 (s, 2H), 3.8 (s, 3H), 3.7 (s, 2H), 2.8 (d, 2H), 2.5 (d, 2H), 2.3 (m, 5H), 1.2 (s, 3H); MS (M+1 ) 497.4.

METHOD J'

Example 24 (corresponding to entry 796 in table 1):

(2,5-bis(trifluoromethyl)phenyl)-N-(((1S,5R,6r)-3-((1-methyl-1H-ben2o[d]imidazol- 2-yl)methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl) amine In a flask under N₂, added 694 mg (2.7 mmol) of ((1S,5R,6R)-3-((1-methyl-1H- benzo[d]imidazol-2-yl)methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl) amine to a solution of 660 mg (2.7 mmol) of (2,5-bis(trifluoromethyl)benzaldehyde in 10 mL of ethanol at room temperature. After 18 hours of stirring, solvent is stripped in vacuo, 10 mL of 1 ,2-dichloroethane 687 mg (3.2 mmol, 1.2 eq) of sodium triacetoxyborohydride was added and the suspension was stirred at room temperature for 2 hours. The suspension was diluted with CH₂CI₂ and extracted three times with 1 N NaOH. The organic layer was dried over anhydrous MgSO₄, filtered and stripped in vacuo to yellow oil. The crude material was purified via flash chromatography, eluting from 0% methanol/Dichloromethane to 5% methanol/dichloromethane to yield 1016 mg of desired compound. 400 MHz ¹H NMR (CDCI₃) δ 8.0 (s, 1 H), 7.7 (triple, 2 H), 7.6 (d, 1 H), 7.2- 7.3 (m, 3H), 4.9 (s, 2H), 3.9 (s, 2H), 3.8 (s, 3H), 2.8 (d, 2H), 2.5 (d, 4H), 1.3 (m, 1 H), 1.2 (s, 2H); MS (M+1 ) 483.4. Example 25(corresponding to entry 797 in table 1):

N-(2,5-bis(trifluoromethyl)benzyl)-N-(((1S,5R_>6r)-3-((1-methyl-1 H- benzoIdlimidazol-Σ-yOmethyO-S-aza-bicycloIS.I.Olhexan-e-ylJmethyOpentan-i -amine

In a vial, added 33 mg (0.059 mmol) of N-(2,5-bis(trifJuoromethyl)benzyl)-((1S,5R,6R)- 3-((1-methyl-1 H-benzo[d]imidazol-2-yl)methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl) amine, 5 m!_ of 1 ,2-dichloroethane, 5.6 mg (0.065 mmol, 1.1 eq) of pentanal, 0.033 mL (0.23 mmol, 4 eq) of triethylamine, 15 mg (0.071 mmol, 1.2 eq) of sodium triacetoxyborohydride at room temperature. After 18 hours of stirring, the suspension was diluted with CH₂CI₂ and extracted three times with 1 N NaOH. The organic layer was dried over anhydrous MgSO4, filtered and stripped in vacuo to yellow oil. The crude material was purified via flash chromatography, eluting from 0% methanol/dichloromethane to 5% methanol/dichloromethane to yield 25 mg of desired compound. 400 MHz ¹H NMR (CDCI₃) δ 8.3 (s, 1 H), 7.7 (d, 1 H), 7.6 (d, 1 H), 7.4 (d, 1H), 7.2- 7.3 (m, 3H), 3.8 (s, 2H), 3.75 (s, 2H), 3.7 (s, 3H), 2.6 (d, 2H), 2.4 - 2.5 (m, 4H), 2.3 (d, 2H), 1.4 (m, 2H), 1.2 (m, 4 H), 1.13 (s, 2 H), 1.06 (m,1 H), 0.8 (m, 3 H); MS (M+1) 553.4.

Other examples prepared using method J' are listed in table 1. METHOD K' (SCHEME XVII)

Example 26 (corresponding to entry 792 in table 1):

1-Methyl-2-(((1S,5R, 6R)-6-((2-o-tolylpyrrolidin-1-yl)methyl)-3-aza- bicyclo[3.1.0]hexan-3-yl)methyl)-1H-benzo[d]imidazole

In a 10 mL CEM microwave vial was combined 30 mg (0.11 mmol, 1 eq) of 2- (((IS.δR.eRVδ-^hloromethyO-S-aza-bicyclotS.I .Olhexan-S-yOmethyO-i-methyl-I H- benzo[d]imidazole, 81 mg (0.50 mmol, 4.6 eq) of 2-o-tolylpyrrolidine, 30 mg of potassium carbonate (0.22 mmol, 2 eq) and catalytic amount of tetrabutylammonium bromide in 1 mL of anhydrous Tetrahydrofuran at room temperature. The vial was heated to 200⁰C for 10 minutes under microwave (CEM Explorer). The mixture was purified via flash chromatography, eluting from 0% Methanol/Dichloromethane to 10% methanol/dichloromethane to yield 39 mg of desired compound. 400 MHz ¹H NMR (CDCI₃) δ 7.70 (d, 1 H), 7.68 (d, 1 H), 6.94 - 7.30 (m, 4H), 3.82 (d, 2H), 3.74 (s, 3H), 3.38 (m, 2H), 2.8 (d, 2H), 2.68 (d, 2 H), 2.4 (m, 3H), 2.27 (s,3 H), 2.18 (m, 2 H), 1.75 - 1.89 (broad, 3 H), 1.06 - 1.60 (m, 3H); MS (M+1 ). 405.2 METHOD L' (SCHEME XX)

PREPARATION 44 tert-Butyl(1 R,5S,6s)-3-((1 -methyl-1 H-benzo[d]imidazol-2-yl)methyl)-3-aza- bicyclo[3.1.0]hexan-6-ylcarbamate To a solution of 1 -methyl-1 H-benzo[d]imidazole-2-carbaldehyde (3 g, 18.73 mmol) in

100 ml dichloroethane, (3-Aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester (3.71 g, 18.73 mmol) was added and the mixture was stirred under N₂ for one hour at room temperature. Then, sodium triacetoxyborohydride (5.93 g, 28.1 mmol) was added into the mixture sequentially. The mixture was stirred at room temperature overnight. The mixture was washed by saturated sodium bicarbonate aqueous solution, and then extracted by dichloromethane, washed by brine and dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated under reduced pressure to yield tert-butyI(1 R,5S,6s)-3-((1-methyl- 1H-benzo[d]imidazol-2-yl)methyl)-3-aza-bicyclo[3.1.0] hexan-6-ylcarbamate (6.14 g); MS⁺ 343.1. PREPARATION 45

Hydrochloride salt of (1R,5S,6s)-3-((1 -methyl-1 H-benzo[d]imidazol-2-yl)methyl)- 3-aza-bicyclo[3.1.0]hexan-6-amine

To a solution of tert-butyl(1R,5S,6s)-3-((1 -methyl-1 H-benzo[d]imidazol-2-yl)methyl)-3- aza-bicyclo[3.1.0]hexan-6-ylcarbamate (1.01 g, 2.95 mmol) in 5 ml of dichloromethane, 5 ml of 4 N hydrochloride in dioxane and 5 ml methanol were added into the solution. After addition, reaction mixture was stirred for one and half hour under room temperature. The mixture was filtered over celite and concentrated under reduced pressure to yield hydrochloride salt of (1R,5S,6S)-3-((1 -methyl-1 H-benzo[d]imidazol-2-yl)methyl)-3-aza- bicyclo[3.1.0]hexan-6-amine (1.1 g). MS⁺ 243.1. Example 27 (Corresponding to entry 813 in table 1) :

(1 R,5S,6S)-N-(2-f luoro-3-(trif luoromethvnbenzvn-3-((1 -methyl-1 H- benzord1imidazol-2-yl)methyl)-3-aza-bicvclor3.1.01hexan-6-amine

To a solution of 2 ml ethanol, hydrochloride salt of (1 R,5S,6S)-3-((1 -methyl-1 H- benzo[d]imidazol-2-yl)methyl)-3-aza-bicyclo[3.1.0]hexan-6-amine (50 mg, 0.179 mmol), 2- fluoro-3-(trifluoromethyl)benzaldehyde (34.5 mg, 0.179 mmol) and triethyl amine (90.8 mg, 0.898 mmol) was added sequentially. The mixture was stirred under room temperature for 30 minutes, then it was flushed by nitrogen and 6 ml of ethanol was added into. The reaction mixture was then hydrogenated under 45 psi for three hours. The mixture filtered over diatomaceous earth and the solvent was removed in vacuo. The residue purified using silica gel chromatography (0% to 5% MeOH/CH₂CI₂) to yield (1R,5S,6s)-N-(2-fluoro-3- (trifluoromethyl)benzyl)-3-((1-methyl-1 H-benzo[d]imidazol-2-yl)methyl)-3-aza- bicyclo[3.1.0]hexan-6-amine (44.2 mg). MS (M+1) 419.4. Example 28 (corresponding to entry 878 in table 1):

(M R,5S,6s)-N-(2-fluoro-3-(trifluoromethyl)benzyl)-N-methyl-3-((1 -methyl-1 H- benzord1imidazol-2-yl)methyl>-3-aza-bicvclor3.1.01hexan-6-amine

To a solution of (1R,5S,6S)-N-(2-fluoro-3-(trifluoromethyl)benzyl)-3-((1 -methyl-1 H- benzo[d]imiclazol-2-yl)methyl)-3-aza-bicyclo[3.1.0]hexan-6-amine (50 mg, 0.1 mmol) in 2 ml dichloroethane, paraformaldehyde (30 mg, 0.33 mmol) and triethyl amine (72.5 mg, 0.71 mmol) were added sequentially and the mixture was stirred for one hour at room temperature. Then, sodium triacetoxyborohydride (50 mg, 0.23 mmol) was added into the mixture. The mixture was stirred at room temperature over night. The mixture was purified using silica gel chromatography (0% to 5% MeOH/CH₂CI₂) to yield ((1 R,5S,6s)-N-(2-fluoro-3- (trifluoromethyl)benzyl)-N-methyl-3-((1 -methyl-1 H-benzo[d]imidazol-2-yl)methyl)-3-aza- bicyclo[3.1.0]hexan-6-amine, and converted to corresponding hydrochloride salt (25.6 mg); MS⁺ 433.4.

Table 1 - Examples with Data

The following specific compounds were prepared following the similar procedures of the preparations and examples described above.

O. Biological Protocols

In vitro assays

Procedure for mGluR2 Potentiator Screen NLB methods EC10-EC20 challenge

Cell Culture and Plating:

Cells used for this screen are HEK cells stably transfected with the mGluR2 receptor (metabotropic glutamate receptor 2) and the Gα15 G protein. Clones were identified by functional activity (FLIPR). Cells are grown in growth media containing: DMEM High Glucose with Glutamine and Na Pyruvate (GIBCO), 10% (v/v) Heat inactivate FBS (GIBCO), G418 500 ug / ml (from 50 mg/ml stock) (GIBCO) and Blasticidin 3 ug / ml (from 5 mg/ml stock made in H₂O) (Invitrogen).

2 days before the assay cell are trypsinized with 0.25% trysin/EDTA (GIBCO), spun down at 1000 rpm for 5 minutes, resuspended in growth media and plated on polystyrene 384 well black wall / clear bottom poly-D-lysine coated plates at a density of approximately 18,000 cells / well in a volume of 50 μl_ per well. One day before the assay the growth media is removed from the plates by flicking, and replaced with media containing DMEM High Glucose without Glutamine and Na Pyruvate (GIBCO) and 10% (v/v) dialyzed FBS (GIBCO). The reason for the removal of glutamine the day before the assay is to minimize the amount of glutamate that will be present during the assay, as endogenous glutamate released from the cells can reduce the fluorescent response and interfere with the FLIPR screen.

FLIPR Methods and Data Analysis:

On the day of the assay, the FLIPR assay is performed using the following methods:

Assay buffer:

Compound g/L MW [ ] (concentration)

NaCl 8.47 58.44 145 mM

Glucose 1.8 180.2 1O mM

KCI .37 74.56 5 mM

MgSO₄ 1 ml IM Stock 246.48 1 mM

HEPES 2.38 238.3 1O mM CaCI₂ 2 ml 1 M Stock 110.99 2 mM

The pH is adjusted to 7.4 with 1 M NaOH. Prepare a 2 mM (approx.) stock solution of

Fluo-4,am (Molecular Probes) dye in DMSO - 22 μl_ DMSO per 50 ug vial (440 μl_ per 1 mg vial). Make a 1 mM (approx.) flou-4, PA working solution per vial by adding 22 μl of 20% pluronic acid (PA) (Molecular Probes) in DMSO to each 50 ug vial (440 μL per 1 mg vial).

Prepare a 250 mM Probenecid (Sigma) stock solution by dissolving 0.71 g into 5 ml 1N NaOH and 5 ml assay buffer (for each liter of assay wash buffer). Make 4 uM (approx.) dye incubation media by adding 2 50 ug vials per 11 ml DMEM high glucose without glutamine

(220 ml per 1 mg vial). Add 110 μl probenecid stock per 11 ml (2.5 mM final [concentration]). To the dye media add 3 units / ml of glutamic-pyruvic transaminase (GPT, Sigma) and 3 mM Na Pyruvate. The assay has worked with dye concentrations from 2 uM to 8 uM dye as well. To the assay buffer from drug preparation, add 1.83 mis DMSO and 400 μL 15.8% P104 (from New Leads biology) per liter for final concentrations of 0.18% DMSO and 0.006% P104. To the assay buffer for cell washing, add probenecid in the same manner and concentration that was used for the dye media.

Remove growth media from cell plates by flicking. Add 50 μl / well dye solution. Incubate 1 hour at 37 ⁰C and 5% CO₂. Remove dye solution and wash 3 times with assay buffer + probenecid (100 μL probenecid stock per 10 ml buffer), leaving 30 μL / well assay buffer. Wait at least 10-15 minutes. Compounds and agonist challenge additions are performed with the FLIPR. The 1^st addition is for test compounds, which are added as 15 μL of 4X [concentration] of potentiator. The second 2^nd addition is 15 μL of 4X [concentration ] of agonist or challenge. This achieves 1X concentration of all compounds only after 2^nd addition. The 1^st and 2^nd additions are performed separately using the FLIPR, which give 2 different data files. Compounds are pretreated at least 30 minutes before agonist addition. Results are analyzed by dividing the peak fluorescent value of the FLIPR response by the time point after agonist addition to achieve a ratio response. The ratios are then analyzed by curve fitting programs. Since potent compounds can give an inverted U dose response curve (due to effects on endogenous glutamate by the potentiators), points are deleted at concentrations higher than the concentration that gives the maximum effect. Maximum values for dose response curves (forced fitting) are derived from standards on the plate.

Compound Preparation and Glutamate Challenge:

Compounds are delivered as 10 mM DMSO stocks or as powders. Powders are solubilized in DMSO at 10 mM (as solubility allows). Compounds are sonicated in a heated water bath (35-40 ⁰C) for at least 20 minutes. Compounds are then added to assay drug buffer as 40 μL top [concentration] (4X the 10 uM top screening concentration).

In order to test compounds against an EC10 to EC20 concentration of glutamate, multiple glutamate challenge plates for the 2^nd FLIPR addition are prepared. The best challenge for a particular assay is determined by examining the glutamate dose response and 1-4 test plates.

EC_{5 0} values of the compounds of the invention are preferably 10 micromolar or less, more preferably 1 micromolar or less, even more preferably 100 nanomolar or less. When introducing elements of the present invention or the exemplary embodiment(s) thereof, the articles "a," "an," "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations to the invention, the scope of which is defined by the appended claims.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

Formula I wherein:

Y₁ is selected from the group consisting of O, C(H)R¹⁸ and NR¹⁸, wherein R¹⁸ is selected from the group consisting of hydrogen, S(O)R , S(O)₂R , alky!, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl, wherein the R¹⁸ alky), alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R¹⁰¹, -OR¹⁰¹, and -NR¹⁰¹R¹⁰²;

-X²- represents a bond or is -C(O)-, S(O)₂ or -(CHR¹)_n1- n1 = 1 , 2, or 3; n = 0, 1 , 2, or 3 each R¹ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, and cycloalkenyl, wherein each R¹ aikyl, alkenyl, cycloalkyl, or cycloalkenyl is optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R¹⁰¹, -OR¹⁰¹, -NR¹⁰¹R¹⁰², C(O)NR¹⁰¹R¹⁰², NR¹⁰¹C(O)R¹⁰³, and C(O)R¹⁰³; each R and each R is independently at each occurrence selected from the group consisting of hydrogen, alky), alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; wherein each R¹⁰¹ and R¹⁰² alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl optionally substituted with one or more halogen or alkoxy or aryloxy, aryl optionally substituted with one or more halogen or alkoxy or alkyl or trihaloalkyl, heterocycloalkyl optionally substituted with aryl or heteroaryl or =O or alkyl optionally substituted with hydroxy, cycioalkyl optionally substituted with hydroxy, heteroaryl optionally substituted with one or more halogen or alkoxy or alky! or trihaloalkyl, hydroxyalkyl, alkoxy, aryloxy ; each R¹⁰³ is independently at each occurrence selected from the group consisting of alkyl, alkenyl, cycioalkyl, aryl, heterocycloalkyl and heteroaryl and is independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl optionally substituted with one or more halogen or alkoxy or aryloxy, aryl optionally substituted with one or more halogen or alkoxy or alkyl or trihaloalkyl, heterocycloalkyl optionally substituted with aryl or heteroaryl or =0 or alkyl optionally substituted with hydroxy, cycioalkyl optionally substituted with hydroxy, heteroaryl optionally substituted with one or more halogen or alkoxy or alkyl or trihaloalkyl, hydroxyalkyl, alkoxy, aryloxy ;

R² is selected from the group consisting of alkyl, aryl, heterocycloalkyl, cycioalkyl and heteroaryl wherein the R² substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R²⁰¹, - C(O)R²⁰³, -C(O)NR²⁰¹R²⁰², -OR²⁰¹, -NR²⁰¹R²⁰², -NR²⁰¹C(O)R²⁰³, -NR²⁰¹C(O)OR²⁰³; each R²⁰¹ and each R²⁰² is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycioalkyl, aryl, heterocycloalkyl and heteroaryl; each R²⁰³ is independently selected from the group consisting of alkyl, alkenyl, cycioalkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R²⁰¹, R²⁰² and R²⁰³ alkyl, alkenyl, cycioalkyl, aryl, heterocycloalkyl and heteroaryl are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, -R²¹¹,

-C(O)R²¹³, -C(O)OR²¹³ , -C(O)NR²¹¹R²¹², -OR²¹¹, -OC(O)R²¹³, -NR²¹¹R²¹², -NR²¹¹C(O)R²¹³, -NR²¹¹C(O)OR²¹³, -NR²¹¹S(O)₂R²¹³, -S(O)₅R²¹³, -S(O)₂NR²¹¹R²¹² ; s is 0, 1 or 2; each R²¹¹ and each R²¹² is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycioalkyl, aryl, heterocycloalkyl and heteroaryl, each R²¹³ is independently selected from the group consisting of alkyl, alkenyl, cycioalkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R²¹¹, R²¹² and R²¹³ alkyl, cycioalkyl, aryl, heterocycloalkyl and heteroaryl substituents are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkenyl, aryl, heterocycloalkyl, heteroaryl, haioalkyi, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl;

R¹⁷ is selected from the group consisting of alkyl, alkenyl, cycioalkyl, and cycloalkenyl, wherein the R¹⁷ alkyl, alkenyl, cycioalkyl, or cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R⁵⁰¹, -OR⁵⁰¹, -NR⁵⁰¹R⁵⁰², -S(O)_VR⁵⁰³ , -S(O)₂ NR⁵⁰¹R⁵⁰², -NR⁵⁰¹ S(O)₂R⁵⁰³, OC(O)R⁵⁰³,-C(O)OR⁵⁰³, C(O)NR⁵⁰¹R⁵⁰², NR⁵⁰¹C(O)R⁵⁰³, and C(O)R⁵⁰³; v is 0, 1 or 2; wherein each R⁵⁰¹ and each R⁵⁰² is independently selected from the group consisting of hydrogen, alky], alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl; and wherein each R⁵⁰³ is independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl;

R⁴, R⁵' R⁶ and R⁷ are each independently selected from the group consisting of halogen, cyano, -R⁴⁰¹, -C(O)OR⁴⁰¹, -C(O)NR⁴⁰¹R⁴⁰², -OR⁴⁰¹, -OC(O)R⁴⁰², -NR⁴⁰¹R⁴⁰², and -NR⁴⁰¹C(O)R⁴⁰²; wherein each R⁴⁰¹ and each R⁴⁰² is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl; wherein the R⁴⁰¹ and R⁴⁰² alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl substituents are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R⁴¹¹, -C(O)R⁴¹³-C(O)OR⁴¹³ , -C(O)NR⁴¹¹R⁴¹², -OR⁴¹¹, -OC(O)R⁴¹³, -NR⁴¹¹R⁴¹²,

-NR⁴¹¹C(O)R⁴¹³, -NR⁴¹¹C(O)OR⁴¹³, -NR⁴¹¹S(O)₂R⁴¹³, -S(O)₁R⁴¹³, -S(O)₂NR⁴¹¹R⁴¹²; t is O, 1 or 2; each R⁴¹¹ and each R⁴¹² is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl ; each R⁴¹³ Is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R⁴¹¹, R⁴¹² and R⁴¹³ alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl substituents are each independently optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl; or wherein

(a)R^1T and R⁷, taken together with the atoms connecting R¹⁷ and R⁷, form a 5-8 membered heterocyclic ring or

(b) R⁴ and R⁵, taken together with the atoms connecting R⁴ and R⁵, form a 5-8 membered heterocyclic or carbocyclic ring; or

(c) R⁵ and R⁶, taken together with the atoms connecting R⁵ and R⁶, form a 5-8 membered heterocyclic or carbocyclic ring; or (d) R⁶ and R⁷, taken together with the atoms connecting R⁶ and R⁷, form a 5-8 membered heterocyclic or carbocyclic ring; and

R⁸ is hydrogen, flourine or alkyl optionally substituted with one or more fluorines.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Yi is O.

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y₁ is C(H)R¹⁸.

4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y₁ is NR¹⁸.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula Il

formula Il wherein

-X²- is a bond or -CO-; and

R¹⁷ is selected from the group consisting of alky! and cycloalkyl; wherein the R¹⁷ alkyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, -R¹⁰¹, -OR¹⁰¹, -NR¹⁰¹R¹⁰², -S(O)_VR¹⁰¹, and -C(O)OR¹⁰¹; or R¹⁷ and R⁷, taken together with the atoms connecting R¹⁷ and R⁷, can form a 5-8 membered heterocyclic ring.

6. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein each of R⁴, R⁵, R⁶ and R⁷ is independently is selected from the group consisting of hydrogen, cyano and halogen.

7. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R¹⁷ is selected from the group consisting of alkyl and cycloalkyl, wherein the R¹⁷ alkyl and cycloalkyl substituent is optionally substituted as in the compound of claim 5.

8. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the formula III,

formula Il I wherein:

R¹⁷ is selected from the group consisting of alky! and cycloalkyl; wherein the R¹⁷ alkyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl;

R⁴ is selected from the group consisting of hydrogen and halogen;

R⁵ is selected from the group consisting of hydrogen, halogen, cyano, alkyl, amino, heterocycloalkyl and heteroaryl;

R⁶ is selected from the group consisting of hydrogen, halogen, cyano, alkyl, heterocycloalkyl and heteroaryl;

R⁷ is selected from the group consisting of hydrogen, halogen, alkyl, aryl, heterocycloalkyl and heteroaryl; and wherein the R⁵, R⁶, or R⁷ alkyl, heterocycloalkyl, heteroaryl and aryl are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl.

9. A compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R² is aryl, optionally substituted as in the compound of claim 8.

10. A compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R² is phenyl or naphthalenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R²⁰¹, - C(O)R²⁰¹, -C(O)OR²⁰VOR²⁰¹, -NR²⁰¹R²⁰²;

R²⁰¹, R²⁰² are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R²⁰¹ and R²⁰² alkyl, cycloalkyl, aryl , heterocycloalkyl and heteroaryl substituents are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R²¹¹, -C(O)R²¹¹, -OR²¹¹, -NR²¹¹R²¹², -S(O)₃R²¹¹; s = 0, 1 , 2;

R²¹¹, R²¹² are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; and wherein the R ₁ R and R alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl substituents are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkenyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl.

11. A compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R² is phenyl or naphthalenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R²⁰¹, -

OR²⁰¹; each R²⁰¹substituent is independently selected from the group consisting of alkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R²⁰¹ alkyl, aryl , heterocycloalkyl and heteroaryl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R²¹¹, -C(O)R²¹¹, and -OR^211; each R²¹¹ is independently selected from the group consisting of alkyl and aryl, wherein R²¹¹ alkyl and aryl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl.

12. A compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R² is heterocycloalkyl or heteroaryl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen and alkyl, wherein the alkyl is optionally substituted with one or more halogen substituents.

13. A compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R¹⁷ is selected from the group consisting of alkyl and cycloalkyl; wherein the R¹⁷ alkyl and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl;

R² is selected from the group consisting of alkyl, aryl, heterocycloalkyl, cycloalkyl and heteroaryl, wherein R² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl; R⁴ is selected from the group consisting of hydrogen and halogen;

R⁵ is selected from the group consisting of hydrogen, halogen, cyano, alkyl, haloalkyl, amino, heterocycloalkyl and heteroaryl ; R⁶ is selected from the group consisting of hydrogen, halogen, cyano, alkyl, aryl, heterocycloalkyl and heteroaryl; and

R⁷ is selected from the group consisting of hydrogen, halogen, alkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R⁵, R⁶ or R⁷ alkyl heterocycloalkyl and heteroaryl are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl.

14. A compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R¹⁷ is methyl;

R² is phenyl; wherein the R² substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl;

R⁴ is hydrogen, fluoro or bromo; R⁵ is hydrogen, cyano, halogen, methyl or amino; R⁶ is selected from the group consisting of hydrogen, bromo, fluoro, cyano, methyl, methoxy and methoxypyridinyl; and R⁷ is selected from the group consisting of bromo, fluoro, phenyl and methoxypyridinyl.

,

15. A compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R¹⁷ is methyl, cyclopropyl, fiuoroethyl, fluoromethyl, methoxyethyl or methoxymethyl;

R² is selected from the group consisting of alkyl, aryl, heterocycloalkyl, cycloalkyl and heteroaryl, wherein R² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl; R⁴ is hydrogen; R⁵ is hydrogen; R⁶ is hydrogen; and R⁷ is hydrogen.

16. A compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein R² is aryl or heteroraryl wherein R² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyi, carboxy, alkoxy and alkoxycarbonyl.

17. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein

-X²- is a bond and

R² is selected from the group consisting of the following substituents:

2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2-chloro-4,5- dimethylphenyl, 2-chloro-4-butylphenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 2- chloro-5-trifluoromethyl, 2-fluoro-4-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl, 2-fluoro-6- chlorophenyl, 2-trifluoromethylphenyl, phenyl, phenylphenyl, quinolinyl, tetrahydronaphthalenyl, 2,3,6-trifluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6- difluorophenyl, 2-chloro-5-trifluoromethylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3,4- difluorophenyl , 3,5-dichlorophenyl, 3,5-ditrifluoromethylphenyl, 3-chlorophenyi, 3- fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-chloro-5- trifluorophenyl, 3-phenylphenyl, 2,5,6-trifluorophenyl, 2,4-dichlorophenyl, 3,5- trifluoromethylphenyl, isoquinolinyl, ([3-fluorophenyl, 5-propyl]triazoiy))phenyl, 1-chloro-5- methyiphenyl, 2,3,4-trifluorophenyl, 2,3,5-trimethylphenyi, 2,3-dichloro-4-fluorophenyl, 2,3- difluoro-4-methylphenyl, 2,3-dimethyl-4-fluorophenyl, 2,3-dimethyiphenyl, 2,4- dimethoxyphenylphenyl, 2,4-dimethylphenyl, 2,5-dimethoxyphenylphenyl, 2,5-dimethylphenyl, 2,5-dimethyIphenylphenyl, 2,6-difluoro-3-methylphenyl, 2,6-difluorophenyl, 2,5- difluorophenylphenyl, 2-benzisoxazolyl-4-chloro-5-methylphenyl, 2-benzotriazolyI-4- methylphenyl, 2-benzthiazolyl-4-methoxyphenyl, 2-benzthiazolyl-5-methylphenyl, 2- benzthiazolyl-6-methylphenyl, 2-bromo-4-phenylphenyl, 2-chloro-3,4-difluorophenyl, 2-chloro- 3-cyano-4-fluorophenyl, 2-chloro-3-ethenyl-4-fluorophenyl, 2-ch!oro-3-ethyl-4-fluorophenyl, 2- chioro-3-fluorophenyl, 2-chloro-3-methyl-4-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chIoro-4- phenylphenyl, 2-cyano-3-chloro-4-fluorophenyl, 2-cyano-4-fluorophenyl, 2-cyanophenyl, 2- cyclopropyl-4-fluorophenyl, 2-ethoxyphenyl, 2-ethyl-3-chloro-4-fluorophenyl, 2-ethyl-4,5- dimethylphenyl, 2-ethy!-4-methylphenyl, 2-fluoro-3-ch)orophenyl, 2-fluoro-4- methylphenylphenyl, 2-fluoro-5-methylcarbonylphenylphenyl, 2-fluoro-5-methylphenyl, 2- fluoro-5-methylphenylphenyl, 2-fluorophenylphenyl, 2-isoxazoIyl-4,6-dichlorophenyl, 2- isoxazolyl-4-bromophenyl, 2-isoxazolyl-4-chlorophenyl, 2-isoxazolyl-4-methyIphenyl, 2- methoxy-3-methyl-4-fluoropheny!, 2-methoxy-4-cyanophenyl, 2-methoxy-4-fluoropheny!, 2- methoxy-4-methylphenyl, 2-methoxy-5-chlorophenylphenyl, 2-methoxy-5-cyanophenylphenyl, 2-methoxy-5-fluorophenylphenyI, 2-methoxy-5-methylphenyl, 2-methoxy-6-fluorophenyl, 2- methoxy phenyl, 2-methoxyphenylphenyI, 2-methyl-3,4-difluorophenyl, 2-methyl-3-chloro-4- fluorophenyl, 2-methyl-3-methoxy-4-fluorophenyl, 2-methyl-4-chlorophenyl, 2-methyl-4- fluorophenyl, 2-methyl-4-methylphenyl, 2-methyl-5-fluorophenylphenyl, 2-methyl-6- chlorophenyl, 2-methylphenyl, 2-methylpheny!phenyl, 2-methylpyrimidinyl, 2-phenyl, A- butylphenyl, 2-propylphenyl, 2-trifluoromethoxyphenylphenyl, 2-trifluoromethyIphenylphenyl, 3,4-dichlorophenyl, 3,4-dichIorophenylcarbonyl, 3,4-dicyanophenyl, 3,4-difluorophenylphenyl, 3,4-dimethoxyphenylphenyI, 3,4-dimethylphenyl, 3,5-difluorophenyl, 3,5-dibutylphenylphenyl, 3,5-difluorophenyl, 3,5-dimethyl-4-cyanophenyl, 3,5-dimethylpheny), 3-butylphenyl, 3-chloro- 4-cyanophenylphenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methylphenyl, 3-cyano-4- fluorophenylphenyl, 3-cyano-4-methoxyphenylphenyl, 3-cyanophenyl, 3-ethoxyphenyl, 3- ethylphenyl, 3-fluoro-4-chlorophenyl, 3-fluoro-4-cyanophenyl, 3-fluoro-4-cyanophenylphenyl, 3-fluoro-4-methoxyphenylphenyl, 3-fluoro-4-methylphenylphenyl, 3-fluorophenylphenyl, 3- methoxyphenyl, 3-methoxyphenylphenyl, 3-methyl-4-chlorophenyl, 3-methyl-4-fluorophenyl, 3-methyl-4-methoxyphenyIphenyl, 3-propylphenyl, 3-trifluoromethyl-4-methoxyphenylphenyl, 3-trifluoromethylphenylphenyl, 4-butylphenyl, 4-chlorophenylcarbonyl, 4-cyanoethylphenyl, 4- cyanomethylphenyl, 4-cyanophenyl, 4-cyanophenylphenyl, 4-ethylphenyl, 4-flυoro-3- methylphenylphenyl, 4-fluorophenylcarbonyl, 4-fluorophenylphenyl, 4-methoxy-3- fluorophenylphenyl, 4-methoxy-3-trifluoromethylphenylphenyl, 4-methoxymethylphenyl, 4- methoxyphenyl, 4-methoxyphenylcarbonyl, 4-methoxyphenylphenyl, 4-methylphenyl, 4- propylpheπyl, beπzo[d][1 ,3]dioxolylphenyl, benzofuranylphenyl, benzthiazoiylphenyl, bromopyridinyl, chlorophenyltriazolylphenyl, chloropyridinyl, cyanophenylphenyl, dibenzo[b,d]furanyl, difluoromethoxyphenylphenyl, dihydro-1 H-indenyl, dihydrobenzofuranyl, ethoxyphenyl, fluorodihydrobenzofuranyl, fluorodihydroindenyl, fluoronaphthalenyl, imidazolylphenyl, isoxazolylphenyl, methoxyphenylphenyl, methylbenzothiazolylphenyl, methylcarbonylbenzofuranylphenyl, methylcarbonylphenylphenyl, methylcarbonylthiophenyl, methyldihydro-1 H-indenyl, methyldihydrobenzo[b][1 ,4]oxazinylphenyl, methylindolyl, methylphenylphenyl, methylpyrazolylphenyl, methylpyridinyl, methylquinolinylphenyl, methylthiazolylphenylphenyl, methylthiopyrimidinyl, naphthalenyl, oxazolylphenylphenyl, oxodihydro-1H-indenylphenyl, phenylcarbonyl, propylphenyl, propylphenylphenyl, propylpyridinyl, pyridinyl, pyrrolylphenyl, quinolinylphenyl, quinoxalinyl, quinoxalinylphenyl, thiadiazolylphenyl, thiadiazolylphenylphenyl, triazolylphenyl, trifluoromethoxyphenylphenyl, trifluoromethylphenyl, trifluoromethylphenylphenyl, trifluoromethylpyridinyl and 2,4,5- trifluorophenyl.

18. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R¹⁷ is selected from the group consisting of cyclopropyl, fluoroethyl, fluoromethyl, methoxyethyl, methoxymethyl and methyl.

19. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R⁸ is hydrogen or alkyl.

20. A compound selected from the group consisting of the compounds disclosed in Table 1 , or a pharmaceutically acceptable salt thereof.

21. A method for the treatment or prevention of a condition selected from the group consisting of cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine, urinary incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, mood disorders, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, tardive dyskinesia, sleep disorders, attention deficit/hyperactivity disorder, and conduct disorder in a mammal, comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to the mamma).

22. A method for treating or preventing neurological and psychiatric disorders associated with glutamate dysfunction, comprising administering to a patient in need thereof an amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, effective in treating such disorders.

23. The method of claim 21, further comprising administering a metabotropic glutamate receptor agonist.

24. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. A composition for treating or preventing a condition selected from the group consisting of cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine, urinary incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, mood disorders, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, tardive dyskinesia, sleep disorders, attention deficit/hyperactivity disorder, and conduct disorder in a mammal, wherein the composition contains an amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in the treatment or prevention of such conditions.

26. The composition of claim 25, further comprising a metabotropic glutamate receptor agonist.