WO2007135529A2 - Azabenzimidazolyl compounds as mglur2 potentiators - Google Patents

Azabenzimidazolyl compounds as mglur2 potentiators Download PDF

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WO2007135529A2
WO2007135529A2 PCT/IB2007/001293 IB2007001293W WO2007135529A2 WO 2007135529 A2 WO2007135529 A2 WO 2007135529A2 IB 2007001293 W IB2007001293 W IB 2007001293W WO 2007135529 A2 WO2007135529 A2 WO 2007135529A2
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alkyl
group
aryl
heteroaryl
heterocycloalkyl
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PCT/IB2007/001293
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WO2007135529A3 (en
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Helen Berke
Allen Jacob Duplantier
Ivan Viktorovich Efremov
Stanton Furst Mchardy
Weimin Qian
Bruce Nelson Rogers
Lei Zhan
Qian Zhang
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Pfizer Products Inc.
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Publication of WO2007135529A3 publication Critical patent/WO2007135529A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems

Definitions

  • the present invention comprises a novel class of azabenzimidazolyl 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.
  • 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 pheromo ⁇ e receptors, and taste receptors (Pin et al., Pharmacol. Then, 2003, 98, 325-354).
  • GPCR G-protein coupled receptor
  • 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 111 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.
  • Allosteric ligands 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.
  • 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.
  • 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.
  • 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 general
  • the invention is directed to a class of compounds, including the pharmaceutically acceptable salts of the compounds, having the structure of formula I:
  • Y 1 is selected from the group consisting of O, C(H)R 18 and NR 18 , wherein R 18 is selected from the group consisting of hydrogen, S(O)R 103 , S(O) 2 R 103 , alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl, wherein the R 18 alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl is heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R 101 , -OR 101 , -NR 101 R 102 ;
  • each R 1 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, and cycloalkenyl, wherein each R 1 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, -R 101 , -OR 101 , -NR 101 R 102 , C(O)NR 101 R 102 , NR 101 C(O)R 103 , and C(O)R 103 ; each R 101 and each R 102 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heterocyclo
  • R 2 is selected from the group consisting of alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl wherein the R 2 substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R 201 , - C(O)R 203 , -C(O)NR 201 R 202 , -OR 201 , -NR 201 R 202 , -NR 201 C(O)R 203 , -NR 201 C(O)OR 203 ; each R 201 and each R 202 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; each R 203 is independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R 201
  • each R 211 and each R 212 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, each R 213 is independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R 211 , R 212 and R 213 alky
  • R 17 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, and cycloalkenyl, wherein the R 17 alkyl, alkenyl, cycloalkyl, or cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R 501 , -OR 501 , -NR 501 R 502 , -S(O ⁇ R 503 , -S(O) 2 NR 501 R 502 , -NR 501 S(O) 2 R 503 , -OC(O)R 503 ,-C(O)OR 503 , -C(O)NR 501 R 502 , -NR 501 C(O)R 503 , and -C(O)R 503 ; v is 0, 1 or 2; wherein each R 501 and each R 502 is independently selected from the group consisting of hydrogen
  • X 4 N or CR 7
  • X 9 N or CR 6
  • X 6 N or CR 4 wherein one or two of X 4 , X s , X 6 and X 9 are N;
  • R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of halogen, cyano, -R 401 , -C(O)OR 401 , -C(O)NR 401 R 402 , -OR 401 , -NR 401 R 402 , and -NR 401 C(O)R 402 ; wherein each R 401 and each R 402 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl; wherein the R 401 and R 402 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, -R 411 , -C(O)R 413 -C
  • each R 411 and each R 412 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl ; each R 413 is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R 411 , R 412 and R 413 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, heterocyclo
  • R 17 and R 7 taken together with the atoms connecting R 17 and R 7 , form a 5-8 membered heterocyclic ring
  • R 4 and R 5 taken together with the atoms connecting R 4 and R 5 , form a 5-8 membered heterocyclic or carbocyclic ring
  • R 5 and R 6 taken together with the atoms connecting R 5 and R 6 , form a 5-8 membered heterocyclic or carbocyclic ring
  • R 6 and R 7 taken together with the atoms connecting R 6 and R 7 , form a 5-8 membered heterocyclic or carbocyclic ring; and R 8 is hydrogen, fluorine or alkyl, wherein R 8 alkyl is optionally substituted with one or more fluorines.
  • R 2 is selected from the group consisting of aryl, heterocycloalkyl, cycloalkyl and heteroaryl, optionally substituted as defined in formula I.
  • R 17 is selected from the group consisting of alkyl and cycloalkyl; wherein the R 17 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;
  • R 4 is selected from the group consisting of hydrogen and halogen;
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, alkyl, amino, heterocycloalkyl and heteroaryl ;
  • R 6 is selected from the group consisting of hydrogen, halogen, cyano, alkyl, heterocycloalkyl and heteroaryl
  • R 7 is selected from the group consisting of hydrogen, halogen, alkyl, aryl, heterocycloalkyl and heteroaryl
  • the R 5 , R 6 or R 7 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.
  • R 401 and R 402 are each independently selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl
  • the compound of formula I has the formula II,
  • -X 2 - is a bond or -CO-
  • R 17 is selected from the group consisting of alkyl and cycloalkyl; wherein the R 17 alkyl and cycloalkyl substituents are substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, -R 101 , -OR ,101 -NR 101 R 102 ,
  • one of X 4 , X 9 , X 5 and X 6 is N and three of R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, wherein the R 5 , R 6 or R 7 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl substituents are each optionally independently substituted as in the compound of formula I.
  • three of R 4 , R 5 , R 8 and R 7 are each independently selected from the group consisting of hydrogen and halogen.
  • R 17 is selected from the group consisting of alkyl and cycloalkyl, wherein the R 17 alkyl and cycloalkyl substituent is optionally substituted as in the compound of formula II.
  • R 17 and R 7 together with the atoms connecting them form a 5-8-membered heterocyclic ring.
  • the compound of formula I has the formula
  • R 17 is selected from the group consisting of alkyl and cycloalkyl; wherein the R 17 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; and R 2 is selected from the group consisting of alkyl, aryt, heterocycloalkyl, cycloalkyl and heteroaryl, wherein the R 2 substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano,
  • one of X 4 , X 5 , X 6 and X 9 is N, and three of R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, aryl, amino, alkylamino, dialkylamino, heterocycloalkyl and heteroaryl; wherein the three of R 4 , R 5 , R 6 and R 7 alkyl, heterocycloalkyl, heteroaryl or aryl area each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl.
  • two of X 4 , X 5 , X 6 and X 9 are N, and two of R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, aryl, amino, alkylamino, dialkylamino, heterocycloalkyl and heteroaryl; wherein the two of R 4 , R 5 , R 6 and R 7 alkyl, heterocycloalkyl, heteroaryl or aryl are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl.
  • R 2 is aryl, optionally substituted as in the compound of formula III.
  • 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, cya ⁇ o, -R 201 , -C(O)R 201 , -C(O)OR 201 , -OR 201 , -NR 201 R 202 ;
  • R 201 , R 202 are independently selected from the group consisting of hydrogen, alky ) , cycloalkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R 201 and R 202 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, -R 211 , -C(O)R 211 ,-OR 211 , -NR 211 R 212 , -S(O) 3 R 211 ;
  • R 211 , R 212 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; and wherein the R 211 , R 212 and R 213 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, alkoxyand alkoxycarbonyl.
  • R 2 is phenyl or naphthalenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R 201 , - OR 201 ; each R 201 substituent is independently selected from the group consisting of alkyl, aryl, heterocycloalkyl and heteroaryl; wherein the R 201 alkyl, aryl, heterocycloalkyl and heteroaryl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R 211 , -C(O)R 211 , and -OR 211; each R 211 is independently selected from the group consisting of alkyl and aryl; and the R 211 alkyl and aryl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroary
  • R 2 is tetrahydronaphthalenyl, optionally substituted as in the compound of formula III.
  • R 2 is heterocycloalkyl or heteroaryl optionally substituted as in the compound of formula 111.
  • the R 2 heterocycloalkyl or heteroaryl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen and -R 201 ;
  • R 201 is independently selected from the group consisting of hydrogen and alkyl; wherein the R 201 alkyl substituents are optionally substituted with one or more halogen substituents.
  • R 17 is selected from the group consisting of alkyl and cycloalkyl; wherein R 17 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl;
  • R 2 is selected from the group consisting of alkyl, aryl, heterocycloalkyl, cycloalkyl and heteroaryl, wherein R 2 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.
  • R 2 is aryl, cycloalkyl, heterocycloalkyl, and 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.
  • one of X 4 , X 5 , X 8 and X 9 is N, wherein three of R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, aryl, haloalkyl, amino, heterocycloalkyl and heteroaryl, wherein the three of R 4 , R 5 , R 6 and R 7 alkyl, heterocycloalkyl, aryl or heteroaryl are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl.
  • two of X 4 , X 5 , X 8 and X 9 are N 1 wherein two of R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, aryl, haloalkyl, amino, heterocycloalkyl and heteroaryl, wherein the two of R 4 , R 5 , R 6 and R 7 alkyl, heterocycloalkyl, aryl or heteroaryl are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl.
  • one of X 4 , X 5 , X 6 and X 9 is N, and three of R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, aryl, alkoxy, heterocycloalkyl, alkoxyheteroaryl, cyano, alkyl, haloalkyl, amino, alkoxyheteroaryl and alkoxyheterocycloalkyl.
  • two of X 4 , X 5 , X 6 and X 9 are N, and two of R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, aryl, alkoxy, heterocycloalkyl, alkoxyheteroaryl, cyano, alkyl, haloalkyl, amino, alkoxyheteroaryl and alkoxyheterocycloalkyl.
  • R 17 is alkyl, cycloalkyl, haloalkyl or alkoxyalkyl
  • R 2 is selected from the group consisting of heterocycloalkyl and heteroaryl which 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.
  • R 17 is methyl;
  • R 2 is phenyl; wherein R is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alky!, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyi, carboxy, alkoxy and alkoxycarbonyl; and
  • R 17 is methyl
  • R 2 is phenyl; wherein R 2 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;
  • X 6 is CR 4 ;
  • X 5 is N ;
  • X 4 is CR 7 ;
  • X 9 is CR 8 .
  • R 17 is methyl
  • R 2 is phenyl; wherein R 2 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;
  • R 17 is methyl
  • R 2 is phenyl; wherein R 2 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;
  • R 17 is methyl, cyclopropyl, fluoroethyl, fluoromethyl, methoxyethyl or methoxymethyl;
  • R 2 is selected from the group consisting of alkyl, aryl, heterocycloalkyl, cycloalkyl and heteroaryl, wherein R 2 maybe 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.
  • R 2 is aryl, cycloalkyl, heterocycloalkyl, aryl and heteroraryl wherein R 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyi, carboxy, afkoxy and alkoxycarbonyl; and either
  • X 4 , X 5 , X 8 and X 9 are N, and two of R 4 , R 5 , R 6 and R 7 are each hydrogen.
  • exemplary embodiments of the invention include embodiments wherein -X 2 - is a bond and R 2 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-butyIphenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 2- chloro-5-trifluoromethyl, 2-fluoro-4-chlorophenyI, 2-fluoro-5-trifluoromethylphe ⁇ yl, 2-fluoro-6- chlorophe ⁇ yl, 2-trifluoromethylphenyl, phenyl, phenylphe ⁇ yl, qui ⁇ oli ⁇ yl, 2-triflu
  • R 7 taken together with the atoms connecting R 17 and R 7 , form a 5-8 membered heterocyclic ring.
  • the compound of formula I has the formula IV,
  • R 17 is selected from the group consisting of alkyl and cycloalkyl; wherein the R 17 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;
  • R 2 is aryl; wherein the R 2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, -R 201 and -OR 201 ;
  • R 201 is independently selected from the group consisting of hydrogen and alkyl; wherein the R 201 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;
  • X 4 N or CR 7
  • X 9 N or CR 6
  • X 4 , X 9 , X 5 X 6 , R 4 , R 5 ' R 8 and R 7 are defined as in the compound of formula I.
  • the compound of formula I has the formula V,
  • R 2 is selected from the group consisting of alkyl, aryl, heterocycloalkyl and heteroaryl wherein the R 2 substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R 201 , - C(O)R 203 , -, -C(O)OR 203 , -C(O)NR 201 R 202 , -OR 201 , -OC(O)R 203 , , -NR 201 R 202 , -NR 201 C(O)R 203 , -NR 201 C(O)OR 203 ;
  • R 201 , R 202 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;
  • R 203 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; wherein the R 201 , R 202 and R 203 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, -R 211 , -C(O)R 211 , , - C(O)OR 211 , -C(O)NR 211 R 212 , -OR 211 , -OC(O)R 212 , -NR 211 R 212 , -NR 211 C(O)R 212 , - NR
  • R 211 , R 212 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;
  • R 213 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; wherein the R 211 , R 212 and R 213 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; and wherein one or two of X 4 , X 9 , and X 5 are N.
  • R 2 is preferably selected from the group consisting of aryl, heterocycloalkyl and heteroaryl wherein the R 2 substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R 201 , -C(O)R 203 , -C(O)OR 203 , -C(O)NR 201 R 202 , -OR 201 , -OC(O)R 203 , -NR 201 R 202 , -NR 201 C(O)R 203 , -NR 201 C(O)OR 203 .
  • the R 101 is heterocycloalkyl containing a nitrogen directly bonded to R 1 , and the R 101 heterocycloalkyl nitrogen is optionally substituted as defined in formula I.
  • R 101 is heteroaryl that containing a nitrogen directly bonded to R 1 , and the R 101 heterocycloalkyl nitrogen is optionally substituted as defined in formula I.
  • -C(O)R 103 is -CO-heterocycloalkyl, wherein the heterocycloalkyl contains a nitrogen directly bonded to CO, wherein the R 103 heterocycloalkyl in the C(O)R 103 is optionally substituted as defined in formula I.
  • -C(O)R 103 is -CO-heteroaryl, wherein the heteroaryl contains a nitrogen directly bonded to CO, wherein the R 103 heteroaryl in the C(O)R 103 is optionally substituted as defined in formula I.
  • the R 201 is heterocycloalkyl containing a nitrogen directly bonded to R 2 , and the R 201 heterocycloalkyl nitrogen is optionally substituted as defined in formula I.
  • the R 201 heterocycloalkyl is a lactam radical or a carbamate radical wherein the lactam or carbamate nitrogen is the nitrogen directly bonded to R 2 .
  • the R 201 is heteroaryl containing a nitrogen directly bonded to R 2 , and the R 201 heteroaryl nitrogen is optionally substituted as defined in formula I.
  • the R 201 heteroaryl or its tautomer is a lactam radical wherein the lactam nitrogen is the nitrogen directly bonded to R 2 .
  • -C(O)R 203 is -CO-heterocycloalkyl, wherein the heterocycloalkyl contains a nitrogen directly bonded to CO, wherein the R 203 heterocycloalkyl in the C(O)R 203 is optionally substituted as defined in formula I.
  • -C(O)R 203 is -CO-heteroaryl, wherein the heteroaryl contains a nitrogen directly bonded to CO, wherein the R 203 heteroaryl in the C(O)R 203 is optionally substituted as defined in formula I.
  • R 8 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, Hu ⁇ ti ⁇ gton'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
  • 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.
  • 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.
  • 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 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.
  • 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
  • composition may also further comprise another active agent.
  • an active agent may be, for example, a metabotropic glutamate receptor agonist.
  • 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 from one to twenty carbon atoms; in one 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.
  • substitue ⁇ ts examples 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.
  • 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.
  • alkenyl examples include ethenyl (also known as vinyl), allyl, propenyl (including 1-propenyl and 2- propenyl) and butenyl (including 1-butenyl, 2-butenyl and 3-butenyl).
  • alkenyl embraces substituents having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • benzyl refers to methyl radical substituted with phenyl, i.e., the following
  • 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 “phe ⁇ alenyl”), fluorenyl, and decalinyl.
  • 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.
  • cycloalkyl refers to a saturated carbocyclic substituent having three to fourteen carbon atoms. In one embodiment, a cycloalkyl substituent has three to ten carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkyl also includes substituents that are fused to a C 6 -C 10 aromatic ring or to a 5-10-membered heteroaromatic ring, wherein a group having such a fused cycfoalkyl group as a substituent is bound to a carbon atom of the cycloalkyl group.
  • a fused cycloalkyl group is substituted with one or more substituents, the one or more subsfitutents, unless otherwise specified, are each bound to a carbon atom of the cycloalkyl group.
  • cycloalkenyl refers to a partially unsaturated carbocyclic substituent having three to fourteen carbon atoms, typically three to ten carbon atoms.
  • Examples of cycloalkenyl 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, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. Alternatively, 2 or 3 rings may be fused together, such as bicyclodecanyl and decalinyl.
  • 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.
  • the aryl substituent may have six to fourteen carbon atoms.
  • aryP may refer to substituents such as phenyl, naphthyl and anthracenyl.
  • aryl also includes substituents such as phenyl, naphthyl and anthracenyl that are fused to a C 4 -C 10 carbocyclic ring, such as a C 5 or a C 6 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.
  • substituents such as phenyl, naphthyl and anthracenyl that are fused to a C 4 -C 10 carbocyclic ring, such as a C 5 or a C 6 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.
  • aryl groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl”), indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (also known as "phe ⁇ alenyl”), and fluorenyl.
  • the number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix “C x -C y -,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C 1 -C 6 -BlKyI refers to an alkyl substituent containing from 1 to 6 carbon atoms.
  • C 3 -C 6 -cycloalkyl refers to saturated cycloalkyl containing from 3 to 6 carbon ring atoms.
  • the number of atoms in a cyclic substituent containing one or more heteroatoms 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.
  • X-Y- membered wherein wherein x is the minimum and y is the maximum number of atoms forming the cyclic moiety of the substituent.
  • 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.
  • hydrogen refers to hydrogen substituent, and may be depicted as -H.
  • hydroxy refers to -OH.
  • the prefix "hydroxy" indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substitue ⁇ ts.
  • Compounds bearing a carbon to which one or more hydroxy substituents include, for example, alcohols, enols and phenol.
  • hydroxyalkyl refers to an alkyl that is substituted with at least one hydroxy substituent.
  • examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.
  • nitro means -NO 2 .
  • carbonyl means -C(O)-, which also may be depicted as:
  • amino refers to -NH 2 .
  • alkylamino refers to an amino group, wherein at least one alkyl chain is bonded to the amino nitrogen in place of a hydrogen atom.
  • alkylamino substituents include monoalkylami ⁇ o such as methylamino (exemplified by the formula
  • aminocarbonyl means -C(O)-NH 2 , which also may be depicted
  • 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).
  • the halogen is chlorine.
  • 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.
  • haloalkyl refers to an alky! 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.
  • haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl.
  • haloalkoxy refers to an alkoxy that is substituted with at least one halogen substituent.
  • 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.
  • the prefix may identify the halogen substituent.
  • perfluoro means that every hydrogen substituent on the substituent to which the prefix is attached is replaced with a fluorine substituent.
  • perfluoroalkyl refers to an alkyl substituent wherein a fluorine substituent is in the place of each hydrogen substituent. Examples of perfluoroalkyl substituents include trifluoromethyl (-CF 3 ), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, and perfluorodecyl.
  • perfluoroalkoxy refers to an alkoxy substituent wherein each hydrogen substituent is replaced with a fluorine substituent.
  • perfluoroalkoxy substituents include trifluoromethoxy (-0-CF 3 ), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, and perfluorodecoxy.
  • oxy refers to an ether substituent, and may be depicted as -O-.
  • 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.
  • alkylthio means -S-alkyl.
  • methylthio is -S-CH 3 .
  • alkylthio include ethylthio, propylthio, butylthio, and hexyfthio.
  • alkylcarbonyl means -C(O)-alkyl.
  • ethylcarbonyl may be
  • alkylcarbonyl examples include methylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcabonyl, and hexylcarbonyl.
  • aminoalkylcarbonyl means -C(O)-alkyl-NH 2 .
  • aminomethylcarbonyl may be depicted as: **
  • alkoxycarbonyl means -C(O)-O-alkyl.
  • ethoxycarbo ⁇ yl may
  • alkoxycarbonyl examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and hexyloxycarbonyl.
  • the carbon atom of the carbonyl is attached to a carbon atom of a second alkyl, the resulting functional group is an ester.
  • thio and thia mean a divalent sulfur atom and such a substituent may be depicted as -S-.
  • a thioether is represented as "alkyl-thio-alkyl” or, alternatively, alkyl-S-alkyl.
  • thiol refers to a sulfhydryl substituent, and may be depicted as -SH.
  • alkyl-sulfonyl-alkyl refers to alkyl-S(O) 2 -alkyl.
  • alkylsulfonyl include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
  • aminosulfonyl means -S(O) 2 -NH 2 , which also may be depicted
  • sulfinyl or "sulfoxido” means -S(O)-, which also may be depicted as:
  • alkylsulfinylalkyl or “alkylsulfoxidoalkyl” refers to alkyl-S(O)-alkyl.
  • exemplary alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfi ⁇ yl, and hexylsulfinyl.
  • 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).
  • 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.
  • 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.
  • heterocycloalkyl also includes substituents that are fused to a C 6 -C 10 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.
  • 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.
  • 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.
  • heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidi ⁇ yl, and pyridazinyl; 5-membered ring substituents such as triazofyl, 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, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benz
  • the ring atom of the heteroaryl substitue ⁇ t 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.
  • heteroaryl also includes pyridyl N-oxides and groups containing a pyridine N-oxide ring.
  • single-ring heteroaryls include furanyl, dihydrofuranyl, tetradydrofuranyl, thiophenyl (also known as "thiofuranyl"), dihydrothiophenyl, tetrahydrothiophe ⁇ yl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazoiinyl, isothiazolinyl, thiazolidi ⁇ yl, isothiazolidinyl, thiaediazolyl, ox
  • 2-fused-ring heteroaryls include, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridi ⁇ yl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl, i ⁇ dolyl, isoindolyl, indoleninyl, isoi ⁇ dazolyl, benzazinyl, phthalazinyl, qui ⁇ oxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, i ⁇ doxazinyl, anthranilyl, benzodioxolyl, be ⁇ z
  • 3-fused-ri ⁇ g heteroaryls or heterocycloalkyls include 5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline, 4,5-dihydroimidazo[4,5,1-hi]indole,
  • fused-ring heteroaryls include benzo-fused heteroaryls such as indolyi, 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”), benzothiochro
  • heteroaryi also includes substituents such as pyridyl and quinolinyl that are fused to a C 4 -C 10 carbocyclic ring, such as a C 5 or a Ce 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 heteroaryi group or to a heteroatom of the heteroaryi group.
  • the one or more substitutents are each bound to an aromatic carbon of the heteroaryi group or to a heteroatom of the heteroaryi group.
  • 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.
  • hydrogen, halogen, and cyano do not fall within this definition.
  • a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon, oxygen, sulfur or nitrogen of the substituent.
  • 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.
  • monofluoroalkyl is alkyl substituted with a fluoro substituent
  • 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).
  • 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 -NR'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.
  • the heterocyclic ring consists of 3 to 7 atoms.
  • the heterocyclic ring is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazoiyl, pyridyl and thiazolyl.
  • substituent refers to substituents that 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.
  • 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.
  • 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.
  • tetrazolyl which has only one substitutable position
  • 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.
  • alkyicycloalkyl contains two moieties: alkyl and cycloalkyl.
  • Ci-Ce- prefix on C r C 6 -alkylcycloalkyl means that the alkyl moiety of the alkyicycloalkyl contains from 1 to 6 carbon atoms; the CrCe- prefix does not describe the cycloalkyl moiety.
  • the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyl substituent is substituted with one or more halogen substituents.
  • 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.”
  • 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.
  • substituent A-B-C moiety C is attached to the remainder of the molecule.
  • A-B-C-D moiety D is attached to the remainder of the molecule.
  • aminocarbonylmethyl the methyl moiety is attached to the remainder of the molecule, where the substituent may also be be depicted as
  • the compound may exist in the form of optical isomers (enantiomers).
  • the present invention comprises enantiomers and mixtures, including racemic mixtures of the compounds of formulae I through V.
  • the present invention comprises diastereomeric forms (individual diastereomers and mixtures thereof) of compounds.
  • geometric isomers may arise.
  • the present invention comprises the tautomeric forms of compounds of formulae I through V.
  • tautomeric isomerism 'tautomerism'
  • This can take the form of proton tautomerism in compounds of formula I 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.
  • 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.
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
  • the salt preferably is pharmaceutically acceptable.
  • 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.
  • 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, m ethanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids.
  • inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids
  • organic acids such
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • 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, sufa ⁇ ilate, cyclo
  • 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.
  • 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'-dibenzylethyle ⁇ ediamine, chloroprocaine, choline, diethanolamine, ethylenediami ⁇ e, meglumine (N-methylglucamine), and procaine.
  • secondary, tertiary or quaternary amine salts such as tromethamine, diethylamine, N,N'-dibenzylethyle ⁇ ediamine, chloroprocaine, choline, diethanolamine, ethylenediami ⁇ e, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (C 1 -C 6 ) 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.
  • C 1 -C 6 halides
  • dialkyl sulfates e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates
  • long chain halides e.g., decyl, lau
  • 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.
  • '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.
  • solvent molecules for example, ethanol.
  • '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.
  • 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.
  • 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 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S 1 18 F, and 36 CI, respectively.
  • 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.
  • 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.
  • 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.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • the compounds of the invention can also be administered intra ⁇ asally or by inhalation.
  • the compounds of the invention may be administered rectally or vaginally.
  • 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.
  • 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.
  • 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.
  • 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.
  • humans are suitable subjects. Human subjects may be of either gender and at any stage of development. Use in the Preparation of a Medicament
  • 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.
  • compositions for the treatment or prevention of the conditions referred to above, the compound of the invention can be administered as compound per se.
  • pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound.
  • 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 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.
  • the oral administration may be in a powder or granule form.
  • the oral dose form is sub-lingual, such as, for example, a lozenge.
  • the compounds of formulae I through V are ordinarily combined with one or more adjuvants.
  • Such capsules or tablets may contain a controlfed-release formulation.
  • the dosage forms also may comprise buffering agentsor may be prepared with enteric coatings.
  • 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.
  • 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
  • suitable dispersing, wetting agents, and/or suspending agents may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
  • 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.
  • 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.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • 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.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the present invention comprises a rectal dose form.
  • 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.
  • compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • 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.
  • 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.
  • Kits The present invention further comprises kits that are suitable for use in performing the methods of treatment or prevention described above.
  • 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.
  • the kit of the present invention comprises one or more compounds of the invention.
  • 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.
  • Scheme I illustrates a method for the preparation of compounds having the basic structure of formula (Vl), where R 2 , R 17 , X 4 , X 5 , X e , and X 9 are defined as above.
  • a compound of formula (I) [SynLett, 1996, 1097] can be treated with (BOC) 2 O in the presence of a suitable base such as triethylamine, in solvents such as CH 2 Cb, 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 (DEEAD) 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).
  • a suitable coupling reagents for this transformation include dibutylazodicarboxylate(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).
  • acids such as trifluoroacetic acid, hydrochloric acid and the like
  • solvents such as methylene chloride, dioxane, ethyl acetate, THF, dichloroethane and the like
  • suitable reducing agents such as NaHB(OAc) 3
  • scheme Il illustrates a method for the preparation of compounds having the basic structure of formula (Vl), where R 2 , R 17 , X 4 , X 5 , X 6 , and X 9 are defined as above.
  • 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 (VII).
  • the alcohols of formula (VII) 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 (VIII).
  • Compound (VIII) can be treated with R 2 -OH (III) in the presence of a suitable base, such as cesium carbonate, potassium t-butoxide or the like, in a suitable solvent such as acetonitrile, with or without microwave irradiation at elevated temperature around 50 0 C to 200 0 C to yield compounds of formula (Vl).
  • alcohols of formula (VII) can be directly converted to compounds of formula (Vl) under standard alkylation conditions using reagents of formula (III') wherein R 2 is substituted alky!, cycloalkyl and heterocycloalkyl, X is Cl, Br, I, OMs or OTs, in the presence of a suitable base such as, but not limited to, sodium hydride and potassium t-butoxide in a suitable solvent such as DMF, NMP or THF with or without microwave heating at elevated temperature around 50 0 C to 200 0 C.
  • a suitable base such as, but not limited to, sodium hydride and potassium t-butoxide
  • a suitable solvent such as DMF, NMP or THF with or without microwave heating at elevated temperature around 50 0 C to 200 0 C.
  • scheme III illustrates a method for the preparation of compounds having the basic structure of formula (X), where R 2 is an optionally substituted heteroaryl including but not limited to 2-pyridyl, 2-pyrimidine, or 2-pyrazine, R 17 , X 4 , X 5 , X 6 , and X 9 are defined as above.
  • R is hydrogen or any one of the substituents, defined above, that may optionally substitute R 2 .
  • Aldehydes of formula (V) are either commercially available or can be prepared, but not limited to, by general procedures illustrated by scheme IV, wherein R 17 , X 4 , X 5 , X 6 , and X 9 are defined as above.
  • haloheteroaryls (Xl) can be treated with primary amines of formula (XII) in the presence of a suitable base such as potassium carbonate and the like, in a suitable solvent such as dichloromethane at a reaction temperature ranging from room temperature to 100 0 C to give compounds of formula (XIII).
  • diamine of formula (XIV) Hydrogenation of the nitro group using well-precedented conditions such as Pd/C under hydrogen or Fe/EtOH/CaCfe can yield diamine of formula (XIV).
  • the imidazole ring can be formed by treating diamines (XIV) with acetimidates of formula (XVIII), in the presence of acetic acid, in a suitable solvent such as MeOH.
  • the acetal of compounds (XVII) can be removed with acids such as HCI to give the desired aldehydes of formula (V).
  • diamines (XIV) can be condensed with glycolic acid under strong acidic conditions, such as aqueous hydrochloric acid, at elevated temperature such as reflux.
  • the resultant alcohols of formula (XVI) can then be oxidized using a suitable oxidation reagent, such as MnO 2 in a suitable solvent such as methylene chloride, to yield the desired aldehydes of formula (V).
  • a suitable oxidation reagent such as MnO 2 in a suitable solvent such as methylene chloride
  • diamines (XIV) can cyclize with triethylorthoacetate in a suitable solvent such as ethanol at elevated temperature with or without microwave heating to produce imidazoles of formula (XV), which can be subsequently oxidized to the desired aldehydes of formula (V) using selenium dioxide.
  • a suitable oxidation reagent such as MnO 2
  • a suitable solvent such as methylene chloride
  • diamines (XIV) can cyclize with triethylorthoacetate in a suitable solvent such as ethanol at elevated temperature with or without microwave heating to produce imidazoles of formula (XV), which can be
  • Scheme V illustrates a method for the preparation of compounds having a basic structure of formula (XXIII), wherein R 17 , X 4 , X 5 , X 6 and X 9 are defined as above and R is hydrogen or any one of the substituents, defined above, that may optionally substitute R 2 .
  • Oxidation of the Boc-protected [3.1.0] amino alcohol (II) via common oxidizing methods are well known in the art and include methodssuch as Swern Oxidation and Dess-Martin Oxidation, to yield an aldehyde of formula (XIX).
  • compounds of formula (XXIII) can be prepared via the synthetic route illustrated in scheme Vl.
  • the aldehyde (XIX) can be treated with bromomethyl triphenylphosphonium bromide (XX) in the presence of suitable base such as BuLi and NaHMDS, in a suitable solvent such as THF, at reaction temperature from -78 0 C to room temperature to yield the vinyl bromide of formula (XXV) as a mixture of Z/E isomers.
  • a compound of formula (XXVII) then can be prepared via a Suzuki coupling of the vinylbromide (XXV) with boronic acids (XXVI) in the presence of a catalyst such as palladium (O) tetrakis(triphenylphosphine), palladium (II) acetate, allyl palladium chloride dimer, tris(dibenzylideneacetone)dipalladium (O), tris(dibenzylideneacetone)dipalladium (0) chloroform adduct, palladium (II) chloride or dichloro[1,1'-bis(diphe ⁇ ylphosphino)ferroce ⁇ e]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, with sodium carbonate being
  • reaction inert solvent such as dimethyl ethylene glycol ether (DME), 1,4- dioxane, acetonitrile, methyl sulfoxide, tetrahydrofuran, ethanol, methanol, 2-propanol, or toluene and the like, in the presence or absence of water, ranging from about 1% to about 10% water, with about 5% water being preferred, with or without microwave assisted heating at a temperature from about room temperature to about 200 0 C, preferably from about 6O 0 C to about 100 0 C.
  • DME dimethyl ethylene glycol ether
  • Scheme VII illustrates a method for the preparation of compounds having the basic structure of formula (XXVII), wherein R 18 , R 2 , R 17 , X 4 , X 5 , X 6 and X 9 are defined as above.
  • the aldehyde (XIX) can be treated with amines of formula (XXIV) 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 (XXV).
  • suitable reducing agents such as NaHB(OAc) 3
  • solvents such as methylene choride, 1 ,2-dichloroethane or THF
  • (XXV) 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 (XXVI).
  • Compounds of formula (XXVI) 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- dichloroetha ⁇ e or THF, at about room temperature, to produce the corresponding amine of formula (XXVII).
  • Suitable conditions for this transformation include treatment of the amines of formula (XXVI) with aldehydes of formula (V) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH 4 , to produce the desired compounds of formula (XXVII).
  • scheme VIII illustrates a method for the preparation of compounds having the basic general structure of formula (XXXIII) wherein R 2 , R 17 , X 4 , X 5 , X 6 and X 9 are defined as above.
  • the aldehyde of formula (XIX) 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 (XXVIII).
  • suitable reducing agents include NaBH 4 and NaBH 3 CN in solvents such as methanol or ethanol at room temperature.
  • a compound of formula (XXVIII) 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 0 C to produce the corresponding product of formula (XXIX).
  • a compound of formula (XXIX) can be treated with various aldehydes of formula (XXX) in the presence of a suitable reducing agent such as NaHB(OAc) 3 , in solvents such as methylene chloride, 1,2- dichl ⁇ roethane or THF, at about room temperature, to produce the corresponding products of formula (XXXI).
  • Suitable reducing agents include NaBH 4 and NaBH 3 CN in solvents such as methanol or ethanol at room temperature.
  • Compounds of formula (XXXI) 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 intermediates of formula (XXXII).
  • Compounds of formula (XXXII) 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 (XXXIII).
  • suitable reducing agents such as NaHB(OAc) 3
  • solvents such as methylene choride, 1 ,2-dichloroethane or THF
  • Other suitable conditions for this transformation include treatment of the amines of formula (XXXII) with aldehydes of formula (V) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH 4 , to produce the desired compounds of formula (XXXIII).
  • Scheme IX illustrates the synthesis of compounds of formula (XXXIX), wherein R 201 , R 101 , R 17 , X 4 , X 5 , X 6 and X 9 are defined as above.
  • commercially available amines (XXXIV) 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 (XXXV).
  • the Boc-protecting group of compounds of formula (XXXV) can be removed under acidic conditions, such as hydrochloric acid and trifluoroacetic acid.
  • the resultant amines (XXXVI) can then be treated with aldehydes of formula (XXXVII) in the presence of a suitable catalyst, such as Pd/C, under hydrogen (25-50 PSl) in a solvent such as etha ⁇ ol with a suitable base, such as triethylamine, at about room temperature to produce the corresponding secondary amines of formula (XXXVIII).
  • W-Methyl-3-nitropyridin-2-amine (58.14 g, 0.38 mol) was dissolved in 1 ,2 dimethoxyethane (400 mL) under vigorous stirring. The obtained solution was refluxed with activated charcoal (2.9 g) for 2 h and kept overnight at room temperature. The reaction apparatus was flushed with dry nitrogen, and the catalyst (Pd/C 10%, 1.75 g) was added. The mixture was heated to 40 0 C. Hydrazine monohydrate (54 mL, 1.08 mol) was added dropwise to the suspension within 2 h.
  • Methyl 2,2-Diethoxyethanimidoate (63.8. g, 0.4 mol) and glacial acetic acid (21.6 g, 0.36 mol) were added to the solution under stirring. The obtained mixture was stirred at room temperature for 7 h, then refluxed for 40 min. The mixture was concentrated under reduced pressure to dryness, and the residue was purified by chromatography on a silica gel column (ethyl acetate/hexane 1:2) to furnish 2-(Diethoxymethyl)-3-methyl-3H-imidazo[4,5--)]pyridine in 65.6% (55.53 g, 0.236 mol) yield as a yellow liquid.
  • N-Methyl-2-nitropyridin-3-amine (14.1 g, 0.092 mol) was suspended under vigorous stirring in 1,2-dimethoxyethane/methanol mixture (1:1, 400 mL).
  • the reaction apparatus was flushed with dry nitrogen.
  • the catalyst Pd/C 10%, 1.4 g was added to the mixture. Hydrogen was bubbled through the suspension for 7 h.
  • the reaction mixture was diluted with chloroform (300 mL) and passed through a filter with Celite (upper layer, 3 cm) and silica gel (lower layer, 5 cm, diameter 13 cm) to remove the catalyst. The layers were washed with chloroform/methanol mixture (1:1, 500 mL).
  • N-Methylpyridine-2,3-diamine 11.05 g, 97%, 0.09 mol. The product was used for the next stage without additional purification.
  • N-Methylpyridine-2,3-diamine (11.0 g, 0.089 mol) was dissolved in 1 ,2- dimethoxyethane (300 mL).
  • Methyl 2,2-diethoxyethanimidoate (31.0 g, 0.19 mol) and glacial acetic acid (10 mL) were added to the solution under stirring.
  • the obtained mixture was stirred at room temperature for 3 h, then refluxed for 5 h.
  • p-Toluenesulfonic acid monohydrate (0.1 g) was added to the reaction mixture, which was refluxed for 7 h.
  • the mixture was concentrated under reduced pressure, and the residue was diluted with toluene (300 mL).
  • a 0.25 M solution of an aldehyde of general formula (V) was prepared in 1,2- dichloroethane.
  • a 0.25 M solution of sodium triacetoxyborohydride in chloroform was also prepared.
  • 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).
  • the suspension was diluted with dichloromethane and extracted three times with 1N NaOH.
  • the organic layer was dried over anhydrous MgSO4, filtered and stripped in vacuo to oil.
  • the crude material was purified via flash chromatography, eluting from 0% ammonium hydroxide / 0% methanol / dichloromethane to 0.5% ammonium hydroxide / 9.5% methanol / 90% dichloromethane to yield 200 mg of desired compound.
  • Example 4 (corresponding to Entry 48 in Table 1) 2-(f(1 R.5S,6R)-6-(f 2.5-dichlorophenoxy)methyl)-3-aza-bicvclor3.1.OIhexan-3- yl)methv ⁇ -1 -methyl-1 H-imidazor4.5-c]pyridine
  • Benzyl triphenylphosphonium chloride was dissolved in THF (15 mL). The solution was stirred under nitrogen at -78 0 C. 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 -78 0 C 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 then slowly warmed up to room temperature and stirred overnight.
  • the organic layer were extracted and loaded onto large SPE cartridge (hand packed with Na 2 SO4). The extraction was repeated two times. The solvent was removed in vacuo. The residue was dissolved in 5 ml of 1:1 TFA/DCM and the solutions were shaked at room temp overnight. The solvent was removed in vacuo. The residue was re-dissolved in 5 ml of 1:1 MeOH/DCE and loaded onto large SCX SPE cartridges (hand packed Silicycle, ⁇ 3 g), The resin was rinsed with 5 ml of 1:1 MeOH/DCE, the vials switched and eluted with -10 ml of MeOH, followed by switching totared vials and eluted with ⁇ 20 ml of 1 N TEA in MeOH. The solvent was removed in vacuo to give the residues that were used in the next step.
  • Aldehydes of formula (V) (0.075 mmol, 1.25 eq) were dissolved in 0.3 ml of DCE containing TEA (0.1 mmol) and anhydrous MgSO 4 (0.2 mmol) and a solution of the residue from previous step in 0.3 mL DCE were added to each vial. The mixtures were shaked at room temperature for 30 min, then Na(OAc) 3 BH (0.12 mmol) was added. The vials were shaked at room temperature overnight. The mixtures were partitioned between 1.5 ml of 1 N NaOH and 2.5 ml of EtOAc. The organic layers were loaded onto SCX SPE cartridges (Sificycle, 1 g). The extraction was repeated two times.
  • the aldehyde of formula (V) (2.8 mmol) was dissolved in 20 m!_ of DCE and to the solution was added (3-Aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester (XXXIV) (2.8 mmol) neat. 5 ml of NMP and Hunig's base (3.22 mmol) were added subsequently. The mixtures were snaked at room temp for ⁇ 1 hour and then Na(OAc) 3 BH (4.2 mmol) was added. The reaction mixtures were shaked at room temp overnight. The mixtures were partitioned between 1 N NaOH aqueous solution and DCM.
  • Cells used for this screen are HEK cells stably transfected with the mGluR2 receptor
  • Clones were identified by functional activity (FLIPR). Cells are grown in growth media containing: DMEM High Glucose with Glutamine and Na Pyruvate (GIBCO) 1 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).
  • DMEM High Glucose with Glutamine and Na Pyruvate G418 500 ug / ml (from 50 mg/ml stock) (GIBCO)
  • Blasticidin 3 ug / ml from 5 mg/ml stock made in H2O
  • the FLIPR assay is performed using the following methods: Assay buffer:
  • the pH is adjusted to 7.4 with 1 M NaOH.
  • Make a 1 mM (approx.) flou-4, PA working solution per vial by adding 22 ⁇ l of 20% pluronic acid (PA) (Molecular Probes) in DMSO to each 50 ug vial (440 ⁇ L per 1 mg vial).
  • PA pluronic acid
  • 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.
  • 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 0 C) for at least 20 minutes. Compounds are then added to assay drug buffer as 40 ⁇ L top [concentration] (4X the 10 uM top screening concentration).
  • EC 5 o 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.

Abstract

Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein R17, R2, X4, X9, X5, X6, R8, X2, Y1 and n are as defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

Description

AZABENZIMIDAZOLYL COMPOUNDS
FIELD QF THE INVENTION
The present invention comprises a novel class of azabenzimidazolyl 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 pheromoπe 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 111 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 reports have 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. Then, 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:
Figure imgf000005_0001
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)R103 , S(O)2R103 , alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl, wherein the R18 alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl is heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R101, -OR101, -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 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, dialkyiamino, alkyl optionally substituted with one or more halogen or hydroxy 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 alky) optionally substituted with hydroxy, cycloalkyl optionally substituted with hydroxy, heteroaryl optionally substituted with one or more halogen or alkoxy or alkyl or trihaloalkyl, alkoxy, aryloxy,; each R103 is independently 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 hydroxy 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, alkoxy, aryloxy;
R2 is selected from the group consisting of alkyl, aryl, cycloalkyl, heterocycloalkyl 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, hydroxy, 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, cycloalkyl, 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^R503 , -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, 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;
X4 = N or CR7 X9 = N or CR6
X5 = N or CR5
X6 = N or CR4 wherein one or two of X4, Xs, X6 and X9 are N;
R4, R5, R6 and R7 are each independently selected from the group consisting of halogen, cyano, -R401, -C(O)OR401, -C(O)NR401R402, -OR401, -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 0, 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, hydroxyalkyi, 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, fluorine or alkyl, wherein R8 alkyl is optionally substituted with one or more fluorines.
In one embodiment of the invention, Y1 is O. In another embodiment of the invention, Y1 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)ni- 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, 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 another embodiment, R401 and R402 are each independently selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl
In one embodiment of the invention, the compound of formula I has the formula II,
Figure imgf000009_0001
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 substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, -R 101 , -OR ,101 -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. In another embodiment of the compound of formula II, one of X4, X9, X5 and X6 is N and three of R4, R5, R6 and R7 are each 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 substituents are each optionally independently substituted as in the compound of formula I. Preferably, three of R4, R5, R8 and R7 are each independently selected from the group consisting of hydrogen 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
Figure imgf000010_0001
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; and R2 is selected from the group consisting of alkyl, aryt, 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,
3201 ,203 ,201Q202 nitro, -RZU1, -C(O)R* -C(O)NFT11R -OR201, -NR201R202, -NR201C(O)R203, -NR201C(O)OR203.
In one embodiment of Formula III, one of X4, X5, X6 and X9 is N, and three of R4, R5, R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, aryl, amino, alkylamino, dialkylamino, heterocycloalkyl and heteroaryl; wherein the three of R4, R5, R6 and R7 alkyl, heterocycloalkyl, heteroaryl or aryl area 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 Formula III, two of X4, X5, X6 and X9 are N, and two of R4, R5, R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, aryl, amino, alkylamino, dialkylamino, heterocycloalkyl and heteroaryl; wherein the two of R4, R5, R6 and R7 alkyl, heterocycloalkyl, heteroaryl or 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 another embodiment of the compound of formula III, R2 is aryl, optionally substituted as in the compound of formula III. 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, cyaπo, -R201, -C(O)R201, -C(O)OR201, -OR201, -NR201R202;
R201, R202 are independently selected from the group consisting of hydrogen, alky), 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, alkoxyand 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 -OR211; each R211 is independently selected from the group consisting of alkyl and aryl; and the 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 111. 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 -R201;
R201 is independently selected from the group consisting of hydrogen and alkyl; wherein the R201 alkyl substituents are 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 R17 is 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. Preferably, R2 is aryl, cycloalkyl, heterocycloalkyl, and 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.
In one aspect of this embodiment, one of X4, X5, X8 and X9 is N, wherein three of R4, R5, R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, aryl, haloalkyl, amino, heterocycloalkyl and heteroaryl, wherein the three of R4, R5, R6 and R7 alkyl, heterocycloalkyl, aryl or heteroaryl 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 aspect of this embodiment, two of X4, X5, X8 and X9 are N1 wherein two of R4, R5, R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, aryl, haloalkyl, amino, heterocycloalkyl and heteroaryl, wherein the two of R4, R5, R6 and R7 alkyl, heterocycloalkyl, aryl or 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, one of X4, X5, X6 and X9 is N, and three of R4, R5, R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, aryl, alkoxy, heterocycloalkyl, alkoxyheteroaryl, cyano, alkyl, haloalkyl, amino, alkoxyheteroaryl and alkoxyheterocycloalkyl.
As another example, two of X4, X5, X6 and X9 are N, and two of R4, R5, R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, aryl, alkoxy, heterocycloalkyl, alkoxyheteroaryl, cyano, alkyl, haloalkyl, amino, alkoxyheteroaryl and alkoxyheterocycloalkyl.
As another example, R17 is alkyl, cycloalkyl, haloalkyl or alkoxyalkyl, R2 is selected from the group consisting of heterocycloalkyl and heteroaryl which 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 embodiment of the compound of formula III,
R17 is methyl; R2 is phenyl; wherein R is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alky!, aryl, heterocycloalkyl, heteroaryl, haloalkyl, hydroxyalkyi, carboxy, alkoxy and alkoxycarbonyl; and
X6 is N; Xs is CR5 ; X4 is CR7; and X9 is CR8. In another embodiment of the compound of formula III,
R17 is methyl;
R2 is phenyl; 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; X6 is CR4; X5 is N ; X4 is CR7; and X9 is CR8.
In another embodiment of the compound of formula III,
R17 is methyl;
R2 is phenyl; 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;
X6 is CR4; Xs is CR5; X4 is N; and X9 is CR8.
In another embodiment of the compound of formula III,
R17 is methyl;
R2 is phenyl; 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;
X6 is CR4; Xs is CR5; X4 is CR7; and X9 is N.
In another embodiment of the compound of formula I, 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 maybe 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. 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, hydroxyalkyi, carboxy, afkoxy and alkoxycarbonyl; and either
(a) one of X4, Xs, X6 and X9 is N, and three of R4, R5, R6 and R7 are each hydrogen; or
(b) two of X4, X5, X8 and X9 are N, and two of R4, R5, R6 and R7 are each 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-butyIphenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 2- chloro-5-trifluoromethyl, 2-fluoro-4-chlorophenyI, 2-fluoro-5-trifluoromethylpheπyl, 2-fluoro-6- chloropheπyl, 2-trifluoromethylphenyl, phenyl, phenylpheπyl, quiπoliπyl, tetrahydronaphthalenyl, 2,3,6-trifluorophenyl, 2,4-dichloropheπyl, 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- trifluorophenyl, 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- phenylpheπyl, 2-cyaπo-3-chlora-4-fluorophenyl, 2-cyaπo-4-fluoropheπyl, 2-cyaπopheπyl, 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-JSOXaZoIyM-ChIOrOPhOn^, 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-fluorophenylphenyl, 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-phenyl, 4- butylphenyl, 2-propylphenyl, 2-trifluoromethoxyphenylphenyl, 2-trifluoromethylphenyIphenyl, 3,4-dichlorophenyl, 3,4-dichlorophenylcarbonyl, 3,4-dicyanophenyl, 3,4-difluorophenylphenyI, 3,4-dimethoxyphenylphenyl, 3,4-dimethylphenyl, 3,5-difluorophenyl, 3,5-dibutylphenylphenyl, 3,5-difluorophenyl, 3,5-dimethyl-4-cyanophenyl, 3,5-dimethylphenyl, 3-butylpheπyl, 3-chloro- 4-cyaπophenylpheπyl, 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-methoxyphenylpheπyl, 3-methyl-4-chlorophenyl, 3-methyl-4-fluoropheπyl, 3-methyl-4-methoxyphenylphenyl, 3-propylpheπyl, 3-trifIuoromethyl-4-methoxyphenylpheπyl, 3-trifluoromethylphenylpheπyl, 4-butylphenyl, 4-chlorophenylcarbonyl, 4-cyanoethylphenyl, 4- cyanomethylphenyl, 4-cyanophenyl, 4-cyanophenylphenyl, 4-ethylphenyl, 4-fluoro-3- methylpheπylphenyl, 4-fluoropheπylcarbonyl, 4-fluorophenylphenyl, 4-methoxy-3- fluorophenylphenyl, 4-methoxy-3-trifluoromethylphenylphenyl, 4-methoxymethylphenyl, 4- methoxyphenyl, 4-methoxyphenylcarbonyl, 4-methoxyphenylphenyl, 4-methylphenyl, 4- propylphenyl, beπzo[d][1 ,3]dioxolylphenyl, benzofuranylphenyl, benzthiazolylphenyl, bromopyridinyl, chloropheπyltriazolylphenyl, chloropyridinyl, cyanopheπylphenyl, dibenzo[b,d]furanyl, difluoromethoxyphenylphenyl, dihydro-1H-indenyl, dihydrobenzofuranyl, ethoxyphenyl, fluorodihydrobenzofuranyl, fluorodihydroindenyl, fluoronaphthalenyl, imidazolylphenyl, isoxazolylpheπyl, methoxyphenylphenyl, methylbenzothiazolylphenyl, methylcarbonylbenzofuranylphenyl, methylcarbonylphenylphenyl, methylcarbonylthiophenyl, methyldihydro-1 H-indenyl, methyldihydrobenzo[b][1 ,4]oxaziπylphenyl, methylindolyl, methylphenylphenyl, methylpyrazolylphenyl, methylpyridinyl, methylquinolinylphenyl, methylthiazolyfpheπylphenyl, methylthiopyrimidinyl, naphthalenyl, oxazolylphenylphenyl, oxodihydro-1H-indenylphenyl, phenylcarbonyl, propylphenyl, propylphenylphenyl, propylpyridinyl, pyridiπyl, pyrrolylphenyl, quiπolinylphenyl, quiπoxaliπyl, quinoxaliπylpheπyl, thiadiazolylphenyl, thiadiazolylphenylphenyl, triazolylphenyl, trifluoromethoxyphenylpheπyl, trifluoromethylphenyl, trifluoromethylphenylphenyl, trifluoromethylpyridinyl and 2,4,5-trifluorophenyl. 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,
Figure imgf000016_0001
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 aryl; wherein the R2 aryl is 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;
X4 = N or CR7 X9 = N or CR6
X5 = N or CR5 X6 = N or CR4 wherein
X4, X9, X5 X6, R4, R5' R8 and R7 are defined as in the compound of formula I. In another embodiment of the invention, the compound of formula I has the formula V,
Figure imgf000017_0001
Formula V or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of alkyl, aryl, heterocycloalkyl 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)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, -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; and wherein one or two of X4, X9, and X5 are N. In the compound of formula V, R2 is preferably selected from the group consisting of aryl, heterocycloalkyl 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)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 one example of this embodiment, the R201 heterocycloalkyl is a lactam radical or a carbamate radical wherein the lactam or carbamate nitrogen is the nitrogen directly bonded to R2.
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 one example of this embodiment, the R201 heteroaryl or its tautomer is a lactam radical wherein the lactam nitrogen is the nitrogen directly bonded to R2.
In another embodiment of the invention, -C(O)R203 is -CO-heterocycloalkyl, wherein the heterocycloalkyl contains a nitrogen directly bonded to CO, wherein the R203 heterocycloalkyl in the C(O)R203 is optionally substituted as defined in formula I. In another embodiment of the invention, -C(O)R203 is -CO-heteroaryl, wherein the heteroaryl contains a nitrogen directly bonded to CO, wherein the R203 heteroaryl in the C(O)R203 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, Huπtiπgton'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 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 claim 1 that is effective in the treatment or prevention of such conditions. The composition may be, as another example, a composition comprising an mGluR-2 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
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
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 from one to twenty carbon atoms; in one 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 substitueπts 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:
Figure imgf000023_0001
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 "pheπalenyl"), 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 one 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 cycfoalkyl 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 subsfitutents, 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-Ce alkyl, Ca-C1O 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 cycloalkenyl 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, cyclopentadienyl, 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 "aryP 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 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 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-C10 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 "pheπalenyl"), 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 "Cx-Cy-," wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "C1-C6-BlKyI" 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 substitueπts. 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
Figure imgf000025_0001
The 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 monoalkylamiπo such as methylamino (exemplified by the formula
dialkylamiπo such as
Figure imgf000025_0002
The term "aminocarbonyl" means -C(O)-NH2, which also may be depicted
Figure imgf000025_0003
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 alky! 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. EΞxamples 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 hexyfthio. The term "alkylcarbonyl" means -C(O)-alkyl. For example, "ethylcarbonyl" may be
depicted as:
Figure imgf000027_0001
. 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:
Figure imgf000027_0002
**
The term "alkoxycarbonyl" means -C(O)-O-alkyl. For example, "ethoxycarboπyl" may
be depicted as:
Figure imgf000027_0003
. 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 "throne" refers to =S.
The term "sulfonyl" refers to -S(O)2-, which also may be depicted as:
Figure imgf000027_0004
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
Figure imgf000027_0005
The term "sulfinyl" or "sulfoxido" means -S(O)-, which also may be depicted as:
Figure imgf000028_0001
Thus, for example, "alkylsulfinylalkyl" or "alkylsulfoxidoalkyl" refers to alkyl-S(O)-alkyl. Exemplary alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfiπyl, 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-Ci0 aromatic ring or to a 5-10-membered heteroaromatic ring may be optionally substituted with halogen, CrC6 alkyl, C3-C10 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, pyrimidiπyl, and pyridazinyl; 5-membered ring substituents such as triazofyl, 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, benzisoxazolyl, 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 substitueπt, the ring atom of the heteroaryl substitueπt 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, tetrahydrothiopheπyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazoiinyl, isothiazolinyl, thiazolidiπyl, isothiazolidinyl, thiaediazolyl, oxathiazolyl, oxadiazolyl (including oxadiazolyl, 1 ,2,4-oxadiazolyi (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-dioxazolyl), 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-diazinyr), pyrimidinyl (also known as "1 ,3-diazinyl" or "pyrimidyl"), 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-triazinyl), 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, naphthyridiπyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl, iπdolyl, isoindolyl, indoleninyl, isoiπdazolyl, benzazinyl, phthalazinyl, quiπoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, iπdoxazinyl, anthranilyl, benzodioxolyl, beπzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, beπzisoxazinyl, and tetrahydroisoquinoliπyl.
Examples of 3-fused-riπg 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 indolyi, 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"), anthraπilyl, 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-benzoxazinyl , 2,3,1 -benzoxazinyl , or 3,1,4-benzoxazinyl ), benzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-beπzisoxazinyl), tetrahydroisoquinolinyl , carbazolyl, xanthenyl, and acridinyl.
The term "heteroaryi" also includes substituents such as pyridyl and quinolinyl that are fused to a C4-C10 carbocyclic ring, such as a C5 or a Ce 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 heteroaryi group or to a heteroatom of the heteroaryi group. When such a fused heteroaryi group is substituted with one more substituents, the one or more substitutents, unless otherwise specified, are each bound to an aromatic carbon of the heteroaryi group or to a heteroatom of the heteroaryi group. The fused C4-Ci0 carbocyclic or 4-10-membered heterocyclic ring may be optionally substituted with halogen, Ci-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 -NR'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, isoxazoiyl, 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 "alkyicycloalkyl" contains two moieties: alkyl and cycloalkyl. Thus, a Ci-Ce- prefix on CrC6-alkylcycloalkyl means that the alkyl moiety of the alkyicycloalkyl contains from 1 to 6 carbon atoms; the CrCe- 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
Figure imgf000032_0001
. In a substituent trifluoromethylaminocarbonyl, the carbonyl moiety is attached to the remainder of the molecule, where the substituent may also be depicted as
Figure imgf000032_0002
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 substitueπt(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 I 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, m ethanesulfonic, 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, sufaπilate, 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'-dibenzylethyleπediamine, chloroprocaine, choline, diethanolamine, ethylenediamiπe, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups may be quaternized 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, 17O, 31P, 32P, 35S1 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, Ie1,, 3H, and carbon-14, Le11 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 intraπasally 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 controlfed-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 (3rd 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 hereinbelow. Unless otherwise indicated, the substituents in the Schemes are defined as above. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.
In the schemes below, the numerals used, 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.
The following schemes are exemplary of the processes for making compounds of formula I. Scheme I illustrates a method for the preparation of compounds having the basic structure of formula (Vl), where R2, R17, X4, X5, Xe, and X9 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 CH2Cb, 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 (DEEAD) 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 dibutylazodicarboxylate(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 to also produce the desired compounds of formula (Vl). Scheme 1
Figure imgf000042_0001
(V) (Vl)
Alternatively, scheme Il illustrates a method for the preparation of compounds having the basic structure of formula (Vl), where R2, R17, X4, X5, X6, and X9 are defined as above. Referring to scheme Il 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 (VII). The alcohols of formula (VII) 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 (VIII). Compound (VIII) can be treated with R2-OH (III) in the presence of a suitable base, such as cesium carbonate, potassium t-butoxide or the like, in a suitable solvent such as acetonitrile, with or without microwave irradiation at elevated temperature around 50 0C to 200 0C to yield compounds of formula (Vl). Alternatively alcohols of formula (VII) can be directly converted to compounds of formula (Vl) under standard alkylation conditions using reagents of formula (III') wherein R2 is substituted alky!, cycloalkyl and heterocycloalkyl, X is Cl, Br, I, OMs or OTs, in the presence of a suitable base such as, but not limited to, sodium hydride and potassium t-butoxide in a suitable solvent such as DMF, NMP or THF with or without microwave heating at elevated temperature around 500C to 2000C. Scheme Il
Figure imgf000043_0001
(V) (VIl)
(VIII)
Figure imgf000043_0002
(Vl)
Alternatively, scheme III illustrates a method for the preparation of compounds having the basic structure of formula (X), where R2 is an optionally substituted heteroaryl including but not limited to 2-pyridyl, 2-pyrimidine, or 2-pyrazine, R17, X4, X5, X6, and X9 are defined as above. Referring to scheme III below, and R is hydrogen or any one of the substituents, defined above, that may optionally substitute R2. alcohols (VIII) can be treated with halo- heteroaryls (formula IX) in the presence of a suitable base such as potassium t-butoxide or sodium hydride and the like, 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 (X). Scheme 111
Figure imgf000044_0001
(VIIi) PO
Aldehydes of formula (V) are either commercially available or can be prepared, but not limited to, by general procedures illustrated by scheme IV, wherein R17, X4, X5, X6, and X9 are defined as above. Referring to scheme IV below, haloheteroaryls (Xl) can be treated with primary amines of formula (XII) in the presence of a suitable base such as potassium carbonate and the like, in a suitable solvent such as dichloromethane at a reaction temperature ranging from room temperature to 100 0C to give compounds of formula (XIII). Hydrogenation of the nitro group using well-precedented conditions such as Pd/C under hydrogen or Fe/EtOH/CaCfe can yield diamine of formula (XIV). The imidazole ring can be formed by treating diamines (XIV) with acetimidates of formula (XVIII), in the presence of acetic acid, in a suitable solvent such as MeOH. The acetal of compounds (XVII) can be removed with acids such as HCI to give the desired aldehydes of formula (V). Alternatively, diamines (XIV) can be condensed with glycolic acid under strong acidic conditions, such as aqueous hydrochloric acid, at elevated temperature such as reflux. The resultant alcohols of formula (XVI) can then be oxidized using a suitable oxidation reagent, such as MnO2 in a suitable solvent such as methylene chloride, to yield the desired aldehydes of formula (V). In addition, diamines (XIV) can cyclize with triethylorthoacetate in a suitable solvent such as ethanol at elevated temperature with or without microwave heating to produce imidazoles of formula (XV), which can be subsequently oxidized to the desired aldehydes 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 IV
Figure imgf000045_0001
(V)
Scheme V illustrates a method for the preparation of compounds having a basic structure of formula (XXIII), wherein R17, X4, X5, X6 and X9 are defined as above and R is hydrogen or any one of the substituents, defined above, that may optionally substitute R2. Oxidation of the Boc-protected [3.1.0] amino alcohol (II) via common oxidizing methods are well known in the art and include methodssuch as Swern Oxidation and Dess-Martin Oxidation, to yield an aldehyde of formula (XIX). Wittig olefination using Phosphonium salts of formula (XX) 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, provide olefins of formula (XXI) as a mixture of Z/E isomers. Hydrogenation of the olefin 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 amines of formula (XXII). Amines (XXII) can then 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 productsof formula (XXIII). Scheme V
Figure imgf000046_0001
(XXII) (XXIII)
Alternatively, compounds of formula (XXIII) can be prepared via the synthetic route illustrated in scheme Vl. The aldehyde (XIX) can be treated with bromomethyl triphenylphosphonium bromide (XX) in the presence of suitable base such as BuLi and NaHMDS, in a suitable solvent such as THF, at reaction temperature from -780C to room temperature to yield the vinyl bromide of formula (XXV) as a mixture of Z/E isomers. A compound of formula (XXVII) then can be prepared via a Suzuki coupling of the vinylbromide (XXV) with boronic acids (XXVI) in the presence of a catalyst such as palladium (O) tetrakis(triphenylphosphine), palladium (II) acetate, allyl palladium chloride dimer, tris(dibenzylideneacetone)dipalladium (O), tris(dibenzylideneacetone)dipalladium (0) chloroform adduct, palladium (II) chloride or dichloro[1,1'-bis(dipheπylphosphino)ferroceπe]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, with sodium carbonate being preferred. Typically this reaction is 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 and the like, in the presence or absence of water, ranging from about 1% to about 10% water, with about 5% water being preferred, with or without microwave assisted heating at a temperature from about room temperature to about 2000C, preferably from about 6O0C to about 1000C. Hydrogenation of (XVIi) 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 amines of formula (XXII). Amines (XXII) 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 products of formula (XXIII).
Scheme Vl
Figure imgf000047_0001
(XXII) (XXIII)
Scheme VII illustrates a method for the preparation of compounds having the basic structure of formula (XXVII), wherein R18, R2, R17, X4, X5, X6 and X9 are defined as above.
Referring to scheme VII, the aldehyde (XIX) can be treated with amines of formula (XXIV) 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 (XXV). Other suitable conditions for this transformation include treatment of the aldehyde of formula (XIX) with amines of formula
(XXIV) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH4, to produce the desired compounds of formula (XXV). Compounds of formula
(XXV) 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 (XXVI). Compounds of formula (XXVI) 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- dichloroethaπe or THF, at about room temperature, to produce the corresponding amine of formula (XXVII). Other suitable conditions for this transformation include treatment of the amines of formula (XXVI) with aldehydes of formula (V) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH4, to produce the desired compounds of formula (XXVII).
Scheme VII
Figure imgf000048_0001
(XXVI)
(XIX) (XXV)
(XXVII)
Figure imgf000048_0002
Alternatively, scheme VIII illustrates a method for the preparation of compounds having the basic general structure of formula (XXXIII) wherein R2, R17, X4, X5, X6 and X9 are defined as above. Referring to scheme VIII, the aldehyde of formula (XIX) 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 (XXVIII). Other suitable reducing agents include NaBH4 and NaBH3CN in solvents such as methanol or ethanol at room temperature. A compound of formula (XXVIII) 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 900C to produce the corresponding product of formula (XXIX). A compound of formula (XXIX) can be treated with various aldehydes of formula (XXX) in the presence of a suitable reducing agent such as NaHB(OAc)3, in solvents such as methylene chloride, 1,2- dichlσroethane or THF, at about room temperature, to produce the corresponding products of formula (XXXI). Other suitable reducing agents include NaBH4 and NaBH3CN in solvents such as methanol or ethanol at room temperature. Compounds of formula (XXXI) 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 intermediates of formula (XXXII). Compounds of formula (XXXII) 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 (XXXIII). Other suitable conditions for this transformation include treatment of the amines of formula (XXXII) with aldehydes of formula (V) in solvents such as methanol or ethanol at room temperature, followed by treatment with NaBH4, to produce the desired compounds of formula (XXXIII).
Scheme VIII
Figure imgf000049_0001
(XlX) (XXVIII) (XXIX)
Figure imgf000049_0002
Scheme IX illustrates the synthesis of compounds of formula (XXXIX), wherein R201, R101, R17, X4, X5, X6 and X9 are defined as above. Referring to scheme IX below, commercially available amines (XXXIV) 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 (XXXV). The Boc-protecting group of compounds of formula (XXXV) can be removed under acidic conditions, such as hydrochloric acid and trifluoroacetic acid. The resultant amines (XXXVI) can then be treated with aldehydes of formula (XXXVII) in the presence of a suitable catalyst, such as Pd/C, under hydrogen (25-50 PSl) in a solvent such as ethaπol with a suitable base, such as triethylamine, at about room temperature to produce the corresponding secondary amines of formula (XXXVIII). Treatment of amines (XXXVIII) with aldehydes of formula (XXXX) 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, produced the desired compounds of formula (XXXIX).
Scheme IX
Figure imgf000050_0001
(XXXVI)
Figure imgf000050_0002
(XXXVIII) (XXXIX)
N. Working Examples The following illustrates 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.
Preparation 1 : 1 -Methyl-1 H-imidazo[4,5-clPVridine-2-carbaldehvde Dihydrochloride Dihvdrate
4-Chloro-3-nitropyridine (70.0 g, 0.44 mol) was suspended in chloroform (280 ml_) under stirring for 15 min. The suspension was cooled in an ice bath and diluted with ethanol (280 ml_). Aqueous 40% w/w solution of methylamine (98.2 ml_) was added dropwise to this mixture under vigorous stirring and cooling. The reaction mixture was stirred at room temperature for 2 h and allowed to stay overnight. The mixture was diluted with chloroform (200 rnl_). The yellow precipitate was separated and washed with hot chloroform (400 mL). The filtrate was concentrated under reduced pressure to dryness, and the residue was dissolved in chloroform (800 mL). The solution was washed with water (2 * 800 mL) and dried over Na2SO4. The solvent was removed under reduced pressure, and the solid residue was recrystallized from acetone (750 mL) to give compound W-Methyl-3-nitropyridiπ-4-amine (38.8 g, 57.4%, 0.25 mol) as a yellow crystalline solid.
/V-Methyl-3-nitropyridiπ-4-amiπe (49.43 g, 0.323 mol) was suspended under vigorous stirring in methanol (500 mL). Activated carbon (2.0 g) was added to the suspension, which was refluxed for 2.5 h and then allowed to stay overnight at room temperature. The reaction apparatus was flushed with dry nitrogen, and the catalyst (Pd/C 10%, 4.9 g) was added to the mixture. Hydrogen was bubbled through the mixture for 21 h under stirring at room temperature. The obtained mixture was passed through Celite (upper layer, 3 cm) and silica gel (lower layer, 5 cm, diameter 13 cm) to remove the catalyst. The layers were washed with methanol (3 * 300 mL). The filtrate was concentrated under reduced pressure to afford //-Methylpyridine-S^-diamine (39.54 g, 99.5%, 0.32 mol) as a brown crystalline solid. The obtained product was used for the next stage without additional purification.
Sodium (12.0 g, 0.52 mol) was dissolved in anhydrous methanol (450 mL). A solution of diethoxyacetonitrile (75 g, 0.58 mol) in anhydrous methanol (210 mL) was added dropwise to the solution of sodium methoxide under stirring. The obtained mixture was stirred at room temperature for 2 h and allowed to stay overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (300 mL). The solution was shaken with chloroform (200 mL), and the layers were separated. The aqueous layer was additionally treated with chloroform (2 x 150 mL). The organic extracts were combined and dried over Na2SO4. The solvent was removed to give Methyl 2,2-Diethoxyethanimidoate (63.82 g, 68%, 0.4 mol) as a pale-yellow liquid.
//-Methylpyridine-S^-diamine (39.54 g, 0.32 mol) was added to a solution of Methyl 2,2-Diethoxyethanimidoate (52.02 g, 0.323 mol) in anhydrous methanol (150 mL). The obtained mixture was diluted with anhydrous methanol (50 mL) and cooled in an ice bath. 4 M HCI in dioxane (86 mL) was added dropwise to the mixture under stirring for 15 min. The mixture was refluxed for 5 h and concentrated under reduced pressure. The residue was dissolved in a mixture of chloroform (300 mL) and water (300 mL). The layers were separated, and the aqueous layer was treated with chloroform (3 * 250 mL) to extract the product. The extracts were combined, dried over Na2SO4, and evaporated to give a red mass (45 g). The latter was chromatographed (silica gel, chloroform/ethanol 40:1). The solvent was removed to give 2-(Diethoxymethyl)-1-methyl-1H-imidazo[4,5-c]pyridine (31.85 g, 42%, 0.135 mol) as a red liquid.
2-(Diethoxymethyl)-1~methyl-1H-imidazo[4,5-c]pyridine (36.9 g, 0.157 mol) was mixed under vigorous stirring with 4 M HCI (103 mL). The reaction mixture was stirred at 60 0C for 3 h and evaporated to dryness. The residue was mixed with dioxane (150 mL), and the mixture was concentrated under reduced pressure to remove residual water. The operation was repeated to give a crystalline solid, which was triturated with anhydrous ether (150 mL). The pale-yellow precipitate was separated by filtration and washed with ether to furnish 1-Methyl- 1H-imidazo[4,5-c]pyridiπe-2-carbaldehyde Dihydrochloride Dihydrate (36.35 g, 92%). Preparation 2:
3-Methyl-3H-imidazof4.5-biPVridine-2-carbaldehvde Hydrochloride Hydrate 2-chloro-3-nitropyridine 70.0 g, 0.44 mol) was dissolved in recently distilled acetonitrile (400 ml_) under stirring. Sodium acetate (55.2 g, 0.67 mol) and 30% aqueous solution of methylamine (111 mL) were added under vigorous stirring. The obtained suspension was stirred at room temperature for 30 min, refluxed for 1 h, and kept overnight at room temperature. The yellow reaction mixture was concentrated under reduced pressure to remove approximately 30O mL of the solvent. The residue was diluted with 20% aqueous solution of K2CO3 (1 L) under stirring. The yellow precipitate was filtered off, washed with water (3° x 200 mL), and dried to afford /v-Methyl-3-nitropyridin-2-amiπe in 86% (58.14 g, 0.38 mol) yield as bright yellow crystals.
W-Methyl-3-nitropyridin-2-amine (58.14 g, 0.38 mol) was dissolved in 1 ,2 dimethoxyethane (400 mL) under vigorous stirring. The obtained solution was refluxed with activated charcoal (2.9 g) for 2 h and kept overnight at room temperature. The reaction apparatus was flushed with dry nitrogen, and the catalyst (Pd/C 10%, 1.75 g) was added. The mixture was heated to 40 0C. Hydrazine monohydrate (54 mL, 1.08 mol) was added dropwise to the suspension within 2 h. The obtained mixture was refluxed for 2 h, cooled, and passed through Celite (upper layer, 3 cm) and silica gel (lower layer, 5 cm, diameter 13 cm) to remove the catalyst. The layers were washed with 1 ,2-dimethoxyethane (300 mL). The filtrate was concentrated under reduced pressure to afford Λ/2-methylpyridine-2,3-diamine in 98% (46.2 g) yield as a brown crystalline solid. The product was used for the next stage without additional purification. /v^-methylpyridine^.S-diamine (44.33 g, 0.36 mol) was dissolved in 1,2- dimethoxyethane (200 mL). Methyl 2,2-Diethoxyethanimidoate (63.8. g, 0.4 mol) and glacial acetic acid (21.6 g, 0.36 mol) were added to the solution under stirring. The obtained mixture was stirred at room temperature for 7 h, then refluxed for 40 min. The mixture was concentrated under reduced pressure to dryness, and the residue was purified by chromatography on a silica gel column (ethyl acetate/hexane 1:2) to furnish 2-(Diethoxymethyl)-3-methyl-3H-imidazo[4,5--)]pyridine in 65.6% (55.53 g, 0.236 mol) yield as a yellow liquid.
2-(Diethoxymethyl)-3-methyl-3H-imidazo[4,5-6]pyridine (53.54 g, 0.228 mol) was mixed under vigorous stirring with 4 M HCI (150 mL). The reaction mixture was stirred at 60 0C for 3 h and evaporated to dryness. The residue was mixed with dioxane (150 mL), and the mixture was concentrated under reduced pressure to remove residual water. The operation was repeated to give a crystalline solid, which was triturated with anhydrous ether (150 mL). The yellow precipitate was filtered off and washed with ether to furnish 3-Methyl-3H- imidazo[4,5-6]pyridine-2-carbaldehyde Hydrochloride Hydrate in 100% (45.4 g) yield. Preparation 3:
1 -Methyl-1 H-imidazof4.5-b]pyridine-2-carbaldehvde Hydrochloride Hydrate 3-Methoxy-2-πitropyridine (25.15 g, 0.163 mol) and 33% w/w solution of methylamine in ethanol (82 ml_, 0.65 mol) were placed into a reactor vessel of MILESTONE Microwave Labstation. The reaction mixture was treated with microwave radiation under stirring at an internal temperature of 105 0C for 4.5 h. The reaction mixture was cooled and diluted with chloroform (200 rπL). The obtained suspension was concentrated under reduced pressure to dryness, and the residue was purified by column chromatography (silica gel, 1 kg, chloroform/1 ,2-dimethoxyethane, 50:1, ~3 L). The eluate was evaporated to dryness. The residue was purified by column chromatography (silica gel, 1 kg, chloroform, 5 L→chloroform/1 ,2-dimethoxyethane, 200:1, 7 L). The second fraction containing the product was concentrated under reduced pressure, and the residue was recrystallized from 1 ,2-dimethoxyethane/hexane mixture 1:1 to give N-Methyl-2-nitropyridin-3-amine (14.18 g, 57%, 0.093 mol).
N-Methyl-2-nitropyridin-3-amine (14.1 g, 0.092 mol) was suspended under vigorous stirring in 1,2-dimethoxyethane/methanol mixture (1:1, 400 mL). The reaction apparatus was flushed with dry nitrogen. The catalyst (Pd/C 10%, 1.4 g) was added to the mixture. Hydrogen was bubbled through the suspension for 7 h. The reaction mixture was diluted with chloroform (300 mL) and passed through a filter with Celite (upper layer, 3 cm) and silica gel (lower layer, 5 cm, diameter 13 cm) to remove the catalyst. The layers were washed with chloroform/methanol mixture (1:1, 500 mL). The solvent was removed under reduced pressure, and the residue was mixed with acetonitrile. The mixture was concentrated under reduced pressure to give N-Methylpyridine-2,3-diamine (11.05 g, 97%, 0.09 mol). The product was used for the next stage without additional purification.
N-Methylpyridine-2,3-diamine (11.0 g, 0.089 mol) was dissolved in 1 ,2- dimethoxyethane (300 mL). Methyl 2,2-diethoxyethanimidoate (31.0 g, 0.19 mol) and glacial acetic acid (10 mL) were added to the solution under stirring. The obtained mixture was stirred at room temperature for 3 h, then refluxed for 5 h. p-Toluenesulfonic acid monohydrate (0.1 g) was added to the reaction mixture, which was refluxed for 7 h. The mixture was concentrated under reduced pressure, and the residue was diluted with toluene (300 mL). The mixture was refluxed for 7 h, cooled, and mixed with a solution of Na2CO3 (20 g) in water (500 mL). The product was extracted with ethyl acetate (3 x 300 mL) and chloroform (400 mL). The combined extracts were dried over MgSO4 and concentrated under reduced pressure to give a dark brown solid, which was chromatographed on silica gel (chloroform/1,2-dimethoxyethaπe 1:1, 900 ml_). 2-(diethoxymethyl)-1-methyl-1H-imidazo[4,5- b]pyridine was obtained (8.3 g, 39.5%, 0.35 mol).
2-(Diethoxymethyl)-1-methyl-1H-imidazo[4,5-b]pyridine (8.3 g, 0.035 mol) was mixed under vigorous stirring with 4 M HCI (25 m!_). The reaction mixture was stirred at 57-58 0C for
5 3 h and evaporated to dryness. The residue was mixed with dioxane (150 mL), and the mixture was concentrated under reduced pressure to remove residual water. The operation was repeated to give a crystalline solid, which was triturated with anhydrous ether (150 mL).
The yellow precipitate was separated by filtration and washed with ether (3 * 250 mL) to furnish 1-Methyl-1H-imidazo[4,5-b]pyridine-2-carbaldehyde hydrochloride hydrate (7.3 g,
10 96%, 0.034 mol).
Preparation 4:
3-methyl-3H-imidazo[4,5-c1pyridine-2-carbaldehvde
To a solution of 3-bromo-4-nitropyridine N-oxide (0.5 g, 2.28 mmol) in 2 ml ethyl alcohol, methylamine (33% weight in ethyl alcohol) (0.57 ml, 4.56 mmol) was added and the
15 mixture was heated by microwave under 900C for 20 minutes. The mixture was concentrated under reduced pressure to yield Methyl-(4-nitro-1-oxy-pyridin-3-yl)-amine (0.38 g); MS+ 170.1.
To a solution of Methyl-(4-nitro-1-oxy-pyridin-3-yl)-amine (0.38 g, 2.28 mmol) in 4 ml acetic acid, iron powder (383 mg, 6.849 mmol) was added and the mixture was heated by microwave under 1800C for 30 minutes. The mixture was basified to pH 12 by 1 N NaOH
20 solution. The resulting mixture was extracted by DCM, dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue purified using silica gel chromatography (0% to
10% MeOH/CH2CI2) to yield 2,3-dimethyl-3H-imidazo[4,5-c]pyridine (0.1 g); GC-MS 147.
To a solution of 2,3-dimethyI-3H-imidazo[4,5-c]pyridine (0.31 g, 2.14 mmol) in 3.5 ml 1,4-dioxine, selenium dioxide (356 mg, 3.21 mmol) was added and the mixture was heated by 25 microwave under 1500C for 30 minutes. The mixture was filtered and the solvent was removed in vacuo. The residue purified using silica gel chromatography (0% to 10% MeOH/CH2CI2) to yield 3-methyl-3H-imidazo[4,5-c]pyridine-2-carbaldehyde (0.15 g); GC-MS 161.
Preparation 5: 30 5.6-dihvdro-4H-imidazor4.5.1 -iil-1.7-naphthyridine-2-carbaldehyde
A 500 mL high pressure Parr vessel, was charged with 1 ,7-naphthyridin-8-amine
(Aldrich, 6.0 g, 41.3 mmol), Pd(OH)2/C (20%) (Aldrich, 3.0 g), cone. HCI (8.26 mL, -83 mmol), ethanol (100 mL). The mixture was closed and hydrogenated in Parr apparatus at 40 psi for 5 days. LCMS showed completed reaction. The mixture was filtered through celite and
35 evaporated to give yellow residue of HCI salt. This residue was dissolved in 20 mL of water, basified to pH 12 with NaOH, and extracted with DCM (4x100 mL). The extract was dried over
, Na2SO4 and evaporated to give 6.00 g (97%) of 1,2,3,4-tetrahydro-1,7-πaphthyridin-8-amiπe as a tan solid. LCMS (M+H): 150.3; 1H NMR (300 MHz, CDCI3): δ 7.28 (d, J = 5.28 Hz, 1H), 6.45 (d, J = 5.1 Hz, 1H), 4.14 (br., 2H), 3.32 (m, 2H)1 3.20 (br., 1H), 2.69 (m, 2H), 1.90 (m, 2H).
A 250 mL high pressure vessel, equipped with a magnetic stirring bar, was charged with 1,2,3,4-tetrahydro-1,7-naphthyridiπ-8-amiπe (6.00 g, 40.27 mmol), methylorthoformate (60 mL), and 99% formic acid (4 mL). The mixture was closed and heated at 100 0C for 14 h. Then the mixture was evaporated under vacuum and the dark residue was mixed with 1O mL of sat Na2CO3. The mixture was extracted with DCM (3x100 mL). The extract was dried over Na2SO4 and evaporated. The crude dark oil was purified by column (DCM 46%, ether 46%, MeOH 5%, Et3N 3%, Rf = 0.18 in the same system) to give 5.13 g (80%) of 5,6-dihydro-4H- imidazo[4,5,1-ij]-1,7-naphthyridine as a yellow solid. LCMS (M+H): 160.1; 1H NMR (300 MHz1 CDCI3): δ 8.47 (d, J = 4.89 Hz, 1H), 8.06 (s, 1H), 6.99 (d, J = 4.89 Hz1 1H), 4.30 (t, J = 5.75 Hz, 2H), 3.02 (t, J = 6.03 Hz, 2H), 2.30 (m, 2H).
A 500 mL, 3-neck round bottomed flask, equipped with a magnetic stirring bar, nitrogen gas inlet, thermometer, and a septum, was charged with 5,6-dihydro-4H- imidazoμ.δ.i-ifl-i^-naphthyridine (5.42 g, 34.09 mmol), and anhydrous THF (220 mL). The suspension was heated to completely dissolve the material, then cooled to RT to form fine suspension. This suspension was cooled to -75 0C and then LDA (2M in heptaneAΗF/ethylbenzene, 18.76 mL, 37.51 mmol) was added dropwise to keep temperature below -60 0C. The mixture was stirred at -70 0C for 3 h, then anhydrous DMF (7.95 mL, 102.26 mmol) was added over 5 min at temperature below -60 0C and slowly warmed to RT, then stirred at room temperature for 12 h. The mixture was cooled with an ice bath and then saturated aqueous solution of NaH2PO4 was added until pH = 8.0 - 8.5. The mixture was extracted with DCM (4x300 mL), the extract was dried over Na2SO4 and evaporated to give crude residue, which was recrystallized by dissolving in 12 mL of MeOH, then addition of 70 mL of EtOAc followed by 70 m L of hexane. The precipitate was filtered and dried to give 5.5 g (86%) of 5,6-dihydro-4H-imidazo[4,5,1-ij]-1,7-naphthyridine-2-carbaldehyde as a yellow solid. LCMS (M+H): 188.4; 1H NMR (300 MHz1 CDCI3): δ 10.18 (s, 1H)1 8.65 (d, J = 4.71 Hz, 1H)1 7.13 (d, J = 4.71 Hz1 1H)1 4.67 (t, J = 5.83 Hz1 2H), 3.06 (t, J = 6.12 Hz1 2H)1 2.33 (m, 2H). METHOD A (SCHEME I)
To a solution of (3-aza-bicyclo[3.1.0]hex-6-yl)-methanol-HCI (11.8gm, 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 % MeOH/CH2CI2. The product containing fractions were collected and concentrated to yield (1S,5R,6R)-ferf-butyl-6-(hydroxyme%l)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (15.6 gm). 1H NMR (400 MHz, CDCI3) δ 3.4-3.6 (m, 4H), 3.2-3.7 (m, 2H), 1.72 (brs, 1H), 1.4-1.4 (m, 10 H), 0.9-0.9 (m, 1H); MS (M+1) 213.2.
Prepared a 2 M stock solution of (1S,5R,6R)-førf-butyl-6-(hydroxymethyl)-3-aza- bicyclo[3.1.0]hexane-3-carboxylate 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. Manually added 0.600 mL of the DEΞAD solution, followed by 0.750 mL of toluene. Manually 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 m L 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. The solvent was evaporated solutions to dryness and the resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (Vl) MCTHOD B (SCHEME I)
Prepared a 2 M stock solution of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3-aza- bicyclo[3.1.0]hexane-3-carboxylate 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 β-fhydroxymethyO-S-aza-bicycloβ.i.Olhexane-S-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 vial 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.
A 0.25 M solution of an aldehyde of general formula (V) was prepared in 1,2- dichloroethane. A 0.25 M solution of sodium triacetoxyborohydride in chloroform was also prepared. 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).
Preparation 6:
(πS.5R,6RV3-((1-methyl-1H-imidazof4.5-biDyridin-2-yl)methvn-3-aza- bicvclor3.1.01hexan-6-yl)methanol
1000 mg (5.1 mmol) of 1-methyl-1 H-imidazo[4,5-b]pyridine-2-carbaldehyde is dissolved in 20 ml of 1 ,2-dichloroethane / methanol (1:1),, added 2.8 ml (20 mmol, 4 eq) of triethylamine, 1000 mg of magnesium sulfate, 757 mg (5.1 mmol) of (1S,5R,6R)-3-aza- bicyclo[3.1.0]hexan-6-ylmethanol, stirred at room temperature for 60 min, 1286 mg (6.1 mmol, 1.2 eq) of sodium triacetoxyborohydride was added and the suspension was stirred at room temperature for 16 hours. The suspension was diluted with dichloromethane and extracted three times with 1N NaOH. The organic layer was dried over anhydrous MgSO4, filtered and stripped in vacuo to oil. The crude material was purified via flash chromatography, eluting from 0% ammonium hydroxide / 0% methanol / dichloromethane to 0.5% ammonium hydroxide / 9.5% methanol / 90% dichloromethane to yield 200 mg of desired compound. 1H NMR (400 MHz, CDCI3) δ 8.3 (d, 1H), 7.5 (d, 1H), 7.0(m, 1H), 3.8 (s, 2H), 3.6 (s, 3H), 3.3 (d, 2H), 2.7 (d, 2H), 2.4 (d, 2H), 1.3 (m, 1 H), 1.2 (s, 2H); MS (M+1 ) 259.3. Method C (Scheme 10
Various benzyl bromides (0.1 mmol) were weighed into 2-dram vials. To these vials was added ((1 S,5R,6R)-3-((1 -methyl-1 H-imidazo[4,5-b]pyridin-2-yl)methyl)-3-aza- bicyclo[3.1.0]hexan-6-yl)methanol (0.05 mmol) as a slurry in 0.4 ml of dry 1:3 NMP/THF. 1 N KOt-Bu in THF (0.1 ml, 0.1 mmol) was added via syringe to each vial and the mixtures were shaked at overnight. The mixtures were partitioned between 1.5 ml of H2O and 2.5 ml of DCM. The vials were centrifuged for good layer separation. The organic layers were extracted and load onto SCX SPE (Silicycle, 1 g) and the cartridges were eluted with 7.5 ml of 1 N TEA in MeOH. The eluants were concentrated to dryness and 0.5 ml of 15/485 TFA/DCM was added to each vial and the solvent was removed under vacuo. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (Vl)
Method D (Scheme IO
Preparation 7: (1 S.5R.6R)-fert-butyl 6-(hvdroxymethylV3-aza-bicvclof3.1.OIhexane-3-carboxylate
To a solution of (1S,5R,6R)-6-(hydroxymethyl)-3-aza-bicyclo[3.1.0]hexane (5 g, 33.4 mmol) in 100 ml dichloromethane, triethylamine (7 ml, 50.12 mmol) was added and the mixture was cooled to 0 0C. Then, BOC-anhydride (7.6 g, 35 mmol) was added. The mixture was stirred under Nitrogen and warmed up to room temperature over night. The mixture was then concentrated under reduced pressure. The residue purified using silica gel chromatography (0% to 100% EtOAc/Hexane) to yield (1S,5R,6R)-terf-butyl 6- (hydroxymethyO-S-aza-bicycloβ.i.Olhexane-S-carboxylate (3.5 g); GC-MS 213.
Preparation 8:
((1 S.SR.βRVS-fferf-butoxycarbonyO-S-aza-bicvclora.1.Olhexan-6-vDmethyl methanesulfonate
To a solution of (1S,5R,6R)-terf-butyl 6-(hydroxymethyl)-3-aza-bicyclo[3.1.0]hexane- 3-carboxylate (1 g, 4.68 mmol) and triethylamine (0.98 ml, 7 mmol) in 12 ml of dichloromethane, Methanesulfonyl chloride (0.4 ml, 5 mmol) was added under 0 0C and nitrogen protection. After addition, the ice bath was removed and the mixture stirred under room temperature for two hours. The mixture was washed by saturated sodium bicarbonate solution, extracted by DCM and dried over sodium sulfate. The solvents was removed in vacuo to yield ((IS.δR.δRJ-S-^ert-butoxycarbonyO-S-aza-bicyclolS.I.OJhexan-β-yOmethyl methanesulfonate (1.2 g); MS+ 583.5 Preparation 9:
(1S.5R.6F0-terf-butyl e-fβ-chlorophenoxyϊmethvπ-S-aza-bicyclofS.I.Olhexane-S- carboxylate
To a solution of 8 ml acetonitrile, ((1S,5R,6R)-3-(terf-butoxycarboπyl)-3-aza- bicyclo[3.1.0]hexaπ-6-yl)methyl methaπesulfonate (1.58 g, 5.4 mmol), 3-chloropheπol (0.69 g,
5.4 mmol) and cesium carbonate (2.65 g, 8.1 mmol) was added sequentially. The mixture was heated by microwave under 1200C for 10 minutes. The mixture filtered and the solvent was removed in vacuo. The residue purified using silica gel chromatography (0% to 30%
EtOAc/Hexane) to yield (1S,5R,6R)-terf-butyl 6-((3-chlorophenoxy)methyl)-3-aza- bicyclo[3.1.0]hexane-3-carboxylate (1.1 g); MS+ 647.2
Preparation 10:
(1 S.SR.eRΪ-θ-fP-chlorophenoxyϊrriethvD^-aza-bicvclore.1.Olhexane
To a solution of (1S,5R,6R)-tert-butyl 6-((3-chlorophenoxy)methyl)-3-aza- bicyclo[3.1.0]hexane-3-carboxylate (0.5 g, 1.5 mmol) in 3 ml dichloroethane, 4 N hydrochloride in dioxane (3 ml, 12 mmol) was added and the mixture was stirred for one hour at room temperature. The solvents was removed in vacuo to yield hydrochloride salt of
(1S,5R,6R)-6-((3-chlorophenoxy)methyl)-3-aza-bicyclo[3.1.0]hexane (0.4 g); MS+ 224.1.
Example 1 f corresponding to Entry 52 in Table 1)
2-(((1 S.δR.eRy-e-ro-chlorophenoxyϊmethviyS-aza-bicvclore.1.Qlhexan-3-yl)rπethyl)- 1-methyl-1H-imidazof4.5-blPVridine
To a solution of (1S,5R,6R)-6-((3-chlorophenoxy)methyl)-3-aza-bicyclo[3.1.0]hexane (0.4 g, 1.5 mmol) in 5 ml dichloroethane, 1-methyl-1H-imidazo[4,5-b]pyridine-2-carbaldehyde (0.33 g, 1.54 mmol), magnesium sulfate (75 mg) and triethyl amine (1 ml, 7.7 mmol) were added sequentially and the mixture was stirred for one hour at room temperature. Then, sodium triacetoxyborohydride (0.5 g, 2.3 mmol) was added into the mixture. The mixture was stirred at room temperature over night. The mixture filtered and was purified using silica gel chromatography (0% to 5% MeOH/CH2CI2) to yield 2-(((1S,5R,6R)-6-((3- chlorophenoxy)methyl)-3-aza-bicyclo[3.1.0]hexan-3-yl)methyl)-1 -methyl-1 H-imidazo[4,5- b]pyridine (0.35 g). 1H NMR (400 MHz, CDCI3) δ 8.47 (m, 1H), 7.58 (d, 1H), 7.13 (m, 2H), 6.86 (d, 1H), 6.80 (m, 1H), 6.70 (d, 1H), 3.93 (s, 2H), 3.78 (s, 3H), 3.68 (d, 2H), 2.96 (d, 2H), 2.56 (d, 2H), 1.55 (m, 1H), 1.42 (s, 2H); MS+ 369.1.
Example 2 (corresponding to Entry 92 in Table 1)
3-methyl-2-(((1 S.5R,6R)-6-fphenoxymethyl)-3-aza-bicvclof3.1.Olhexan-3-vOmethyl)- 3H-imidazof4.5-clpyridine To a solution of (1S,5R,6R)-6-(pheπoxymethyl)-3-aza-bicyclo[3.1.0]hexane (58 mg,
0.3 mmol, prepared following a similar procedure to preparation 7-9 ) in 2 ml dichloroethane and 0.2 ml dimethylformamide, 1 -methyl-1 H-imidazo[4,5-c]pyridine-2-carbaldehyde (50 mg, 0.3 mmol), magnesium sulfate (20 mg) and triethyl amine (0.13 ml, 0.93 mmol) were added sequentially and the mixture was stirred for one hour at room temperature. Then, sodium triacetoxyborohydride (0.1 g, 0.46 mmol) was added into the mixture. The mixture was stirred at room temperature overnight. The mixture filtered and was purified using silica gel chromatography (0% to 10% MeOH/CH2CI2) to yield 3-methyl-2-(((1S,5R,6R)-6- (phenoxymethyl)-3-aza-bicyclo[3.1.0]hexan-3-yl)methyl)-3H-imidazo[4,5-c]pyridiπe (45 mg); MS+ 335.4.
Example 3 (corresponding to Entry 98 in Table 1)
1 -f ((1 R.5S.6R)-6-((2.5-dichlorophenoxy)methyl)-3-aza-bicvclor3.1.OIhexan-3- yl)methvπ-7.8-dihvdro-6H-imidazo[4.5.1-ii'|[1.7lnaphthyridine
In a vial, added 100 mg (0.53 mmol) of 7,8-dihydro-6H-imidazo[4,5,1- ij][1,7]naphthyridiπe-1-carbaldehyde and 0.3 ml (2.1 mmol) of triethylamine to a suspension of 137 mg (0.53 mmol) of (1R,5S,6R)-6-((2,5-dichlorophenoxy)methyl)-3-aza- bicyclo[3.1.0]hexane in 5 mL of anhydrous 1 ,2-dichloroethane at room temperature. After 60 minutes of stirring, 135 mg (0.64 mmol, 1.2 eq) of sodium triacetoxyborohydride was added and the suspension was stirred at room temperature for 16 hours. The suspension was diluted with dichloromethane and extracted three times with 1 N NaOH. The organic layer was dried over anhydrous MgSO4, filtered and stripped in vacuo to oil. The crude material was purified via flash chromatography, eluting from 0% methanol / dichloromethane to 10% methanol / dichloromethane to yield 131 mg of the desired compound. 1H NMR (400 MHz, CDCI3) δ 8.29 (d, 1H), 7.16 (d, 1H), 6.82 (d, 1H), 6.76 (m, 2H), 4.12 (m, 2H), 3.86 (s, 2H), 3.76 (d, 2H), 2.91 (d, 2H), 2.85 (m, 2H), 2.50 (d, 2H), 2.14 (d, 2H), 1.55 (m, 1H), 1.41 (s, 2H); MS (M+1) 429, 431.
Example 4 (corresponding to Entry 48 in Table 1) 2-(f(1 R.5S,6R)-6-(f 2.5-dichlorophenoxy)methyl)-3-aza-bicvclor3.1.OIhexan-3- yl)methvπ-1 -methyl-1 H-imidazor4.5-c]pyridine
300 mg (1.8 mmol) of 1-methyl-1H-imidazo[4,5-c]pyridine-2-carbaldehyde is dissolved in 20 ml of 1,2-dichloroethane / methanol (1:1), added 0.6 ml of triethylamine, 1000 mg of magnesium sulfate, stirred at room temperature for 60 min, stripped, added 40 ml of 1 ,2-dichloroethane, 700 mg (2.3 mmol) of (1 R,5S,6R)-6-((2,5-dichlorophenoxy)methyl)-3-aza- bicyclo[3.1.0]hexane (prepared following a similar procedure to preparation 7-9), 0.6 ml (4.3 mmol) of triethylamine, 1000 mg of magnesium sulfate. After 40 minutes of stirring, 762 mg ( 3.6 mmol, 2 eq) of sodium triacetoxyborohydride was added and the suspension was stirred at room temperature for 16 hours. The suspension was diluted with dichloromethane and extracted three times with 1N NaOH. The organic layer was dried over anhydrous MgSO4, filtered and stripped in vacuo to oil. The crude material was purified via flash chromatography, eluting from 0% methanol / dichloromethane to 10% methanol / dichloromethaπe to yield 465 mg of the desired compound. 1H NMR (400 MHz, CDCI3) δ 9.03 (s, 1H), 8.48 (d, 1H), 7.48 (d, 1H), 7.22 (d, 1H), 6.87-6.82 (m, 2H), 4.01 (s, 2H), 3.91 (s, 3H), 3.84 (d, 2H), 3.03 (d, 2H), 2.67 (d, 2H), 1.63 (m, 1H), 1.56 (s, 2H); MS (M+1) 403.3
Method E Example 5 (corresponding to Entry 99 in Table 1)
1-Methyl-2-((πS,5R.6R)-6-((4-ftrifluoromethyl)Dhenoxy)methyl)-3-aza- bicvclore.1.Qlhexan-3-vDmethyl)-1 H-imidazof4,5-b1pyridine
In a 10 ml CEM microwave vial was combined 60 mg (0.23 mmol, 1 eq) of ((1S, 5R,
6R)-3-((1 -methyl-1 H-imidazo[4,5-b]pyridin-2-yl)methyl)-3-aza-bicyclo[3.1.0]hexan-6- yl)rnethanol, 0.7 ml (0.5 mmol, 2.2 eq) of 1-chloro-4-(trifluoromethyl)benzene and one pellet of Potassium hydroxide in 1 mL of anhydrous tetrahydrofuran at room temperature. The vial was heated to 15O0C for 40 minutes under microwave (CEM Explorer). The mixture was purified via flash chromatography, eluting from 0% methanol / dichloromethane to 10% methanol / dichloromethane to yield 2.5 mg of desired compound. 1H NMR (400 MHz1 CDCI3) δ 8..53 (s, 1H), 7.64 (d, 1H), 7.50 (d, 2H), 7.21 (m, 1H), 6.90 (d, 2H), 4.05 (broad s, 2H), 3.85
(s, 3H), 3.81 (d, 2H)1 3.08 (broad s, 2H), 2.71 (broad s, 2H), 1.53 (broad m, 3H); MS (M+1).
403.1.
Method F (Scheme NA
Preparation 11: 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-Martiπ Periodinaπe (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 then 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. 1H-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, 2H1 broad), 1.69 (m, 1 H)1 1.42 (s, 9H).
Preparation 12:
Benzyl triphenylphosphonium 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 then slowly warmed up to room temperature and stirred overnight. The reaction was quenched by water (5 mL) and then diluted with EtOAc (100 mL) and then 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 then put on a hydrogeπation 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), 3.40 (d, 2H, 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, 1H), 1.20 (m, 2H).
Preparation 13:
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 then 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 CH2CI2: iPrOH (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 C13H17N m/z 188 (M+Hf Example 6 (corresponding to Entry 84 in Table 1)
1-Methyl-2-(6-pheπethyl-3-aza-bicvclof3.1.OIhex-3-ylmethvO-i H-imidazor4.5- bipyridiπe
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-1H-imidazo[4,5-b]pyridine- 2-carbaldehyde.1.25HCMH2O (29 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 27 mg white solid, 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)-1H-imidazo[4,5-b]pyridine. MS (ESI+) for C21H24N4 m/z 333 (M+H)+. Method G (Scheme Vi) Preparation 14:
To a stirred solution of 6-hydroxymethyl-3-aza-bicyclo[3.1.0]hexaπe-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. 1H-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 15:
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 then 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(PPh3J4. The mixture was then heated to reflux and stirred overnight. The mixture was cooled to room temperature and 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. 1H-NMR (CD3OD, 400 MHz) δ (ppM): 7.61 (d, 2H, J = 8.3 Hz), 7.50 (d, 2H, J = 8.3 Hz), 6.43 (d, 1H, 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, 1H), 1.39 (s, 9H). Preparation 16:
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-trifluoromethyl-phenyl)-ethyl]- 3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. 1H-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).
Preparation 17:
To a stirred solution of 6-[2-(4-trifluoromethyl-pheπyl)-ethyl]-3-aza- bicyclo[3.1.0]hexane-3-carboxy!ic 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 Ci4Hi6F3N m/z 256 (M+H)+ Example 7 (corresponding to Entry 90 in Table 1)
1 -Methyl-2-(6-r2-(4-trifluoromethyl-phenylVethvn-3-aza-bicvclof3.1.Olhex-3-ylmethvD- 1 H-imidazof4.5-biPVridine
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-1H-imidazo[4,5-b]pyridine-2-carbaldehyde.1.25HCMH2O (29 mg, 0.13 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, 1% to 6% MeOH in CH2CI2) to give 21 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 25 mg 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 C22H23F3N4 m/z 401 (M+H)+. The following example was prepared following similar procedures:
Example 8 (corresponding to Entry 91 in Table H
2-(6-[2-(4-Fluoro-phenyl)-ethyll-3-aza-bicvclor3.1.01hex-3-ylmethyl)-1 -methyl-1 H- imidazor4.5-blpyridine. MS (ESl^ for C21H^FN1 m/z 351 (M+Hf .
Method H (Scheme VIIh Preparation 18:
6-f(Benzyl-methyl-amino)-methvn-3-aza-bicvclo f3.1.0lhexane -3-carboxylic acid tert- butyl 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. 1H NMR (400 MHz, CDCI3) δ 7.2-7.3 (m, 5H)1 3.6 (d, 1H), 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 19:
6- Methylaminomethyl-3-aza-bicvclo f3.1.0lhexane -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. 1H NMR (400 MHz, CDCI3) δ 3.6 (d, 1H), 3.5 (d, 1H), 3.3 (t, 2H), 2.5 (m, 2H), 2.4 (s, 3H), 2.1 (broad s, 1H), 1.4 (s, 9H), 1.3 (m, 2H), 0.8 (m, 1H); MS (M+1) 227.2. Preparation 20:
Various aldehydes (1.4 mmol, 1.4 eq) were weighed into 16-mL septa capped vials and diluted with 1 ml of DCE. 6- methylaminomethyl-3-aza-bicyclo[3.1.0]hexane -3-carboxylic acid tert-butyl ester (1 mmol) was dissolved in 1 ml of DCE and added to each vial. The vials were snaked at room temp for -1 h to pre-form imine. Then Na(OAc)3BH (2.5 mmol) was added and the mixtures were snaked at room temp overnight. The mixtures were partitioned between 5.5 ml of 1 N NaOH and 10 ml of DCM. The organic layer were extracted and loaded onto large SPE cartridge (hand packed with Na2SO4). The extraction was repeated two times. The solvent was removed in vacuo. The residue was dissolved in 5 ml of 1:1 TFA/DCM and the solutions were shaked at room temp overnight. The solvent was removed in vacuo. The residue was re-dissolved in 5 ml of 1:1 MeOH/DCE and loaded onto large SCX SPE cartridges (hand packed Silicycle, ~3 g), The resin was rinsed with 5 ml of 1:1 MeOH/DCE, the vials switched and eluted with -10 ml of MeOH, followed by switching totared vials and eluted with ~20 ml of 1 N TEA in MeOH. The solvent was removed in vacuo to give the residues that were used in the next step.
Aldehydes of formula (V) (0.075 mmol, 1.25 eq) were dissolved in 0.3 ml of DCE containing TEA (0.1 mmol) and anhydrous MgSO4 (0.2 mmol) and a solution of the residue from previous step in 0.3 mL DCE were added to each vial. The mixtures were shaked at room temperature for 30 min, then Na(OAc)3BH (0.12 mmol) was added. The vials were shaked at room temperature overnight. The mixtures were partitioned between 1.5 ml of 1 N NaOH and 2.5 ml of EtOAc. The organic layers were loaded onto SCX SPE cartridges (Sificycle, 1 g). The extraction was repeated two times. Switched vials and eluted with 5 ml of MeOH. Switched to tared vials and eluted with 7.5 ml of 1 N TEA in MeOH. The solvent was removed in vacuo and the residues were purified with preparative LC/MS chromatography to yield compounds of general formula (XXXIII). Method I (Scheme IX)
The aldehyde of formula (V) (2.8 mmol) was dissolved in 20 m!_ of DCE and to the solution was added (3-Aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester (XXXIV) (2.8 mmol) neat. 5 ml of NMP and Hunig's base (3.22 mmol) were added subsequently. The mixtures were snaked at room temp for ~1 hour and then Na(OAc)3BH (4.2 mmol) was added. The reaction mixtures were shaked at room temp overnight. The mixtures were partitioned between 1 N NaOH aqueous solution and DCM. The organic layer were extracted and loaded onto large SPE cartridge (hand packed with Na2SO4). The extraction was repeated two times. The solvent was removed in vacuo and the residues were dissolved in 8 ml of 1:1 TFA: DCM. The mixtures were shaked at room temp overnight and were then concentrated in vacuo. The residues were loaded onto large SCX SPE cartridges (hand packed Silicycle, ~3 g). Rinsed twice with 5 ml of 1:1 MeOH/DCE. Switched vials and eluted with -20 ml of MeOH. Switched to tared vials and eluted with -20 ml of 1 N TEA in MeOH. The solvent was removed in vacuo to give the residues that were used in the next step.
Various aldehydes or ketones (0.096 mmol, 1.2 eq) were weighed into 2-dram vials and a solution of previous residue in MeOH (0.08 mmol/0.4 ml) was added to each vial, followed by the addition of triethyamine (0.24 mmol) and dry 3A molecular sieves. The vials were shaked at room temp for 1 h, then NaBH4 (0.24 mmol) was added to each vial and the reaction mixtures were shaked at room temp overnight. The mixtures were partitioned between 1.5 ml of 1 N NaOH and 2.5 ml of EtOAc. The organic layers were loaded onto SCX SPE cartridges (Silicycle, 1 g). The extraction was repeated two times. Switched vials and eluted with 5 ml of MeOH. Switched to tared vials and eluted with 7.5 ml of 1 N TEA in MeOH. The solvent was removed in vacuo and the residues were purified with preparative LC/MS chromatography to yield compounds of general formula (XXXVIIl).
Specific Examples with Data The following specific compounds were prepared using the preparations and examples described above.
Table 1
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
* Half value of the expected mass observed due to di-ionization under Mass conditions 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 Ga 15 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)1 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 ]
NaCI 8.47 58.44 145 mM Glucose 1.8 180.2 1O mM
KCI .37 74.56 5 mM
MgSO4 1 ml 1M Stock 246.48 1 mM
HEPES 2.38 238.3 1O mM
CaCI2 2 ml 1M 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 μ L per 1 mg vial). Prepare a 250 mM Probenecid (Sigma) stock solution by dissolving 0.71g 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 μLprobenecid 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 1st addition is for test compounds, which are added as 15 μL of 4X [concentration] of potentiator. The second 2nd addition is 15 μL of 4X [concentration] of agonist or challenge. This achieves 1X concentration of all compounds only after 2nd addition. The 1st and 2nd 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 2nd FLIPR addition are prepared. The best challenge for a particular assay is determined by examining the glutamate dose response and 1-4 test plates.
EC5 o 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 embodiments) 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:
Figure imgf000080_0001
Formula I wherein: Yi 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)R103 , S(O)2R103 , alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl, wherein the R18 alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, -R101, -OR101, -NR101R102;
-X2- represents a bond or is -C(O)- , S(O)2 or-(CHR1)nr n1 = 1, 2, or 3; n = O, 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 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 hydroxy 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, alkoxy, aryloxy; each R103 is independently selected from the group consisting of alkyl, alkeπyl, 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 hydroxy 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, , alkoxy, aryloxy;
R2 is selected from the group consisting of alkyl, aryl, cycloalkyl, heterocycloalkyl 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, alkeπyl, 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, hydroxy, 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 O1 1 or 2; each R211 and each R212 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, 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, cyaπo, πitro, -R501, -OR501, -NR501R502, -S(O)7R503 , -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;
X4 = N or CR7
X9 = N or CR6 X5 = N or CR5
X6 = N or CR4 wherein one or two of X4, X5, X6 and X9 are N;
R4, R5, R6 and R7 are each independently selected from the group consisting of halogen, cyano, -R401, -C(O)OR401, -C(O)NR401R402, -OR401, -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 0, 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, fluorine or alky), wherein R8 alky) is optionally substituted with one or more fluorines.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y1 is O.
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y1 is C(H)R18.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y1 is NR18.
5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of aryl, heterocycloalkyl, cycloalkyl and heteroaryl, optionally substituted with a substituent as defined in claim 1.
6. The compound according to claim 1, 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, alkyf, 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.
7. The compound according to claim 1, wherein the compound of formula I has the formula II,
Figure imgf000084_0001
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,
,101 «102
-NR1U1R1U*, -S(O)vR ,110u11, 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.
8. The compound according to claim 1, wherein the compound has the formula
Figure imgf000084_0002
Formula III or a pharmaceutically acceptable salt thereof, wherein: R17 is selected from the group consisting of alkyl and cycloalkyl; wherein the R17 alkyi and cycloalkyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl; and 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.
9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein one of X4, X5, X6 and X9 is N, and three of R4, R5, R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, aryl, amino, alkylamino, dialkylamino, heterocycloalkyl and heteroaryl; wherein the three of R4, R6, R6 and R7 alkyl, heterocycloalkyl, heteroaryl or aryl are each optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy and alkoxycarbonyl.
10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R2 is aryl, optionally substituted as in the compound of claim 8.
11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the R2 aryl is preferably phenyl or naphthalenyl, optionally substituted as in the compound of claim 8.
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the R2 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, -O R211, -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 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, heterocycloafkyl, heteroaryl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl.
13. The compound of claim 12, 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 -OR211= each R211 is independently selected from the group consisting of alkyl and aryl; and the 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.
14. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein the R2 heterocycloalkyl or heteroaryl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halogen and -R201;
R201 is independently selected from the group consisting of hydrogen and alkyl; wherein the R201 alkyl substituents are optionally substituted with one or mors halogen substituents.
15. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein
R17 is methyl;
R2 is phenyl; 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; and X6 is N; X5 is CR5 ; X4 is CR7; and X9 is CR6.
16. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R17 is methyl;
R2 is phenyl; 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;
X6 is CR4; X5 is N ; X4 is CR7; and X9 is CR6.
17. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein
R17 is methyl; R2 is phenyl; 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;
X6 is CR4; Xs is CR5; X4 is N; and X9 is CR6.
18. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein
R17 is methyl;
R2 is phenyl; 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;
X6 is CR4; Xs is CR5; X4 is CR7; and X9 is N.
19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
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 maybe 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.
20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein 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; and either (a) one of X4, X5, X6 and X9 is N, and three of R4, R5, R6 and R7 are each hydrogen; or
(b) two of X4, Xs, X6 and X9 are N, and two of R4, R5, R6 and R7 are each hydrogen.
21. The compound of 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-chloropheπyl, 2-fluorophenyl, 3,4- difluorophenyl , 3,5-dichlorophenyl, 3,5-ditrifluoromethylphenyl, 3-chlorophenyl, 3- fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-chloro-5- trifluorophenyl, 3-phenylphenyl, 2,5,6-trifluorophenyl, 2,4-dichlorophenyl, 3,5- trifluoromethylphenyl, isoquinoliπyl, ([3-fluorophenyl, 5-propyl]triazolyl)phenyl, i-chloro-5- methylphenyl, 2,3,4-trifluoropheπyl, 2,3,5-trimethylphenyl, 2,3-dichloro-4-fluorophenyl, 2,3- difluoro-4-methylphenyl, 2,3-dimethy!-4-fluorophenyl, 2,3-dimethylphenyl, 2,4- dimethoxyphenylphenyl, 2,4-dimethylphenyl, 2,5-dimethoxyphenylphenyl, 2,5-dimethylphenyl, 2,5-dimethylpheπylpheπyl, 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-bromopheπyl, 2-isoxazolyl-4-chlorophenyl, 2-isoxazolyl-4-melhylphenyl, 2- methoxy-3-methyl-4-fluorophenyl, 2-methoxy-4-cyaπophenyl, 2-methoxy-4-fluorophenyl, 2- methoxy-4-methylphenyl, 2-methoxy-5-chlorophenylphenyl, 2-methoxy-5-cyanophenylpheπyl, 2-methoxy-5-fluorophenylpheπyl, 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-phenyl, 4- butylphenyl, 2-propylphenyl, 2-trifluoromethoxyphenylphenyl, 2-trifluoromethylphenylphenyl, 3,4-dichlorophenyl, 3,4-dichlorophenylcarbonyl, 3,4-dicyanophenyl, 3,4-difluorophenylphenyl, 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-fluoro-4-chlorophenyl, 3-fluoro-4-cyaπophenyl, 3-fluoro-4-cyaπophenylphenyl, 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-methoxyphenylpheπyl, 3-propylphenyl, 3-trifluoromethyl-4-methoxyphenylphenyl, 3-trifluoromethylphenylphenyl, 4-butylphenyl, 4-chlorophenylcarbonyl, 4-cyaπoethylphenyl, 4- cyaπomethylphenyl, 4-cyanophenyl, 4-cyanophenylphenyl, 4-ethylpheπyl, 4-fluoro-3- methylphenylphenyl, 4-fluorophenylcarbonyl, 4-fluoropheπylphenyl, 4-methoxy-3- fluoropheπylpheπyl, 4-methoxy-3-trifluoromethylphenylphenyl, 4-methoxymethylphenyl, 4- methoxypheπyl, 4-methoxyphenylcarboπyl, 4-methoxyphenylpheπyl, 4-methylphenyl, 4- propylphenyl, benzo[d][1,3]dioxolylphenyl, benzofuraπylphenyl, benzthiazolylphenyl, bromopyridinyl, chlorophenyltriazolylphenyl, chloropyridinyl, cyanopheπylphenyl, 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, oxazolylphenylpheπyl, oxodihydro-1 H-indenylphenyl, phenylcarbonyl, propylphenyl, propylphenylphenyl, propylpyridinyl, pyridinyl, pyrrolylphenyl, quinolinylphenyl, quinoxalinyl, quinoxalinylphenyl, thiadiazolylphenyl, thiadiazolylphenylphenyl, triazolylpheπyl, trifluoromethoxyphenylphenyl, trifluoromethylphenyl, trifluoromethylphenylphenyl, trifluoromethylpyridinyl and 2,4,5- trifluorophenyl.
22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R17 and R7, taken together with the atoms connecting R17 and R7, form a 5-8 membered heterocyclic ring.
23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R8 is hydrogen or alkyl.
24. A compound selected from the group consisting of the compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof.
25. 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 mammal.
26. A method for treating or preventing neurological and psychiatric disorders associated with glutamate dysfunction, comprising administering to a patient in need thereof aπ amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, effective in treating such disorders.
27. The method of claim 26, wherein further comprising administering a metabotropic glutamate receptor agonist.
28. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
29. 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.
30. The composition of claim 29, further comprising a metabotropic glutamate receptor agonist.
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